Oklahoma Heart Inst i tuteOklahoma Heart Inst i tutevolume 2 • number 2 • winter 2006
Take a Bite out of Diabetesby Tobie L. Bresloff, MD
Dual Platelet Therapy: Not for Everyone
by Frank J. Gaffney, MD
Acute Decompensated Heart Failure and Nesiritide
by Alan M. Kaneshige, MD
Closing PFOs to PreventRefractory Migraine Headaches
by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHAA
volume 2 • number 3 • summer 2006
Cardiovascular disease is the number one killer of women. More women die from heart disease than the next seven causes of death combined. In Oklahoma alone, more than 5,000 women die of heart disease each year.*
But you don’t have to become a statistic. Stand up and fight heart disease. Punish it with a low-fat,low-sodium diet. Starve it by not smoking. Make it sweat with regular exercise. And bring heart disease to its knees with the help of Hillcrest Medical Center.
Hillcrest Medical Center offers comprehensive cardiovascular services, including research involving new drugs and devices, diagnostics, interventional and non-invasive procedures, surgery, education and rehabilitation programs. We also have Tulsa’s only outpatient heart failure care center, a comprehensive clinic that helps patients stay healthier and out of the hospital, while improving their quality of life.
Call (918) 579-NEWS to learn more about preventing and managing heart disease.
When It Comes To Heart Disease, Don’t Act Like A Lady.
1120 South Utica Avenue(918) 579-NEWS
www.hillcrest.com
Rebecca L. Smith, MDNoninvasive CardiologistHillcrest Medical Center
*Oklahoma Health Department
OKLAHOMA HEART INSTITUTE AT UTICA1265 S. Utica Avenue
Suite 300
Tulsa, OK 74104
Phone: 918.592.0999
Fax: 918.592.1021
OKLAHOMA HEART INSTITUTEAT SOUTHPOINTE9228 S. Mingo
Suite 200
Tulsa, OK 74133
Phone: 918.592.0999
Fax: 918.878.2499
THE DOCTORS OF OKLAHOMA HEART INSTITUTEWayne N. Leimbach, Jr., MD
Robert C. Sonnenschein, MD
Robert E. Lynch, MD
James J. Nemec, MD
John G. Ivanoff, MD
Gregory D. Johnsen, MD
Alan M. Kaneshige, MD
Ernest Pickering, DO
James A. Coman, Jr., MD
Edward T. Martin, MD
Roger D. Des Prez, MD
Christian S. Hanson, DO
Rebecca L. Smith, MD
Tobie L. Bresloff, MD
David A. Sandler, MD
Raj H. Chandwaney, MD
D. Erik Aspenson, MD
Frank J. Gaffney, MD
Michael J. Fogli, MD
Eric G. Auerbach, MD
Kelly Flesner-Gurley, MD
Created by Publishing Concepts, Inc.Virginia Robertson, President • [email protected]
14109 Taylor Loop Road • Little Rock, AR 72223 / 501.221.9986 / 800.561.4686
For advertising information contact: Suzanne Ramsel at 501.221.9986 or [email protected] visit our website www.pcipublishing.com
Edition 7
I n t h i s i s s u e
To Our Readers 4
Take a Bite out of Diabetes
by Tobie L. Bresloff, MD5
Late Breaking Clinical Trials for Cardiology 2006
by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHAA7
RESEARCH CORNER:
New Treatments for Atrial Fibtillation
by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHA
1 4
Dual Platelet Therapy: Not for Everyone
by Frank J. Gaffney, MD1 9
Acute Decompensated Heart Failure and Nesiritide
by Alan M. Kaneshige, MD2 5
Closing PFOs to PreventRefractory Migraine Headaches
by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHAA
2 9
Cover photo: Butterflies in a Tulsa summer garden. Photo by Rick Stiller
3
4
CARDIOVASCULAR DISEASE IS is the number one cause of death in theUnited States and the world. Over the past decade, some of thegreatest advances in cardiology have been in the area of prevention.Risk factor modification has turned out to be more effective thananticipated. Large clinical trials continue to substantiate thetremendous benefit of aggressive risk factor modification. The currentissue of Oklahoma Heart Magazine summarizes the latest findingsregarding risk factor medication from large clinical trials. These trialsaddress issues ranging from how aggressive we should be in loweringblood pressure and cholesterol, to whether there is any benefit fromlowering homocysteine levels.
In addition, Dr. Bresloff, from the Division of Endocrinology,discusses the newest medications for treating diabetes mellitus, one ofthe major risk factors for cardiovascular disease. With the newermedications, glycemic control can now be achieved without significantincreases in weight.
The number one discharge diagnosis for acute care hospitals in theUnited States continues to be heart failure. Dr. Kaneshige discussesthe use of nesiritide for acute decompensated heart failure and therecent controversy about when it should be used.
Dr. Gaffney highlights recent results from the CHARISMA Trial,which looked at dual platelet therapy with aspirin and clopidogrel, inboth secondary and primary prevention treatment strategies. Dualplatelet therapy may not be for everyone.
This issue of Oklahoma Heart Institute magazine also includes thereport of the MIST trial, which looked at the value of closing PFOs(patent foramen ovale) with percutaneous closure devices in order toprevent refractory migraine headaches.
As always, the Research Corner provides information on thenewest therapies being investigated at Oklahoma Heart Institute. Wehope you enjoy these articles and welcome any comments orsuggestions in regard to magazine content.
Sincerely, Wayne N. Leimbach, Jr., MD
To Our Readers
5
■ by Alan M. Kaneshige, MD
There have been many majoradvances in understanding thepathophysiology and management ofchronic heart failure. Clinical andlaboratory research has led to theusage of angiotensin convertingenzyme (ACE) inhibitors,angiotensin receptor blockers, beta-blockers, and aldosterone inhibitors.These agents have significantlyreduced the risk of morbidi-ty and mortality in chronicheart failure. Despite theseadvances, approximately 1million patients will be hos-pitalized this year with acutedecompensated heart failure(ADHF). The major expen-diture for heart failure ishospitalization, with approx-imately $25 billion spentannually on inpatient man-agement of ADHF. Any ther-apy that could improve diag-nosis and treatment andshift care to the outpatientwould have a favorableimpact on the massive eco-nomic costs associated withthis disease.
In the past, tools to diag-nose ADHF beyond the his-tory and physical examina-tion were limited. The B-type natriuretic peptide(BNP) blood test marks a
significant advance in the evaluationof patients presenting with symp-toms that may represent acute heartfailure. The BNP level also has prog-nostic value. Elevated BNP levelsare associated with increased mor-tality and worsening clinical out-comes.
The understanding of hemody-namic mechanisms of heart failure
(HF) has led to the development ofnew agents to treat ADHF. The B-type natriuretic peptide, in additionto being a reliable biomarker foracute and chronic heart failure, hasalso become a reliable treatment forADHF. The protein is mainly synthe-sized in, and released from, the ven-tricular myocardium. Other mem-bers of the human natriuretic peptide
Acute Decompensated Heart Failure and Nesiritide
6
family include atrial natriuretic pep-tide (ANP), C-type natriuretic pep-tide (CNP), and dendroaspis natri-uretic peptide (DNP).
The B-type natriuretic peptide(BNP) is a counter regulatory neu-rohormone released when there arechanges in left ventricular wallstretch and volume overload. It is a“distress hormone,” more specific toventricular disorders than the othernatriuretic peptides. BNP is apotent natriuretic, diuretic, andvasorelaxant peptide. It promotesvascular relaxation and lowersblood pressure, especially in a stateof volume overload. It also inhibitssympathetic tone, the renin-angiotensin axis, and the synthesisof vasoconstrictors, such as the cat-echolamines, angiotensin II, aldos-terone, and endothelin. In doing so,BNP improves central hemodynam-ics, suppresses cardiac growth, andprevents compensatory cardiachypertrophy. Its renal effectsinclude increasing glomerular filtra-tion rate and enhancing sodiumexcretion.
In both chronic and acute HF, sig-nificant neurohormonal changeshappen, including upregulation of
vasoconstrictors, such as norepi-nephrine, angiotensin II, andendothelin. There are increased lev-els of aldosterone and argeninevasopressin that promote salt andfree water retention. Oral treatmentwith ACE inhibitors, ARBs, andbeta-blockers as well as aldosteroneinhibitors and diuretics are the cur-
rent standard therapies for thesealterations.
Intravenous therapy for ADHFincludes positive inotrope activity.These produce symptomatic short-term benefits. Agents such as milri-none, however, have raised seriousquestions concerning routine usage.Hypotension and dysrhythmias arecommon. In addition, small studieshave shown improved symptomaticoutcomes with dobutamine in ADHF,but long-term beneficial results havenot been supported in larger studies.Routine use of dobutamine has beenassociated with an increase in dys-rhythmic events and death. ChronicIV inotropic therapy makes thepatients feel better, but can shortenlife expectancy. Therefore, it is notuse chronically anymore.
Intravenous vasoactive therapybegan with nitroglycerin. Althoughused for many years, there was littledata to guide usage. Hemodynamiceffects including lowering systemicvascular resistance, increase instroke volume, and improvement inclinical status. More recently, nesiri-tide infusion has been very effective.Infusion of nesiritide (recombinantBNP) at a specified dose willincrease circulating BNP up to 5times higher than measured in typi-cal heart failure patients. This sub-sequent overwhelming effect on the
7
system results in beneficial changesfor HF patients. Changes that occurinclude peripheral vasodilatation,diuresis, improvement in pulmonarycapillary wedge pressure (left ven-tricular filling pressure), and reduc-tion in angiotensin and norepineph-rine levels. Compared to intra-venous nitroglycerin, nesiritide has amore rapid onset of action, greaterlowering of pulmonary capillarywedge pressure, and earlier improve-ment in patients’ symptoms of dysp-nea and global well-being.Symptomatic hypotension can occurin approximately 4%, similar to nitro-glycerin. A small proportion (
8
Several smaller, single-centerstudies have also shown that nesiri-tide can be administered safely andeffectively in the outpatient settingfor those with chronic decompensat-ed HF. Data from these studies andfrom FUSION I have prompted thedevelopment of a larger outpatienttrial called FUSION II. FUSION II isa randomized double-blind studyinvolving 900 patients with chronicHF at high risk for rehospitalization.Patients will be randomized to 1 of 4treatment arms and will receive seri-al infusions of placebo or nesiritide(dosed at 0.01 micrograms/kg/minafter a standard bolus of 2 micro-grams/kg) once or twice a week for12 weeks followed by 12 weeks offollow-ups. FUSION II will also con-trol for increased counseling andeducation that is typical for diseasemanagement clinics.
Clinical outcomes are improvedby early and more accurate diagnosisof ADHF. Heart failure shares manysigns and symptoms of other chronicillnesses common to the elderly pop-ulation. Endogenous BNP levels areelevated in patients with ADHF, andthe extent of the elevation correlateswith HF severity. Patients withchronic decompensated HF mayrequire intravenous administration ofvasoactive agents if their disease isrefractory to standard therapy.Though intermittent infusions ofinotropic agents may improve short-term hemodynamics, these agentsare no longer recommended for longterm usage because of the increasein adverse events. Intermittent nesir-itide infusions may be a safe andeffective adjunct to oral pharma-cotherapy. Nesiritide is generallywell tolerated, though symptomatichypotension may occur occasionally.Evidence from the FUSION I trialwas favorable for outpatient heart
failure treatment. FUSION II willexplore the efficacy and safety ofoutpatient nesiritide infusions incomparison to placebo in high-riskpatients. Although a recent meta-analysis of 3 trials reported thatnesiritide may be associated withincreased mortality risk, inpatientusage of nesiritide continues to besupported and effective for treatingADHF. FUSION II has been allowedto go to completion and will giveinsight for further assessment of out-
patient intermittent nesiritide infu-sion for high-risk HF patientsthrough a specialized disease man-agement clinic. Until then, nesiritideinfusion will need to be monitoredclosely and held off from chronicintermittent outpatient infusion.
(Alan M. Kaneshige, MD is a nonin-vasive cardiologist with subspecialtyexpertise in adult echocardiography,stress echocardiography and trans-esophageal echocardiography.)
Inpatient usage of nesiritide continuesto be supported and effective fortreating ADHF
13
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To Come
14
Atrial fibrillation is a major car-diovascular problem. Because ofthe risk of embolic events, espe-cially strokes, chronic anticoagu-lation is necessary in patientswith atrial fibrillation.
Currently, warfarin is the onlyeffective chronic anticoagulationtherapy available for patients withatrial fibrillation but necessitatesthe inconvenience of frequentmonitoring of prothrombin timesand INRs. In addition, the onsetof warfarin is slow, requiring daysto achieve a therapeutic state.Reversal of the anticoagulatedstate is also a slow process fol-lowing cessation of warfarin.Because of these limitations,newer anticoagulants are beinginvestigated. One of these isdabigatran. Dabigatran is a directthrombin inhibitor that can betaken orally. Dabigatran hasfavorable pharmacokinetics com-pared with warfarin. There ismore rapid and predictable onsetand offset of action. Dabigatranproduces an anticoagulated statewithin hours of taking the firstdose. In addition, the anticoagu-lated state is reversed within 12to 24 hours of stopping the dabi-gatran. This allows continuedtreatment up to 24 hours prior toany invasive procedures.
In order to better evaluate theefficacy and safety of dabigatran,Oklahoma Heart Institute isinvolved in the RELY trial. TheRELY trial (Randomized Evaluationof Long-term AnticoagulantTherapy), compares efficacy andsafety of two blinded doses ofdabigatran etexilate with openlabel warfarin for the preventionof stroke and systemic emboliza-tion in patients with non-valvularatrial fibrillation. It is a perspec-tive, multi-center, parallel group,non-inferiority trial.
Patients with non-valvular atri-al fibrillation of moderate to highrisk for stroke or systemicembolization will be randozimedto receive either warfarin, usingstandard dosing to maintain theINR in the therapeutic range of 2to 3, versus one of two doses ofdabigatran; patients will eitherreceive 110 mg bid or 150 mg bid.There will be 5,000 patients ineach of the randomization arms.
Patients with renal insufficien-cy (creatinine clearance less than30 mls per minute) will be exclud-ed. Aspirin and Plavix will beallowed, if indicated for other rea-sons.
Patients will be followed forthree years on the randomizeddrug strategy. Both efficacy and
safety will be evaluated duringthe study.
The efficacy of direct thrombininhibitors, such as dabigatran,has already been demonstrated intrials involving a similar directthrombin inhibitor, ximelagatran.The efficacy of ximelagatran wasclearly established. However,there was increased risk of livertoxicity with ximelagatran.Dabigatran appears to have amuch lower risk of liver toxicitythan ximelagatran. Therefore,this drug appears to be a verypromising agent which mayreplace warfarin in the treatmentof patients with atrial fibrillation.
The main advantage of partici-pating in the trial is that patientsare closely monitored by theresearch nurses. In addition, theyhave a two out of three chance ofgetting the newer agent. This willminimize the inconvenience ofblood draws associated with war-farin therapy. In addition, thedrug may be safer than warfarinand easier to manage.
If physicians have patientsthey would like to refer for consid-eration for the RELY trial, they cancontact Dr. Leimbach or ask forone of the Research Nurses atOklahoma Heart Institute by call-ing 918-592-0999.
R E S E A R C H C O R N E R■ by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHA
New Treatments for Atrial Fibtillation
15
SERVICES OF OKLAHOMA HEART INSTITUTENoninvasive Cardiology• Nuclear Cardiology• Echocardiography & Doppler Studies• Nuclear and Echocardiographic
Exercise & PharmacologicalStress Testing
• Transesophageal Echocardiography• Arterial Venous Peripheral Vascular
Imaging & Doppler Studies• Peripheral Arterial Doppler
and Duplex Imaging• Cardiovascular Magnetic
Resonance Imaging• External Counterpulsation
(ECP) Therapy
Invasive Cardiology• Cardiac Catheterization• Coronary Angioplasty• Atherectomy• Rotablator Atherectomy• Thrombolytic Therapy• Coronary Stents• Intravascular Ultrasound• Myocardial Biopsy• Pericardiocentesis• Intravascular Radiation Therapy• Peripheral Angioplasty• Peripheral Stents• Percutaneous PFO Closures• Percutaneous ASD Closures• Intracardiac Echocardiography
Electrophysiology• Electrophysiology Studies• Ablation Therapy• Pacemaker Implantation• Pacemaker and Lead Extraction• Pacemaker Programming• Pacemaker Monitoring & Clinic• Implantable Cardioverter Defibrillator
(ICD) Replacement• ICD and Hardware Removal• ICD Programming• ICD Monitoring and Clinic• Holter Monitoring and Interpretation• 30 Day Cardiac Event Monitors• Implantation and Interpretation
of Long-Term Heart Monitors• Signal Averaged EKG’s and
Interpretation• Head Up Tilt Testing and Interpretation
• Direct Current Cardioversion• Antiarrhythmic Drug Loading
and Monitoring
Metabolic Disorders• Diabetes• Thyroid• Hypertension• Hyperlipidemia• Other Endocrine Problems
Specialty Clinics• Executive Health Clinic• Adolescent & Adult Congenital
Heart Clinic• Lipid & Wellness Clinic• Heart Failure Clinic• Dysrhythmia & Pacer Clinic• Metabolic Syndrome Clinic
OKLAHOMA HEART INSTITUTEAT UTICA1265 S. Utica Avenue
Suite 300
Tulsa, OK 74104
Phone: 918.592.0999
Fax: 918.592.1021021
OKLAHOMA HEART INSTITUTEAT SOUTHPOINTE9228 S. Mingo
Suite 200
Tulsa, OK 74133
Phone: 918.592.0999
Fax: 918.878.2499
16
Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHADr. Leimbach is a subspecialist in interven-tional cardiology, including cardiac catheteri-zation, coronary angioplasty and related inter-
ventional proceduressuch as stents, atherec-tomy, laser, intravascu-lar ultrasound imagingand direct PTCA foracute myocardial infarc-tion. He is Director of theCardiac andInterventionalLaboratories at Hillcrest
Medical Center. Dr. Leimbach is Co-Director ofthe Lipid and Wellness Clinic at OklahomaHeart Institute. He is Director of the James D.Harvey Center for Cardiovascular Research atHillcrest Medical Center, as well as Director ofthe Oklahoma Heart Research and EducationFoundation. He also serves as ClinicalAssociate Professor of Medicine at theUniversity of Oklahoma College of Medicine –Tulsa. Dr. Leimbach completed a ClinicalCardiology Fellowship and a ResearchFellowship at the University of Iowa Hospitalsand Clinics. He also completed his InternalMedicine Internship and Residency programsat Iowa, where he was selected Chief Residentin Medicine. He received his medical degreefrom Northwestern University in Chicago andhis Bachelor of Science degree from theUniversity of Michigan.
Board certified in Internal Medicine, CardiovascularDisease and Interventional Cardiology
Robert C. Sonnenschein, MD, FACC, ASE, RVTDr. Sonnenschein specializes in echocardiog-raphy and noninvasive peripheral vascularimaging. He is Director of Peripheral Vascular
Ultrasound Imaging atHillcrest Medical Centerand Oklahoma HeartInstitute and serves asClinical AssociateProfessor of Medicine atthe University ofOklahoma College ofMedicine – Tulsa. Hecompleted his
Cardiology Fellowship at the State Universityof New York Upstate Medical Center inSyracuse, where he also completed hisInternal Medicine Internship and Residencyprograms. Dr. Sonnenschein received hismedical degree from Rush Medical College inChicago and his Bachelor of Arts degree fromthe University of Pennsylvania.
Board certified in Internal Medicine, CardiovascularDisease, and Adult EchocardiographyRegistered Vascular Technologist
Robert E. Lynch, MD, FACCDr. Lynch is a specialist trained in
noninvasive and invasive cardiology. He is former Chief of Cardiology at HillcrestMedical Center, where he also has served as
Chief of Medicine andPresidentof the medical staff. Dr.Lynch is Co-Director of theLipid and WellnessClinicat Oklahoma HeartInstitute and Director ofthe Executive Health
Program. He is also a Clinical AssistantProfessor at the University of OklahomaCollege of Medicine – Tulsa. He completed hisCardiology Fellowship, as well as his InternalMedicine Internship and Residency, at theUniversity of Oklahoma Health SciencesCenter. Dr. Lynch received his medical degreefrom the University of Oklahoma School ofMedicine and his Bachelor of Science degreefrom the University of Tulsa. Before establish-ing his practice in Tulsa, he served as Chief ofMedicine at the U.S. Army Hospital, Bangkok,Thailand.
Board certified in Internal Medicine andCardiovascular Disease
James J. Nemec, MD, FACCDr. Nemec is a subspecialist in echocardiog-raphy, stress echocardiography and nuclear
cardiology. He servesas Director of NuclearCardiology forOklahoma HeartInstitute. Dr. Nemechas served asAssistant Professor ofInternal Medicine,Division of Cardiology,at Creighton University
and as Assistant Professor, Department ofRadiology, also at Creighton University. Hecompleted his Clinical Cardiology Fellowshipat the Cleveland Clinic Foundation and hisInternal Medicine Internship and Residencyat Creighton University. Dr. Nemec also com-pleted a year of training in pathology at theUniversity of Missouri, Columbia, MO. Hereceived his medical degree from CreightonUniversity, where he also received hisBachelor of Arts degree.
Board certified in Internal Medicine andCardiovascular Disease
John G. Ivanoff, MD, FACC, FSCAIDr. Ivanoff specializes in interventionalcardiology, including cardiac catheterization,coronary angioplasty and relatedinterventional procedures such as stents,atherectomy and direct PTCA for acutemyocardial infarction. He is Director of theCatheterization Laboratories at SouthCrestHospital. Dr. Ivanoff serves as ClinicalAssociate Professor of Medicine at theUniversity of Oklahoma College of Medicine –Tulsa. He has also served as AssistantProfessor of Medicine at the Medical Collegeof Pennsylvania, as well as Associate Directorof the Coronary Care Unit and AssistantProfessor of Medicine at Hahnemann
University Hospital, where he also completedhis Cardiology Fellowship. He completed hisInternal Medicine Internship and Residency at
the Medical College ofPennsylvania, where heserved as ChiefResident. Dr. Ivanoffalso received his med-ical degree from theMedical College ofPennsylvania. He com-pleted his Mastersdegree in biochemistry
at Columbia University and received hisBachelor of Arts degree from the University ofPennsylvania.
Board certified in Internal Medicine,Cardiovascular Disease and InterventionalCardiology
Gregory D. Johnsen, MD, FACCDr. Johnsen is an interventional cardiologistwith expertise in cardiac catheterization,angioplasty and related interventional proce-
dures, such as stentsand atherectomy. He isDirector of CardiacRehabilitation atHillcrest MedicalCenter and Director ofthe Hillcrest Exerciseand LifestylePrograms. He complet-ed his Clinical
Cardiology Fellowship at the University ofOklahoma – Oklahoma City, where he thenfinished an extra year of dedicated trainingin interventional cardiology. He completedhis Internal Medicine Internship andResidency training at the University ofOklahoma – Oklahoma City, where he alsoreceived his medical degree. Dr. Johnsenreceived his Bachelor of Science degree fromOklahoma StateUniversity.
Board certified in Internal Medicine,Cardiovascular Disease and InterventionalCardiology
Alan M. Kaneshige, MD, FACCDr. Kaneshige is a noninvasive cardiologistwith expertise in adult echocardiography,stress echocardiography and trans-
esophageal echocar-diography. He is Chiefof Cardiology atHillcrest MedicalCenter. Dr. Kaneshigeis also the Director ofthe Adolescent andAdult Congenital HeartClinic at OklahomaHeart Institute and
Director of the Congestive Heart FailureC.A.R.E. Center at Hillcrest Medical Center.Dr. Kaneshige completed his InternalMedicine Internship and Residency atCreighton University School of Medicine,where he also received his medical degree.He received a Bachelor of Science in chem-istry at Creighton University. Dr. Kaneshigecompleted his Clinical Cardiology Fellowshipat Creighton, where he also served as Chief
THE DOCTORS OF OKLAHOMA HEART
INSTITUTE
17
Cardiology Fellow for two years. He complet-ed an additional Cardiac UltrasoundFellowship at the Mayo Clinic in Rochester,MN. Dr. Kaneshige served as AssistantProfessor of Medicine at Creighton UniversitySchool of Medicine, where he was Director ofthe Noninvasive Cardiovascular Imaging andHemodynamic Laboratory.
Board certified in Internal Medicine andCardiovascular DiseaseBoard certified in Adult and TransesophogealEchocardiography
Ernest Pickering, DO, FACOIDr. Pickering is a cardiology specialisttrained in noninvasive and invasive cardiolo-gy with subspecialty expertise in cardiac
catheterization andangioplasty. He is Chiefof Cardiology atSouthCrest Hospitaland past Chief ofCardiology at TulsaRegional MedicalCenter. He completed aCardiovascular DiseaseFellowship at Baylor
College of Medicine in Houston, TX. Dr.Pickering’s Internal Medicine Residency wascompleted at Oklahoma OsteopathicHospital in Tulsa. He received his medicaldegree from Philadelphia College ofOsteopathic Medicine and his Bachelor ofScience degree from Shelton College,Ringwood, NJ.
Board certified in Internal Medicine andCardiovascular Disease
James A. Coman, MD, FACCDr. Coman is a subspecialist in cardiac elec-trophysiology, ablation therapy and pace-makers. He is Director of Electrophysiology
at Hillcrest MedicalCenter. Dr. Coman alsoserves as ClinicalAssociate Professor ofMedicine at theUniversity of OklahomaCollege of Medicine –Tulsa. He completed anElectrophysiologyFellowship at the
Cleveland Clinic Foundation, where he wasChief Fellow. His Cardiology Fellowship wasalso performed at the Cleveland ClinicFoundation. Dr. Coman’s Internal MedicineInternship and Residency training were com-pleted at the University of Alabama,Birmingham, AL. He received his medicaldegree from the University of AlabamaSchool of Medicine and his Bachelor ofScience degree in biomedical engineeringfrom Vanderbilt University, Nashville, TN.
Board certified in Internal Medicine,Cardiovascular Disease andElectrophysiology
Edward T. Martin, MS, MD, FACC, FACP, FAHADr. Martin is a noninvasive cardiologist withsubspecialty expertise in non-invasive imag-ing. He is Director of Cardiovascular
Magnetic Resonance Imaging at OklahomaHeart Institute, SouthCrest Hospital andHillcrest Medical Center. Dr. Martin is also
Director of NuclearCardiology atSouthCrest Hospital. Inaddition, he is aClinical AssociateProfessor of Medicineat the University ofOklahoma College ofMedicine – Tulsa. Dr.Martin has specialty
training in Nuclear Medicine, as well asadditional training dedicated toCardiovascular Magnetic ResonanceImaging. He completed his CardiologyFellowship at the University of Alabama. Dr.Martin’s Internal Medicine Internship andResidency training were performed atTemple University Hospital in Philadelphia.He received his medical degree from theMedical College of Ohio. Dr. Martin complet-ed his Master of Science degree in mechani-cal engineering at the University ofCincinnati and his Bachelor of Sciencedegree in physics at Xavier University. Dr.Martin is a founding member of the Societyof Cardiovascular Magnetic Resonance andis an editorial board member of the Journalof Cardiovascular Magnetic Resonance.
Board certified in Internal Medicine andCardiovascular Disease
Roger D. Des Prez, MD, FACCDr. Des Prez is a noninvasivecardiologist with subspecialty expertisein echocardiography, nuclear cardiology and
transesophagealechocardiography. Heis Director ofEchocardiography andPeripheral VascularUltrasound Imaging atSouthCrest Hospital.Dr. Des Prez receivedhis medical degree andBachelor of Arts degree
from Vanderbilt University. He completed hisResidency in Internal Medicine andPediatrics at University Hospital ofCleveland. Dr. Des Prez practiced for sixyears as an internist with the Indian HealthServices in Gallup, NM. He returned toVanderbilt University as a member of theInternal Medicine Faculty, at which time healso completed his cardiology training. Inaddition to noninvasive cardiology, Dr. DesPrez is interested in outcomes researchand computers in medicine.
Board certified in Internal Medicine, Pediatrics, CriticalCare and Cardiovascular DiseaseBoard certified in Adult and TransesophagealEchocardiography
Christian S. Hanson, DO, FACEDr. Hanson is a specialist in Endocrinology,Metabolism and Hypertension at OklahomaHeart Institute with expertise in diabetes,lipids and hypertension. He also serves asClinical Associate Professor of Medicine in
the College of Osteopathic Medicine –Oklahoma State University. He completed aFellowship in Endocrinology, Metabolism
and Hypertension atthe University ofOklahoma inOklahoma City. Dr.Hanson’s InternalMedicine Residencyand RotatingInternship were com-pleted at TulsaRegional Medical
Center. He received his medical degreefrom Oklahoma State University and hisBachelor of Science degree fromNortheastern Oklahoma State University inTahlequah.
Board certified in Internal MedicineBoard certified in Endocrinology and Metabolic Diseases
Rebecca L. Smith, MDDr. Smith is a noninvasive cardiologist withsubspecialty expertise in transesophagealechocardiography, intra-operative echocar-
diography, stress andpharmacologicalechocardiography andcontrast echo-cardiog-raphy. She completedan Advanced CardiacImaging Fellowship atthe Cleveland ClinicFoundation and herCardiology Fellowship
at the University of New Mexico HealthSciences Center, Albuquerque, NM. Dr.Smith’s Internal Medicine Internship andResidency training were performed at theUniversity of Arizona Health Sciences Centerin Tucson. She received her medical degreefrom the Medical College of Ohio. Dr. Smithcompleted her Bachelor of Science degree atCleveland State University.
Board certified in Internal MedicineBoard eligible in Cardiovascular Disease
Tobie L. Bresloff, MDDr. Bresloff is a specialist in Endocrinology,Metabolism and Hypertension, with expert-ise in diabetes, lipids, hypertension and
thyroid diseases. Shealso serves asAssistant Professor inClinical Medicine atthe University ofOklahoma College ofMedicine - Tulsa. Shecompleted an NIHFellowship inEndocrinology and
Metabolism at Vanderbilt University inNashville, TN. Dr. Bresloff's InternalMedicine Internship and Residency werecompleted at Sinai Hospital of Detroit,Detroit, MI. She received her medicaldegree from Wayne State University Schoolof Medicine in Detroit and her Master ofScience and Bachelor of Science degrees atthe University of Michigan, Ann Arbor, MI.
18
David A. Sandler, MDDr. Sandler is a cardiologist with subspe-cialty expertise in electrophysiology. Hecompleted his Cardiac Electrophysiology
Fellowship and hisCardiovascularMedicine Fellowshipat New York UniversityMedical Center, NewYork, NY. Dr. Sandler'sInternal MedicineInternship andResidency were per-formed at Mount Sinai
Medical Center, New York, NY. He earnedhis medical degree from GeorgetownUniversity School of Medicine inWashington, DC. Dr. Sandler received hisBachelor of Arts degree at the University ofPennsylvania in Philadelphia.
Board certified in Internal Medicine andCardiovascular DiseaseBoard certified in Cardiac Electrophysiology
Raj H. Chandwaney, MD, FSCAIDr. Chandwaney is an interventionalcardiologist with expertise in cardiaccatheterization, coronary angioplasty and
related interventionalprocedures such ascoronary stents,atherectomy, intravas-cular ultrasound andperipheral vascularinterventional proce-dures. He completedhis Clinical CardiologyFellowship at
Northwestern University Medical School inChicago, IL., where he also completed anInterventional Cardiology Fellowship. Dr.Chandwaney's Internal Medicine Internshipand Residency were performed at BaylorCollege of Medicine in Houston, TX. Hereceived his medical degree from theUniversity of Illinois at Chicago. Dr.Chandwaney completed his Master ofScience degree at the University of Illinoisat Urbana Champaign, where he alsoreceived his Bachelor of Science degree.
Board certified in Internal Medicine andCardiovascular DiseaseBoard certified in Interventional Cardiology
D. Erik Aspenson, MD, FACE, FACPDr. Aspenson is a subspecialist inEndocrinology, Metabolism andHypertension at Oklahoma Heart Institute,with expertise in diabetes, lipids, hyperten-sion and thyroid diseases. He completed aFellowship in Endocrinology at Wilford Hall
Medical Center,Lackland AFB, Texas.Dr. Aspenson'sInternal MedicineInternship andResidency were com-pleted at David GrantMedical Center,Travis AFB, Californiawhere he served as
Chief Resident. He received his medicaldegree from the University of Oklahomaand his Bachelor of Science degree atOklahoma State University.
Board certified in Internal MedicineBoard certified in Endocrinology and MetabolicDiseases
Frank J. Gaffney, MDDr. Gaffney is an invasive and noninvasivecardiologist with subspecialty expertise intransesophageal echocardiography. He
completed hisCardiovascularMedicine Fellowshipat Scott & WhiteMemorial Hospital inTemple, Texas. Dr.Gaffney completed hisInternal MedicineInternship andResidency at Brooke
Army Medical Center in San Antonio. Hethen remained on staff at Scott & WhiteMemorial Hospital for several years, beforeentering his Fellowship in CardiovascularMedicine. Dr. Gaffney earned his medicaldegree from New York Medical College,Valhalla, New York, and he received hisBachelor of Arts degree at HofstraUniversity in Hempstead, New York.
Board certified in Internal MedicineBoard certified in Cardiovascular Disease
Michael J. Fogli, MDDr. Fogli is a subspecialist in magnetic reso-nance imaging, nuclear cardiology, echocar-diography, stress echocardiography and
transesophagealechocardiography. Hecompleted a fellow-ship in AdvancedCardiac Imaging atthe University ofTexas, SouthwesternMedical Center inDallas, TX. HisCardiology fellowship
was also performed there, as were hisInternal Medicine Internship and Residency.Dr. Fogli earned his medical degree at the
University of California, San Francisco Schoolof Medicine and his Bachelor of Arts degreeat the University of California, Berkley.
Board certified in Internal Medicine Board certified in Cardiovascular Disease
Eric G. Auerbach, MDDr. Auerbach is a subspecialist in magneticresonance imaging, nuclear cardiology,echocardiography, stress echocardiography
and transesophagealechocardiography. Hecompleted hisCardiovascularMagnetic ResonanceImaging fellowship atOklahoma HeartInstitute, Tulsa, OK. HisCardiology fellowshipwas performed at the
University of Miami/Jackson MemorialHospital in Miami, FL. Dr. Auerbach’s InternalMedicine Internship and residency were alsocompleted at the University ofMiami/Jackson Memorial Hospital in Miami.Prior to that, he performed a SurgeryInternship at New York Hospital/CornellMedical Center, New York, NY. Dr. Auerbachearned his medical degree at the Universityof Miami School of Medicine, Miami, Floridaand his A.B. degree at Princeton University,Princeton, New Jersey.
Board certified in Internal Medicine Board certified in Cardiovascular Disease
Kelly Flesner-Gurley, MDDr. Flesner-Gurley is a subspecialist inEndocrinology, Metabolism andHypertension at Oklahoma Heart Institute,
with expertise in dia-betes, lipids, hyperten-sion and thyroid dis-eases. Prior to joiningOklahoma Heart, shewas at St. John MedicalCenter in Tulsa. Shecompleted her fellow-ship in Endocrinologyat the University of
Texas at Galveston. Her Internal MedicineInternship and Residency were completed atthe University of Texas in Houston, whereshe also received her medical degree. Sheearned her Bachelor of Science degree atTexas A&M University in College Station, TX.
Board certified in Internal Medicine and Endocrinology, Diabetes and Metabolic Diseases
19
What do a Gila monster from thedesert and many overweight people inAmerica have in common? How arethey different?• Gila monsters eat huge amounts at
once, far more than their bodiesneed at that time. But they eat only 3or 4 times per year, total. Unfor-tunately, many people also eat farmore at one time than they need, butthey do it several times every day.
• Gila monsters store the extra calo-ries as inert fat in their tails. Peoplestore it as intra-abdominal fat,which is metabolically active inmany detrimental ways.
• Gila monsters do not develop dia-betes. People do.
• These observations prompted onescientist to see why the Gila monsterdoesn’t develop diabetes mellitus.The super-sizing of America is a
fact. More people are more over-
weight than ever before. A much high-er percentage of the population ismorbidly obese. This trend is obvi-ously the result of too many caloriesingested and too little activity. Wenow know that obesity is more thanjust a cosmetic problem. The intra-abdominal fat cells are metabolicallyactive and the substances these fatcells make greatly increase the ratesof diabetes and vascular disease. We
know that obesity is a riskfactor for diabetes, as well asan independent risk factor forcardiac and vascular disease.
The number of diabetics inAmerica is increasing eachyear. We now diagnoseteenagers and pre-teens withtype 2 diabetes fairly fre-quently. We are also diagnos-ing pre-diabetes, impaired glu-cose tolerance, insulin resist-ance and metabolic syndromeat much higher rates.
By preventing obesity, wecan help to eliminate the
problems which are caused by obesity– diabetes and vascular disease.
Once someone has a diagnosis ofdiabetes, elevated blood sugars mustbe treated. Most traditional diabetestreatments increase the serum insulinand are associated with weight gain.Even people on TZDs, which act bydecreasing insulin resistance, tend togain weight.
Metformin has been the one agentso far that does not result in weight
gain. However, there are people whocannot tolerate the GI side effects ofmetformin and some patients cannotuse it due to renal insufficiency.
What is needed is a hypoglycemicagent that allows patients to controlblood sugar and lose weight at thesame time. We finally have it.
Byetta (exenatide) is a recentlyFDA approved drug that represents anew therapeutic class called “IncretinMimetics.” This protein is found inthe saliva of the Gila monster lizard. Itmimics the glucagons-like peptide 1(GLP-1) that is released in the humangut in response to food, and helpsmaintain glucose homeostasis.
The Story Behind ByettaIn the 1980s, Dr. John Eng, an
endocrinologist researcher, was work-ing for the Veterans Administrationtrying to find new hormones. UsingGila monster venom he purchasedfrom a lab in Utah, he discovered ahormone that he named exendin-4. Itwas similar in structure and action tohuman GLP-1 which regulates bloodsugar, slows gastric emptying andincreases satiety. The major differenceis that, while GLP-1 has a half-life ofseveral minutes, exendin-4 is measura-ble in plasma up to 10 hours afterinjection. Dr. Eng published his workin 1992. He realized that this hormonemight be developed into a diabetestreatment. Dr. Eng patented the com-pound and ultimately licensed thepatent to Amylin.
Take a Bite out of Diabetes
■ by Tobie L. Bresloff, MD
In 1999, Amylin filed a new drugapplication with the FDA. In April2005, Byetta was approved forglycemic control in type 2 diabetics.By the way, Gila monsters are notused in making the drug. It is synthe-sized in a lab.
What is an Incretin Mimetic?Incretins (substances that INcrease
seCRETion of insulin from the pan-creas) are secreted from the GI tractupon the ingestion of food. Theincretin mimetic increases the “firstphase” insulin response (causes moreto be released) to an oral glucoseload. An incretin mimetic producesthe same effect as naturally occurringGLP-1, but the effect is sustained for alonger period.
What does Byetta do?1. Increases glucose dependant
insulin secretion. This insulin thendecreases as glucose approachesnormal, even with the sameamount of exenatide being present.This means little hypoglycemia,except when used with insulin orinsulin secretagogues.
2. Decreases glucagon secretion,causing less hepatic glucose pro-duction.
3. Slows gastric emptying. Nutrientsget absorbed more slowly. Bloodsugar rise is slower. Patients feelfull sooner and satiated longer.
4. Has a direct CNS effect to increasesatiety and reduce food intake.All of these add up to decreased
post-prandial hyperglycemia,decreased nocturnal glucose produc-tion, decreased hunger and decreasedfood intake. Best of all, the beta cellworkload is decreased, which shouldhelp preserve beta cell function.
IndicationFrom the package insert:Adjunctive therapy to improve
glycemic control in patients withtype 2 diabetes who are taking met-formin, a sulfonylurea, or a combi-nation of metformin and a sulfony-lurea, but have not achieved adequateglycemic control.
Results of UsePhase 3 randomized, double blind,
placebo controlled trials of Byettaadded to previous treatment, showedsignificant reductions in fasting glu-cose, post-prandial glucose, HbA1C,and more patients achieved targetHbA1C goals. In addition, weight lossoccurred, and was most impressive, inthose whose BMIs started the highest.The average weight loss may not seemhuge, 6-7 pounds in 30 weeks, but forthese people any loss is an improve-ment. In addition, weight loss appearsto continue and not taper off, as itdoes with most diets and weight lossmedicines.
What patients need to know?Byetta is a sub-cutaneous injection
given twice a day before the morningand evening meals. It is NOT insulin!All patients start with 5mcg BID and,if well tolerated, increase to 10mcg inone month.
The major side effect is nausea,which, if it occurs, is usually at thestart of treatment or after increases indosages. It generally spontaneouslysubsides. The other major side effectis hypoglycemia. This usually occurs ifthe patient is on a sulfonylurea. Toprevent hypoglycemia, the sulfony-lurea dose can be halved or stoppedwhen starting Byetta, and added backif needed.
PrecautionsAbsorption of other drugs may be
delayed due to slowed gastric empty-ing. If rapid GI absorption for a med-ication is needed, the medicine maybe given at least 1 hour before theByetta.
Byetta is also not recommended forpatients with a creatinine clearance ofless than 30 ml/min. The dose doesnot need to be adjusted for mild tomoderate renal impairment.
How To Start a PatientMany patients fear injections.
Demonstrating the pen needle helpsthem realize that the injections are notto be feared.
Other Diabetes NewsSymlin – Pramlintide generic
name, also made by Amylin, hassome of the same actions as Byetta.It can be used in type 1 or 2 diabet-
ics. It is used along with insulin toreduce post meal hyperglycemia. Itmust be taken with each meal, bysub-cutaneous injection. It can causesevere hypoglycemia, so insulindoses need to be adjusted carefully.It can also cause nausea and slowgastric emptying. Some patients loveit, since it stabilizes their post mealglucose excursions. It also helpswith weight loss by improving satietyand reducing insulin dose, as well asfood intake. Patients need to be care-fully selected for this drug, and it issomewhat tricky to start. Studies arebeing done to see if it can help withweight loss in non-diabetics.
Rimonabant – A drug being devel-oped to decrease overeating is nowbeing looked at by the FDA. Thebrand name will be Acomplia if it isapproved. This drug works by block-ing the endocannabinoid system.These are the receptors that are stim-ulated by marijuana and cause “themunchies,” as well as impulsivebehavior and disinhibition. Blockingthe system decreases cravings forfood and possibly other habits, likesmoking. Rimonabant leads todecreases in waist circumference,triglycerides and insulin resistance,while increasing HDL cholesterol.
Exubera is the first inhaled insulinto be FDA approved. Marketing maystart in the summer of 2006. I suspectit will be mainly for type 2 diabetics. Itwill need to be used with each meal,since it is a short acting insulin. It willnot substitute for basal insulin doses.There may also be restrictions on whoshould use it, based on pulmonaryfunctions. Pulmonary toxicity maystill be a concern.
In summary, it is exciting times forthose of us who take care of diabetics.Byetta shows huge promise, and hasalready made a major difference tosome patients. Our bag of tricks isgreatly expanding to allow us to bettertreat diabetics, and to minimize orreverse some of the weight gain thathas been such a major problem.
(Tobie L. Bresloff is a specialist in Endocrinology, Metabolism and Hypertension with expertise in diabetes, lipids, hypertension and thyroid diseases.)
20
A PFO (Patent Foramen Ovale) isa small defect between the rightatrium and left atrium. The defectcan be opened by increased pres-sure in the thoracic cavity (i.e., acough). Because of this defect, par-adoxical emboli can cross the PFOand cause a stroke. It is also possi-ble that vaso-active chemicals andhormones cross the PFO, triggeringmigraine headaches.
Currently we are closing PFOspercutaneously, using one of twotypes of devices. One is theCardioseal closure device and theother is the Amplatzer SeptalOccluder device. Both of thesedevices are placed percutaneouslyby going through the femoral veins.
Patients who have had paradoxi-cal embolic events while oncoumadin anticoagulation are eligi-ble for closure of their PFO. Therelationship between PFOs andmigraines was recognized becauseof reports by patients who had theirPFOs closed to prevent recurrentstrokes. Some of these patientsalso had significant migraineheadaches. With the closure oftheir PFO, a marked decrease in thefrequency of their migraineheadaches was reported. Somepatients had complete resolution oftheir migraine headaches followingclosure of their PFO.
25
Closing PFOs to PreventRefractory Migraine Headaches
■ by Wayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHAA
26
It is known that greater than 50%of migraine patients have intracar-diac shunts, such as a PFO. This isin contrast to 10 to 15% of the gener-al population. In addition, PFOs inmigraine patients tend to be largerthan the PFOs in autopsy studies ofthe general population. Because ofthe complete resolution of migraineheadaches in some patients afterPFO closure, it has been speculatedthat many patients have migraineheadaches because of chemical orhormonal shunting across the PFO.These chemicals or hormones wouldnormally be filtered out in the lung.By crossing over to the systemic cir-culation through the PFO, they actas triggers for migraines. In orderto test this theory, the MIST trialwas performed in England. In this
trial, patients with refractorymigraine headaches were random-ized to either a percutaneous clo-sure of their PFO using a closuredevice or were randomized to asham procedure.The patients werefollowed to seewhether they hadimprovement or res-olution of theirmigraine headaches.
To be approvedin the United Statesfor the treatment ofmigraine headaches,it is usually neces-sary for a drug todemonstrate a 50%reduction inmigraine events. It
should also be noted that in normaldrug trials, there can be up to a 23%reduction in migraine events withplacebo therapy. Therefore, it mightbe expected that a trial looking atthe effectiveness of PFO closure intreating migraine headaches wouldalso have as its endpoint a 50%reduction in migraine events.
In this trial, however, investiga-tors pursued a much more aggres-sive primary endpoint. The primaryend point for the MIST trial wascomplete cessation of migraineheadaches.
Needless to say, the trial failed toachieve its primary endpoint.However, the trial did demonstratea significant reduction in headachedays. In regards to the endpoint of
a 50% reduction inmigraine events,42% of the PFOclosure patientsachieved the end-point, compared toa 23% reduction inthe sham-treatedgroup. Headacheburden, which isdefined as frequen-cy times duration,resulted in a 37%reduction in theimplant patients,as compared to a
16% reduction in the sham treatedpatients. Thus, it appears thatsome patients with migraineheadaches and PFOs do experiencesignificant decreases in theirheadache burden with closure ofthe PFO.
Closing a PFO for the treatmentof migraines is still experimental,
and there is not FDA approval ofthe procedure for this indication.Additional trials are ongoing to bet-ter clarify the utility of PFO closurefor prevention of migraines. Fromthe current MIST trial, it is clearthat not all migraine headaches aresecondary to shunting across thePFO in those patients who havemigraine headaches and PFOs.However, the study does suggestthat many patients with refactorymigraine headaches could havetheir headaches abolished, or atleast significantly reduced, by a per-cutaneous procedure with only anovernight stay in the hospital.
(Dr. Wayne N. Leimbach Jr. is a sub-specialist in interventional cardiolo-gy including cardiac catheterization,coronary angioplasty and relatedinterventional procedures such asstents, atherectomy, laser, intravas-cular ultrasound imaging and directPTCA for acute myocardial infarc-tion and PFO and ASD closures.)
The relationship
between PFOs and
migraines was recog-
nized because of
reports by patients
who had their PFOs
closed to prevent
recurrent strokes.
AMPLATZER
The cardioSEAL Septal Occlusion System
27
In our last issue we discussed thefindings of the COMMIT and CLARI-TY trials regarding the expandedrole for clopidogrel (Plavix) in STElevation Myocardial Infarction.Both studies showed clopidogrelcould be safely added to the currentregimen of aspirin, and, when appro-priate, heparin, fibrinolytics and PCI(percutaneous coronary interven-tion) without increased risk of bleed-ing and with a statistical reduction inthe study endpoints.
The benefits of adding clopidogrelto aspirin in patients with acute coro-nary syndromes, or in those undergo-ing percutaneous coronary interven-tion, have already been demonstratedin a number of trials, including theCURE and CREDO trials.
Additionally, the CAPRIE studycompared clopidogrel and aspirin inthe secondary prevention of cardiacevents in patients who had a recentMI, a recent stroke, or peripheralvascular disease. The main resultshowed was an 8.7% relative riskreduction in the combined end pointof MI, stroke or vascular death withclopidogrel. Patients with peripheralarterial disease experienced thelargest advantage with clopidogrel;those with a previous stroke bene-fited less substantially, and post-MIpatients showed a trend toward abetter effect with aspirin.
In the April 20th issue of TheNew England Journal of Medicine,the results of the CHARISMA trialwere presented. This trial wasdesigned to test the hypothesis that
“long-term treatment with a combi-nation of clopidogrel plus aspirinmay provide greater protectionagainst cardiovascular events thanaspirin alone in a broad populationof patients at high risk.”
Patients were eligible to enroll inthe trial if they were 45 years of ageor older and had one of the follow-ing conditions: multipleatherothrombotic risk factors, docu-mented coronary disease, docu-mented cerebrovascular disease, ordocumented symptomatic peripher-al arterial disease.
In the study, 15,603 patients witheither clinically relevant cardiovas-cular disease (secondary preventiongroup) or multiple risk factors (pri-mary prevention group) were ran-domized to clopidogrel 75 mg/dayplus low-dose aspirin (75-162mg/day) or placebo plus low-doseaspirin. More than three quarters ofthe patients had established cardio-vascular disease and the remainingpatients had multiple atherothrom-botic risk factors. They were fol-lowed for a median of 28 months.The primary end point was a com-posite of myocardial infarction,stroke, or death from cardiovascularcauses. During the study, threequarters of the patients took statins,half took beta-blockers, two thirdstook an ACE inhibitor and a quartertook angiotensen II-receptor block-ing agents.
The results for the total popula-tion revealed no significant benefitassociated with clopidogrel plus
aspirin, as compared with placeboplus aspirin, in reducing the inci-dence of the primary end point ofmyocardial infarction, stroke, ordeath from cardiovascular causes.There was a moderate, though signif-icant, benefit in reducing the second-ary composite end point of myocar-dial infarction, stroke, and deathfrom cardiovascular causes or hospi-talization for unstable angina tran-sient ischemic attack or revascular-ization.
The rate of severe bleeding wasnot significantly greater with clopi-dogrel than with placebo, but a trendprompting concern was noted.
There was benefit in symptomaticpatients with established vasculardisease (secondary prevention) – therate of the primary end point amongthese patients was 6.9% with clopido-grel and 7.9% with placebo (p=0.046).The risk of moderate or severebleeding in the symptomatic patientswas greater in the clopidogrel thanwith placebo, although there was noincrease in intracranial or fatalbleeding.
The rate of the primary end pointin the asymptomatic, or primary-pre-vention, patients was 6.6% with clopi-dogrel and 5.5% with placebo(p=0.20). Although the primary endpoint was not significantly different,the rate of death from cardiovascularcauses was 3.9% among those receiv-ing clopidogrel and 2.2% in those tak-ing placebo (p=0.01), suggesting pos-sible harm in the asymptomatic pri-mary prevention group.
Dual Platelet Therapy: Not for Everyone
■ by Frank J. Gaffney, MD
28
In conclusion, the authors suggest“the combination of clopidogrel plusaspirin was not significantly moreeffective than aspirin alone in reduc-ing the rate of myocardial infarction,stroke, or death from cardiovascularcauses among patients with multiplecardiovascular risk factors.
Furthermore, the risk of moderate-to-severe bleeding was increased.Our findings do not support the useof dual antiplatelet therapy acrossthe broad population tested. Therewas benefit in symptomatic patientswith established vascular disease.Data on mortality rates suggest that
dual antiplatelet therapy should notbe used in patients without a historyof established vascular disease.”
(Frank J. Gaffney, MD is an invasiveand noninvasive cardiologist withsubspecialty expertise in trans-esophageal echocardiography.)
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■ by FWayne N. Leimbach, Jr., MD, FACC, FSCAI, FCCP, FAHAA
The practice of cardiology continuesto change and rapidly evolve. We arenow in the era of evidence-based medi-cine, and in order to determine the bestclinical practice patterns, large ran-domized clinical trials are being done.Over the past year, several clinical tri-als have been presented at the nationalmeetings, the results of which werepresented at the Oklahoma HeartResearch & Education FoundationSpring Symposium. The following is asummary of the outcomes of several ofthese trials.
What’s New in RiskFactor Modification?
We now know that aggressive riskfactor modification can dramaticallyreduce the chances of heart attackand stroke. A major question hasalways been, how aggressive shouldwe be in risk factor modification?That is, how much should we lowerthe blood pressure and how muchshould we lower the cholesterol lev-els? Five studies have recentlyaddressed this issue.
The TROPHY study looked at howmuch blood pressure in patients atrisk should be lowered. The TROPHYstudy is a trial targeting the preven-tion of hypertension. In this trial,patients with pre-hypertension wererandomized to either treatment withthe angiotension receptor blocker,candasartin, or a placebo.
The seventh report of the JointNational Committee on Prevention,
Detection, Evaluation and Treatmentof High Blood Pressure (the JNC 7Report) defined normal blood pres-sure as blood pressures less than 120mm Hg, systolic and diastolic lessthan 80 mm Hg. Systolic blood pres-sures between 120 and 139 mm Hgand diastolic blood pressures between80 and 89 mm Hg were defined as pre-hypertension. The TROPHY studyrandomized 772 patients with pre-hypertension to either candasartin 16mgs a day for two years or a placebo.After two years, all the patients weretreated with placebos. The study last-ed a total of four years. The popula-tion was relatively young, with themean age being 48 years. The meansystolic blood pressures for the can-dasartin and placebo groups at base-line were 133.9 mm Hg and 134 mmHg respectively. At the end of twoyears, 154 patients taking placebo and53 patients taking candasartin devel-oped hypertension. This representeda 66.3% reduction in the developmentof hypertension at 2 years in the can-dasartin group. Over the four-yearduration of the study, the candasartin-treated patients had their risk ofdeveloping hypertension reduced by15.6%. This was a significant reduc-tion. During the four-year period,stage one hypertension developed innearly two thirds of the patients withuntreated pre-hypertension (the place-bo group). Treatment of pre-hyperten-sion with candasartin appeared to bewell tolerated and reduced the risk of
incident hypertension during thisstudy group. This study would there-fore suggest that there may be signifi-cant value to treating patients withpre-hypertension with an angeoten-sion receptor blocker in order to pre-vent the development of hypertension.Further studies will need to be doneto confirm this.
Just as blood pressure target levelsare decreasing, so are the target goalsfor LDL cholesterol. A major questionhas been how low should LDL choles-terol be in patients at risk of coronaryartery disease. The IDEAL study ran-domized 8,888 patients with a historyof a myocardial infarction to eithermoderate LDL lowering with simvas-tatin 20 to 40 mgs a day versus moreaggressive lipid lowering, with ator-vastatin 80 mgs a day. The median fol-low-up was 4.8 years. The mean LDLcholesterol for the simvastatin treat-ment group was 104 mg/dl. The meanLDL cholesterol for the atorvastatingroup was 81 mg/dl. At the end of 4.8years, the more aggressive LDL lower-ing with atorvastatin reduced majorcardiac events by 11% with the moreaggressive therapy. Non-fatal myocar-dial infarctions were reduced 17%, andany coronary heart disease event wasreduced 16%. These findings correlatewith previous findings in the TNTtrial, which looked at the use of ator-vastatin 10 mg a day versus atorvas-tatin 80 mg a day. In that study, signif-icant reductions in cardiac eventswere also found with more aggressive
Late Breaking Clinical Trials for Cardiology 2006What’s New in Risk Factor Modification?
29
30
lowering of the LDL cholesterol.The recent ASTERIOD trial used a
technique called intravascular ultra-sound to accurately measure plaquevolume in coronary artery disease.Patients were treated with rosuvas-tatin 40 mgs a day (Crestor) for twen-ty-four months. Patients receivedcoronary angiograms and intravascu-lar ultrasound studies at baseline andat follow-up two years later. Threehundred forty nine patients completedthe study with good baseline and fol-low-up intravascular ultrasound stud-ies. LDL cholesterols dropped from amean of 130.4 to 60.8 mg/dl. This rep-resented a 53% reduction in LDL cho-lesterol. Importantly, the group as awhole had their mean LDL cholesteroldecreased to 60.8 mg/dl. HDL choles-terol increased from 43 to 49 mg/dl.Triglycerides decreased from 152 to121 mg/dl.
After two years, the intensive treat-ment with rosuvastatin 40 mgs perday reduced the atheroma volume ofthe indexed vessel and also produceda significant reduction in the athero-ma volume in the most diseased sub-segment of the vessel. Both IVUS effi-cacy parameters showed a highly sig-nificant regression at two years forthe group. Thus, very intensive treat-ment with rosuvastatin 40 mgs perday in a group of patients with coro-nary artery disease successfullyreduced the LDL cholesterol to 60.8mg/dl and raised the HDL cholesterolby 14.7%, resulting in a significantregression in the atheroma plaque bur-den in the coronary artery. Regressionoccurred in 64% to 78% of subjectstreated, depending on the efficacyparameter used. The adverse eventsobserved were low. This study raisesthe question as to whether fixed LDLcholesterol goals should be followed,or whether the lowest level of LDLcholesterol achievable withoutadverse events should be the optimalstrategy for treating patients at risk.The study does provide scientific evi-dence supporting the newer guide-lines for LDL cholesterol target goalsof LDL cholesterol less than 70 mg/dlfor patients with known coronaryartery disease,
When discussing cholesterol riskfactor modification, another signifi-cant issue is how aggressive weshould be in the relatively low risk
patient. The MEGA study, presentedat the American Heart Association inNovember 2005, looked at primaryprevention of cardiovascular diseasein Japan, using mild to modest reduc-tions of LDL cholesterol with pravas-tatin in low risk patients. The diseaseburden of ischemic heart disease issubstantially lower in Japan than inthe United States for many differentreasons, including diet. The questionwas whether use of statin therapy inpatients at low risk will produce anysignificant reduction in cardiovascularevents.
8,214 patients were randomized toeither diet therapy or diet plus pravas-tatin therapy, 10 to 20 mgs per day.The average follow-up was 5.3 years.The mean LDL cholesterol in the twogroups was approximately 156 mg/dl;the mean HDL cholesterol in the twogroups was elevated at 56 mg/dl. Theprimary end point of cardiovascularevents was decreased by 33% at 5years for the statin treatment group.This represented a significant reduc-tion. All cardiovascular events weredecreased by 26%. Total mortalitywas significantly decreased by 28% at5 years. In this low risk population, a33% risk reduction in coronary heartdisease events was found, eventhough patients had higher HDL cho-lesterol levels and lower triglyceridelevels at baseline than the averageAmerican population.
The MEGA trial raises the veryintriguing question as to how aggres-sive we should be in treating our lowrisk population in the United States.Low risk is defined as a less than 5%risk of a cardiovascular event over 10years. The 33% risk reduction in car-diovascular events in the MEGA trialusing a statin therapy in a low riskpopulation, when applied to the twen-ty-five million low risk patients in theUnited States, would predict that125,000 cardiovascular events couldbe prevented over a ten-year period byusing statin therapy. Interestingly, forany other disease, 125,000 events overten years would be considered an epi-demic problem. The MEGA trial,therefore, will require re-analysis as towho should and who should not betreated with lipid-lowering agents.
High homocysteine blood levelshave been correlated with anincreased risk of cardiovascular dis-
ease. While the use of folic acid and Bvitamins will decrease homocysteinelevels, there have been conflictingreports as to the clinical value of low-ering homocysteine levels for the pre-vention of cardiovascular events.
The HOPE-2 trial looked at thevalue of homocysteine-lowering inpatients with vascular disease, usingfolic acid and B vitamins. 5,522patients were randomized in thisstudy. The study demonstrated thatsupplements containing folic acid,vitamin B-6 and B-12 did not reducethe risk of major cardiovascularevents in patients with vascular dis-ease. This finding was confirmed byanother recent trial called theNORVID trial, which looked at homo-cysteine-lowering for the preventionof subsequent cardiovascular eventsafter an acute myocardial infarction.This study also found that treatmentwith B vitamins and folic acid did notlower the risk of recurring cardiovas-cular disease after an acute myocar-dial infraction. In fact, there was atrend towards possible harm.Therefore, it was felt that routine low-ering of homocysteine levels with highdoes folic acid and B vitamins shouldnot be routinely recommended. Loweris better for the management of bloodpressure and cholesterol, but the con-cept does not apply to the treatmentof elevated homocysteine levels.
References:
For TROPHY Trial:Julius S, et al; NEJM 2006; 354:16: 1685– 1697
For ASTERIOD Trial:Nissen, S, et al; JAMA 2006; 295: 1556-1565
For NORVIT Trial:Bonaa, K, et al; NEJM 2006; 354:1578-1588, Apr 13, 2006For HOPE Trial:
Lonn, E, et all; NEJM 2006; 354:1567-1577, Apr 13, 2006
(Dr. Wayne N. Leimbach Jr. is a subspe-cialist in interventional cardiology includ-ing cardiac catheterization, coronaryangioplasty and related interventionalprocedures such as stents, atherectomy,laser, intravascular ultrasound imagingand direct PTCA for acute myocardialinfarction and PFO and ASD closures.)
9 1 8 . 5 9 2 . 0 9 9 9 / 1 2 6 5 S O U T H U T I C A A V E . / 9 2 2 8 S O U T H M I N G O / w w w . o k l a h o m a h e a r t . c o m
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Heart disease doesn’t fight fair.We can help you fight back.The next time you think a heart attack is something that happens to other people, here are a
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Heart disease is still the #1 killer of American adults. And more women die each year from heart
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THINKS HE’STOO YOUNG.
THINKS IT DOESN’THAPPEN TO WOMEN.
THINKS MAYBE IT WILL JUST GO AWAY.
When seconds count, SouthCrest-Tulsa’s Heart Hospital is ready and standing by at 91st and Highway 169. Call 294-DOCS or visit our Web site at www.southcresthospital.com
