Chicago, IL—Value-based purchasing(VBP), a program created by the Af-fordable Care Act (ACA) and adminis-tered by the Centers for Medicare &Medicaid Services (CMS), uses pay forperformance for hospital payment ofinpatient acute care services to shift theemphasis to paying for care quality notquantity. Physicians should under-stand VBP, because it represents an op-portunity to work with hospitals to
increase their own compensation, saidGregory D. Timmers, MD, Prairie Car-diovascular Consultants, Springfield,OH, at the 2012 American College ofCardiology meeting. Physician compensation is changing
in concert with changes in healthcaredelivery. The shift of ancillary servicesfrom the physician office to the hospi-tal outpatient setting is one example
Value-BasedCareCardiometabolic Health
FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS ®
inTM
HEALTH ECONOMICS . . . . . . . . . . .6Coronary CTA cost-effective in CADWhat parameters determine value in CVD imaging?
HYPERTENSION . . . . . . . . . . . . .13New JNC-8 guidelines expected by year endConsider combination therapy for low- and high-risk hypertension
ATRIAL FIBRILLATION . . . . . . . .17New drug therapies for difficult-to-control AF
HEART FAILURE . . . . . . . . . . . . .21Blood test for galectin-3 identifies patients at risk in the community setting Advances in stem-cell therapy for HF
CVD MANAGEMENT . . . . . . . . .23Gene expression a new way to identifyobstructive CADValue of remote disease management of arrhythmia highlighted at ACC 2012
PAYER PERSPECTIVE . . . . . . . .28
INS IDE
MAY 2012, VOL 1, NO 1
Lipid-Lowering Drug Pipeline:There Is Life After StatinsBy Wayne Kuznar
New Oral Anticoagulants ShowSuperior Efficacy versus Warfarin,and No Need for MonitoringBy Wayne Kuznar
Value-Based Purchasing:Cardiologists Urged to Movefrom Quantity to Quality of CareBy Mary Mosley
Continued on page 6
Chicago, IL—Kicking off the newLegends of Cardiovascular Medicineseries during the 2012 American Col-lege of Cardiology meeting, EugeneBraunwald, MD, FRCP, Distinguished
Hersey Professor of Medicine at Har-vard Medical School, and Chairmanof the Thrombolysis In MyocardialInfarction (TIMI) Study Group at
Continued on page 23
Chicago, IL—“There is life beyondstatins, and the next 10 years will be asexciting, and hopefully beneficial, topatients as the statin era has been,”said Evan A. Stein, MD, PhD, Director,Metabolic and Atherosclerosis Re-search Center, Cincinnati, OH, in re-view of the current landscape forlipid-modifying drugs at the 2012 An-nual Meeting of the American Collegeof Cardiology.He summarized the current data be-
hind 2 new classes of drugs: apolipo -protein (Apo) B antisense drugs andproprotein convertase subtilisin/kexin9 (PCSK9) inhibitors.
ApoB Antisense DrugsMipomersen is an injectable ApoB
antisense drug that inhibits the release
of Apo B-100, an important structuraland functional component of lipopro-teins, from the liver. Blocking Apo B-100 release blocks the production ofvery-low-density lipoprotein, low-density lipoprotein (LDL), and lipopro -tein (Lp) (a), said Dr Stein.The drawback to studying ApoB an-
tisense drugs has been the 6 months ittakes to achieve maximum effect onApoB and LDL cholesterol (LDL-C)levels, “making it difficult to do dose-ranging studies,” he said.Although the primary effect of
mipomersen is on ApoB production, ithas an equal effect on LDL-C reduc-tion, Dr Stein pointed out. It has dose-dependent efficacy; at 400 mg weekly,mipomersen monotherapy reduces
Continued on page 16
AMERICAN COLLEGE OF CARDIOLOGY 2012 HIGHLIGHTS*
Chicago, IL—The new oral anticoagu-lants—the factor Xa inhibitors rivarox-aban (Xarelto) and apixaban (Eliquis),and the direct thrombin inhibitor dabi-gatran (Pradaxa)—are superior to war-
farin (Coumadin) in preventing strokeand systemic embolism in patientswith atrial fibrillation (AF), accordingto a review/meta-analysis conducted
Continued on page 20
Photo taken at ACC 2012.
ACC Launches Legends ofCardiovascular Medicine SeriesEugene Braunwald on advances in acute myocardial infarctionBy Mary Mosley
*This publication is not endorsed by nor associated with the American College of Cardiology.
Focusing on what mattersImproving glycemic control for adult patients with type 2 diabetes
Indication and Important Limitations of Use
TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
TRADJENTA has not been studied in combination with insulin.
Important Safety Information
CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.
WARNINGS AND PRECAUTIONS USE WITH MEDICATIONS KNOWN TO CAUSE HYPOGLYCEMIAInsulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in
a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.
MACROVASCULAR OUTCOMESThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.
ADVERSE REACTIONSAdverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.
Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.
TRADJENTA (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR
In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure [1 per 538 person-years]) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.
DRUG INTERACTIONSThe effi cacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.
USE IN SPECIFIC POPULATIONSThere are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.
It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when TRADJENTA is administered to a nursing woman.
The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.
TJ PROF ISI FEB132012
References: 1. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle H-J, Dugi K. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on fi le. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and effi cacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. 4. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28:447-459.
Please see brief summary of full Prescribing Information on the adjacent page.
TRADJENTA delivers proven glycemic control
TRADJENTA: Experience dosing simplicity
No dose adjustment required, regardless of declining renal function or hepatic impairment4
TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing
One dose, once daily for adult patients with type 2 diabetes
TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients
† A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insuffi cient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. Results are adjusted for a 0.15% mean A1C increase for placebo and 0.5% mean decrease for TRADJENTA in add-on combination with metformin. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.
Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com
Signifi cant A1C reductions from baseline at 24 weeks
* A randomized, multicenter, double-blind, placebo-controlled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Results adjusted for a 0.3% mean A1C increase for placebo and 0.4% mean decrease for TRADJENTA monotherapy. Full analysis population using last observation on study.
Plac
ebo-
adju
sted
mea
n ch
ange
in
A1C
at 2
4 w
eeks
(%)
-0.6%-0.7%
TRADJENTAmonotherapy1,2*
(n=333)
TRADJENTA + metformin2,3†
(n=513)
P<0.0001
P<0.0001
-0.8
-0.6
-0.4
-0.2
0
TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut
TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients
TRADJENTA
5 MG #30
Sig:i PO QD
x2 REFILLS
Tradjenta™ (linagliptin) tablets
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Please see package insert for full Prescribing Information.
INDICATIONS AND USAGETRADJENTA tablets are indicated as an adjunct to diet and exercise to improve gly-cemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRADJENTA has not been studied in combination with insulin.
CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of a hypersensitivity reac-tion to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].
WARNINGS AND PRECAUTIONSUse with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglyce-mia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.
ADVERSE REACTIONSClinical Trials Experience: Because clinical trials are conducted under widely vary-ing conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treat-ment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with piogli-tazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in 5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyn-gitis (5.8% vs 5.5%). Adverse reactions reported in 2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfo-nylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to
49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglyce-mia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was adminis-tered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered pla-cebo in combination with metformin and a sulfonylurea.Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in labora-tory values that occurred more frequently in the TRADJENTA group and 1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.
DRUG INTERACTIONSInducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when admin-istered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be adminis-tered with a P-gp or CYP3A4 inducer.
USE IN SPECIFIC POPULATIONSPregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skel-etal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Lina-gliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been estab-lished. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.
OVERDOSAGEDuring controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointes-tinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a thera-peutically significant degree by hemodialysis or peritoneal dialysis.
Table 1 Adverse Reactions Reported in 2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy
SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)
Mission StatementValue-Based Care in Cardiometabolic Health provides aforum for payers, providers, and the entire cardiometa-bolic team to consider the cost-value issues particular tocardiovascular and metabolic treatments. This uniquefocus is achieved through news coverage from major pro-fessional meetings and the literature, supplemented withcommentaries and perspectives from those involved inevaluating therapies, treating patients, and paying for care.
Contact Information:For subscription information and edi torial queries,please contact: [email protected]
T: 732-992-1892; F: 732-992-1881
Permission requests to reprint all or part of any articlepublished in this publication should be addressed to [email protected].
The ideas and opinions expressed in Value-Based Carein Cardiometabolic Health do not necessarily reflectthose of the Editorial Board, the Editors, or the Pub-lisher. Publication of an advertisement or other prod-uct mentioned in Value-Based Care in CardiometabolicHealth should not be construed as an endorsement ofthe product or the manufacturer’s claims. Readers areencouraged to contact the manufacturers about anyfeatures or limitations of products mentioned. Nei-ther the Editors nor the Publisher assume any respon-sibility for any injury and/or damage to persons orproperty arising out of or related to any use of the ma-terial mentioned in this publication.
POSTMASTER: CORRESPONDENCE REGARDINGSUBSCRIPTIONS OR CHANGE OF ADDRESSshould be directed to CIRCULATION DIRECTOR,Value-Based Care in Cardiometabolic Health, 241 ForsgateDrive, Suite 205A, Monroe Township, NJ 08831. Fax:732-992-1881. YEARLY SUBSCRIPTION RATES: Oneyear: $99.00 USD; Two years: $149.00 USD; Three years:$199.00 USD.
Value-BasedCareCardiometabolic Health
inTM
HEALTH ECONOMICSCost-effective imaging: what parameters determine value?Coronary CTA cost-effective in CADMore…..
ACUTE CORONARY SYNDROMEBenefits of inexpensive glucose-insulin-potassium solutionValue of new oral anticoagulants in ACS still unclearMore…..
HYPERTENSIONNew JNC-8 guidelines expected by year end Combination therapy for low- and high-risk hypertensionMore…..
LIPID DISORDERSLipid-lowering drug pipelineMonoclonal antibody produces powerful LDL-C reductionsMore…..
ATRIAL FIBRILLATIONNew drug therapies for difficult-to-controlAFComparative effectiveness analysis of antithrombotics in older patients More…..
HEART FAILUREBlood test for galectin-3 identifies patients atrisk in the community setting Advances in stem-cell therapy for HFMore…..
CVD MANAGEMENTLevels of gene expression a new, noninvasiveway to identify obstructive CADValue of remote disease management of arrhythmia highlighted at ACCMore…..
PAYER PERSPECTIVEBy Gary M. Owens, MD
EDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health
DEPUTY EDITORSJoseph E. Couto, PharmD, MBAAssistant Professor, Jefferson School of Population HealthDirector, Health Economics and Outcomes Research Fellowship Program
Laura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy
ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT
AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSFProfessor of MedicineMayo Clinic, Rochester, MN
CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie Comprehensive Cancer Center, Northwestern UniversityImmediate Past President, ACCCPast Chair, NCCN Board of Directors
Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan Health Systems
CARDIOLOGYMichael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York
EMPLOYERSWayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE
Arthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, Lake Worth, FL
F. Randy Vogenberg, RPh, PhDPrincipal, Institute of Integrated Healthcare Sharon, MA
ENDOCRINOLOGYJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ
EPIDEMIOLOGYJoshua N. Liberman, PhDVice President, Research OperationsCenter for Health ResearchGeisinger Health System, Danville, PA
GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSenior Counselor, Fleishman-Hillard
HEALTH INFORMATION TECHNOLOGY J. B. Jones, PhD, MBAResearch Associate, Geisinger Health System, Danville, PA
Victor J. Strecher, PhD, MPHProfessor and Director, Center for Health Communications ResearchUniversity of Michigan Schools of Public Health and Medicine, Ann ArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson
HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City
Kavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver
Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA
Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL
HEALTH & VALUE PROMOTION Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA
Albert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Milwaukee
MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA
PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, Washington State University, Spokane, WA
PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation
PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH
PHARMACY BENEFIT DESIGN Joel V. Brill, MDChief Medical Officer, Predictive Health, Phoenix, AZ
William J. Cardarelli, PharmDDirector of Pharmacy, Atrius HealthHarvard Vanguard Medical Associates
Leslie S. Fish, PharmDSenior Director of Pharmacy ServicesFallon Community Health Plan, MA
Michael S. Jacobs, RPhNational Clinical Practice LeaderBuck Consultants, Atlanta
Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT
Paul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA
Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System, Danville, PA
POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health Care Retirement PolicyAmerican Enterprise Institute
Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City
Walid F. Gellad, MD, MPHAssistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health
Alex Hathaway, MD, MPH, FACPMPresident & Founder, J.D. BioEdgeHealth quality & biomedical research
J. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at Chicago
RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA
SPECIALTY PHARMACYAtheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty Pharmacy Swartz Creek, MI
James T. Kenney, Jr, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA
6 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Health Economics
Chicago, IL—Diagnostic accuracy isthe primary determinant of cost-effec-tiveness of medical imaging for pa-tients with chronic coronary arterydisease (CAD), stated Matthew J.Budoff, MD, Professor of Medicine atDavid Geffen School of Medicine atUniversity of California Los Angeles(UCLA), and Director of Cardiac CT atHarbor-UCLA Medical Center, Tor-rance, CA, at the 2012 American Col-lege of Cardiology meeting. Coronary computed tomography an-
giography (CTA) as currently per-formed has the highest diagnosticaccuracy, with a sensitivity of 95% andspecificity of 83%, followed by pharma-cology nuclear imaging (89% sensitivity,75% specificity). Exercise electrocardio -gram has the lowest diagnostic accu-
racy (68% sensitivity, 77% specificity). Patient selection for testing is poor,
and improvement is needed to achievecost-effectiveness. A total of 62% of pa-tients sent to the diagnostic catheteri-zation laboratory to rule out CAD donot have it, according to data from the2005 to 2007 National CardiovascularData Registry published in 2010. On average, catheterization labora-
tory testing costs >$10,000 per patient;this adds hundreds of millions of dol-lars in healthcare costs, according toDr Budoff.
CTA as a “Gatekeeper” to InvasiveCoronary AngiographyCTA can prevent the need for inva-
sive coronary angiography (ICA) in apercentage of patients. A recent study
showed a combined 73% rate of false-positives in 241 patients with abnor-mal findings on myocardial perfusionimaging (MPI)—23% had normal coro-nary arteries, 40% had nonsignificantdisease, and 10% had mild disease(Patel N, et al. Am J Cardiol. 2012;109:165-168). This translated to a net sav-ings of $1295 per patient (a 51% sav-ings) and a total savings of $320,000,based on Medicare costs.A larger, 2007 study also provides ev-
idence that “correlates to the idea thatdollars can be saved by not having toperform invasive coronary angiogra-phy,” commented Dr Budoff. In 421 pa-tients with intermediate risk of CADand an abnormal MPI result, an 80% re-duction in ICA with CTA was demon-strated. Safety of this strategy wasconfirmed by event-free survival at 15months. Of the total patients, 6 had alate ICA, 1 patient had revasculariza-
tion, and no myocardial infarctions ordeaths occurred.A 2007 study of 206 patients with
mildly abnormal or equivocal tests(only 32% had obstructive CAD)showed that selective catheterizationsaved $1454 per patient. Dr Budoffnoted the relation between cost-sav-ings and pretest probability of preva-lence of disease, with CTA saving themost money in lower-probability pa-tients and the savings decreasing asthe probability increased. “At a preva-lence of CAD of about 80%, CTA iscost-effective as a gatekeeper to ICA,”said Dr Budoff.
Cost per Correct Diagnosis,Quality-Adjusted Life-YearImaging can save downstream costs,
and the savings differ by imagingmodality. In a 2008 study of patients atintermediate risk for CAD, the down-
Continued on page 7
of decreasing revenue for physiciangroups. Dr Timmers advised physi-cians to be proactive and engage withhospitals regarding VBP to reduce costsand improve resource utilization, withsavings being a metric for reimburse-ment to offset lost revenue streams. The majority of the initial clinical
process care measures are cardiologyrelated, representing a concrete oppor-tunity for cardiologists to lead. VBP be-gins in October 2012 (fiscal year 2013).
VBP and Care IntegrationVBP, along with accountable care or-
ganizations (ACOs), is part of a newconcept established by CMS—a caremodel that moves from volume tovalue. Physicians and ACOs will be ac-countable for quality and efficiency,including lower costs per patient en-
counter and per capita (ie, utilization)and improved coordination across thecare continuum. CMS has 3 stated aimswith VBP—better care for individuals,better health for populations, andlower per-capita costs. Regardless ofthe disposition of the ACA, a private–public dynamic related to quality andcosts will continue, said Dr Timmers. The VBP program has 2 components
—compensation for core measures(70% of total score) and compensationfor patient satisfaction (30% of totalscore). The development of the coremeasures began in 2002 by the JointCommission and CMS. The VBP coremeasures are a subset of this list of fullcore measures. A large proportion ofthe core measures are based on cardio-vascular (CV) components, which DrTimmers said is not surprising, becauseCV care comprises approximately 40%of the Medicare dollars spent. Provider-based billing incentivizes
the integration of care providers (ie,hospitals and physicians) and betterdecision-making for healthcare expen-ditures by patients who will be payingmore through deductibles and copaysunder healthcare reform. The move-ment of ancillary services to the hospi-tal from the physician office is onemotivator for integration. A notable change that is coming for
cardiologists, as part of the popula-tion-risk management goal, is thatCMS is first increasing costs to pa-tients and then directing patients tothe provider who can deliver their CVcare, rather than patients selectingtheir provider. This will have a signif-
icant impact on cardiologists, becausean estimated 60% to 65% of their cur-rent patient population comprisesMedicare patients.
How VBP WorksVBP represents a continuation of the
existing inpatient quality reporting.Value-based payments are made tohospitals that meet performance stan-dards. Initially there are 12 core clinicalmeasures and 8 patient satisfactionmeasures, called HCAHPS (HospitalConsumer Assessment of HealthcareProviders and Systems). In year 1,there is a 1% reduction in diagnosis-related group payments to the hospitalin fiscal year 2013, increasing 0.25%annually up to 2% at 5 years. VBP is a revenue-neutral program,
with Medicare withholding paymentsand hospitals earning back funds basedon the performance measures. HC-AHPS represents an effort by Medicareto ensure that patients who are directedto specific hospitals or physician
groups are receiving fair, equitable, andgood care, according to Dr Timmers.
How Does VBP ImpactPhysicians?Care integration strategies and the
employment of physician groups rep-resent the greatest impacts on physi-cians. Physicians excel at coordinatingdelivery of care and providing highpatient satisfaction. One approach isfor physicians to work with the hos-pital to substitute these new VBPmeasures, which have real dollars at-tached to them, for the current metricsused for physician compensation. A recent survey by MedAxiom
shows that of the hospital-acquiredphysician groups, 57% have incen-tives to improve quality and 47% haveincentives to improve other metrics.Cardiologists can use the VBP compo-nents that have compensation fromMedicare for these incentives, Dr Tim-mers recommended. Medical director agreements and CV
comanagement agreements also includebonus options and represent an oppor-tunity to include VBP performance-based measures required of hospitals;physicians increase their compensation,and hospitals meet their mandates.Physician groups that include the
VBP revenue component in theiragreements with hospitals have thepotential to recoup revenue lost whenancillary services were moved to thehospital. The shift to value-based carewill continue, and understanding thevarious programs and incentives willbenefit the CV community. �
� VBP is part of a new conceptfor a care model that movesfrom volume to value
� The VBP program has 2components: compensation forcore measures and for patientsatisfaction
� A notable change forcardiologists is that CMS is firstincreasing costs to patients andthen directing patients to theprovider who can deliver theirCV care, rather than patientsselecting their provider
Value-Based Purchasing: Cardiologists Urged... Continued from page 1
Key Points
Coronary Computed Tomography Angiography Cost-Effective in CADBy Mary Mosley
VBP represents anopportunity for physicians towork with hospitals toincrease their owncompensation. VBP, alongwith ACOs, is part of a caremodel that moves fromvolume to value.
—Gregory D. Timmers, MD
7MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Health Economics
stream costs in patients without knownCAD was $1572 for CTA (N = 1647)and $2531 for single-photon emissioncomputed tomography (N = 6588) at 1year, based on Medicare data. The average savings was $1075,
which increased to $1838 per personwhen the observation was expandedto include 39,174 patients. CTA was shown in one series to be
cost-effective in terms of cost per cor-rect diagnosis in patients with a lowprevalence of CAD, whereas ICA per-formed better in patients with higherprobability of disease, which Dr Bud-off noted is concordant with other tri-als. In patients with a 10% diseaseprobability, CTA alone reduces costs, ata cost per correct diagnosis of $81,591
compared with $349,880 for ICA. The cost for CTA per correct diag-
nosis was $17,516 with a 30% CADprobability, $9847 with a 40% proba-
bility, and $5281 with a 50% probabil-ity; the corresponding costs with ICAwere $73,175, $43,008, and $25,315,respectively. The cost per quality-adjusted life-
year (QALY), the gold standard for
measuring cost-effectiveness, varies byage but not by sex. For example, at a30% CAD probability, the cost perQALY for CTA alone is $18,862 and$594,264 for ICA at age 60 years; thisshifts to $21,636 and $162,229, respec-tively, at age 80 years. For patients in their 40s and 50s, the
cost for CTA alone is $39,574 and$23,440, respectively, but ICA was thedominant strategy in this series.
CTA: Cost-Effective Triage forAcute Coronary SyndromeIn a 2007 single-center study of 197
patients presenting with chest pain atthe emergency department, CTA usedimmediately to exclude or identifyCAD resulted in an approximate 15%
cost-savings, at a cost of $1586 per pa-tient compared with $1872 in the stan-dard-of-care arm. The time to diagnosis was signifi-
cantly reduced with CTA comparedwith standard of care (3.4 hours vs 15.0hours, respectively), and its diagnosticaccuracy was 75%.The 16-center, international Coro-
nary Computed Tomographic Angiog-raphy for Systematic Triage of AcuteChest Pain Patients to Treatment (CT-STAT) trial exhibited a significant 38%reduction in cost of care with CTA($2137 with CTA, $3458 with MPI) in699 patients presenting to the emer-gency department and a 54% reductionin time to diagnosis (Goldstein JA, et al.J Am Coll Cardiol. 2011;58:1414-1422).�
Coronary Computed Tomography Angiography Cost... Continued from page 6
“At a prevalence of CAD of about 80%, CTA is cost-effective as agatekeeper to ICA.”
—Matthew J. Budoff, MD
Chicago, IL—The rapid growth ofmedical imaging in cardiovascular(CV) medicine, as well as downwardpressure on reimbursement havebrought an increased focus on cost andthe need to show cost-effectiveness. Imaging is estimated to be growing
at a rate of 13% to 22% annually, ac-cording to a US Government Account-ability Office and Medicare PaymentAdvisory Commission study, com-pared with 9% annually for otherphysician services, stated Rita F. Red-berg, MD, MSc, FACC, Professor ofMedicine and Director, Women’s Car-diovascular Services, Division of Car-diology, University of California, SanFrancisco Medical Center, in a sessionat the 2012 American College of Car -diology (ACC) meeting. Healthcarespending is projected to double to$4.1 trillion by 2016, an estimated 20%of the US gross domestic product, andan increase from 16% in 2012.Yet, how to define value and cost-
effectiveness for medical imagingis “not straightforward,” said RoryHachamovitch, MD, MSc, FACC, Sec-tion of Cardiovascular Imaging, De-partment of Cardiovascular Medicine,Cleveland Clinic, OH. The nature ofimaging makes determining its cost-effectiveness complex, in part becauseof its relation to outcomes—the usualdenominator in cost-effectivenessequations—that can be indirect, and itsunclear metric. Change in subsequenttreatment may be the best end point,stated Dr Hachamovitch. Data for cost-effectiveness of CV medical imagingare in their infancy. Little prospectivedata are available, although ongoingstudies may soon start to provide thenecessary evidence. “Imaging provides an immediate re-
sult and information that may be usedto avoid or implement a treatment strat-egy,” said Dr Redberg. She noted thatthe bar is higher for the cost-effective-ness of diagnostic testing, because itdoes not translate directly to outcomes. “We must consider how the informa-
tion will change management, and howchange in management will lead tochange in outcomes, and whether thatsame end point could be achieved with-out doing the test,” Dr Redberg said.Historically, diagnostic end points,
such as coronary anatomy or presenceor absence of disease, have been used,but this is shifting to prognostic or out-comes-based end points. Net reclassi-fication improvement (NRI), that is,“what is the net gain in reclassifyingpatient risk status with the addition ofdata, with the notion that this opti-mally enhances subsequent patient
management,” is now a popular metricto show the value of an imaging test. One application of the NRI metric
was shown by Shaw and colleagues ina study of more than 4500 patientswho were prospectively enrolled in amulticenter registry (JACC CV Imaging.2010;3:1139-1148). A weighted multi-variable model of prognostically im-portant information from nuclearstudies and treadmill score datashowed that NRI was approximately 3times greater with nuclear studies, butthe cost was nearly 40 times greater(both compared with a treadmill exer-cise test). The cost-effectiveness ratio,calculated as cost per NRI, was ap-proximately $60 per exercise test andmore than $600 for nuclear imaging,Dr Hachamovitch said. The challengeis, “what is a clinically meaningful ef-fect in terms of diagnosis?”The results of imaging tests must be
used to drive subsequent treatment forit to be cost-effective and clinically rel-evant. A study by Ling and colleagues(J Am Coll Cardiol. 2012;59:E2143) pre-sented at the 2012 ACC FellowshipYoung Investigators Award session il-lustrated the concept of the “interfacebetween what is seen on the test andwhat is best for the patient to achievebenefit,” said Dr Hachamovitch. In this single-site study of 661 pa-
tients (average 30% ejection fraction,34% abnormal myocardium) who un-derwent stress/rest positron emissiontomography with fluorodeoxyglucoseimaging, complete revascularizationcompared with medical therapy wasassociated with improved survival,whereas incomplete revascularizationincreased risk.Other issues for determining value-
based cost-effectiveness of imaging
include downstream costs resultingfrom information obtained from im-aging; false-positives that may lead tomore tests or unnecessary treatment;direct costs for performing and inter-preting a test; indirect costs, such asthose incurred as a consequence ofmedical care (eg, loss of work time);temporal changes (short-term vs long-term); and variations in cost by geog-raphy and payer.Cost-effectiveness—a comparison
of 2 alternative treatments on out-comes—is a method to obtain bettervalue for healthcare dollars spent. Ingeneral, cost-effectiveness studies inthe United States use a cut-off of$50,000 per quality-adjusted life-yearsaved; below that figure a new tech-nology or treatment is considered tobe cost-effective. In imaging, this ismost often the comparison of one im-aging modality against another. Dr Hachamovitch stated that cost-
effectiveness data need to be definedfor CV imaging tests. �
Cost-Effective Imaging: What Parameters Determine Value?By Mary Mosley
� Imaging is estimated to begrowing at a rate of 13% to22% annually
�Determining its cost-effectiveness is complex
� Imaging tests must drivetreatment decisions for cost-effective management
� The cost-effectiveness ratiowas approximately $60 perexercise test and more than$600 for nuclear imaging in arecent study
“Imaging provides animmediate result andinformation that may be used to avoid or implement a treatment strategy.”—Rita F. Redberg, MD, MSc, FACC
Key Points
Chicago, IL—Atrial fibrillation (AF) isassociated with a 5-fold increased riskfor ischemic stroke, and its prevalenceis rapidly increasing, representing asubstantial burden for patients andhealthcare consumption. Recent trials ofnew oral anticoagulants have shownthem to be an effective alternative towarfarin (Coumadin) for stroke preven-tion in patients with nonvalvular AF. Steven Deitelzweig, MD, Associate
Professor, Tulane School of Medicine,Vice President of Medical Affairs,Chairman of Department of Medicine,Ochsner Clinic Foundation, New Or-leans, LA, presented the results of re-search on the impact of these emergingagents on medical costs for patientswith AF, at the 2012 American Collegeof Cardiology meeting. Dr Deitelzweig and colleagues
found that compared with warfarin,the use of dabigatran (Pradaxa), riv -aroxaban (Xarelto), and the investiga-tional apixaban (which is approved inEurope but not in the United States)was associated with a reduction in themedical costs related to the manage-ment of clinical events in patients withAF. This finding is based on the resultsrelated to clinical events reported withdabigatran in the Randomized Evalu-ation of Long-Term AnticoagulantTherapy (RE-LY) trial, rivaroxaban inthe ROCKET-AF trial, and apixaban inthe Apixaban for the Prevention ofStroke in Subjects with Atrial Fibrilla-tion (ARISTOTLE) trial.The total annual medical cost for clin-
ical events with warfarin was $2084 perpatient. This was reduced to $1599 withapixaban, $1905 with dabigatran, and$1995 with rivaroxaban. The investiga-tors determined the 1-year incrementalcosts for each category of clinical eventin patients with AF using publisheddata and expert reports. Their analysis
showed that a hemorrhagic stroke wasthe costliest event at $51,659 comparedwith $39,511 for an ischemic stroke,$37,446 for a myocardial infarction (MI),and $34,617 for major bleeding. Allcosts were inflation-adjusted to 2010costs using the Consumer Price Indexfor Medical Care.The clinical events included in this
analysis were ischemic or uncertaintype of stroke, hemorrhagic stroke, sys-temic embolism, MI, pulmonary em-
bolism, deep-vein thrombosis, andmajor bleeding, excluding hemor-rhagic stroke, clinically relevant non-major bleeding, and other minorbleeding events. The clinical event ratewith each of the new oral anticoagu-lants was derived from weighting ofthe reported relative risk using thewarfarin clinical event rate that was es-timated as the averages weighted bythe sample size of each of the trials.The new anticoagulants reduced the
total medical costs based on their esti-mated lower absolute risk for a clinicalevent. The total medical cost for is-chemic and hemorrhagic strokes, theprimary efficacy end points, was low-est with dabigatran (150 mg). For is-chemic stroke, the costs were $373 withdabigatran compared with $461 withrivaroxaban, $451 with apixaban, and$490 with warfarin. For hemorrhagicstroke, the costs were $59, $133, $115,and $225, respectively.For the secondary end point of MI,
the costs were $292 with warfarin, $371with dabigatran, $237 with rivaroxa-ban, and $257 with apixaban. The costsfor major bleeding, a safety end point,were $998 with warfarin, $1030 withdabigatran, $1106 with rivaroxaban,and $715 with apixaban.The study results were consistent
even when other scenarios were evalu-ated, such as using the median ratherthan the mean, using incremental med-ical costs for patients with AF, or whenthe clinical events in each trial wereconsidered separately rather than the
weighted average. These scenarios andthe sensitivity analyses were performedto reflect the variety of the real-worldsettings. The study main limitation isthat the results cannot be applied in thereal-world setting, because the eco-nomic analysis did not include factorssuch as drug costs, local healthcarecosts, drug adherence, and variance inpopulation risk, among others. �
8 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Health Economics
� AF is associated with a 5-foldincreased risk for ischemicstroke, and its prevalence israpidly increasing, representing asubstantial burden for patientsand healthcare consumption
� The use of dabigatran,rivaroxaban, and apixaban isassociated with a reduction inmedical costs related to treatingclinical events in patients with AF
� The total annual medical costfor clinical events with warfarinwas $2084 per patient, whichwas reduced to $1599 withapixaban, $1905 with dabigatran,and $1995 with rivaroxaban
� The total medical costs forischemic and hemorrhagicstrokes were lowest withdabigatran and highest withwarfarin
The totalannualmedical costfor clinicalevents withwarfarin was$2084 per
patient. This was reduced to$1599 with apixaban, $1905with dabigatran, and $1995with rivaroxaban.
—Steven Deitelzweig, MD
Novel Oral Anticoagulants Reduce Total Medical Costs inPatients with Nonvalvular Atrial FibrillationBy Mary Mosley
See also Atrial Fibrillation
Key Points
Chicago, IL—A cost analysis comparingthe use of apixaban (Eliquis) and aspirinin patients with atrial fibrillation (AF)shows a net reduction in total medicalcosts with apixaban, based on datafrom the AVERROES (Apixaban versusAcetyl salicylic Acid to Prevent Strokes)trial, said Alpesh N. Amin, MD, MBA,FACP, Associate Professor of Medicine,Executive Director, Hospitalist Pro-gram, University of California, IrvineSchool of Medicine, at the 2012 Amer-ican College of Cardiology meeting. The multicenter, multinational, dou-
ble-blind AVERROES trial compared thenew oral anticoagulant apixaban (whichis approved in Europe but not yet in theUnited States) with aspirin in 5559 pa-tients with AF and at least 1 other strokerisk factor who were unable or unwill-ing to take warfarin (Coumadin).
In 42% of the patients, the interna-tional normalized ratio could not bemaintained within the required thera-peutic range with warfarin use. Thistrial was terminated early, because ofthe superior benefit with apixaban forthe primary end point of stroke or sys-temic embolism event. A total of 51events occurred with apixaban com-pared with 113 with aspirin (hazardratio for apixaban, 0.45). However,major bleeding events were more com-mon with apixaban than with aspirin. Dr Amin and colleagues calculated
the costs of apixaban or aspirin basedon the rates of primary, secondary, andsafety end points in the trial and theirassociated cost. Compared with aspirin,apixaban was associated with a $655per patient-year reduction in total med-ical costs. The largest reduction ($546)
was for the cost associated with an is-chemic stroke. Other reductions were$51 for hemorrhagic stroke, $77 for my-ocardial infarction, and $55 for systemicembolism. However, the cost for bleed-
ing increased by $75 with apixaban. The estimated total cost reduction
with apixaban compared with aspirinwere consistent across sensitivity analy-
ses and models with varying clinicalevent rates and associated costs.“These results serve to start and fur-
ther the discussion at a hospital systemlevel about which of the new anticoag-ulants should be included in their for-mulary, and how AF will be managedoverall,” said Dr Amin. “Also, hospitals and physician
groups across the United States areworking toward the so-called ‘tripleaim’ of the Centers for Medicare &Medicaid Services: improved resourceutilization, quality, and service. In thisregard, the new oral anticoagulants im-prove resource utilization, as they aremore cost-effective across the board,potentially providing better quality,because they have better efficacy out-comes, with a similar safety profile thatcontributes to patient service.”—MM �
AVERROES: Cost Comparison of Apixaban versus Aspirin
“These results serve to startand further the discussion at a hospital system levelabout which of the newanticoagulants should beincluded in their formulary.”—Alpesh N. Amin, MD, MBA, FACP
Call for Papers
American Health & Drug Benefits offers an open forum for all healthcare participants to exchangeideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit designmodels that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers,Providers, Purchasers, Regulators, and Researchers.
Readers are invited to submit articles that aim at improving the quality of patient care and patient well-beingwhile reducing or controlling costs, enhancing the health of communities and patient populations, as well as othertopics relevant to benefit design with specific implications to policymakers, payers, and employers.
Follow the Manuscript Instructions for Authors at www.AHDBonline.comFor more information, call 732-992-1892 or e-mail [email protected]
Areas of High Interest Include:
• Adherence Concerns
• Benefit Design
• Case Studies
• Comorbidities and Cost Issues
• Comparative Effectiveness Research
• Cost Analyses
• Decision-Making Tools
• Ethics in Medicine
• Health Economics Research
• Health Plan Initiatives
• Health Information Technology
• Industry Trends
• Innovations in Healthcare
• Literature Reviews
• Medicare/Medicaid
• Patient Advocacy/Patient Care
• Pharmacoeconomics
• Policy Issues
• Prevention Initiatives
• Reimbursement Strategies
• Social Media and Health
• Survey Results
• Value-Based Healthcare
• Wellness Programs
Trends in Biologic Therapies for RA
91
www.AH
DBonline
.com l Am
erican He
alth & Dr
ug Benef
its l
Vol 5, N
o 2 l Ma
rch/Apri
l 2012
Biologic Therapies for Rheumatoid Arthritis: It’s All about Value
Value has
been defi
ned as th
e relation
ship betw
een
benefits
and costs
. Using
mathemat
ical conc
epts,
value ha
s been de
scribed as
“value =
benefits/
cost” or
the units
of benefit
derived
from a gi
ven num
ber of
units of c
osts. App
lying this
definitio
n, if we w
ish to
maximize
the valu
e of a ther
apy, there
are only 2
ways
to achie
ve it: ei
ther by
increasing
the ben
efits
obtained
from the
therapy, o
r by decr
easing the
cost
paid for t
hat thera
py.
Value in h
ealthcare
is also a fu
nction of
perspectiv
e.
What ma
y be con
sidered v
aluable to
an indiv
idual
patient u
ndergoin
g treatme
nt or to
a physici
an pre-
scribing t
hat treatm
ent to a s
imilar gro
up of pat
ients
may not n
ecessarily
be consid
ered valua
ble to the
same
extent by
a payer, w
ho must n
ot only pa
y for that
indi-
vidual’s t
reatment
but who
also has
to manag
e the
needs of
multiple
groups of
patients
and/or m
embers
with equa
lly compel
ling medi
cal condi
tions and
prior-
ities. Opt
imizing v
alue with
in the he
althcare s
ystem
means tha
t physici
ans and p
ayers mus
t be align
ed in
the way th
ey view t
he variou
s benefits
and costs
of a
given trea
tment.
Achievin
g such op
timization
is where
the artic
le by
Ms Green
apple in th
is issue of
American Health & Drug
Benefitsfits i
n. In her
article,
Ms Green
apple sho
ws
that prov
iders and
payers, at
least whe
n it comes
to the
use of bio
logics for
the treatm
ent of rhe
umatoid a
rthri-
tis, have m
uch more
in comm
on than n
ot when
look-
ing at val
ue within
this drug
class. Th
e finding
s from
this surve
y have s
everal im
portant im
plications
to
providers
, payers, a
nd patien
ts/plan me
mbers.
PROVIDERS: Providers
can p
ractice
more
autonom
ously in a
ddressing
the need
s of the p
atient
with rheu
matoid ar
thritis. T
hey can d
o this by
follow-
ing evide
nce-based
guideline
s as they
initiate
treat-
ment wit
h disease-
modifyin
g antirheu
matic dru
gs, and
only prog
ress to m
ore costly
biologic
therapies
when
they need
to improv
e treatme
nt benefit
s, thereby
opti-
mizing the
value of
treatmen
t. Such st
aged man
age-
ment is a
ligned wit
h payer c
overage p
olicies.
PAYERS: For paye
rs, this iss
ue is a ma
tter of exp
ec-
tation. Kn
owing tha
t provider
s practice
using the
same
specialty g
uidelines
that paye
rs follow w
ill allow p
ayers
to expect
that their
contract
ed provid
ers will “d
o the
right thin
g” when
it comes
to promo
ting evide
nce-
based med
icine whe
n treating
patients
with rheu
ma-
toid arthr
itis.
PATIENTS/PLAN MEMBERS: When
provider
practice i
s aligned
with plan
policy, p
atients or
plan
members
are the u
ltimate w
inners. A
s is descri
bed in
this artic
le, with 8
4% of pro
viders rep
orting app
roval
rates of at
least 61%
of reques
ts for rheu
matoid ar
thritis
biologics (
and 55%
reporting
approvals
of at least
81%
of such r
equests),
patients w
ho need
more inte
nsive
treatmen
t for thei
r arthriti
s can rece
ive it in
a more
timely an
d coordina
ted manne
r.
MEDICAL DIRECTORS: Does th
is mean
that
payers sh
ould stop
enforcing
step the
rapies or
other
such stra
tegies? Re
gretfully,
not yet; c
omplete
buy-in
to evide
nce-base
d medic
ine has
not yet
been
achieved
, and we c
ontinue to
see treat
ment irre
gular-
ities for c
ertain dis
ease state
s. Perhap
s one day
soon,
with the
advancem
ent of me
aningful
use param
eters
by provid
ers, alon
g with e
lectronic
medical
records
and decis
ion supp
ort system
s promoti
ng evide
nce-
based me
dicine, we
will be a
ble to get
there. Af
ter all,
reaching s
uch a go
al for rhe
umatoid
arthritis,
or any
other sig
nificant
condition
, would
not only
be
admirabl
e, but mo
re importa
nt, it wou
ld provid
e great
value in
healthca
re.
Albert Tzeel,
MD, MHSA, FACPE
National
Medical D
irector, H
umanaOn
e
Milwauke
e, WI
STAKEHOLDER PERSPECTIVE
Continued
BUSINESS
271
www.AHDBonline.com l American Health & Drug Benefits l
Vol 4, No 5 l September 2011
I n forecasting the future of cardiovascular disease
(CVD), the American Heart Association calls for
preventive strategies, with particular attention to
obesity. 1 The facts related to the current obesity epi-
demic are familiar, stark, and bode bad news not only
for the physical health of the US population but also for
its economic health. Obesity is a common denominator
in and a risk factor for many chronic conditions,
including diabetes, coronary artery disease (CAD),
stroke, and hypertension. 2,3
Dr Colombi is Corporate Medical Director, PPG Industries,
Pittsburgh, PA; Mr Wood is a Senior Biostatistician, Center
for Health Research, Geisinger Clinic, Danville, PA.
ORIGINAL RESEARCHObesity in the Workplace: Impact on
Cardiovascular Disease, Cost, and
Utilization of CareAlberto M. Colombi, MD, MPH; G. Craig Wood, MS
Background: In forecasting the future of cardiovascular disease (CVD), the American Heart
Association calls for preventive strategies with particular attention to obesity. The association
between obesity and CVD, including coronary artery disease (CAD) and diabetes, is well
established. The rising prevalence of obesity in the workforce may have additional implications
for employers and employees besides the demonstrated effects on absenteeism and work-
ers’ compensation.Objective: This study was undertaken to determine the impact of population obesity on care
utilization and cost of cardiovascular conditions such as hypertension, CAD, and cerebrovas-
cular disease (or stroke) in a large US population of employees engaged in a major corporate
wellness program.Study sample: Using data from a single large industrial employer across 29 geographically
distinct worksites in the United States, 179,708 episodes of care from 2004 to 2007 for
10,853 employees were included.
Methods: The population-based economic impact of obesity was calculated on the basis of
the frequency of episodes of care per 1000 employees and on the amount eligible for pay-
ment per episode of care in US dollars. Data were obtained from a wellness program data-
bases, episode of illness inventories, and pharmacy and medical claims. High and low preva-
lence rates of obesity, by obesity quartile, were used to create linear mixed models to examine
associations with disease outcomes, while controlling for correlation within each worksite.
Results: Worksites with a high rate of obesity (ie, in the fourth quartile) had 348.4 more
episodes of care of any kind per 1000 employees (P <.001), 38.6 more hypertension episodes
of care per 1000 employees (P <.001), and 2.5 more cerebrovascular disease episodes of care
per 1000 employees (P = .017) compared with worksites in the lower 3 quartiles. A worksite
in the fourth obesity rate quartile had $223 greater cost per any kind of episode (P <.001), $169
greater cost per hypertension episode (P = .003), and $1620 more per CAD episode (P = .005)
compared with worksites in the lower 3 quartiles. The overall economic impact per 1000
employees was calculated by combining episode frequency and eligible amount for payment
per episode. For sites in the lower 3 quartiles of obesity, the eligible amount per 1000 employ-
ees for any kind of care was $4.01 million. However, for sites in the highest obesity quartile, the
eligible amount for payment per 1000 employees was $5.26 million. This translates into $1250
greater cost per employee. Similar calculations were used to evaluate the effect of obesity on
the amount eligible for payment per employee for hypertension, CAD, and cerebrovascular dis-
ease episodes, with an estimated $69, $89, and $8 greater cost, respectively, per employee.
Conclusion:Worksites with greater obesity prevalence rates were associated with numerically
more frequent and more expensive episodes of care than worksites with low obesity prevalence.
Am Health Drug Benefits.2011;4(5):271-278www.AHDBonline.comDisclosures are at end of text
Stakeholder Perspective,page 278
Alberto Colombi
EDITORIAL
American Health & Drug Benefits: Reflections on the First 5 YearsGary M. Owens, MD
The Business Case for Ending Homelessness: Having a Home ImprovesHealth, Reduces Healthcare Utilization and Costs Daniel G. Garrett, RPh, MS, FASHP
BUSINESS
Beyond the Cost of Biologics: Employer Survey Reveals Gap inUnderstanding Role of Specialty Pharmacy and Benefit DesignF. Randy Vogenberg, RPh, PhD; Cheryl Larson, BA; Margaret Rehayem, MA; Larry Boress, MPA
Stakeholder Perspective by Atheer A. Kaddis, PharmD
REGULATORY
Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Nowand in Preparation for Healthcare Reform Sarah Collins, MBA
Stakeholder Perspective by Gary M. Owens, MD
CLINICAL
Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted TimeSeries AnalysisR. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD; Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm
Stakeholder Perspective by Matthew Mitchell, PharmD, MBA
INDUSTRY TRENDS
Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape
THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™
FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS
10 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Health Economics
Chicago, IL—Glucose-insulin-potas-sium (GIK) solution, given by para-medics very early after symptomonset in patients with an acute coro-nary syndrome (ACS), can reduce therisk for cardiac arrest or death by 50%during the first 30 days after the ACSevent, according to results of a newstudy presented at the 2012 AmericanCollege of Cardiology meeting. Although the treatment did not pre-
vent myocardial infarction (MI), theGIK solution did reduce infarct size,said co–lead investigator Harry Selker,MD, MSPH, Executive Director of theInstitute for Clinical Research and
Health Policy Studies, Tufts MedicalCenter, Boston. The IMMEDIATE (Immediate My-
ocardial Metabolic Enhancement Dur-ing Initial Assessment and Treatmentin Emergency Care) clinical trial wasfunded by the National Heart, Lung,and Blood Institute.
GIK Solution Costs Approximately $50Previous clinical trials have shown
no consistent effect with GIK, likely be-cause it was given to patients in thehospital approximately 6 hours afterthe onset of ischemia, which was too
late to help. IMMEDIATE was the firsttrial to test real-world effectiveness of
administering GIK at the very firstsigns of an ACS in the community.
IMMEDIATE: Early Use of Inexpensive Glucose-Insulin-Potassium Solution Can Prevent Cardiac Arrest in ACSBy Wayne Kuznar
Table IMMEDIATE End Points: Intention-to-Treat Analysis
End point GIK, % Placebo, % Risk ratio P value
Progression to MI 49 53 0.88 .28
30-day mortality 4 6 0.72 .27
Cardiac arrest or hospital mortality
4 9 0.48 .01
30-day mortality or hospitalization for HF
6 8 0.73 .24
GIK indicates glucose-insulin-potassium; HF, heart failure; MI, myocardial infarction.
Chicago, IL—The evaluation of pa-tients presenting to the emergency de-partment with symptoms of an acutecoronary syndrome (ACS) with coro-nary computed tomography angiogra-phy (CTA) resulted in faster diagnosis,shorter length of stay, and more directdischarge compared with standardevaluation, according to Udo Hoff-mann, MD, MPH, Cardiac Radiologist,Director of Cardiac Imaging, Massa-chusetts General Hospital, Boston, andlead investigator of the multicenterstudy Rule Out Myocardial Infarctionby Computer-Assisted Tomography(ROMICAT) II. In ROMICAT II, 1000 patients (mean
age, 54 years) at 9 centers were ran-domized to CTA or standard evalua-tion by a local physician. The length ofhospital stay, the primary end point,was significantly shorter with CTA: 23
hours compared with 30 hours withstandard evaluation. This differencewas driven by the shorter length of stayin the patients who were not diagnosedwith ACS (17.2 hours vs 27.2 hours, re-spectively). In patients diagnosed withACS, the length of stay was similar.
Cost Results MixedThe cost data were mixed. Although
costs were reduced for the emergencydepartment with CTA compared withstandard evaluation, hospital costswere higher with CTA, and total costswere similar for both strategies (Table). The investigators were pleased to see
that total costs were similar, becauseMedicare data suggested there was adoubling in procedures and costs afterCTA compared with function testing inthe observational ROMICAT I study.However, CTA examination was lim-
ited in ROMICAT II to business week-day hours; expansion to 24-hour avail-ability could impact costs. With a 1-second scan, CTA can accu-
rately and noninvasively determinethe extent of coronary artery disease(CAD), whereas standard evaluationtypically requires 24 to 36 hours andrequires additional work-up to rule outCAD. CTA has been shown to have ahigh predictive value for ruling out
CAD. ROMICAT I showed that pa-tients presenting with chest pain had alow 8% prevalence of ACS, that mostpatients did not have CAD or obstruc-tive plaque, and that CTA had a veryhigh negative predictive value to pre-dict events over the next 2 years.Of note, in ROMICAT II, early CTA
led to advanced discharge in patientswithout an ACS diagnosis. Of patientsundergoing CTA, 50% were dis-charged within 8 hours compared with28 hours with standard evaluation,said Dr Hoffmann. A diagnosis of ACSwas made in 8.6% of patients who hadCTA and in 6.4% of the standard-eval-uation patients.
Care and Discharge DifferencesDirect discharge rate from the
emergency department was 4-foldhigher with CTA (46%) than withstandard evaluation (12%). Fewer pa-tients in the CTA arm were admittedto the hospital. The time to diagnosiswas shorter by approximately 8 hourswith CTA for patients with and with-out ACS (10 hours vs 18.7 hours withstandard evaluation). Repeat visits tothe emergency department for chestpains were reduced 13% with CTAcompared with 19% with standardevaluation.Testing was significantly higher in
the clinical trial arm, and was prima-rily driven by the higher number of pa-tients in the standard-evaluation armwho did not have any tests (22% vs 2%,respectively). More patients who hadCTA had 1 test (75%) and >2 tests(23%) compared with 67% and 10.6%of the standard-evaluation arm.There was no missed ACS diagnoses
in either arm. Two periprocedural com-plications occurred in the CTA arm.At 28 days, 2 major adverse events(defined as death, myocardial infarc-tion, unstable angina pectoris, or theneed for urgent revascularization) oc-curred in the CTA group and 5 in thestandard-evaluation arm.Invasive coronary angiography was
performed in 12% of the CTA patientsand 8% of the standard-evaluation pa-tients. There were also more interven-tions (6.4%) in the CTA arm than withstandard evaluation (4.2%). �
Comparative Effectiveness Analysis: Emergency DepartmentCTA versus Standard ACS Symptom EvaluationBy Mary Mosley
Table Cost Comparison: CTA versus Standard Evaluation
Care setting CTA cost, $
Standard evaluation cost, $ Difference, % P value
Emergency departmenta
2053 2532 –19 <.001
Hospital 1950 1297 +50 .17
Total 4004 3828 +5 .72
aThe cost for the emergency department includes the observation unit.NOTE: Cost is per person for a subset of 650 patients from 5 study centers. CTA indicates computed tomography angiography.
Early CTA led to quickdischarge of patients withoutACS; 50% were dischargedwithin 8 hours comparedwith 28 hours with standard evaluation.
Continued on page 11
Acute Coronary Syndrome
“Because the trial is the first toshow GIK as effective when used byparamedics in real-world communitysettings, it could have important im-plications for the treatment of heartattacks,” said Dr Selker.
For the study, paramedics in 36emergency medical services (EMS)systems in 13 cities across the UnitedStates were trained to administer GIKafter determining that a patient waslikely having an ACS using electrocar-diograph-based criteria and throm-bolytic predictive instrument decisionsupport that prints patient-specificpredictions in addition to an electro-cardiogram. The paramedics used thepredictive instruments to decide if apatient would likely benefit from treat-ment. There were 911 patients random-ized to receive either GIK or placebo.At 30 days, a similar proportion of
patients in each group progressed toMI (49% in the GIK group vs 53% inthe placebo group), but cardiac arrestor hospital mortality occurred in only4% of patients receiving the GIK solu-tion compared with 9% of those in theplacebo group, for a 52% reduction inrisk (Table, page 10). Patients randomized to receive GIK
were 40% less likely to have cardiac ar-rest, to die, or to be hospitalized be-cause of heart failure. The effect waseven more striking for patients withST-segment elevation MI (STEMI), inwhom immediate GIK was associatedwith a 60% reduction in cardiac arrestor death relative to placebo.
Infarct size as a percentage of left-ventricular mass was 10% in theplacebo group and only 2% in the GIKgroup. In the cohort with STEMI, in-farct size was reduced from 12% in theplacebo group to 3% in the GIK group.“The risks and side effects rates from
GIK are very low,” said Dr Selker, “and
GIK is inexpensive, potentially avail-able in all communities, and deservesfurther evaluation in trials for wide-spread EMS use.”The research team will follow up
with study participants at 6 and 12months to evaluate the longer-termbenefit of the GIK treatment. �
11MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Acute Coronary Syndrome
“Because the trial is the firstto show GIK as effectivewhen used by paramedics inreal-world communitysettings, it could haveimportant implications for thetreatment of heart attacks.”
—Harry Selker, MD, MSPH
Key Points� IMMEDIATE was the first trialto test real-world effectiveness ofadministering GIK at the very firstsigns of an ACS
� Although it did not prevent anMI, GIK reduced infarct size;infarct size as a percentage ofleft-ventricular mass was 10% inthe placebo group versus 2% inthe GIK group
� Patients randomized to receiveGIK were 40% less likely to havecardiac arrest, die, or behospitalized for heart failure
� GIK’s risks and side effects arevery low; it is inexpensive and ispotentially available in allcommunities, making it adesirable treatment
The benefits of NovoTwist® are:
• Less time consuming for patients to attach
• Features an audible and tactile confirmatory click for correct attachment
• Available in 30G (8mm) and 32G Tip (5mm) needles
Available for use with FlexPen® and other compatible Novo Nordisk devices.*
For more information, visit myflexpen.com or call 1-800-727-6500
* Designed to be used with Levemir® FlexPen®, NovoLog® FlexPen®, NovoLog® Mix 70/30 FlexPen®, and other compatible Novo Nordisk delivery devices. Please refer to the delivery device user manual to see if NovoTwist® can be used with your device. Also refer to the user manual for information on assembly and injection.
Needles are sold separately and may require a prescription in some states.
Tell your patients about NovoTwist®, the first and only single-twist needle attachment on the market.
GOODDESIGN
Winner of the US Good Design™ award1
IMMEDIATE: Early Use of Inexpensive... Continued from page 10
12 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Acute Coronary Syndrome
Chicago, IL—The new oral anticoagu-lants rivaroxaban (Xarelto), dabigatran(Pradaxa), and the yet-to-be-approvedapixaban (Eliquis) have been shown tobe superior to warfarin (Coumadin) inpreventing stroke in patients with atrialfibrillation (AF). However, the jury isstill out on their value in patients withacute coronary syndrome (ACS), andthe safety profiles of these agents havenot been fully elucidated, said WilliamDager, PharmD, Clinical Professor ofPharmacy, University of CaliforniaSchool of Pharmacy, San Francisco, andClinical Professor of Pharmacy, Univer-sity of California-Davis School of Med-icine, at the 2012 American College ofCardiology meeting.Issues remain about reversing the
anticoagulant effects of the new drugsin cases of life-threatening bleedingand appropriate monitoring of theiractivity.Most of the data with rivaroxaban,
dabigatran, and apixaban have beencollected in the setting of AF. Both riv -aroxaban and the 150-mg dosage ofdabigatran were shown to reduce therisk for stroke and systemic embolismwith lower rates of intracerebral hem-orrhage (ICH) compared with war-farin in large, randomized clinicaltrials of patients with AF. In the ROCKET-AF trial of rivarox-
aban, there was an increase in the in-cidence of stroke in the rivaroxabanarm during the posttrial transition toopen-label warfarin. Apixaban hasproduced favorable outcomes (pre-vention of stroke or systemic em-bolism) compared with aspirin andwarfarin in separate trials in patientswith AF.
Consider Renal Function When DosingBoth dabigatran and rivaroxaban re-
quire dosing that is sensitive to renalfunction, said Dr Dager. The standardapproved dosage of rivaroxaban forstroke prevention in patients withnonvalvular AF is 20 mg daily, but inpatients with renal impairment—crea-tinine clearance (CrCl) in the range of30 mL/min to 49 mL/min—the dosageshould be reduced to 15 mg once daily.Riv aroxaban’s use should be avoidedin patients with CrCl <15 mL/min.“The way renal failure is calculated
is one thing you have to consider,”said Dr Dager. “In the trials, we usedthe Cockcroft-Gault, using ideal totalbody weight to do renal assess ments;that was for both dabigatran and rivaroxaban.”
The ACS SettingIn the setting of ACS, dabigatran
was associated with an excess of acutemyocardial infarction (MI) of approxi-mately 0.2% compared with warfarinin the RE-LY (Randomized Evaluationof Long-Term Anticoagulation Ther-apy) trial. However, further analysis ofthe RE-LY data showed a nonsignifi-cant increase in the risk for MI withdabigatran, irrespective of risk factors.
A review of 7 clinical trials conductedwith dabigatran in various settingsuncovered a consistently significant in-creased risk for MI or ACS with dabi-gatran against various controls.There was no significant difference
between dabigatran and warfarin in therates of ACS in clinical trials conducted
in patients with deep-vein thrombosis.With bleeding issues unresolved,
rivaroxaban cannot yet be consideredan option in the long-term man -agement of ACS, said Dr Dager. Inlow-risk patients with recent ACS, riv -aroxaban added to aspirin, with orwithout clopidogrel, was associatedwith a significant reduction in the oc-currence of major adverse cardiovas-cular events compared with placebo,but it increased the rates of majorbleeding and ICH, without an in-crease in fatal bleeding.APPRAISE-2A (Apixaban for Pre-
vention of Acute Ischemic Events 2), aclinical trial of apixaban in patientswith ACS, was stopped early becauseof a significant increase in major bleed-ing and ICH in the apixaban group.Vorapaxar, a protease-activated re-
ceptor 1 antagonist, was not effectivein reducing the risk of adverse throm-botic events in addition to standardantiplatelet therapy in patients withnon–ST-segment elevation ACS, whileincreasing bleeding risk.
Can They Be Reversed?A potential drawback to the use of
the new anticoagulants is the so-far
lack of an effective agent to reversetheir anticoagulant effects in the pres-ence of life-threatening bleeding.Prothrombin complex concentrates(PCCs) have been studied in rats andhumans with varying success. There are encouraging signs that ac-
tivated PCC (aPCC) may work in thisregard. The effect of dabigatran wassuccessfully reversed with the use of25 U/kg of aPCC (factor VIII inhibitorbypass activity) in 1 patient with a trans -septal perforation who lost 4 L of bloodduring cardiac ablation, said Dr Dager.
Is Monitoring Needed?Although routine monitoring is not
recommended for the new anticoagu-lants, their activity may need to bemeasured in certain situations. An el-evated thrombin time may indicatethe presence of dabigatran, and achromogenic anti–factor Xa can indi-cate the presence of rivaroxaban, DrDager noted.Quantitative tests are not readily
available for assessing the intensity ofanticoagulation effects with eitheragent. A chromogenic ecarin clottingtime–driven dabigatran level has beendeveloped but requires further study. �
With bleeding issuesunresolved, rivaroxabancannot yet be considered anoption in the long-termmanagement of ACS.
—William Dager, PharmD
Value of New Anticoagulants in Acute Coronary Syndrome Still UnclearBy Wayne Kuznar
See also Atrial Fibrillation
CALL FOR PAPERSCardiometabolic Health Theme Issue
American Health & Drug Benefits will be publishing a Theme Issue on Cardiometabolic Health later this year.Readers are invited to submit articles on topics relevant to the clinical, business, and policy aspects of cardiometa-bolic health. Original research studies, white papers, evidence-based comprehensive reviews, and case studies are ofparticular interest.
All healthcare stakeholders are invited to present their data, best practices, innovations, and initiatives to facilitatemanagement strategies and benefit design to improve cardiometabolic outcomes and prevent common risk factors whilereducing costs for those at risk for cardiovascular disease, diabetes, or obesity.
Readers are invited to submit original, outcomes-based research, white papers, evidence-based comprehensive reviews, and case studies on topics such as:
Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com) Submit articles to [email protected], or call 732-992-1889
• Benefit designs to improve cardiometabolic outcomes• Best practices in diabetes management and prevention
• Best practices in insulin control, lipid management,or blood pressure control
• Comparative effectiveness analyses of best therapiesfor cardiovascular health
• Cost-effectiveness comparisons • Employers’ strategies to enhance cardio metabolicwellness
• New and emerging therapies
• Health plan initiatives in cardiometabolic healthand wellness
• Hot topics in diabetes, obesity, or cardio vascular disease
• Lifestyle strategies and cardiometabolic health• Lipid management in patients with diabetes• Medication adherence and diabetes progression• New biomarkers for assessing cardiometabolic risk • Prevention strategies for diabetes risk reduction • Prevention programs for cardiometabolic comorbidities
13MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Hypertension
Chicago, IL—The long-awaited updateof the hypertension treatment guide-lines, the Eighth Report of the JointNational Committee on Prevention,Detection, Evaluation, and Treatmentof High Blood Pressure (JNC-8), willbe published at the end of 2012. Theprevious guidelines (JNC-7) were lastpublished in 2003. Suzanne Oparil, MD, Professor,
Department of Medicine, Division ofCardiovascular Disease, University ofAlabama, Birmingham, and cochair ofthe expert panel that developed theseguidelines, discussed the process thathas contributed to the lengthy delay inpublishing the JNC-8 guidelines at the2012 American College of Cardiology(ACC) meeting.The new JNC-8 hypertension guide-
lines will answer 3 clinical questions:• When to initiate drug treatment?• How low should blood pressure(BP) be lowered?
• How do you get there?These questions were defined to an-
swer whether health outcomes in pa-tients with hypertension are improvedby initiating antihypertensive pharma-cologic therapy at specific BP thresh-olds, by reaching specific BP goals, andby using different antihypertensivedrugs or classes of drugs that differ incomparative benefits and harms. DrOparil gave no indication of what thespecific recommendations will be. The development of the JNC-8 clin-
ical practice guidelines is part of thecurrent National Heart, Lung, andBlood Institute (NHLBI)-sponsoredadult cardiovascular disease (CVD)prevention guidelines program. TheAdult Treatment Panel guidelines forthe treatment of elevated blood choles-
terol and the overweight and obesityguidelines are being developed simul-taneously. Ultimately, these 3 guide-lines will be integrated into 1 CVDrisk-reduction guideline.Ensuring that the JNC-8 guidelines
are firmly evidence-based is the rea-son that it has taken so long to writethem, said Dr Oparil. This intensifiedfocus is a direct result of an Institute ofMedicine (IOM) report published in2001 about the quality chasm, whichnoted that clinical decision-making isbased on training and experience. The report also advocated patient
care based on the best-available scien-tific knowledge and the elimination ofvariability in healthcare.Dr Oparil noted that only 3 of the
ACC/American Heart Associationguidelines have the top level of evi-dence (level A) for >20% of the recom-mendations in the guideline; the othersrange from 15% to 55%.The new NHLBI-sponsored adult
cardiovascular guidelines, includingJNC-8, will not look like the previousguidelines, Dr Oparil pointed out. Theywill be strictly evidence-based, havemore depth and rigor, be more focused,and use evidence-based strategies fortheir implementation, she explained. The practice guidelines will include
a summary of the evidence for eachclinical question, graded evidencestatements, graded recommendations,and references.
Increased Focus on Level of EvidenceA process for developing the guide-
lines was established to “ensure therigor and to minimize bias,” said DrOparil, and it uses methods to meetmany of the new IOM standards forsystematic reviews. Strict criteria wereestablished for the systematic literaturesearch, rating the study quality withinstruments for different studies, andfor data abstraction and developingevidence tables.The quality of the evidence is rated as
low, moderate, and high. The strengthof a recommendation will range from Afor strong evidence, B for moderate, Cfor weak, D for against, E for expertopinion, and N for no recommendation. There is wide representation of
expertise on the JNC-8 expert panel,ranging from hypertension, primarycare, cardiology, nephrology, researchmethodology, evidence-based medi-cine, epidemiology, and guidelinedevelopment and implementation,among others. The rationale for the clinical ques-
tions driving the JNC-8 guidelines isto assess the evidence for BP level of140/90 mm Hg as a treatment goal; todetermine if this treatment thresholdshould be adjusted for specific diseaseconditions, comorbidities, characteris-tics, or age; and to determine whetherthere is evidence of improved out-comes by lowering BP with a particu-lar drug or drug class.The JNC-8 guidelines will provide
practice guidance for patients aged ≥18years across a number of prespecifiedsubgroups, such as diabetes, chronickidney disease, CVD, older adults, sex,racial and ethnic groups, and smokers. �
New JNC-8 Hypertension Guidelines to Be Released by Year EndEvidence-based guidance for subgroups, including patients with diabetes and kidney diseaseBy Mary Mosley
� The JNC-8 hypertensionguidelines will be published atthe end of 2012 and will addresswhen to initiate drug treatment,how low BP should be lowered,and how to achieve these goals
� The guidelines will have moredepth and rigor, and useevidence-based strategies fortheir implementation
� The clinical questions drivingthe JNC-8 guidelines will assessthe evidence for 140/90 mm Hgas a BP treatment goal and todetermine if it should be adjusted for specific diseases,comorbidities, or age
Key Points
The long-awaited new JNC-8guidelines will use evidence-based strategies for theirimplementation and willprovide guidance acrossprespecified subgroups,including diabetes, chronickidney disease, CVD, olderadults, racial and ethnicgroups, and smokers.
—Suzanne Oparil, MD
See also page 14
Signature (Required) Specialty (Required)
Date Address
Name City/State/Zip
Company E-mail
Title Phone
Request your SUBSCRIPTION to
AmeRicAn HeAltH & DRug Benefits®
Please provide all information indicated, including date and signature.
INCOMPLETE CARDS WILL NOT BE PROCESSED.
� YES! I would like to receive American Health & Drug Benefits as well as related educational supplements.� NO. Please discontinue my subscription.
Fax to: 732.992.1881
14 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Hypertension
Chicago, IL—Combination therapyfrom the start should be considered forall patients in whom pharmacotherapyis chosen for the treatment of hyper-tension, said Kenneth A. Jamerson,MD, Professor of Medicine, Universityof Michigan Health System, AnnArbor, at the 2012 American College ofCardiology meeting.In high-risk patients, combining an
angiotensin-converting enzyme (ACE)inhibitor with amlodipine is superiorto diuretic-based combinations, he said,and in low-risk patients, combinationtherapy from the outset achieves fasterblood pressure (BP) control.Clinical trials in which monothera-
pies were compared were, in essence,trials of combination therapy, becausepatients required multiple drugs toreach prespecified targets, Dr Jamer-son noted.In making his case for target BP and
the choice of therapy, he drew on hisexperience as part of the group thatwrote the International Society on Hy-pertension in Blacks (ISHIB) Consen-sus Statement for the management ofhypertension in blacks.In patients without target-organ
damage or overt cardiovascular dis-ease (CVD), ISHIB consensus state-ment recommended modest loweringof the BP target to <135/85 mm Hg,he said, adding that an attempt tolower BP in these low-risk patientswith up to 3 months of lifestyle mod-ification is reasonable. The lower BP goal is based on clini-
cal trial evidence showing better out-comes with the lower goal versus agoal of <140 mm Hg systolic BP.In low-risk patients, combination
therapy offers more prompt and effi-cient control of BP compared withmonotherapy.For patients with target-organ dam-
age or preclinical/clinical CVD, ISHIBrecommended that BP be lowered andmaintained consistently to <130/80mm Hg.“Combination therapy with an ACE
inhibitor and amlodipine is superior todiuretic-based combination therapy inreducing cardiovascular disease mor-bidity and mortality in high-risk pa-tients,” said Dr Jamerson.The Anglo-Scandinavian Cardiac
Out comes Trial (ASCOT) comparedan amlodipine/perindopril combina-
tion with a combination of atenolol/bendroflumethiazide in patients with
hypertension and at least 3 other car-diovascular (CV) risk factors. All-causemortality and CV mortality occurredsignificantly less often in the amlodi -pine/perindopril arm of the study.Another trial to support the ACE in-
hibitor/amlodipine combination wasAvoiding Cardiovascular Events inCombination Therapy in PatientsLiving with Systolic Hypertension(ACCOMPLISH), in which a combi-nation of benazepril and amlodipineproved superior to benazepril andhydro chlorothiazide as initial therapyon the primary end point of time tofirst CV morbidity/mortality (20%relative risk reduction; P = .002) in pa-tients with high-risk hypertension.Diuretics should no longer be con-
sidered preferred therapy for hyper-tension; in fact, they should berelegated to add-on therapy, said DrJamerson. There is no BP-lowering ad-vantage to diuretics, he said, and theyrequire more laboratory monitoringthan other classes of antihypertensives. In addition, the cost advantage to di-
uretics has disappeared, because mostother antihypertensive drug classesnow have generic formulations. �
Consider Combination Therapy for Patients with Low- and High-Risk HypertensionBy Wayne Kuznar
“Combination therapy withan ACE inhibitor andamlodipine is superior todiuretic-based combinationtherapy in reducingcardiovascular diseasemorbidity and mortality inhigh-risk patients.”
—Kenneth A. Jamerson, MD
Chicago, IL—Patients with uncontrolledhypertension who reported blood pres-sure (BP) readings to their physiciansthrough a web-based portal receivedmore frequent medication adjustmentsand more timely treatment decisionscompared with a group of patients withhypertension who had only conven-tional routine office visits, according toa study presented at the 2012 AmericanCollege of Cardiology meeting.According to the researchers, “Blood
pressure control plays an integral rolein the prevention of cardiovascular dis-ease. Aside from lifestyle changes,pharmacotherapy is the physician’smost effective method of loweringblood pressure.”According to the Centers for Dis-
ease Control and Prevention, as manyas 65 million American adults have el-evated BP, and roughly 74% takemedication for it. In a secondary analysis of this
study, patients (average age, 59 ± 13
years) with uncontrolled hyperten-sion (≥150/90 mm Hg) from 2 largemedical centers were randomized tousual care (N = 121) or telemedicinewith usual care (N = 120). More than
half of the patients (56.8%) were taking1 or 2 BP-lowering medications at thestart of the study. Most patients werewomen; 80% of participants were black.Patients in the telemedicine group
were provided digital sphygmo-manometers and were trained on howto use them. They were instructed toreport their BP, heart rate, weight,daily steps, and tobacco use twiceweekly for 6 months.All patients had baseline and 6-
month follow-up visits. Monthly re-ports on BP and treatment guidelineswere provided to both the patient andthe physician in the telemedicine group.At the end of the study, the patients’ an-tihypertensive medications were com-pared with their baseline therapy.At 6 months, the medications pre-
scribed to those in the usual-caregroup were virtually unchanged, butthere was a small increase in the num-ber of medications ordered for pa-tients in the telemedicine group.There were no differences in resultswith respect to age, ethnicity, educa-tion, or income.Val Rakita, MD, Internal Medicine
Resident at Temple University Hospital,
Philadelphia, PA, and the study’s coin-vestigator, said that prescribing moremedication in the telemedicine groupdid not signify overtreatment but was areflection of more timely decisions to in-crease and/or adjust medications.There was no significant difference
in the decrease in BP between thegroups overall, but the group of non-diabetic patients using telemedicinewas found to have lower BP com-pared with all of the other groups.According to Dr Rakita, the find-
ings suggest that an Internet-basedintervention results in more appropri-ate and effective drug therapy for pa-tients with uncontrolled hyper tension,as well as better BP control and anoverall reduction in cardiovascular risk.“The ongoing monitoring and re-
porting of blood pressure levels seemsto bring about important changes inphysician prescribing habits, whichwe think will ultimately benefit pa-tients,” Dr Rakita pointed out.—WK �
“The ongoing monitoring andreporting of blood pressurelevels seems to bring aboutimportant changes inphysician prescribing habits,which we think will ultimatelybenefit patients.”
—Val Rakita, MD
Patient Web-Based Blood Pressure Reporting May Improve Control
15MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Lipid Disorders
Chicago, IL—A fully human mono-clonal antibody lowered low-densitylipoprotein cholesterol (LDL-C) levelsan additional 40%, to 72% in hypercho-lesterolemic patients already beingtreated with atorvastatin (Lipitor). Theantibody binds to PCSK9 to preventdegradation of LDL receptors, facilitat-ing LDL-C transport from the blood tothe liver, thereby decreasing circulatinglevels of LDL-C, reported lead investi-gator James McKenney, PharmD, Pres-ident and Chief Executive Officer,National Clinical Research, Inc, andlead investigator of this multicenter,randomized clinical trial of the mono-clonal antibody. A 150-mg injection of SAR236553/
REGN727 every 2 weeks loweredLDL-C by 72.4%, from baseline to 12weeks, said Dr McKenney. “This newmechanism may be the next big step, ifit pans out. The data say that [the anti-body] is quite powerful, at least as ifnot more powerful than the statin. It
takes us to another level,” he said.The trial included 183 patients with
LDL-C levels of ≥100 mg/dL who
were already receiving treatment withatorvastatin, 10 mg to 40 mg daily
for at least 6 weeks. They were ran-domized to placebo or injections ofSAR236553/REGN727 every 2 weeks(50, 100, or 150 mg) or every 4 weeks(200 or 300 mg; Table).“Two weeks after administration,
we saw an immediate reduction inLDL cholesterol reaching 31% to 63%,”said Dr McKenney. The reductions in LDL-C from base-
line to week 12 ranged from 39.6%with 50 mg of SAR236553/REGN727every 2 weeks to 72.4% with 150 mgevery 2 weeks. By comparison, the re-duction in LDL-C in the placebo groupwas 5.1%.There were favorable changes in
apolipoprotein B, triglycerides, high-density lipoprotein cholesterol (HDL-C), non–HDL-C, lipoprotein (a), andapolipoprotein A1 in the groups ran-domized to SAR236553/REGN727.All patients assigned to 150 mg
twice weekly of SAR236553/REGN727achieved a final LDL-C <70 mg/dL;their mean baseline LDL-C while re-ceiving atorvastatin was 123.9 mg/dL.The frequency of treatment-emer-
gent adverse events was similaracross all groups—placebo and treat-ment groups—said Dr McKenney. Sixpatients randomized to SAR236553/REGN727 discontinued treatment asa result of treatment-emergent ad-verse events. One of these patients de-veloped leukocytoclastic vasculitisthat resolved after treatment withprednisone.The results support further eval -
uation of SAR236553/REGN727 inlarger, more diverse patient popula-tions, with different background ther-
apies to fully assess efficacy andsafety, said Dr McKenney.“Maybe we have another era in the
treatment of lipid disorders, and moreimportant, in the reduction of heartdisease in this country,” he said.
“This is one of the few drug classesfor which most people who havelooked at the data would bet on mak-ing it to approval. For all kinds of rea-sons, having another major class ofLDL-lowering drugs that is as power-ful as the statins—or more powerful—is a big plus for patients,” commentedSteven Nissen, MD, Chair, Departmentof Cardiovascular Medicine, ClevelandClinic, OH. Further studies of SAR236553/
REGN727 may reveal an incrementalbenefit to driving LDL-C levels lowerthan those currently obtainable, per-haps as low as 50 mg/dL, Dr Nissennoted. �
Monoclonal Antibody Produces Powerful Reductions in LDL CholesterolBy Wayne Kuznar
“For all kindsof reasons,havinganothermajor classof LDL-lowering
drugs that is as powerful asthe statins—or morepowerful—is a big plus forpatients.” —Steven Nissen, MD
“This newmechanismmay be thenext bigstep, if itpans out.
The data say that [theantibody] is quite powerful,at least as if not morepowerful than the statin. Ittakes us to another level.”
—James McKenney, PharmD
Table Changes in LDL Cholesterol, by Treatment Group
Baseline LDL, mg/dL Change at week 12, %
Placebo 130.2 –5.1
SAR236553 50 mg every 2 wk 123.2 –39.6
SAR236553 100 every 2 wk 127.0 –64.2
SAR236553 150 mg every 2 wk 123.9 –72.4
SAR236553 200 mg every 4 wk 128.2 –43.2
SAR236553 300 mg every 4 wk 131.6 –47.7
LDL indicates low-density lipoprotein.
Chicago, IL—A meta-regression analy -sis found that adding a therapy thatraises high-density lipoprotein choles-terol (HDL-C) to a statin is unlikely toproduce a substantial clinical benefit,said Brian A. Ference, MD, MPhil, MSc,FACC, Associate Chief of TranslationalResearch and Clinical Epidemiology,Director of the Cardio vascular Ge-nomic Research Center and AssistantProfessor of Medicine at Wayne StateUniversity School of Medicine, Detroit,MI, at the 2012 American College ofCardiology meeting.Dr Ference and colleagues analyzed
26 statin trials, which included 169,138participants. The investigators esti-mated the effect of raising HDL-C onmajor adverse cardiovascular events,controlling for the effect of reducingthe level of low-density lipoproteincholesterol (LDL-C) with the statin.The risk of major adverse cardiac
events (MACE) was reduced by 19%per each mmol/L reduction in LDL-Cindependent of any change in HDL-C. No reduction in the risk of MACEwas found per mmol/L increase inHDL-C after controlling for the effectof lowering HDL-C.
In a meta-analysis of 5 clinical trialsthat included almost 27,000 partici-pants, adding either fenofibrate (Trior,
Trilipix), niacin (Niacor, Niaspan),torcetrapib, or anacetrapib to a statin toincrease the level of HDL-C did notreduce the risk of MACE, despite aweighted mean increase in HDL-Cof 24.5 mg/dL (0.63 mmol/L) and aweighted mean additional reduction inLDL-C of 16.0 mg/dL (0.41 mmol/L).“Raising HDL is not associated with
any clinical benefit in the presenceof statin therapy to lower HDL,” con-cluded Dr Ference. “Increasing HDLmay be deleterious if raised too high.Large ongoing randomized trials maygive more information.”—WK �
Boosting HDL Provides No Additional Benefit in Patients Already Taking a Statin
“Raising HDL is notassociated with any clinicalbenefit in the presence ofstatin therapy to lower HDL.Increasing HDL may bedeleterious if raised too high.”
—Brian A. Ference, MD, MPhil, MSc, FACC
16 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Lipid Disorders
Chicago, IL—A retrospective analysisof high-risk patients in a managed caresetting shows that those who werenewly prescribed statin therapy wereusually started at low-to-moderatedoses, and approximately 50% of themhad discontinued therapy within 12months, reported Terry A. Jacobson,MD, Professor of Medicine and Direc-tor of the Office of Health Promotionand Disease Prevention, Emory Uni-versity, Atlanta, GA. Dr Jacobson and colleagues con-
ducted a retrospective analysis of11,473 high-risk patients who were notat their low-density lipoprotein choles-terol (LDL-C) goal at baseline and wereprescribed statin therapy. The patientswere identified from a longitudinaldatabase of claims information from alarge, commercially insured populationin the United States. All patients had atleast 1 medical claim for coronary heartdisease (CHD), atherosclerotic vasculardisease, or diabetes before initiating
statin monotherapy and were not at theoptional LDL-C goal of <70 mg/dL forhigh-risk patients.Of the 11,473 patients who were in-
cluded, 7028 had diabetes as their onlyhigh-risk feature, 3052 had CHD oratherosclerotic disease, and 1393 had
diabetes and either CHD or atheroscle-rotic disease.Some 44.7% of the patients were
treated with simvastatin (Zocor) and31.5% were treated with atorvastatin(Lipitor). Most were receiving statins,which were expected to produceLDL-C lowering of 31% to 50%.The mean LDL-C level was 138
mg/dL before statin initiation, whichfell by 24% to 101 mg/dL at the first el-igible postindex date (≥4 weeks aftertreatment initiation).Almost two thirds (64.9%) of pa-
tients experienced a first treatmentchange, with a mean time to change of93.8 days, including 46.9% who dis-continued statin treatment altogether.Of the total patients, 18% wereswitched to a different statin.Of the patients who had a first
treatment change, 13.6% (8.8% of thetotal cohort) had a second treatmentchange, with a mean time to change of178.3 days.
Of the 451 patients who switchedstatins at the first treatment change, 139were switched to a statin at the same po-tency, 187 were switched to a statin witha higher potency, and 125 were switchedto a lower potency statin regimen.Of the 123 patients who switched
statins at a second treatment change,24 patients were switched to one withthe same potency, 75 were switchedto a higher potency regimen, and 24were switched to a lower potencystatin regimen.The majority of patients who had a
treatment change continued to take thesame statin but had the dosage in-creased by 1 level; only 3% who had anincrease in dosage had it increased by2 levels.According to the study authors, the
treatment patterns demonstrate theneed for systemwide improvementsto increase medication adherence, inaddition to more patient and providereducation. �
Low-Potency Statins Initiated in High-Risk Patients in a Managed Care SettingBy Wayne Kuznar
High-riskpatients newlyinitiated onstatin therapyin a managedcare setting
were usually started at low-to-moderate doses, andapproximately 50% of thepatients had discontinuedtherapy within 12 months. —Terry A. Jacobson, MD
both ApoB and LDL-C levels by a me-dian of 70%.The 200-mg weekly subcutaneous
dose was selected for all phase 3 tri-als of mipomersen in patients withhomozygous familial hypercholes -terol emia, heterozygous familialhyper cholesterolemia (HeFH) pluscoronary artery disease (CAD), severehypercholesterolemia in HeFH, andhypercholesterolemia plus a high riskof CAD.When used in addition to maximally
tolerated lipid-lowering therapies,mipomersen reduced levels of LDL-Cby 25% to 37% and ApoB by 26% to38% in the above patient groups(Table). It also had a “fairly robust” ef-fect in reducing levels of Lp(a) by 21%to 34%, Dr Stein stated.Because mipomersen is not metabo-
lized through the CYP450 enzyme, ithas no clinically significant drug–druginteractions with statins or ezetimibe(Zetia), he said.
PCSK9 InhibitorsThe other class of agents with im-
pressive potential targets PCSK9, anewly discovered hepatic regulator ofthe LDL receptor. PCSK9 in the plasmabinds to LDL receptors and reducesrecycling, effectively downregulatingLDL receptor activity and resulting inincreased plasma LDL-C.Injectable human PCSK9 mono-
clonal antibodies bind to PCSK9 toblock its effect and prevent the degra-dation of LDL receptors.SAR236553/REGN727. Dr Stein
was the lead investigator of 3 recentlypublished placebo-controlled studies(Stein EA, et al. N Engl J Med. 2012;366:1108-1118) in which the PCSK9monoclonal antibody SAR236553/REGN727 was administered subcuta-
neously every 2 weeks in doses of 50,100, or 150 mg in 51 patients withHeFH or non-HeFH who were beingtreated with atorvastatin 10 to 40mg/day. An additional 150-mg arm(n = 7) was enrolled with no back-ground atorvastatin therapy and base-line LDL-C ≥130 mg/dL.Dose-dependent reductions in LDL-
C of 35% to 61% (150 mg twice weekly)from baseline were observed withSAR236553; a reduction in ApoB levelsof >40% with the highest dose was alsoobserved. Dose-dependent increases in
high-density lipoprotein cholesterolalso occurred.SAR23655. In a larger placebo-con-
trolled multicenter randomized clinicaltrial in patients with primary hyper -cholesterolemia (see article, page 21), asubcutaneous injection of SAR23655every 2 weeks at a dose of 150 mg re-duced LDL-C by 72% in patients whowere already being treated with ator-vastatin (Lipitor).“The effects [of SAR236553] are ad-
ditive rather than synergistic,” said DrStein. The reductions in LDL-C withthe PCSK9 monoclonal antibody occurwithin days, peaking at 2 weeks.AMG145. Another human mono-
clonal antibody against PCSK9 isAMG145. Phase 1 data of this agent in
58 patients being treated with rosu-vastatin (Crestor), atorvastatin, andsimvastatin (Zocor) were reported. Inthe group receiving low-dose to mod-erate-dose statins (N = 40), AMG145given every 2 weeks or every 4 weekslowered LDL-C by an additional 80%.Further, levels of Lp(a) declined by≥30% in the patients receiving low-to-moderate doses of statins who weretreated with AMG145 every 2 weeksand every 4 weeks; the group receiv-ing high-dose statins (N = 7) had a re-duction in Lp(a) that approached 45%.“It appears as if 2-week, possibly
4[-week], dosing is needed to keepvalues stable; there may be differencesbetween different monoclonal anti-bodies,” Dr Stein concluded. �
Lipid-Lowering Drug Pipeline... Continued from page 1
“It appears as if 2-week,possibly 4[-week], dosing isneeded to keep valuesstable; there may bedifferences between differentmonoclonal antibodies.”
—Evan A. Stein, MD, PhD
Table Effect of Mipomersen on Selected Lipids in HeFH: Results from aDose-Ranging Study
Mipomersen groups (dosages in mg/wk)
LipidsPlacebo, % 50, % 100, % 200, %
300 (6 wk),%
300 (13 wk),%
ApoB –6 –9 –9 –20a –33b –43a
LDL –5 –12 –11 –20a –36b –46a
Lp(a) –3 0 –19 –17 –25 –37aP <.02 vs placebo. bP <.01 vs placebo. ApoB indicates apolipoprotein B; HeFH, heterozygous familial hypercholesterolemia; LDL, low-densitylipoprotein; Lp(a), lipoprotein (a). Source: Adkim F, et al. Am J Cardiol. 2010;105:1413-1419.
17MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Atrial Fibrillation
Chicago, IL—“Difficult” atrial fibrilla-tion (AF), for which standard rate-control therapy or standard rhythm-control therapy has not been effective,or AF in the setting of sinus node orother conduction disease, has beenshown to sometimes benefit from non-standard or combination-drug treat-ment, according to James A. Reiffel,MD, Professor of Clinical Medicine,Columbia University Medical Center,New York City.For patients in whom ventricular
rate control cannot be attained withbeta-blockers, calcium channel block-ers, and/or digitalis, nonhepaticallymetabolized beta-blockers may be anoption. Serum concentrations of meto-prolol (Lopressor, Toprol) or propran -olol (Inderal, Inderal LA, InnopranXL), for example, can vary up to 10-fold for the same dose, partially theresult of high first-pass effects. “I would avoid them,” Dr Reiffel
cautioned. “I would use a renallycleared beta-blocker.”
For bradycardia-tachycardia syn-drome, he suggests pindolol (Visken),which increases slow heart rates butblocks exercise rates. Digitalis is effec-tive at slowing resting rates but notwith exercise rates.In patients with vagally induced
AF, anticholinergic agents alone or incombination with traditional antiar-rhythmic drugs may improve rhythmcontrol.Occasionally, AF is associated with
stress, exercise, or stimulant intake. Inthese patients, beta-blockers alone orin combination with traditional an-tiarrhythmic drugs may improverhythm control. “It has long beenknown that the electrophysiologic ef-fects of antiarrhythmic drugs can bereversed by catecholamines,” Dr Reif-fel noted.
This reversal of drug effects can beprevented by concomitant adminis-tration of beta-blockers and a drugsuch as verapamil (Calan, Covera,Isoptin, Verelan).
Evidence for the efficacy of combi-nation treatment comes from severalstudies. In one trial of patients withpersistent AF randomized to eitheramiodarone (Cordarone, Pacerone)
alone or with verapamil and to fle-cainide (Tambocor) alone or with ver-apamil, at the 3-month follow-up, theverapamil groups had lower first-re-currence rates (20% vs 35%) and lower
New Drug Therapies for Difficult-to-Control Atrial FibrillationBy Wayne Kuznar
For patients in whomventricular rate controlcannot be attained with beta-blockers, calcium channelblockers, and/or digitalis, “I would avoid [metoprololand propranolol]. I would use a renally cleared beta-blocker.”
—James A. Reiffel, MD
Continued on page 18
second-recurrence rates (68% vs 88%).For rhythm control, novel antiar-
rhythmic drugs such as ranolazine(Ranexa) can be considered. Trials ofranolazine in patients with previousantiarrhythmic drug therapy for per-sistent AF showed good tolerance anda success rate of ≥75% in reducing the
frequency or duration of persistent AF,said Dr Reiffel.
Combination Therapy: The Future?Dr Reiffel is enthusiastic about the
future of antiarrhythmic drug combi-nations in improving efficacy. In a ret-rospective chart review in his own
practice from 1990 to 2010, Dr Reiffelfound that he used antiarrhythmicdrug combinations in highly sympto-matic AF patients who were refrac-tory to multiple antiarrhythmic drugs,including amiodarone. Combinationsthat provided clinically significant im-provement included:
• Amiodarone plus propafenone(Rhythmol)
• Amiodarone plus disopyramide(Norpace)
• Amiodarone plus ranolazine• Dronedarone (Mutlaq) plus ranolazine.No proarrhythmia occurred in these
patients, Dr Reiffel noted.
In reviewing charts from 1980 to1995, he encountered 9 patients whohad effective AF control with quini-dine or disopyramide, with eachdosed to efficacy. Gastrointestinal in-tolerance was ameliorated with acombination of these agents, each athalf the previously effective dose.A study of ibutilide (Corvert) and
propafenone in combination had a suc-cess rate of 71.4%, and a study of amio-darone plus wenxin granules showedthat at 6 months, normal sinus rhythmhad been restored in 65.1% of patients. For chronic maintenance of sinus
rhythm, the combination of quinidineplus verapamil was studied. Patientsrandomized to digoxin or to verapamilwere dosed until rate control had beenachieved (<100 beats per minute). Con-version within 6 hours occurred in 84%of patients assigned to quinidine plusverapamil versus 45% of those as-signed to quinidine plus digoxin, withno serious morbidity or mortality ineither group.As adjunctive therapy, Dr Reiffel
says to consider improvement of con-comitant disorders/underlying patho-physiologic alterations (“upstreamtherapies”), such as with angiotensin-converting enzyme inhibitors, an-giotensin 2 receptor blockers, or theircombination. Associated bradycardiashould be treated and/or ablated andthen the previous antiarrhythmicdrugs retried. Consider having the pa-tient enroll in a clinical trial of an in-vestigational agent.Dr Reiffel concluded by saying that
the efficacy rate of an antiarrhythmicdrug is lower when tried after a priorantiarrhythmic drug failure. “None -theless, drug therapy can be effective.Not all patients need to go to ablation.But just remember, as is true elsewhere,therapy is not perfect in all cases.” �
18 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Atrial Fibrillation
New Drug Therapies for Difficult-to-Control... Continued from page 17
Associated bradycardiashould be treated and/orablated and then theprevious antiarrhythmic drugsretried. Consider having thepatient enroll in a clinical trialof an investigational agent.
19MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Atrial Fibrillation
Chicago, IL—Similar outcomes werefound with 2 different antithromboticstrategies in a comparative effec -tiveness study in patients with atrialfibrillation (AF) after a non–ST-seg-ment elevation myocardial infarction(NSTEMI). But a trend toward morebleeding with intensified treatmentwas found. Emil L. Fosbøl, MD, PhD, Fellow,
Department of Cardiology, Copen-hagen University Hospital Gentofte,Hellerup, Denmark, explained thereare no robust data to support the rec-ommendation of the American Collegeof Cardiology (ACC)/American HeartAssociation guidelines to add warfarin(Coumadin) to dual antiplatelet ther-apy (DAPT) with aspirin and clopido-grel. The study was presented at the2012 ACC meeting. The evidence from ongoing clini -
cal trials with rivaroxaban (Xarelto),dabigatran (Pradaxa), and apixaban(Eliquis) is awaited to provide cleareranswers about the best treatment strat-egy. The prevalence of coexisting AFand NSTEMI is 25% in this patient pop-ulation, yet “we do not know how totreat these patients, and whether dualantiplatelet therapy is sufficient to pre-vent future events,” said Dr Fosbøl. The investigators linked observa-
tional data from the CRUSADE Reg-istry with Medicare data to look at lon-gitudinal outcomes. The CRUSADERegistry—a national quality improve-ment initiative to promote evidence-based treatment of hospitalizedpatients with NSTEMI acute coronarysyndromes (ACS)—included datafrom 200,000 patients from 500 hospi-tals across the United States from 2001to 2006.
In this comparative effectivenessanalysis, the registry of patients withAF who received coronary stentingand were discharged on either DAPT(N = 1200) or DAPT plus warfarin(N = 448) were included. The in-hospi-tal major bleeding rate was 16.3% in
the DAPT group and 13.5% in theDAPT plus warfarin group, and the in-hospital stroke rate was similar at 0.4%and 0.5%, respectively. The median age was 78 and 77
years, respectively. Although thisanalysis included patients aged ≥65years only, based on Medicare data, itreflects the typical population with AF.“This is the patient most commonlyseen,” said Dr Fosbøl, “but physiciansare hesitant about antithrombotic treat-ment, because of their age and frailty.”At 1 year after discharge, there was
a similarly high rate of the compositeend point of myocardial infarction(MI), ischemic stroke, and death, at20.6% in the DAPT group and 19.4%in the DAPT plus warfarin group.These rates remained similar after ad-justing for confounders and clinicalcharacteristics. The incidences of bleeding requir-
ing hospitalization at 1 year were11.9% and 14.4%, respectively. Thedifference between the groups did notreach significance, but there was atrend toward more bleeding withDAPT plus warfarin. “Their predictive risk for ischemic
events and bleeding was similar, andwe feel fairly confident that the 2groups are similar,” in this analysis,
said Dr Fosbøl. The median scores forCHADS2 (approximately 2.0) andAnticoagulation and Risk Factors inAtrial Fibrillation (ATRIA; nearly 6)were similar in the DAPT and DAPTplus warfarin patients. CHADS2 pre-dicts the risk of a thromboembolicevent, and ATRIA, a fairly new score,assesses longitudinal bleeding. TheATRIA score includes previous hospi-talization for bleeding, sex, and age,among other factors, and ranges from0 to 10. The strongest predictor forlong-term bleeding is a previousbleeding incident.The use of drug-eluting stents (DES)
was similar in both groups at 80%. Thetype of stent did not influence thebleeding risk in the 2 groups, but moreMIs, strokes, and deaths were reportedin the patients with a DES comparedwith a bare-metal stent.Although efficacy was similar with
the 2 treatment strategies, the trend to-ward higher rates of bleeding withDAPT plus warfarin is a concern. How-ever, Dr Fosbøl noted that clinical trialdata are needed to determine the besttreatment strategies for these patients. For now, physicians must individu-
alize the treatment to the patient andinclude the patient in the discussion toselect the treatment strategy. �
Comparative Effectiveness Analysis of Antithromboticsin Older Patients with Post-ACS Atrial FibrillationBy Mary Mosley
The prevalence of coexistingAF and NSTEMI is 25% inthis patient population, yet“we do not know how totreat these patients, andwhether dual antiplatelettherapy is sufficient toprevent future events.”
—Emil L. Fosbøl, MD, PhD
Continued on page 20
Cardiac Resynchronization Therapy Still Challenging in Patients with Atrial Fibrillation and Heart FailureChicago, IL—Cardiac resynchroniza-tion therapy (CRT) in the setting ofatrial fibrillation (AF) and heart failure(HF) has clear challenges, and the ev-idence is mixed about its benefit. Randomized clinical trial evidence
is needed, including the use of atri-oventricular junction (AVJ) ablation,according to Jonathan S. Steinberg,MD, FACC, Cardiologist and Profes-sor of Medicine at Columbia Univer-sity, College of Physicians andSurgeons of New York, and Directorof the Arrhythmia Institute at ValleyHealth System in New York and NewJersey, at the 2012 American Collegeof Cardiology meeting.The prevalence of AF ranges from
approximately 10% in patients withmild HF to 50% in patients with NewYork Heart Association (NYHA) classIV HF. AF markedly worsens the prog-nosis of HF and the clinical course inthose with left ventricle dysfunction
and those with an implantable car-dioverter-defibrillator. AF also affectsventricular arrhythmias, increases thelikelihood of ventricular tachycardiafibrillation, and causes hemodynamicdeterioration.The benefit of CRT may depend on
ventricular rate control in patients withAF, independent of resynchronization,making it more complicated to assessthe alternate effects of CRT in the pop-ulation with AF. Dr Steinberg noted that US Food
and Drug Administration approval ofCRT was based on clinical trials ofpatients with sinus rhythm, and thebenefit of CRT may be mediated inpart by optimizing atrioventriculartiming in patients with sinus rhythm;however, this timing is not relevant ifthe patient is experiencing AF. CRT is more challenging in patients
with permanent AF than in those withsinus rhythm.
Biventricular Pacing NeededBiventricular pacing is needed virtu-
ally all the time in patients with CRT toaccrue the most benefit. Yet, this can bechallenging in patients with AF andcompeting asynchronous rhythm. Pac-ing options are designed to try tomaintain biventricular pacing whenCRT is used in patients with AF, but nobenefit has been proved. Medical ther-apy to slow the ventricular rate andblock atrioventricular nodal conduc-tion is often unsuccessful.A challenge to achieving consistent
biventricular capture is the need for ahigher programmed pacing rate for ahigher intrinsic heart rate. Frequentfusion and pseudofusion beats canoccur and represent ineffective biven-tricular capture, “in which only asmall amount of left-ventricularmyo cardium is captured by the left-ventricular pacing, negating the in-tended effects of CRT,” Dr Steinberg
Approximately 66% ofpatients with AF ultimatelyhave AVJ ablation, which is a stepwise process based on clinical responseand capture rates.—Jonathan S. Steinberg, MD, FACC
20 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Atrial Fibrillation
New Oral Anticoagulants Show Superior Efficacy... Continued from page 1
said. Inaccurate assessment of biven-tricular capture on device counters—the gold standard to assess properdelivery of CRT—can occur.
Benefit of CRTIn terms of left-ventricular ejection
fraction (LVEF) and NYHA class, CRTshowed benefit in some studies andequivalence in others in a meta-analy-sis. Dr Steinberg presented a prospec-tive study in patients with permanentAF receiving CRT that showed that ef-fective pacing improved NYHA class,reverse remodeling, and LVEF; how-ever, effective pacing occurred in only44% of the patients in that study. This study also identified a high
rate of inaccurate recording of the ab-solute percentage of biventricular pac-ing, as much as 40% of the >90%doc umented pacing.
AVJ ablation improved survival aswas shown in a large observationalstudy of CRT in patients with AF andsinus rhythm. Dr Steinberg noted thatthis is strong evidence for the need for
AVJ ablation, which is the ultimate atri-oventricular nodal blockade and forcescompletely effective ventricular cap-ture, although this is an observationalstudy. Similar results were shown in 2subsequent observational studies.
Who Should Receive CRT?Dr Steinberg said that appropriate
patients for CRT are those with perma-nent AF meeting the clinical criteria forCRT, those who have mild HF and leftbundle branch block only, and patientswith advanced HF and left bundlebranch blockage. Approximately 66%of patients with AF ultimately have AVJablation, which is a stepwise processbased on clinical response and capture
rates, according to Dr Steinberg. Candidates for AVJ ablation are pa-
tients with moderately rapid ventricu-lar rates that cannot be slowed and willnot have pacing capture (performedwith CRT implantation); those withpacing counters that do not reach≥90% (subsequent AVJ ablation); andnonresponders whose electrocardio-gram and Holter recordings show highpercentages of ineffective capture. Pa-tients with relatively slow rates whoare pharmacologically controlled at thetime of CRT implantation are followed.Careful attention to rate control is re-
quired, and physicians should not relysolely on pacing counters to ensure ef-fective CRT capture.—MM �
The prevalence of AF rangesfrom approximately 10% inpatients with mild HF to 50% in patients with NYHA class IV HF.
Cardiac Resynchronization... Continued from page 19
by Mark J. Eisenberg, MD, MPH, As-sociate Professor of Medicine, Direc-tor of McGill Cardiology FellowshipPrograms at McGill University, Mon-treal, Quebec, Canada, and colleaguesat the 2012 American College of Car-diology meeting.These newer agents have been
shown to be superior to warfarin onefficacy end points and to reduce therisk for a major bleeding event com-pared with warfarin, although theydo appear to increase the risk for gas-trointestinal (GI) bleeding.
Superior Efficacy in StrokePreventionThis review encompassed the 3 large,
randomized controlled trials Random-ized Evaluation of Long-Term Antico-agulant Therapy (RE-LY); Apixaban forthe Prevention of Stroke in Subjectswith Atrial Fibrillation (ARISTOTLE);and An Efficacy and Safety Study of Ri-varoxaban with Warfarin for the Preven-tion of Stroke and Non-Central NervousSystem Systemic Embolism in Patientswith Non-Valvular Atrial Fibrillation(ROCKET-AF). Dr Eisenberg’s group used a random
effects model to pool the efficacy andsafety data across the 3 trials, in whichmore than 40,000 patients were ran-domized to one of these new oral anti-coagulants or to warfarin.Patients randomized to one of the
new oral anticoagulants had a 22%decreased risk for a composite endpoint of all stroke and systemic em-bolism compared with patients ran-domized to warfarin.In this analysis, compared with
warfarin, the new oral anticoagulants
were associated with a:• 23% reduction in the relative riskfor ischemic and unidentified stroke
• 55% risk reduction of hemorrhagicstroke
• 12% risk reduction of all-cause mor-tality
• 13% risk reduction of vascular mor-tality.
The risk for myocardial infarction wassimilar between warfarin and the newanticoagulants.
Reduced Risk for Major Bleeding,but Increase for GI Bleeding In addition, the relative risk for
major bleeding was 12% lower withthe new anticoagulants compared withwarfarin, but the relative risk for GIbleeding was increased by >25% withthe newer agents.“These new oral anticoagulants are
easily administered and do not requiremonitoring, making them promisingalternatives for prevention of strokeand systemic embolism in patientswith AF,” Dr Eisenberg stated. Corey Miller, a medical student at
McGill University and a coinvestigatorin this analysis, said that the resultssuggest notable trends with the newanticoagulants. More research will berequired to confirm the suggestion fordecreased risk for major bleeding andincreased GI bleeding with the newagents. Although cost was not in-cluded in this meta-analysis, he notedthat the extra cost for the new medica-tions may be offset by the significantcost associated with monitoring pa-tients receiving warfarin.These same 3 trials, along with the
PETRO (Stroke Prevention in Patientswith AF by Treatment with Dabiga-tran, with and without Aspirin, Com-pared to Warfarin) trial, were used toindirectly compare the newer anticoag-ulants regarding efficacy and safetyend points using a random effectsmodel, which was performed byWilliam L. Baker, PharmD, AssistantProfessor of Pharmacy, University ofConnecticut Schools of Pharmacy andMedicine, Farmington, and colleagues.When compared with dabigatran,
apixaban was associated with 26%lower odds for major bleeding and42% lower odds for GI bleeding.In comparing dabigatran and riv -
aroxaban, the odds of the compositeoutcome of stroke or systemic em-bolism was 25% lower with dabiga-tran, as were the odds for ischemicstroke (33% lower) and hemorrhagicstroke (55% lower).Compared with rivaroxaban, apixa-
ban was associated with 32% lowerodds for a major bleeding event, butrivaroxaban was superior in prevent-ing systemic emboli by nearly 400%.The researchers concluded head-to-
head clinical trials are needed to con-firm these findings. �
“These new oralanticoagulants are easilyadministered and do notrequire monitoring, makingthem promising alternativesfor prevention of stroke andsystemic embolism inpatients with AF.”
—Mark J. Eisenberg, MD, MPH
� The newer oral anticoagulantsapixaban, dabigatran, andrivaroxaban are superior towarfarin in preventing stroke andsystemic embolism in AF
� These newer agents alsoreduce the risk for majorbleeding, although they increasethe GI bleeding risk comparedwith warfarin
� The new anticoagulantsshowed a 23% risk reduction ofischemic and unidentifiedstroke, 55% risk reduction ofhemorrhagic stroke, 12% riskreduction of all-cause mortality,and 13% risk reduction ofvascular mortality
� These oral agents are easilyadministered and do not requiremonitoring of patients as withwarfarin
Key Points
21MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
Atrial Fibrillation
Chicago, IL—A blood test for galectin-3,a unique protein that binds to carbo-hydrates known as “beta-galactosides,”appears to be a reliable predictor of in-cident heart failure (HF) and of theresponse to treatment for HF, reportedJennifer E. Ho, MD, a practicing car-diologist in San Francisco, CA, usingdata from the National Heart, Lung,and Blood Institute’s FraminghamHeart Study, at the 2012 AmericanCollege of Cardiology meeting.Galectin-3 has been implicated in bi-
ologic processes important to the de-velopment and progression of HF, andis believed to be a primary mediator ofprogressive cardiac fibrosis.Data have demonstrated that higher
levels of galectin-3 are associated witha more aggressive form of HF, andthat ≥33% of patients with mild-to-
moderate HF have elevated levels ofgalectin-3.In a study presented at the meeting,
higher levels of galectin-3 were asso-ciated with an increased risk of new-onset HF and all-cause mortality inthe community.The study included 3353 participants
(mean age, 59 years) of the Framing-ham Offspring Cohort whose galectin-3 levels were measured and who werefollowed for development of HF over10 years. Of this population, 10% to 25%had an elevated level of galectin-3.Incident HF was more common as
galectin-3 levels increased. In multi-variate analyses, each standard devia-tion (SD) increase in galectin-3 levelswas associated with a 23% increase inthe hazard ratio (HR) for incident HF,and on sex- and age-adjusted analyses,
each SD increase was associated witha 28% increase in HR.
Galectin-3 was also associated withall-cause mortality, with a multivari-able-adjusted HR of 1.15.
The study provides further confirma-tion that elevated levels of galectin-3 inthe general population are associatedwith a markedly increased risk of HFdevelopment over the subsequent 10years, said Dr Ho.The findings suggest “that cardio-
vascular injury due to fibrosis may beevident long before the clinical onset ofheart failure,” Dr Ho said.A second analysis found a differential
effect of treatment on HF based on pa-tients’ galectin-3 levels. Investigatorsled by Inder S. Anand, MD, FRCP,FACC, Professor of Medicine at theUniversity of Minnesota, and Directorof the Heart Failure Program at theMinneapolis VA Medical Center,looked at treatment response in theValsartan Heart Failure Trial (Val-HeFT), in which patients with HF
Blood Assay for Galectin-3 Identifies Heart Failure Risk of Patients in the Community SettingTest may also predict response to therapyBy Wayne Kuznar
Continued on page 22
Heart Failure
The study provides furtherconfirmation that elevatedlevels of galectin-3 in thegeneral population areassociated with a markedlyincreased risk of HFdevelopment over thesubsequent 10 years.
—Jennifer E. Ho, MD
Dabigatran Safe and Effective AnticoagulantPostablation in Patients with Atrial FibrillationBy Mary Mosley
Chicago, IL—In patients with atrial fib-rillation (AF) who underwent catheterablation, the new anticoagulant dabi-gatran (Pradaxa), an oral direct throm-bin inhibitor, was found to effectivelyprevent thromboembolic events in asmall prospective study presented byCharlotte Eitel, MD, Department ofElec trophysiology, Heart Center Leipzig,Germany, at the 2012 American Collegeof Cardiology meeting. Patients withAF are known to be at increased risk forthromboembolic events.Dr Eitel and colleagues conducted
this study from July 2010 to September2011 to determine the longer-termsafety and efficacy of dabigatran in thissetting, because existing evidence withpostablation dabigatran was limited toa small, 30-day study. A total of 89 patients with AF (aver-
age age, 63 years) were prospectivelystarted therapy with dabigatran theevening of their catheter ablation, ifpermitted by the status of the femoralpuncture site, or with low-molecular-weight heparin until dabigatran couldbe started. Renal insufficiency was astudy exclusion criterion. The results of the serial 7-day Holter
electrocardiograms and CHA2DS2-
VASc score drove the decision aboutwhether to continue anticoagulation.The average follow-up was 274 days(interquartile range, 59, 497).
Twice-daily dabigatran was given at110-mg doses to 78% and at 150-mgdoses to 22% of study patients, respec-tively. Paroxysmal AF was found in57% of the study patients (78% men).The left atrial parasternal long axis di-ameter was 42 mm.The study patients had an interme-
diate risk of thromboembolic eventswith an average CHA2DS2-VASc scoreof 2 (interquartile range, 0, 5) and low
risk of bleeding with a HAS-BLED(hypertension, abnormal renal/liverfunction, stroke, bleeding history orpredisposition, labile internationalnormalized ratio, elderly [> 65 years],drugs/alcohol concomitantly) score of1 (interquartile range, 0, 3).In terms of AF-related findings, re-
currences of arrhythmia were found in34%, 25%, and 21% of patients at their3-month, 6-month, and 12-month clin-ical follow-ups, respectively. Becauseof arrhythmia recurrence, 9 patientsrequired electrical cardioversion. Trans -esophageal echocardiography was re -quired in only 1 patient, because of thediscontinuation of dabigatran.The investigators reported that the ef-
fectiveness of this anticoagulation strat-egy was shown by the lack of anyprespecified clinical events of strokeand systemic embolism at the mid-termfollow-up. Safety was identified by nooccurrence of minor or major hemor-rhage. Patient acceptance of anticoagu-lation with dabigatran was high.The investigators stated that antico-
agulation with dabigatran in patientswith AF who underwent catheter ab-lation was an “attractive alternative tothe conventional approach with war-
farin” because of its predictable dose–response relationship. In addition, this strategy does not
re quire laboratory monitoring, whereaswarfarin use does. �
� In patients with AF whounderwent catheter ablation,dabigatran, an oral directthrombin inhibitor, was found toeffectively preventthromboembolic events
� The effectiveness of thisanticoagulation strategy wasshown by the lack of anyprespecified clinical events ofstroke and systemic embolismat the mid-term follow-up
� Anticoagulation withdabigatran in this patientpopulation is an attractivealternative to warfarin, becauseof its predictable dose–responserelationship
� Unlike warfarin, dabigatrandoes not require laboratorymonitoring
Key Points
Anticoagulation withdabigatran in patients withAF who underwent catheter ablation was an“attractive alternative to the conventional approach with warfarin,”because of its predictabledose–response relationship.
22 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Heart Failure
Chicago, IL—A phase 2 study of au-tologous bone marrow–cell therapy inpatients with chronic ischemic heartdisease and left-ventricular dysfunc-tion showed no significant differencesfor the primary end points, but therewere hints of benefit from the pre-specified exploratory analyses thatpoint to refinements for future studiesthat will build on these results, ac-cording to the study’s lead investiga-tor, Emerson C. Perin, MD, PhD,Director of Clinical Research for Car-diovascular Medicine, Texas Heart In-stitute, Houston. The results werepresented at the 2012 American Col-lege of Cardiology meeting.The First Mononuclear Cells Injected
in the US (FOCUS) CardiovascularCell Therapy Research Network(CCTRN) study is the largest trial touse a patient’s own stem cells in a pa-tient population. A key element of theCCTRN is a biorepository of samplesfrom all study patients, which Dr Perinexplained is a treasure trove for re-searchers to tease out cell functionsfrom and try to correlate them withother end points in this study and ad-ditional clinical outcomes. “Develop-ing a cell biorepository is a huge stepforward for the future of autologoustherapy, because the composition andfunction of cells in the bone marrowmay play a significant role in out-come,” Dr Perin noted.This double-blind randomized mul-
ticenter study of 61 treated patientsand 31 controls (median age, 62 years)used first-generation cell product—one of the most studied clinically. Thepatients’ qualifying left-ventricularejection fraction (LVEF) was approxi-mately 30%.
In this ongoing study, the patientsare chronically ill and are out of treat-ment options; these patients belong toa population for whom we need tofind treatment solutions, said Dr Perin.Medical therapy is insufficient, notenough hearts are available for trans-plants, and left-ventricular assistdevices are expensive and have com-plications. “I believe cell therapy willbe one of the solutions for these pa-tients,” he maintained.
The 6-month data showed thatLVEF, an exploratory end point, wassignificantly improved by 2.7% in thetreated patients—an increase of 1.7%versus a decline of 1.3% in the controlpatients. No differences between thetreated and control patients were seenin the primary end points of changefrom baseline in maximal oxygen con-sumption, change in left-ventricularend systolic volume on echocardiogra-phy, and change in ischemic defect size
as assessed by single-photon emissiontomography imaging.
Stem-Cell Variation in IndividualPatientsThere is a large variation within in-
dividuals’ own cells, noted Dr Perin,and the potency of the cells depends onthe individual—which is much differ-ent from giving a fixed dose of a drugin a tablet. Younger patients respondedsignificantly, which may reflect effectsof aging, comorbidities, genetics, andpossible unknown factors. In this trial, patients aged ≤62 years
had a significant 4.7% change in LVEFfrom baseline compared with only a0.6% change in patients aged >62years. The researchers also found thatcertain cell types provided clinical ben-efit. There was a relationship betweenCD34+ and CD133+, endothelial pro-genitor cells, and improvement inLVEF, as shown by a multiple variablemodel that included age and treat-ment. For each 3% higher level ofCD34+ cells, there was an associatedaverage 3.0% absolute unit increase inLVEF. Each 3% higher level of CD133+cells was associated with an average5.9% absolute unit increase in LVEF.The investigators found that
younger patients had distinctly betterbone marrow–cell function, which wasalso seen in the prior pilot and smallphase 1 FOCUS-HF studies. Change inmaximal oxygen consumption, a goodevaluation of the patient’s ability toperform, was significantly positivelyaffected in the younger patients in theprior studies and in FOCUS CCTRN. Dr Perin noted that maximal oxygen
consumption status is used to movepatients on and off the transplant list;although the results of this study can-not be used in that regard, it does showthat the small changes achieved withthis therapy have a significant impact.For example, maximal oxygen con-sumption changed from 14.6 to 15.3 inthe treated patients and from 15.2 to
13.4 in the control patients. Despite thesmall difference between the 2 groups,the change is sufficient to move thetreated patients off the transplant list,whereas the control patients would beadded to the list.
“These are meaningful things thatwe are seeing, and perhaps we can usethis information prospectively to selectthose patients and those cells that canfine-tune the therapy for the next gen-eration of studies,” said Dr Perin, whonoted that new related studies werebeginning soon.Roberto Bolli, MD, FAHA, Professor
of Medicine and Executive Vice Presi-dent, Department of Medicine andChief, Division of CardiovascularMedicine, University of Louisville, KY,commented in a press conference thatthere is a huge potential for the bonemarrow to become useful therapeuti-cally, but there is much that is un-known about bone marrow and whatit does and how it works. “The sub-analyses from FOCUS give us somevery tantalizing hints that we may beable to select out patients in whombone marrow transplantation is thera-peutically beneficial. If we can selectthe patients in whom the bone marrowis still functional, we will see a benefi-cial effect,” Dr Bolli pointed out. �
Advances in Stem-Cell Therapy for Heart FailureDespite negative primary end points, positive clues are promisingBy Mary Mosley
“Developinga cellbiorepositoryis a hugestep forwardfor the future
of autologous therapy,because the composition andfunction of cells in the bonemarrow may play a significantrole in outcome.”
hints that we may be able toselect out patients in whombone marrow transplantationis therapeutically beneficial.”
—Roberto Bolli, MD, FAHA
were randomized to valsartan (Dio-van) or placebo in addition to othertherapies for HF.Plasma samples were available for
approximately 30% of the Val-HeFTparticipants. Compared with placebo,valsartan caused a significant 44% re-duction in hospitalizations for HF ina subgroup of patients with galectin-3 below the median. No effect of val-sartan was observed in the subgroupwith galectin-3 above the median.Another subanalysis of a major
study, the landmark Multicenter Au-tomatic Defibrillator ImplantationTrial with Cardiac ResynchronizationTherapy (MADIT-CRT), suggests that
galectin-3 may be used to prioritizepatients with early-stage HF for car-diac resynchronization therapy (CRT),said Kenneth Stein, MD, Senior VicePresident and Chief Medical Officer,Cardiac Rhythm Management atBoston Scientific, Minneapolis.The data revealed that CRT con-
veyed an important benefit in pa-tients with low and high galectin-3levels. However, because of themarkedly higher incidence of eventsin patients with high levels ofgalectin-3, the absolute benefit ofCRT was approximately double thatof the benefit in patients with lowgalectin-3 levels. �
Blood Assay for Galectin-3 Identifies...Continued from page 21
The American Diabetes Associa-tion provides new resources forproviders and for patients regardingcardiometabolic risk factors and as-sessment, including a patient educa-tion toolkit and a detailed discussionof the cardiometabolic risk factors.Key cardiometabolic risk factors
discussed include obesity, hyperten-sion, smoking, and abnormal lipidmetabolism.To download the patient educa-
tion toolkit, or for more information,visit http://professional.diabetes.org/ResourcesForProfessionals.aspx?cid=60379.
Cardiometabolic Risk Initiative Resource Center
23MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
CVD Management
Brigham and Women’s Hospital inBoston, discussed the advances made intreating acute myocardial infarction(AMI) over the past century, and pre-sented an intriguing view of researchareas anticipated to bring even greatersuccess. Dr Braunwald is associatedwith many of the groundbreaking ad-vances in cardiovascular (CV) medicine.Illustrating the magnitude of the
problem of AMI, Dr Braunwald saidthat every 34 seconds an American suf-fers an infarction. He pointed out thatduring his 25-minute lecture, 44 Amer-icans will have had an AMI, and 6 ofthem would have died. “We cannot reston our laurels,” he warned.Ongoing research is focused on
postinfarction treatment, building onknowledge gained from research, in-cluding the benefits of myocardialreperfusion. Three promising areas are:• Prevention of lethal myocardialreperfusion injury
• Inhibition of thrombin generation• Cell therapy.
Prevention of Lethal MyocardialReperfusion Injury Post-AMIRemote ischemic preconditioning,
performed with cyclic ischemia andreperfusion in tissue remote from thecoronary occlusion, reduces infarctsize. More myocardium was saved at30 days when remote ischemic pre-conditioning was performed in theambulance in patients who subse-quently underwent percutaneouscoronary intervention (PCI) comparedwith those who did not have precon-ditioning, as proved in a recent study.A pharmacologic approach to is-
chemic preconditioning also limitedlethal myocardial injury. An injectionof cyclosporine A immediately beforePCI significantly reduced infarct size.Pilot studies of these 2 approaches are
under way and are expected to moveinto phase 3 trials, said Dr Braunwald.
Inhibition of Thrombin Generation Post-AMIRecurrent occlusion post-AMI re-
mains a problem, despite treatmentwith coronary stents and dual anti -platelet therapy (DAPT), and can befatal. The inhibition of excess thrombingeneration, which occurs for monthspost-AMI, by blocking factor Xa ap-pears to be a promising approach. Vi-
tamin K antagonists cannot be usedsafely, because excessive bleeding canoccur in patients receiving DAPT.Rivaroxaban (Xarelto), one of the
new factor Xa anticoagulants thatblocks thrombin formation, was asso-ciated with significant reductions inCV death and all-cause mortality in theAnti-Xa Therapy to Lower Cardiovas-cular Events in Addition to Aspirinwith/without Thienopyridine Ther-apy in Subjects with Acute CoronarySyndrome 2 (ATLAS ACS2)-TIMI 51trial. Dr Braunwald, a lead investigatorof this study, said that this reductionwas achieved with the lowest dose ofrivaroxaban studied—2.5 mg twicedaily—given for 2 years in addition toguidelines-based treatment, includingDAPT. Despite an increase in bleeding,no increase in fatal bleeding or in-tracranial hemorrhage occurred.
Cell Therapy Post-AMIReduced infarct size and improved
left-ventricular ejection fraction (LVEF)were achieved in the REPAIR (RenalProtection Against Ischaemia Reperfu-sion in Transplantation) trial, one of themost promising first-generation trialsof bone marrow–derived (BMD) pro-genitor cells. The cells were injected di-rectly into the infarct-related artery,and patients were followed for 2 years.Event-free survival was also superiorin the treated patients compared with
patients in the control group.Following on these findings, the re-
cently announced BAMI (Effect ofIntracoronary Reinfusion of Bone Mar-row–Derived Mononuclear Cells onAll-Cause Mortality in Acute Myocar-dial Infarction) trial will study the effectof intracoronary infusion of BMDmononuclear cells compared with stan-dard care in approximately 3000 pa-tients with a low LVEF (<45%). The cellswill be injected within 3 to 6 days aftersuccessful reperfusion, and the goal isto reduce 3-year mortality by 25%. Thismultinational trial will begin enroll-ment in the second quarter of 2012.Two proof-of-principle trials, SCI-
PIO (Stem Cell Infusion in Patientswith Ischemic Cardiomyopathy) andCADUCEUS (Cardiosphere-Derived
Auto logous Stem Cells to ReverseVentricular Dysfunction), suggest thatcardiac-derived stem cells from a pa-tient can lead to scar resorption andtissue regeneration, and can improvemyocardial function.The discovery that stem cells reside
in the heart by Piero Anversa, MD,Professor of Medicine and Anesthesia,and Director of the Center of Regener-ative Medicine, Brigham and Women’sHospital, Harvard Medical School,Boston, provided the foundation forthe approach studied in SCIPIO, whichwas led by Roberto Bolli, MD, FAHA,Professor of Medicine, Physiology andBiophysics, and Executive Vice Chair,Department of Medicine, University ofLouisville, KY. Coronary arterial infusion of autol-
ogous BMD progenitor cells reducedthe size of the infarct from baseline at4 months and 12 months and im-proved ejection fraction by approxi-mately 30%, as shown by cardiacmagnetic resonance. Dr Braunwaldnoted that these results are not yetpublished and are provided courtesyof Dr Bolli. The cells were obtainedduring bypass surgery from the rightatrial appendage by Dr Bolli’s group,and the cells were isolated and ex-panded by Dr Anversa’s group.The recently published results of the
CADUCEUS trial demonstrated a re-duction in infarct size, an increase inviable myocardium, and greater thick-ening of infarct segments—all reflect-ing better systolic performance, DrBraunwald stated. The investigatorsperformed subendocardial biopsies inpost-AMI patients with left-ventricu-lar dysfunction to obtain the cardiacstem cells that grew into clusterscalled “cardiospheres.” The cardios-pheres were injected into reperfusedinfarct-related arteries. “Reperfusion therapy of an infarc-
tion is a major success story,” said DrBraunwald, “with early mortalityfalling by 75% over a 25-year period inclinical trials.” This therapy stands onthe work of Dr Braunwald and othersto understand myocardial reperfusionand led to the “open-artery hypothe-sis,” with the 90-minute window es-tablished to improve outcomes. The approaches used, with newer
ones replacing earlier approaches, in-clude intracoronary thrombolysis, in-travenous thrombolysis, intravenousstrep tokinase, aspirin, tissue plas-minogen activator, primary PCI,stenting, and thrombectomy. “I amhonored that these and other thera-peutic and preventive options willbring this important condition undermore control early in the second cen-tury,” said Dr Braunwald. �
� Advances in post-AMItreatment include prevention oflethal myocardial reperfusioninjury, inhibition of thrombingeneration, and cell therapy
� The inhibition of excessthrombin generation by blockingfactor Xa appears to be apromising treatment forrecurrent occlusion post-AMI
� Rivaroxaban, a new factor Xaanticoagulant, is associated withsignificant reductions in CVdeath and all-cause mortality
� Reperfusion therapy of aninfarction has reduced earlymortality by 75% over a 25-year period
“Reperfusion therapy of an infarction is a major success story, with earlymortality falling by 75% over a 25-year period in clinical trials.”
—Eugene Braunwald, MD, FRCP
ACC Launches Legends of Cardiovascular... Continued from page 1
Key Points
Photo taken at ACC 2012.
24 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
CVD Management
Chicago, IL—Remote disease manage-ment is effective and more efficient forpatients, their caregivers, and forphysicians. Although there are fewdata on its cost-effectiveness, the valuefor the patient and for guiding treat-ment is high, by reducing hospitaliza-tions and improving management ofarrhythmias. The value and benefits ofremote disease management and its ef-fect on improving clinical outcomeswere the focus of a clinical session atthe 2012 American College of Cardiol-ogy (ACC) meeting.
Remote Monitoring for ArrhythmiasRemote monitoring of arrhythmias
is defined as daily and continuous sur-veillance through a device that allowsassessment of arrhythmia burden, pa-tient status, and device integrity. Re-mote follow-up refers to contact with apatient that replaces a clinic visit.“Remote device monitoring can
identify arrhythmia and atrial fibrilla-tion earlier,” said George H. Crossley,III, MD, President of Mid-State Cardi-ology, St. Thomas Heart, Nashville, TN.A 45% reduction in office visits over a15-month follow-up period was shownin the 2010 Lumos-T Safely ReducesRoutine Office Device Follow-Up(TRUST) study of automatic remotemonitoring of implantable cardioverter-defibrillators (ICDs). Dr Crossley saidthis shows a “huge amount of the effi-ciency value” of monitoring.Event detection was faster in the
TRUST study, “showing the effective-ness of monitoring,” Dr Crossleynoted. Clinically relevant asympto-matic events were detected 41 dayssooner with wireless remote monitor-ing compared with traditional in-officefollow-up. All arrhythmia events weredetected 35 days sooner. Adherenceto the follow-up schedule was sig -nificantly improved with remote mon-itoring compared with traditionalmonitoring (94% vs 88%, respectively).An informal study in Dr Crossley’s
office showed that remote follow-upsaves time and requires approximately7 minutes, including the call to the pa-tient, compared with approximately 20minutes for an in-office visit. Remotefollow-up can also be used for taking apatient’s history, which can contributeto shorter office visits, and for thenurse to report data to the patient.The Clinical Evaluation of Remote
Notification to Reduce Time to ClinicalDecision (CONNECT) study showed a
significant reduction in the time to cre-ate a treatment plan (approximately 4days vs 22 days in the control group)after a clinically actionable event wasidentified in patients with an ICD(Crossley GH, et al. J Am Coll Cardiol.2011;57:1181-1189).
Healthcare utilization was also re-duced with remote monitoring in theCONNECT study, including hospital-ization and emergency departmentvisits. Length of hospitalization wassignificantly reduced in patients withan ICD and with a cardiac resynchro-nization therapy defibrillator; the cost-savings in the remote monitoring armwas $1793 per patient.In patients with a pacemaker, the
2009 PREFER study showed that re-mote pacemaker follow-up was moreeffective in identifying clinically ac-tionable events over 12 months thantranstelephonic monitoring (TTM). Inthe CareLink arm, 45% of patients hadan event, of which 66% were detectedremotely. In the TTM arm, 38% had anevent, of which only 2% was detectedvia TTM. TTM requires the patient tomanually send the data via the tele-phone, whereas remote monitoringusing the CareLink device automati-cally sent the data.
Remote Monitoring of Atrial FibrillationMore devices are capable of storing
electrograms and event counter diag-nostics, which can be retrieved re-motely through a modem connected tothe internet. These diagnostics are re-viewed by a remote monitoring centerand can be directly retrieved by thephysician’s office. The availability ofnewer devices with this capabilitymakes it more feasible to conductprospective studies to evaluate theirbenefits and costs in patients withatrial fibrillation, said Paul A. Levine,MD, Professor of Medicine, LomaLinda University School of Medicine,University of California, Los Angeles.“A wealth of information is obtained
from continuous rhythm monitoring,”said Dr Levine. This includes details
about the onset of sustained arrhyth-mias, arrhythmia burden, correlationof symptoms with arrhythmias, im-proved understanding of the rhythms,and timely intervention and the re-sponse to the intervention.Yet, there are a number of limita-
tions and cautions that clinicians mustconsider, Dr Levine pointed out. Asthe devices and their uses mature,many of these will be addressed. Thelarge volume of data obtained requiressorting out what is a clinically action-able event in a timely fashion. There is marked variation in the
recordings, and the clinician must de-termine when intervention is war-ranted. Device diagnostics presumethat the diagnosis is correct, but inde-pendent validation is needed. For ex-ample, was a recorded episode trulybrief, or was it a result of signal drop-out during transmission? What is therole of the cumulative burden or theduration of individual episodesrecorded in evaluating the data and
determining treatment? In terms ofphysicians using the data accumulatedfrom remote device monitoring, howdoes it impact the work flow in the of-fice or clinic? Is there a legal liability ifthe physician doesn’t use the data?There are currently no data regard-
ing the impact of continuous monitor-ing and early notification on long-termoutcomes.
What Is the Cost-Benefit Ratio and for Whom?“There is a paucity of cost data,”
said Mark H. Schoenfeld, MD, ClinicalProfessor of Medicine, Yale UniversitySchool of Medicine, and Director of theCardiac Electrophysiology and Pace-maker Laboratory, Hospital of SaintRaphael, New Haven, CT.Although remote monitoring has
been reimbursed in the United Statessince 2006, this was done withoutdemonstrating a cost-savings, andmost studies so far relate to trans-portation costs. For example, onestudy showed patients saved approx-imately $1377 to $4113 over 5 years
through avoiding transportation costsfor office visits.An informal analysis by Dr Schoen-
feld found a $100 annual cost-savingsper patient by using remote monitoringto reduce the annual clinic visits from 2to 1. The calculation did not includeother costs, such as transportation orcost to payers, and it was limited toMedicare data for Connecticut.For monitoring of a dual-chamber
pacemaker with device interrogationsevery 3 months with 1 annual clinicvisit, the cost was $354.11 using TTMand $378.80 with remote monitoring inthat analysis. This cost was increased to$486.28 for device interrogations every6 months and 2 annual clinic visits. Forremote monitoring of a dual-chamberICD with device interrogations every 3months plus 1 annual office visit, thecost was $504.85. The cost was $606.62for device interrogations every 6months plus 2 annual office visits.Yet, the cost-benefit ratio depends
on the perspective, said Dr Schoenfeld.This differs for the individual patient,the provider, society and taxpayers,payers, the government, and industry.For each of these parties, the cost andbenefit regarding access to care, qual-ity, efficiency, costs, and financial in-centives differ.For the clinician, remote monitoring
provides more patient data and canhelp to provide better care, with fasterfollow-up and without any increasedcosts. For the hospital, there are morenetworked data, perhaps some influ-ence on a better reputation, greater ef-ficiency, and savings from shorterhospital stays that can offset the costsof transmitters, data analysis, and pa-tient education. For the governmentand insurers, this approach providesmore healthcare data, which can con-tribute to better care, increased effi-ciency, and cost control.Whether the cost-benefit ratio is
viewed from the perspective of the pa-tient or of another party is an ongoingissue, said Dr Schoenfeld. Also, officevisits are not eliminated completely,because devices cannot be repro-grammed remotely, and some patientsprefer to see the doctor and opt out ofremote monitoring. Remote devicemonitoring via mobile phones is morechallenging, and many patients nolonger have landline phones. Ad-vances in technology and economicchanges may limit the ability to makesatisfactory financial projections, DrSchoenfeld said. �
Value of Remote Disease Management of Arrhythmia Highlighted at ACC 2012Reduced hospitalization, improved arrhythmia managementBy Mary Mosley
“A wealth of information isobtained from continuousrhythm monitoring.”
—Paul A. Levine, MD
25MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
CVD Management
Faster, Safer Discharge from Emergency Department with Coronary CT AngiographySimilar outcomes in patients at low to intermediate riskBy Mary Mosley
Chicago, IL—In patients at low to in-termediate risk of coronary artery dis-ease (CAD) presenting with chest pain,a rule-out strategy using primary coro-nary computed tomographic angiogra-phy (CTA) versus traditional care wasfound to be safe and effective to deter-mine patients who could be dis-charged directly from the emergencydepartment, according to lead investi-gator Harold I. Litt, MD, PhD, Chief ofCardiovascular Imaging, Departmentof Radiology, the Perelman School ofMedicine, University of Pennsylvania,Philadelphia. Dr Litt presented the re-sults of the multicenter randomizedcontrolled ACRIN (American Collegeof Radiology Imaging Network) PA4005 study in a late-breaking session atthe 2012 American College of Cardiol-ogy meeting.No myocardial infarctions (MIs) or
cardiac deaths had occurred at 30 daysin 89% of patients who had a negativeCTA examination (<50% stenosis),which was the primary end point.ACRIN PA 4005 was sufficiently pow-ered to demonstrate an acceptable pri-mary safety end point of <1% for30-day major adverse cardiovascularevents. These results supported thefindings from previous studies, indi-cating that CTA may be beneficial, inobservational or randomized studies,which were too small to conclusivelyprove safety. Coronary Computed To-mography for Systematic Triage ofAcute Chest Pain Patients to Treat-ment (CT-STAT), a multicenter, ran-domized study showed that CTAcompared with single-photon emis-
sion computed tomography myocar-dial perfusion imaging (SPECT MPI)reduced time to diagnosis and costs,but its numerical reduction in eventswas not significant.
Chest PainThis study addressed a large public
health issue. Chest pain is the secondmost common reason for an emer-gency department visit, leading to 6million to 10 million annual visits. Al-though up to 85% of patients ulti-mately do not have a cardiac cause fortheir chest pain, most are admitted tothe hospital for an evaluation, at a costof several billions of dollars annually.“This represents a tremendous costto society and an inefficient use ofresources,” said Dr Litt, as well ascontributing to overcrowding of emer-gency departments. “A technique thatcan efficiently triage these patients intothose who can be discharged quicklyand the ones who need further evalu-ation is very important,” to reduce thecurrently substantial miss rate of 2% to3% of patients who are dischargedwith an unrecognized heart attack.In the CTA arm, 50% of patients
were discharged directly from theemergency department comparedwith 26% of patients receiving tradi-tional care. Length of stay was reducedby 50% in the overall CTA group andby 50% in the patients who had a neg-ative CTA.ACRIN PA 4005 randomized pa-
tients (aged ≥30 years) who had signsand symptoms of acute coronary syn-dromes and a thrombolysis in MI risk
score of 0 to 2 in a 2:1 fashion to eitherCTA (N = 908) or to traditional care (N= 462). Approximately 60% of the pa-tients were black, and approximately
54% were women. Traditional care wasthe usual protocol for each of the 5study sites, and providers were free tomake all decisions for tests and treat-ments for this group.In the clinical trial arm, 76% of the
cardiac catheterizations were positivecompared with 44% in the traditional-care arm. “Clinical trials were identify-ing patients who needed the cardiaccatheterizations more than traditionalcare,” explained Dr Litt. Revascular-ization occurred in 2.7% of the clinicaltrial group and 1.3% of the traditional-care group, but the difference was notsignificant.
Resource UtilizationDirect discharge from the emer-
gency department was higher (50% vs
23% for traditional care) and the lengthof stay was shorter in the overall CTAgroup (18 hours vs 25 hours), whichimpacted potential cost-savings. Hos-pitalization was even shorter, at 12hours in the negative CTA patientscompared with 25 hours with tradi-tional care.Resource utilization at 30 days was
not significantly different between the2 strategies. A nonsignificant greaternumber of patients having CTA had acardiologist visit (7.1% vs 3.8% tradi-tional care). In-hospital and 30-day cost data are
expected within 6 months, with 1-yearresource utilization and cost-effective-ness data expected later, including fu-ture events, to determine if the CTAstrategy remains safe and cost-effective.Other considerations in terms of cost
will be what happens to the patients inwhom CAD was identified, which was3 times higher with CTA than tra -ditional care (9.0% vs 3.5%). The in -fluence on subsequent care is animportant question. Will it result inmore testing, risk reduction because ofchanges in lifestyle and medications,or prevention of future events?Dr Litt noted that radiation exposure
with CTA is lower than with SPECTMPI—currently what most patientsundergo—and that, as CTA technologyimproves, its radiation will be reduced.“We are replacing a higher-dose tech-nique with a lower-dose technique,”he pointed out.The study has been simultaneously
published online (N Engl J Med. 2012Mar 26). �
“A techniquethat canefficientlytriage thesepatients intothose who
can be discharged quicklyand the ones who needfurther evaluation is veryimportant.”
—Harold I. Litt, MD, PhD
Continued on page 26
Chicago, IL—A noninvasive wholeblood test developed from the expres-sion levels of 23 genes can identifypatients unlikely to have coronary ar-tery disease (CAD) events or requirerevas cularization procedures over thenext 12 months, reported Robert S.Schwartz, MD, FACC, Professor ofMedicine at the University of Min-nesota Medical School, Medical Direc-tor at Minnesota CardiovascularResearch Institute, and a cardiologistat the Minneapolis Heart Institute, at
the 2012 American College of Cardi-ology meeting.Use of a score based on the blood
test (the peripheral blood gene-expres-sion score) may eventually represent apersonalized risk evaluation for thenoninvasive diagnosis of atheroscle-rotic CAD, which is precipitated byan interaction of genetic and environ-mental factors. “Better diagnostic methods are
needed to stratify patients for elec -tive invasive angiography,” said Dr
Schwartz. Most patients undergoingfirst-time angiography do not have ob-
structive CAD: more than 60% of pa-tients with risk factors or symptoms ofCAD who are referred for elective car-diac catheterization for evaluation donot have significant CAD, and 40%have minimal to no CAD.Unlike genetic tests, gene-expres-
sion testing assesses a dynamicprocess, integrating both genetic pre-disposition and behavioral and envi-ronmental influences on the currentdisease state, according to the test’sdeveloper, CardioDx.“Changes in gene expression have
been observed in diseased arterial wall
“Better diagnostic methodsare needed to stratify patientsfor elective invasiveangiography. Changes ingene expression have beenobserved in diseased arterial wall samples.” —Robert S. Schwartz, MD, FACC
Levels of Gene Expression a New Noninvasive Way to Identify Obstructive CADBy Wayne Kuznar
26 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
CVD Management
Chicago, IL—When added to tradi-tional antiplatelet therapy, vorapaxar,an investigational thrombin receptorantagonist, reduced the risk of my-ocardial infarction (MI), stroke, or car-diovascular (CV) death in patientswith established ischemic heart dis-ease or atherothrombotic vascular dis-ease. The results of the secondaryprevention Thrombin-Receptor An-tagonist in Secondary Prevention ofAtherothrombotic Ischemic Events(TRA 2°P TIMI-50) trial were pre-sented by lead investigator David A.Morrow, MD, MPH Associate Professorof Medicine at Harvard Medical School,and Director of the Samuel A. LevineCardiac Unit in the Division of Car-diovascular Medicine at Brigham andWomen’s Hospital, at the 2012 Amer-ican College of Cardiology meeting.The patients who took vor apaxar
had significantly more bleedingevents at 3 years (Table 1). Notably,vorapaxar was stopped after 2 yearsin patients with a history of stroke, be-cause a higher risk of intracranialhemorrhaging (ICH) was found in pa-tients with a history of stroke in theThrombin Receptor Antagonist for
Clinical Event Reduction in AcuteCoronary Syndrome (TRACER) trial.The primary end points of CV death,MI, stroke, hospitalization for is-chemia, and urgent revascularizationin TRACER were not significantly re-duced, but its secondary end pointwas significantly reduced, and itbecame the primary end point of TRA2°P, a maneuver the US Food andDrug Administration calls reactive re-vision to a protocol.
TRA 2°P TIMI-50, a randomized,double-blind, placebo-controlled, mul -t inational study, followed 26,449patients for a mean of 2.5 years. En-rollees had previous MI (67%), stroke(19%), or to peripheral arterial disease
(PAD; 14%). The patients were ran-domized to vorapaxar (2.5 mg oncedaily) or to placebo in addition tostandard antiplatelet therapy of as-pirin and a thienopyridine in a largeproportion of patients.The primary end point of MI, stroke,
or CV death occurred in 9.3% of thevor apaxar group and 10.5% of theplacebo group—a significant 13% re-duction. A 12% reduction was achievedwith vor apaxar for the composite ofCV death, MI, stroke, or urgent coro -nary revascularization (11.2% withvorapaxar vs 12.4% with placebo) anda 14% reduction for CV death or MI(7.3% with vor apaxar vs 8.2% withplacebo). The risk of bleeding with vora-
paxar was greater in patients with ahistory of stroke or transischemic at-tack or those who weighed <60 kg.Patients with a prior MI had a signif-icant 20% reduction in CV death, MI,or stroke. In patients with PAD, therewas a small trend for a benefit, witha 6% reduction.
A Closer Look at Bleeding, by Subgroups In the 5746 patients with a history of
stroke, the absolute increase in theThrombolysis In Myocardial Infarction
non–coronary artery bypass graftmajor bleeding rate was 2%, ICH was1.5%, and fatal bleeding was 0.2%. Inthe 20,699 patients without a history ofstroke, bleeding rates were 0.7%, 0.2%,and 0.1%, respectively.The moderate or severe bleeding
rates in the Global Utilization ofStreptokinase and Tissue Plasmino-gen Activator for Occluded CoronaryArteries (GUSTO) trial at 3 years werehigher with vorapaxar compared withplacebo in patients >75 years, in thosewith lower weight, and in those withstroke or PAD at baseline (Table 2).Vorapaxar is the first in a new class
of investigational protease-activatedreceptor-1 antagonists. “This is thefirst study to show definitively thatblocking pathways reduces the riskof suffering another cardiovascularevent,” said Dr Morrow. The decreasein MI, stroke, or CV death was offsetby the increase in moderate and se-vere bleeding, including ICH. Careful patient selection will be
necessary to balance the antithrom-botic benefit of reduced events againstthis increased bleeding risk. The opti-mal patient cohort appears to be pa-tients who were aged <75 years, thosewho weighed >60 kg, and those whohave not had a prior stroke. �
Vorapaxar, a Novel Antithrombotic Agent, ReducesEvents but Increases BleedingBy Mary Mosley
“This is the first study toshow definitively thatblocking pathways reducesthe risk of suffering anothercardiovascular event.”
—David A. Morrow, MD, MPH
Table 1 Bleeding Rates at 3 Years in the Total Population of the TRA 2°P TIMI-50 Trial
Vorapaxar, % Placebo, % P value
GUSTO moderate/severe 4.2 2.5 <.001
Intracranial hemorrhage 1.0 .5 <.001
No prior stroke .6 .4 .049
Fatal .3 .2 .19
GUSTO indicates Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; TRA 2°P TIMI-50, Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events.
Table 2 GUSTO Moderate or Severe Bleeding at 3 Years in Subgroups
Vorapaxar, % Placebo, % Hazard ratio, %
Age ≥75 yrs 8.4 5.5 1.69
<75 yrs 3.7 2.2 1.65
Weight <60 kg 7.7 3.7 1.95
≥60 kg 4.0 2.4 1.64
Stroke 4.2 2.4 1.93
PAD 7.4 4.5 1.62
MI 3.4 2.1 1.61
GUSTO indicates Global Utilization of Streptokinase and Tissue Plasminogen Activator for OccludedCoronary Arteries; MI, myocardial infarction; PAD, peripheral arterial disease.
samples,” said Dr Schwartz. Thestudy followed more than 1100 non-diabetic patients for 1 year who wereclinically indicated for invasive an-giography and who had their periph-eral blood gene-expression scorecalculated. The gene-expression scoreconsiders age and sex in addition tothe expression of the 23 genes.Of the 1166 patients, 850 were eligi-
ble for subsequent analysis. Over the12 months of follow-up, 14 patientshad a revascularization procedure(percutaneous coronary interventionor coronary artery bypass graft), and11 had a major adverse cardiac event(MACE), including myocardial infarc-tion, stroke/transient ischemic attack,or all-cause mortality; 825 of the 850had no events or procedures.The likelihood of procedures and
events was higher with increasinggene-expression score. At a thresholdgene-expression score of ≤15, thenegative predictive value of thegene-expression score was 91% forprocedures within 30 days and 91%at 12 months. The negative predic-tive value was 99% for MACE within30 days and at 12 months. Patients with low gene-expression
scores (approximately 35% of thestudy population) were at very lowrisk for subsequent MACE and re -vas cularization, Dr Schwartz noted.Only 3 of 1160 patients with a gene-expression score <15 had events at12 months.
Of the 8 patients who underwent laterevascularization, 7 had a gene- expres-sion score >15. Of those with high gene-expression scores (28-40), 39% hadprocedures or MACE; 28% of thosewith medium scores (16-27) had MACEor revascularization procedures. �
Levels of Gene Expression... Continued from page 25
At a threshold gene-expression score of ≤15, the negative predictive valueof the gene-expressionscore was 91% forprocedures within 30 daysand 91% at 12 months. Thenegative predictive valuewas 99% for MACE within30 days and at 12 months.
27MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
CVD Management
Chicago, IL—A triple-antiplatelet reg-imen that is popular in Asia was as ef-fective as a high-dose clopidogrel dualregimen used commonly in the UnitedStates for preventing events in the first30 days after percutaneous coronaryintervention (PCI). The study was pre-sented at the 2012 American College ofCardiology meeting by lead investiga-tor Hyo-Soo Kim, MD, PhD, Directorof Cardiac Catheterization and Coro-nary Intervention, Seoul National Uni-versity Hospital, Republic of Korea.The 3-drug regimen consists of
cilostazol (Pletal), clopidogrel (Plavix),and aspirin. The dual regimen doublesthe dose of clopidogrel in combinationwith aspirin.The finding came from a large ran-
domized trial, Harmonizing OptimalStrategy for Treatment of Coronary Ar-tery Stenosis—Safety & Effectivenessof Drug-Eluting Stents & AntiplateletRegimen (HOST-ASSURE), which in-cluded patients undergoing PCI at 40hospitals in the Republic of Korea.
Cilostazol is used widely in Koreaand Japan to prevent embolization afterPCI, because it is thought to have vas-cular biologic benefit in addition to itsantiplatelet activity, explained Dr Kim.Cilostazol may have vasodilatory andrenoprotective properties in addition topreventing stent restenosis, he said.In HOST-ASSURE, the triple-drug
approach was compared with the 2-drugregimen in 3755 patients with >50% oc-clusion of any coronary artery or ve-nous or arterial bypass graft. The studywas designed to demonstrate noninfe-riority of the triple-drug regimen.Inhibiting platelet reactivity in the
first month after PCI is critical to pre-vent thrombotic events, said Dr Kim. Inprevious trials of patients with acutecoronary syndromes undergoing PCI,1 week of double-dose clopidogrel im-proved outcomes at 1 month comparedwith conventional-dose clopidogrel.Patients enrolled in HOST-ASSURE
received 300 to 600 mg of clopidogrelplus 300 mg of aspirin before PCI, withor without a loading dose of 200 mg ofcilostazol. In the group assigned totriple-antiplatelet therapy, 100 mg ofcilostazol twice daily was added todual-antiplatelet therapy for 1 monthafter the procedure; in the group as-signed to double-dose dual-antiplatelet
therapy, the maintenance regimen ofclopidogrel was 150 mg daily.The primary end point—a composite
of cardiac death, nonfatal myocardialinfarction (MI), stroke, definite or prob-able stent thrombosis, and major bleed-
ing—occurred in 23 patients (1.22%) re-ceiving triple-antiplatelet therapy and27 patients (1.44%) assigned to double-dose dual-antiplatelet therapy. The ab-solute risk difference of –0.22% met thecriterion specified for noninferiority.
The group assigned to triple-anti -platelet therapy had 1 spontaneous MIafter discharge compared with 5 spon-taneous MIs in the group assigned todouble-dose dual-antiplatelet therapy(nonsignificant). �
Triple-Antiplatelet Therapy Equal to Double-Dose DualTherapy After Percutaneous Coronary InterventionBy Wayne Kuznar
Inhibiting platelet reactivity in the first month after PCI is critical to preventthrombotic events.
28 VOL 1 NO 1 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH MAY 2012
Ihave eagerly awaited the opportu-nity to preview the first edition ofValue-Based Care in Cardiometabolic
Health. No area of medicine has moreimpact on patients, creates more use ofmedical resources, and drives cost morethan cardiometabolic disease.From a health plan perspective, car-
diovascular disease (CVD) and diabetesare 2 of the most prevalent chronic con-ditions in the US population. Althoughwe have made great strides in the di-agnosis, prevention, and treatment ofheart disease, it still remains the num-ber one killer of Americans today. Sim-ilarly, diabetes is growing at epidemicproportions, following the wave ofobesity in the United States. For mosthealth plans, medical spending onCVD is the largest category of spend-ing among the major chronic illnesses.And CVD drugs, including drugs forhyperlipidemia and hypertension, aswell as diabetes drugs, account for amajor portion of the resources spentunder the pharmacy benefit. According to the latest Express
Scripts’ Drug Trend Report, drugs for di-abetes, hyperlipidemia, and hyperten-sion account for approximately 30% ofthe traditional pharmacy spending.1 Arecent report from the Centers for Dis-ease Control and Prevention estimatesthat 45% of adults in the United Stateshave one of the conditions treated bymedications in these top 3 therapyclasses when diagnosed and undiag-nosed prevalence is considered.2 Andthings may only get worse. We onlyhave to look at the data (Figure) pub-lished in an article by Huang and col-leagues3 to get a sense of the impactdiabetes will continue to have on thealready financially challenged health-care system.It is imperative that health plans
keep up with the latest developmentsin the field of cardiometabolic diseases,because of the major impact that theseillnesses have on the plan’s resources.In addition to keeping abreast of thenew developments in cardiometabolichealth, we must also be able to under-stand the economic impact of changesin technology, and how changing tech-nology could potentially add value tothe plan’s members, both clinically andeconomically.
New Technologies For instance, diagnostic testing
modalities are areas of near-explosivegrowth. Health plans must assess thesenew technologies in a timely manner so
as not to withhold coverage of promis-ing technologies from their members,while at the same time balancing thefiscal responsibility of not wasting re-sources on ineffective or marginally ef-fective new technology. To help with this task, Value-Based
Care in Cardiometabolic Health brings awealth of information to my (virtual)
desktop. For instance, in this issue weread about the use of a gene-expres-sion test to assist in the evaluation ofchest pain (page 25) and about the useof galectin-3 to assess heart failure risk(page 21).As we know, the evaluation of chest
pain can be complex and costly. Cur-rent evaluative modalities can lead toinvasive procedures in a significantnumber of patients, with up to 60% ofthose who undergo elective cardiaccatheterization having minimal or nodisease. This is an area that is ripe fora better way to stratify patients withdisease from those who have minimalrisk for a cardiac-related event. Report-ing on work presented by Robert S.Schwartz, MD, FACC, we gain insightabout a gene-expression test for use insymptomatic, nondiabetic patients.This “noninvasive whole blood testfrom the expression levels of 23 genescan identify patients unlikely to havecoronary artery disease events or re-quire revascularization proceduresover the next 12 months.” It is most im-pressive that “at a threshold gene-expression score of ≤15, the negativepredictive value of the gene-expressionscore was 91% for procedures within 30days and 91% at 12 months.” Doctorsnow have access to a simple, noninva-sive way to risk-stratify patients withnonacute chest pain more effectively,
potentially avoiding costly and riskyinvasive procedures in patients whoare unlikely to have significant disease.Regarding heart failure, we learn
that “a blood test for galectin-3, aunique protein that binds to carbo -hydrates known as ‘beta-galactosides,’appears to be a reliable predictor of in-cident heart failure (HF) and of the re-sponse to treatment for HF.” Again,clinicians will have the potential to bet-ter risk-stratify those who are at riskfor severe complications or even deathfrom heart failure. These are just 2 ex-amples of timely information on pos-sible “game-changing” technology thatshould prove invaluable to busy med-ical and pharmacy directors.
Cost Considerations In this issue we also learn about
a simple, low-cost, glucose-insulin-potassium solution has the potential tosave lives from those experiencing anacute coronary event when used in thefield. On the cost side, there is a call todetermine the cost-effectiveness of car-diac imaging procedures—one of thefastest growing areas of medical tech-nology today. Finally, I read with interest the arti-
cle that reviews the physicians’ evolv-ing role in value-based purchasing(page 1). Understanding this approachis essential for those of us who leadchange in medical reimbursement aswe try to move the system from a vol-ume-based purchasing system to aquality-based system.Keeping up with the technology,
policy changes, and clinical advancesin cardiology or diabetes care can be adaunting task. Yet we are called on todo this not only in these fields, but inall areas of medicine. After reviewingthe content of this first issue of Value-Based Care in Cardiometabolic Health, Iam optimistic that this journal will be-come a trusted resource for providersand payers who must keep abreast ofnew information in this most promi-nent area of chronic illness. �
References1. Express Scripts. 2011 Drug Trend Report. April 2012.www.express-scripts.com/research/research/dtr. Ac-cessed May 10, 2012.2. Fryar CD, Hirsch R, Eberhardt MS, et al. Centers forDisease Control and Prevention. Hypertension, highserum total cholesterol, and diabetes: racial and ethnicprevalence differences in US adults, 1999-2006. NCHSdata brief. No 36. April 2010. www.cdc.gov/nchs/data/databriefs/db36.htm. Accessed May 7, 2012.3. Huang ES, Basu A, O’Grady MJ, Capretta JC. Usingclinical information to project federal health carespending. Health Aff (Millwood). 2009;28:w978-w990.Epub 2009 Sept 1.
Value-Based Care in Cardiometabolic Health: A MedicalDirector’s Perspective on the Inaugural EditionBy Gary M. Owens, MDPresident, Gary Owens Associates
No area of medicine has more impact on patients,creates more use of medicalresources, and drives costmore than cardiometabolicdisease.
Payer Perspective
350
300
250
200
150
100
50
020302025202020152010
Figure Projected Direct Spending on Diabetes and Its Complications among Different Diagnosis Cohorts, 2009-2033
Diagnosed 2029-2033Diagnosed 2019-2028Diagnosed 2009-2018Currently have diabetes
Copyrighted and published by Project HOPE/Health Affairs as Huang ES, et al. Using clinical informa-tion to project federal health care spending. Health Aff (Millwood). 2009;28(5):w978-w990. The pub-lished article is archived and available online at www.healthaffairs.org.
Billions of 2007 dollars
29MAY 2012 VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH VOL 1 NO 1
CVD Management
Chicago, IL—A study presented at the2012 American College of Cardiologymeeting potentially opens the door toall-oral therapy for the treatment ofpulmonary embolism (PE), whichwould permit most of the treatment totake place outside of the hospital.The current standard regimen for
treating PE involves injections of enoxa-parin (Lovenox) for 5 to 10 days fol-lowed by oral warfarin (Coumadin), avitamin K antagonist, for 3 to 12 months.In the EINSTEIN-PE study, a novel
oral rivaroxaban (Xarelto) regimenproved noninferior to standard ther-apy in preventing recurrence of ve-nous thromboembolism (VTE) inpatients with primary PE, while caus-ing less major bleeding, said leadinvestigator Harry R. Büller, MD, Pro-fessor of Vascular Medicine, Aca-demic Medical Center, Amsterdam,the Netherlands.“This study was undertaken so there
is increased awareness that VTE or PEcould be treated outside the hospital,”Dr Büller said. “Maybe the patient
needs to be in the hospital for 1 day tobe observed, but it is not necessary tohave patients in the hospital for 5 to 10days, as has been the practice. There-fore, we wanted to make this regimenvery simple.”In the United States, the average hos-
pital stay for patients with symptomatic
PE is 6 or 7 days, according to Dr Büller.EINSTEIN-PE tested a regimen of
oral rivaroxaban, 15 mg twice daily for21 days followed by 20 mg once daily,versus standard therapy of enoxaparintwice daily for at least 5 days plusa vitamin K antagonist (warfarin oracenocoumarol [Sintrom, Sinthrome])titrated to achieve an international nor-malized ratio (INR) of 2.0 to 3.0 in 4833patients with objectively confirmed PEwith or without deep vein thrombosis(DVT). Enoxaparin was discontinuedwhen the INR was >2.0 for 2 consecu-tive days, and the patient had receivedenoxaparin for at least 5 days.A previous study with rivaroxaban
for patients with DVT (EINSTEIN-DVT) used rivaroxaban at 20 mg daily,which proved noninferior to standardmedical therapy in reducing the risk ofsymptomatic recurrent VTE.The new, more intense regimen in
EINSTEIN-PE was developed fromdose-ranging studies that found supe-rior clot dissolution, said Dr Büller.All patients were treated for 3, 6, or
12 months as determined by the clini-cian before entering the study.The primary end point was first re-
currence of symptomatic VTE, whichwas 2.1% in the rivaroxaban group and1.8% in the enoxaparin/vitamin K an-tagonist group, which met the criterionfor noninferiority of efficacy.The principal safety outcome of
major or nonmajor clinically relevantbleeding was similar in the 2 arms—10.3% with rivaroxaban and 11.4% withenoxaparin/vitamin K antagonist. The frequency of major bleeding
events, however, was reduced by 50%in the rivaroxaban group comparedwith the enoxaparin/vitamin K antag-onist group.Older patients (aged >75 years) had
the greatest reduction in risk of bleedingwith rivaroxaban: 23 major bleedingevents with the enoxaparin vitamin Kantagonist regimen versus 5 patientswith rivaroxaban, Dr Büller said.The intensified regimen of rivaroxa-
ban during the first 3 weeks did not resultin an increased rate of hemorrhage.�
Single-Agent Oral Regimen as Effective as CurrentStandard for Pulmonary Embolism, Less Bleeding By Wayne Kuznar
“VTE or PEcould betreatedoutside thehospital.Maybe thepatient
needs to be in the hospitalfor 1 day to be observed, butit is not necessary to havepatients in the hospital for 5 to 10 days.”
—Harry R. Büller, MD
Chicago, IL—In the American Collegeof Cardiology Foundation-the Societyof Thoracic Surgeons Collaborationon the Comparative Effectiveness ofRevas cularization Strategies (AS-CERT), a large nationwide study ofhealth outcomes in nearly 190,000 pa-tients aged ≥65 years with coronary ar-tery disease, long-term survival appearsto be better with coronary artery bypassgrafting (CABG) surgery than with per-cutaneous coronary intervention (PCI).At 4 years, adjusted mortality was16.41% with bypass surgery and 20.8%with PCI. Lead investigator William S.Weintraub, MD, FACC, Chair of Cardi-ology, Christiana Care Health System,Newark, DE, presented the results atthe 2012 American College of Cardiol-ogy (ACC) meeting.“This study should help inform de-
cision-making concerning the choiceof revascularization in patients withstable ischemic heart disease,” said DrWeintraub, who cautioned that the re-sults do not indicate that bypass sur-gery is right for every patient. Theresults, however, reinforce the need to
include the patient in the decision-making, he said, and this study pro-vides evidence for the physician andthe patient to support this process.Furthermore, it should open commu-nication between the interventional-ist, the surgeon, and the patient todetermine the best approach for theindividual patient. The results of thiscomparative effectiveness research(CER) are largely consistent with pre-viously published clinical trials andobservational studies.The researchers combined patient
data from the ACC Foundation Cath-PCI database, the Society of ThoracicSurgeons (STS) CABG database, andthe Medicare claims database to com-pare survival rates among 86,000 by-pass surgery patients and 103,000 PCIpatients who underwent treatmentfrom 2004 to 2007 at 644 sites. David R. Holmes, Jr, MD, Professor
of Medicine at Mayo Clinic College ofMedicine, Consultant in the Depart-ment of Internal Medicine, Division ofCardiovascular Diseases, Mayo Clinic,Rochester, MN, and immediate past
president of the ACC, said that thiscollaboration of ACC and STS initi-ated during his presidency is a land-mark movement for interventionalists
and surgeons to work together, andthat such collaborations to obtainhealth outcomes data are needed intoday’s medicine.Adjusted mortality at 1 year was
similar with both strategies. All pa-tients had 2- or 3-vessel disease, andnone had a previous myocardial infarc-tion. At baseline, more patients in thePCI group had 2-vessel disease; in thebypass surgery group, more had 3-ves-
sel disease and were older and sicker. A surprise finding was the consis-
tency of the data overall and across allsubgroups, regardless of the statisticalmethod used. “Survival was betterwith coronary surgery for all patientsubgroups,” said Dr Weintraub. Eventhe patients whose propensity scoreswere consistent with being selectedfor a PCI had a better survival ratewith surgery. According to Dr Weintraub, another
important contribution of the ASCERTstudy is that it provides critical experi-ence in CER using observational data.Acknowledging that randomized clini-cal trials are the gold standard, he said,observational studies complement theclinical trials, and that both have criticalroles for CER to meet its potential. Fur-thermore, he said, the generalizabilityof clinical trials is a common complaint,and the totality of evidence, includingfrom analyses like these, is needed forbest decision-making. Additional analyses on composite
end points, angiographic outcomes, andeconomics are under way. �
Comparative Effectiveness Analysis of Coronary BypassSurgery and Percutaneous RevascularizationBy Mary Mosley
“This study should helpinform decision-makingconcerning the choice ofrevascularization in patientswith stable ischemic heart disease.”—William S. Weintraub, MD, FACC
Jentadueto™ (linagliptin and metformin hydrochloride) tablets
BRIEF SUMMARY OF PRESCRIBING INFORMATIONPlease see package insert for full Prescribing Information.
WARNING: RISK OF LACTIC ACIDOSISLactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and non-specific abdominal distress.Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.
INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effec-tive in these settings. JENTADUETO has not been studied in combination with insulin.
CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:Renal impairment (e.g., serum creatinine 1.5 mg/dL for men, 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from condi-tions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions]Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions]A history of hypersensitivity reaction to linagliptin (such as urticaria, angio-edema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]
WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumula-tion during treatment with JENTADUETO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medica-tions. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demon-strates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lac-tate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interac-tions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointesti-nal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical prob-lems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a
patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symp-toms and recovery [see Boxed Warning].Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impair-ment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodin-ated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal func-tion and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insu-lin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particu-larly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vita-min B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inad-equate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alco-hol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly dis-continued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Linagliptin/Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in 5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in 5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.
Table 1 Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study
Placebon=72
Linagliptin Monotherapyn=142
Metformin Monotherapyn=291
Combination of Linagliptin with Metforminn=286
n (%) n (%) n (%) n (%)
Nasopharyngitis 1 (1.4) 8 (5.6) 8 (2.7) 18 (6.3)
Diarrhea 2 (2.8) 5 (3.5) 11 (3.8) 18 (6.3)
Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyper-activity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.Linagliptin Monotherapy: Nasopharyngitis was reported in 5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and head-ache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglyce-mia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cat-ionic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interac-tions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly rec-ommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, cal-cium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, met-formin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not tera-togenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations. Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in off-spring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,
based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malforma-tions was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Met-formin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Met-formin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of JENTADUETO in pediatric patients have not been established. Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Metformin: Controlled clinical studies of metformin did not include sufficient num-bers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].
OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or perito-neal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical tri-als in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions].
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAandEli Lilly and Company Indianapolis, IN 46285 USA
Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany
Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED
Improving glycemic control for adult patients with type 2 diabetes
Significant A1C reductions (placebo-adjusted) at 24 weeks*†
Focusing on what matters
Indication and Important Limitations of UseJENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.
JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.
Important Safety Information
CONTRAINDICATIONSJENTADUETO is contraindicated in patients with:
Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).
Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.
WARNINGS AND PRECAUTIONSLACTIC ACIDOSIS
Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.
The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.
Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.
The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
MONITORING OF RENAL FUNCTIONBefore initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.
IMPAIRED HEPATIC FUNCTIONImpaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.HYPOGLYCEMIAInsulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with
an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.VITAMIN B12 LEVELSVitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.ALCOHOL INTAKEAlcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.HYPOXIC STATESCardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued. MACROVASCULAR OUTCOMESThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.ADVERSE REACTIONS
In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.
In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).
Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator).
DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.
The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.
USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed.
It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.
JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.
JD PROF ISI FEB272012
Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.
WARNING: RISK OF LACTIC ACIDOSISLactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.
NOW
APPROVED
*A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study.
† Superiority of both free combination therapies, consisting of the twice daily administration of linagliptin 2.5 mg and met-formin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24. Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001).
‡ JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.
Find out more about JENTADUETO and the Savings Card program at www.jentadueto.com
JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.
