The January CPE activity– Today’s Focus on Cardiology – includes the following articles: • Ten tips for counseling about cardiology drugs. Page 39 • News from AHA’s Scientific Sessions. Page 46 • Anticoagulant therapies: Review of available and upcoming agents. Page 58 CPE Instructions CPE Information Accreditation Information Advisory Board Provider: American Pharmacists Association Target audience: Pharmacists Release date: January 15, 2011 Expiration date: January 15, 2014 ACPE number: 202-000-11-101-H04-P Fee: There is no fee associated with this activity for members of the American Pharmacists Association. There is a $15 fee for nonmembers. The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity Number assigned by the accredited provider is 202-000-11-101-H04-P. Disclosure: The authors, advisory board, and APhA’s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. Development: The activity was developed by the American Pharmacists Association. Learning Objectives At the completion of this activity, the pharmacist will be able to: 1. List important points to make when counseling patients taking dabigatran and other medications for cardiovascular disease. 2. Identify clinical issues with warfarin, undifferentiated and low–molecular weight heparins, indirect and direct factor Xa inhibitors, and direct thrombin inhibitors. 3. Describe results from major new studies of agents for stroke, atrial fibrillation, dyslipidemias, and heart failure. 4. Describe the role of new oral anticoagulants in clinical care of patients with atrial fibrillation, venous thromboembolism, deep-vein thrombosis, pulmonary embolism, and acute coronary syndrome. 5. List seven actions patients and clinicians can take to reduce cardiovascular disease. Jeanine P. Abrons, PharmD, MS, Assistant Professor of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY Amber L. Briggs, PharmD, Clinical Pharmacists/Pharmacy Consultant, Central Peninsula Hospital, Soldotna, AK Read to earn CPE credit! Read designated articles in Pharmacy Today . Go to the Online CPE Quick List at www.pharmacist.com/education, click on the activity title, Today’s Focus on Cardiology , and complete the posttest. To obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at www.pharmacist.com/education. A Statement of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before January 15, 2014, can receive credit. Your Statement of Credit will be available online immediately upon successful completion of the CPE exam. Get your documentation of credit now! Completing a posttest at www.pharmacist.com/education is as easy as 1-2-3. 1. Go to Online CPE Quick List and click on the title of this activity. 2. Log in. APhA members, enter your user name and password. Not an APhA member? Just click “Create one now” to open an account. No fee is required to register. 3. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit. Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected]. CPE credit: 2 hours (0.2 CEUs) ACPE activity type: Knowledge-based Learning level: 1
Transcript
32 PHARMACY TODAY • JANUARY 2011 www.pharmacytoday.org
The January CPE activity–Today’s Focus on Cardiology – includes the following articles:
• Ten tips for counseling about cardiology drugs. Page 39
• News from AHA’s Scientific Sessions. Page 46
• Anticoagulant therapies: Review of available and upcoming agents. Page 58
CPE InstructionsCPE Information
Accreditation Information
Advisory Board
Provider: American Pharmacists AssociationTarget audience: PharmacistsRelease date: January 15, 2011Expiration date: January 15, 2014ACPE number: 202-000-11-101-H04-PFee: There is no fee associated with this activity for members of the American Pharmacists Association. There is a $15 fee for nonmembers.
The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (CPE). The ACPE Universal Activity
Number assigned by the accredited provider is 202-000-11-101-H04-P.
Disclosure: The authors, advisory board, and APhA’s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria.
Development:The activity was developed by the American Pharmacists Association.
Learning Objectives At the completion of this activity, the pharmacist will be able to:
1. List important points to make when counseling patients taking dabigatran and other medications for cardiovascular disease.
2. Identify clinical issues with warfarin, undifferentiated and low–molecular weight heparins, indirect and direct factor Xa inhibitors, and direct thrombin inhibitors.
3. Describe results from major new studies of agents for stroke, atrial fibrillation, dyslipidemias, and heart failure.
4. Describe the role of new oral anticoagulants in clinical care of patients with atrial fibrillation, venous thromboembolism, deep-vein thrombosis, pulmonary embolism, and acute coronary syndrome.
5. List seven actions patients and clinicians can take to reduce cardiovascular disease.
Jeanine P. Abrons, PharmD, MS, Assistant Professor of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY
Amber L. Briggs, PharmD, Clinical Pharmacists/Pharmacy Consultant, Central Peninsula Hospital, Soldotna, AK
Read to earn CPE credit!
Read designated articles in Pharmacy Today. Go to the Online CPE Quick List at www.pharmacist.com/education, click on the activity title,
Today’s Focus on Cardiology, and complete the posttest.
To obtain 2.0 contact hours of CPE credit (0.2 CEUs) for this activity, complete and submit the CPE exam online at www.pharmacist.com/education. A Statement of Credit will be awarded for a passing grade of 70% or better. You will have two opportunities to successfully complete the CPE exam. Pharmacists who successfully complete this activity before January 15, 2014, can receive credit.
Your Statement of Credit will be available online immediately upon successful completion of the CPE exam.
Get your documentation of credit now! Completing a posttest at www.pharmacist.com/education is as easy as 1-2-3.1. Go to Online CPE Quick List and click on the title of this activity.2. Log in. APhA members, enter your user name and password. Not an APhA
member? Just click “Create one now” to open an account. No fee is required to register.
3. Successfully complete the CPE exam and evaluation form to gain immediate access to your documentation of credit.
Live step-by-step assistance is available Monday through Friday 8:30 am to 5:00 pm ET at APhA Member Services at 800-237-APhA (2742) or by e-mailing [email protected].
5. Which of the following agents has the most exten-siveavailableclinicaldatatodateandthemostFDA-approvedindications?a. Fondaparinuxb. Bivalirudinc. Enoxaparind. Dabigatran
10.Whichofthefollowingstatementsbestdescribestheadvantagesofneworalanticoagulantscomparedwithwarfarin?a. Easilyreversiblewithavailableantidotesb. Straightforward dosing with no routine monitoring
www.pharmacist.com JANUARY 2011 • PHARMACY TODAY 39
Medication safety will be the central thread in this year’s Counseling
Corner, with each installment summa-rizing 10 safety tips related to the issue focus. Here is important safety informa-tion for pharmacists and patients for a variety of cardiac conditions.
1. The silent killersUnlike acute infections, hypertension and dyslipidemia are generally associated with minimal or no symptoms in their early stages. Patients may be reluctant to take prescribed therapies as a result. In addition, adverse effects of medications can create reasons not to take drugs.
Patients need to be educated about the seriousness of these conditions, especially if left untreated, and the importance of adhering to prescribed medications. Tell patients these condi-tions are sometimes known as “silent killers” because they may not have any early symptoms but over time can lead to serious events such as heart attacks, strokes, and even sudden death.
2. Medication duplicationPatients are often discharged from the hospital with prescriptions for medica-tions that differ from those they had prior to admission. A major concern is patients who obtain new medications and continue to take previous therapies, including some overlapping or duplicate ones. Actively screen drug profiles to identify medi-cations in the same class and educate patients about the danger of therapeutic duplication. Many cardiac medications are available generically, so patients can be told to look for common endings (e.g., -pril, -sartan, -statin) to help them identify drugs from the same class.
3. Prevent QT prolongationMany cardiac and noncardiac medica-tions affect the QT interval, which can lead to serious and sometimes fatal arrhythmias. This risk increases when more than one offending drug is taken concurrently. Pharmacists need to have
a clear understanding of which medica-tions prolong the QT interval and their associated arrhythmic potential. QT drug lists can be obtained at www.azcert.org, and patient information is also available on this site. Patients should be educated about QT prolongation and the symptoms of arrhythmias, such as fast heartbeat, dizziness, fainting, shortness of breath, and/or sweating.
4. Avoid fallsCounseling patients on fall prevention tips is needed, as many patients taking cardiac medications are older, and some of these therapies (e.g., diuretics, alpha blockers) can increase the risk of falling. Some fall prevention tips for patients include telling them to get out of bed slowly and wear skid-proof slippers or shoes and encouraging them to ask for assistance when needed.
5. Contact 911 soonerMany clinicians continue to instruct patients to take three tablets of sublin-gual nitroglycerin (NTG), each 5 minutes apart, for relief of chest pain and then to call 911 if pain does not improve. In 2007, the American College of Cardiol-ogy/American Heart Association guide-lines for management of unstable angina/non–ST segment elevation myocardial infarction recommended that patients should be instructed to take one NTG tablet and then call emergency services if chest discomfort/pain is unimproved or worsening.
When dispensing NTG, pharmacists should educate patients about the proper use of NTG and ensure that they under-stand when to call for help. The use of up to three NTG tablets is still recom-mended for patients who have significant improvement after the first dose.
6. Anticoagulation pearlsPatients taking anticoagulation therapy need to be aware of numerous safety considerations. Key counseling pearls for these patients include educating them
counselingcorner
about their increased risk of bleeding and signs of symptoms of serious bleeding, encouraging them to let all prescribers know they are receiving anticoagulation, and reinforcing the importance of being adherent with routine monitoring visits and consistent in dietary intake.
7. No grapefruit for youCardiac medications such as certain statins (e.g., atorvastatin [Lipitor—Pfizer], lovastatin, simvastatin) and calcium channel blockers (e.g., felo-dipine, verapamil) interact with grape-fruit. The metabolism of these agents is decreased resulting in greater exposure and the potential for adverse effects. Patients should be told to avoid consum-ing grapefruit or grapefruit juice while taking these therapies.
8. OTC cold products to avoidDecongestants can elevate blood pres-sure and may cause serious problems in patients with underlying cardiac conditions. Pharmacists need to direct patients to OTC cold preparations that are safe to use and tell them which ingre-dients should be avoided.
9. Analgesic selectionNSAIDs cause fluid retention, and all of the agents in this class carry a boxed warning for cardiovascular risks. Edu-cate patients about the risks associated with NSAIDs and recommend alternative analgesics such as acetaminophen when appropriate.
10. Herbal unknownsThe safety of many herbal products remains unknown. These agents are minimally regulated by FDA, and many have not undergone scientific testing. Some herbal products are known to increase the risk of bleeding (e.g., gingko biloba) and others are known to elevate blood pressure (e.g., licorice). Patients should be counseled on the risks asso-ciated with using herbal products and told to discuss the desired use of these products with their pharmacist and other health care providers.
—Maria G. Tanzi, PharmD
Ten tips for counseling about cardiology medications
ISSUE FOCUS: CARDIOLOGY
46 PHARMACY TODAY • JANUARY 2011 www.pharmacytoday.org
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News from AHA’s Scientific SessionsLatest research includes vitamin D, omega-3, eplerenoneHoping to stem the tide of cardiovas-cular-related illness, researchers and health professionals from more than 100 countries met in November for the American Heart Association (AHA) 2010 Scientific Sessions in Chicago.
Their task is daunting. Heart dis-ease and stroke represent the first and fourth leading causes of death in the United States, respectively. These conditions devastate the body and frequently leave patients with serious physical or mental disabilities. The message from the meeting is clear: Improving the world’s cardiovascular health will require a concerted effort from all sectors of health care, and pharmacists must be on the front line of the battle against cardiovascular disease.
Back to basicsWhile advances in pharmaceuticals, improvements in surgical technique, and refinement of clinical practice are positive steps in treating cardiovas-cular disease, AHA President Ralph Sacco, MD, emphasized the importance of seven basic indicators and behaviors that represent ideal cardiovascular health.
AHA calls these “life’s simple seven”: pursuing ideal levels of cholesterol, blood glucose, and blood pressure; avoiding smoking; and maintaining appropriate weight, physical activity, and diet.
“These factors are not new, but our approach is,” Sacco said in his presiden-tial address. “We’re not only urging the avoidance of risk factors; in fact, we’re calling them ‘health factors,’ not risk factors. It may seem like semantics, but we believe that will motivate people to understand and embrace the benefits of healthy living.”
Sacco emphasized that not all risk factors and behaviors can be controlled,
however. Age is a key nonmodifiable risk factor. The projected increase in the elderly population, for example, will present serious challenges for health professionals in the very near future. The U.S. population older than 65 years is expected to grow from 13% in 2010 to 19% by 2030, and by 2050, nearly 4.5% of Americans will be older than 85, Sacco said.
“Without prevention now, managing cardiovascular diseases and stroke will be an enormous challenge in this aging society,” Sacco said.
Pharmacists must be involvedPharmacists must also pay special atten-tion to America’s growing racial and ethnic diversity, as there are already alarming health disparities in certain populations. Latino and Hispanic popu-lations, for example, have statistically higher rates of elevated blood cholesterol and diabetes and are less likely to engage in regular physical activity, according to AHA’s Heart Facts 2010.
Active involvement of pharmacists is critical to efforts to curb cardiovascular disease–related illness and death. Stud-ies such as the Asheville Project have demonstrated that pharmacists provid-ing careful and well-planned patient care services play an important role in improving patient health, reducing health care costs, and increasing work-force productivity.
In one study presented at the AHA Scientific Sessions, Amy M. Franks, PharmD, Assistant Professor at the College of Pharmacy of the University of Arkansas for Medical Sciences, and colleagues demonstrated that phar-macists are critical in intercepting and addressing risk factors before the onset of chronic disease.
In the program studied, pharmacists
heartdiseaseupdate
and student pharmacists conducted indi-vidual education sessions on metabolic syndrome, which has numerous risk fac-tors for coronary heart disease, includ-ing excessive abdominal fat, athero-genic dyslipidemia, insulin resistance, and elevated blood pressure, with 112 patients. Franks and colleagues found that about 30% of patients initially had
metabolic syndrome. When the patients returned 4 months later, after meeting with pharmacists, only 18% met the cri-teria for metabolic syndrome, and many of the participants had significantly reduced their total cholesterol and blood pressure.
Findings like these indicate that pharmacists must not only ensure that medications and treatments are adminis-tered properly, but also reinforce during consultation the importance of healthy living for those patients at risk for heart disease and stroke. Doing so will, ideally, reduce rates of cardiovascular disease now and in the future.
Rethinking vitamin DResearchers using data from the Third National Health and Nutrition Examina-tion Survey of Americans (NHANES-III) conducted between 1988 and 1994 reported at the AHA Scientific Sessions that, contrary to what was expected, vita-min D deficiency does not increase stroke risk among blacks.
Researchers analyzed the health records of a nationally representative group of 7,981 black and white adults. They found that white adults with defi-cient vitamin D levels were twice as likely to die from stroke compared with white patients with higher vita-min D levels. The researchers did not, however, find the same relationship between fatal stroke and vitamin D defi-ciency among black adults. This news came as a surprise to many, because previous studies have indicated that black patients are more likely to have low levels of vitamin D and to suffer strokes.
“We thought … lower vitamin D
ISSUE FOCUS: CARDIOLOGY
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levels might actually explain why black [patients] have higher risks for stroke,” lead researcher Erin Michos, MD, MHS, Assistant Professor of Medicine at Johns Hopkins University School of Medicine, told attendees.
It is possible that black patients have a natural resistance to the negative effects of low vitamin D levels, as there is also a lower frequency of bone fractures in this patient population despite higher prevalence of vitamin D deficiency, Michos said. She added, however, that clinical trials are needed to determine whether treating vitamin D deficiency will help lower stroke risks.
“Since stroke is the number three cause of death in the United States, it’s important for us to consider low vitamin D as a possible risk factor for stroke, at least among white [patients],” Michos said. (Editor’s note: CDC announced in December that stroke has dropped to the number 4 cause of mortality in the United States.)
Atrial fibrillation: ROCKET and prescription omega-3The new anticlotting drug rivaroxa-ban (Bayer) is comparable to warfa-rin in preventing stroke and non–central nervous system embolic events for patients with atrial fibrillation (AF), researchers reported at the AHA Scien-tific Sessions. In ROCKET AF (Stroke Prevention Using the Oral Direct Factor Xa Inhibi-tor Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation), investigators compared rivar-oxaban with warfarin in 14,264 patients with AF. Both drugs are designed to prevent dangerous blood clots by blocking the action of vitamin K–dependent proteins, but rivaroxaban targets factor Xa, a spe-cific clotting factor.
ROCKET AF investigators deter-mined that patients taking rivaroxaban experienced fewer strokes and blood clots, but the difference was not statisti-cally significant to declare the drug supe-rior to warfarin. The frequency of major bleeding complications was comparable in both patient groups.
“Patients and clinicians have been looking for an alternative [to warfarin] for a long time, and the investigation of
oral factor Xa inhibitors provided a good opportunity to see if a different class of drugs could be effective,” said study cochair Keith A.A. Fox, MB, ChB, Presi-dent of the British Cardiovascular Society and Professor of Cardiology at the Uni-versity of Edinburgh.
While it is unclear whether rivaroxa-ban would be recommended for those already experiencing benefits from warfarin, researchers emphasized the importance of exploring new treatment options. “The main implication is that we have an alternative to warfarin,” said Robert M. Califf, MD, Vice Chancellor for Clinical Research at Duke University School of Medicine and one of the prin-cipal ROCKET AF researchers. “Equally important, there was no increase in bleeding, so we have a drug you can take once a day, without monitoring, that is at least as good as warfarin and carries no additional risk.”
Another study related to AF presented at the AHA Scientific Sessions yielded some surprising results. Researchers conducted a prospective, randomized, double-blind trial of 663 patients, com-paring 4 g/d fish oil–derived omega-3 fatty acids with placebo in patients with paroxysmal AF. Their findings suggested that patients who received omega-3 didn’t experience a significant difference from the placebo group in time to first recurrence of symptoms.
A diet rich in omega-3 fatty acids is beneficial for patients with heart failure
and heart attack and is associated with reduced risk of sudden death and death from coronary artery disease. This study, however, did not investigate omega-3 ingested from fish, but rather a product manufactured from fish oil.
“The trial’s major implication is that using prescription omega-3 in the vast majority of paroxysmal atrial fibrillation patients who do not have significant heart disease is fruitless,” said study author Peter R. Kowey, MD, Chief of Cardiology at Main Line Health Hospital System.
DEFINE drug shows promiseThe experimental drug anacetrapib, a cholesterylester transfer protein (CETP) inhibitor, has showed prom-ise as a method of reducing LDL cho-lesterol and boosting HDL levels. The drug acts by blocking the ability of the CETP enzyme to transfer cholesterol particles from HDL to LDL. In DEFINE (Determining the Efficacy and Toler-ability of CETP Inhibition with Anace-
trapib), a randomized, double-blind study of 1,623 patients, researchers saw a 40% drop in LDL cholesterol from 81 to 45 mg/dL and a more than twofold increase in HDL from 41 to 101 mg/dL (see Figure 1).
“These changes are striking because virtually all the patients in the study were already taking cholesterol-lowering drugs and
achieved previously unattainable levels of good and bad cholesterol,”
lead author Christopher P. Cannon, MD, Associate Professor of Medicine at Harvard Medical School and Asso-ciate Physician in the Brigham and Women’s Hospital Cardiovascular Division, said at the AHA Scientific Sessions.
In DEFINE, Cannon and col-leagues found no change in levels
of aldosterone, which affects kidney function and blood pressure. Addition-ally, they found no increases in muscle problems or liver abnormalities, adverse effects associated with some statins.
While the implications of anace-trapib for cardiovascular treatment are clear, the DEFINE study was not designed or powered to assess the effects of the drug on cardiovascular events. A full efficacy and safety evalua-tion will require a larger, Phase III trial. Researchers did, however, observe fewer cardiovascular events in the
heartdiseaseupdate
48 PHARMACY TODAY • JANUARY 2011 www.pharmacytoday.org
heartdiseaseupdate
anacetrapib group than in the statin-only group, and Cannon is optimistic about the future of the drug.
“This agent provides us a very strong add-on treatment to statins,” he said. “If the cardiovascular effects are borne out by future research, it would be a very promising approach to reducing cardio-vascular events in patients with or prone to atherosclerosis.”
ASSERT needs more researchResults were not as strong for RVX-208 (Resverlogix), a new drug designed to raise levels of apolipoprotein A-I (apoA-I), the primary cholesterol transport protein associated with HDL cholesterol. Researchers hoped an increase in apoA-I might help clear plaque from arteries, but the drug did not cause a significant change in apoA-I levels compared with placebo in ASSERT (ApoA-I Synthesis Stimula-tion Evaluation in Patients Requiring Treatment for Coronary Artery Dis-ease), a randomized, double-blind trial in 299 patients with coronary artery disease already taking a cholesterol-lowering drug.
“The study may not have had enough
patients to answer its primary question about apoA-I,” said lead author Stephen J. Nicholls, PhD, Assistant Professor of Molecular Medicine at the Lerner College of Medicine at Case Western Reserve Uni-versity.
While the ASSERT researchers found no significant increase in apoA-I, they reached a secondary finding indicating that RVX-208 did cause a statistically significant increase in blood levels of HDL cholesterol and the largest HDL particles.
“There’s a lot of interest in develop-ing new ways to raise HDL, but we don’t know the best way to do it,” Nicholls said. “One avenue that has been of particular interest for decades is to ask if we could just turn on apoA-I. We think these find-ings suggest that the drug is turning on apoA-I production, resulting in lipid changes that are consistent with more cholesterol transport out of the vessel wall.”
No renal protection with acetylcysteineContrast dye used during coronary arteriograms and angiography proce-dures may adversely affect renal func-tion, especially in elderly patients with
renal failure, congestive heart failure or diabetes. Previous small-scale stud-ies have found mixed results regarding the benefits of acetylcysteine in the minimization of radiocontrast-induced nephropathy.
In ACT (Acetylcysteine for the Pre-vention of Contrast-Induced Neuropa-thy), a trial presented at the AHA Sci-entific Sessions, however, researchers found that acetylcysteine did not pro-tect kidneys from the adverse effects of contrast dye. Researchers randomly assigned 2,308 patients from 46 cen-ters in Brazil to receive acetylcysteine or placebo before and after a cardiac x-ray procedure.
Researchers looked for signs of contrast-induced kidney damage, the third leading cause of kidney failure in hospitals in the United States. Approxi-mately 75% of patients were given a low-osmolar dye, which is more pro-tective for the kidneys; iso-osmolar dye was used in approximately 3% of patients. Patients who received acetyl-cysteine had the same incidence of kid-ney damage (13%) as those who took a placebo.
“The heart and kidneys are con-nected,” said lead author Otavio Ber-
Figure 1. Changes in LDL and HDL cholesterol during 18 months of anacetrapib therapy in 1,623 patients in the DEFINE study.Source: American Heart Association. News release: New drug significantly raises good cholesterol, cuts bad nearly in half. Accessed online at www.newsroom.heart.org/index.php?s=43&item=1201, December 22, 2010.
mg/
dL
www.pharmacist.com JANUARY 2011 • PHARMACY TODAY 49
heartdiseaseupdate
wanger, MD, PhD, Director of the Research Institute at the Hospital do Coração in São Paulo, Brazil. “Some patients need this type of exam to diag-nose if they need revascularization, but it’s not good enough to fix the heart if it harms the kidneys.”
Because acetylcysteine failed to pro-tect patients from renal damage, the next step is to find a contrast dye that is less renally toxic or another drug that can protect patients from the dye, according to Berwanger.
“A lot of research needs to be done,” Berwanger said. “We have different types of contrast, and the newer types claim to be less toxic to the kidney. But we don’t know which new one to choose. We need to use contrast, so we need to give patients the best and safest.”
This group of researchers will next explore whether saline and bicarbonate are more effective in renoprotection. “The ACT II trial is already in the planning phase,” Berwanger said. “We’re compar-ing bicarbonate to normal saline and com-paring different types of contrast.”
No benefit from high-dose clopidogrelFor high-risk patients, high doses of the anticlotting drug clopidogrel are no better than a standard dose in reduc-ing incidence of death, heart attack, or blood clots, according to researchers from the GRAVITAS (Gauging Respon-siveness with a VerifyNow Assay—Impact on Thrombosis and Safety) trial.
Earlier studies have shown that clopidogrel is useful in patients who have received a stent to prop open a blocked artery. Some patients, however, have high residual platelet reactivity, meaning that their blood is still prone to clotting despite the administration of anticlotting medications.
In the 6-month GRAVITAS trial, researchers randomized 2,214 patients with high residual platelet activity to either 150 mg/d clopidogrel or 75 mg/d clopidogrel and an inactive placebo. The rate of death from cardiovascular causes at 6 months in patients taking high doses of clopidogrel was identical to that in the lower dose group.
“Many physicians have been using a high dose of clopidogrel as a default strategy in patients who are nonrespon-sive to the drug,” said lead investigator
Matthew J. Price, MD, Director of the Cardiac Catheterization Laboratory at the Scripps Clinic and Assistant Profes-sor at the Scripps Translational Science Institute. “The high dose of clopidogrel doesn’t appear to improve outcomes, so alternative treatment strategies should be tested.”
While the increased dose of clopi-dogrel did not cut the risk of dangerous cardiovascular events, the GRAVITAS researchers found that higher doses did not cause additional bleeding, and patients did not suffer harm from the additional dose. Price also said that he hopes this method of highly personal-ized research will gain favor in the medi-cal community.
“Traditional trials seek the best treatment for the average patient,” Price noted. “GRAVITAS is using a personal-ized approach, which seeks to identify the best treatment for a particular
individual. This is a paradigm-shifting approach for evidence-based medicine.”
Eplerenone improves survival after heart failureThe aldosterone receptor antagonist eplerenone reduced the combined risk of death and hospitalization by 37% in patients with mild heart failure and mild symptoms, researchers reported at the AHA sessions. In EMPHASIS-HF (Eplerenone in Mild Patients Hospi-talization and Survival Study in Heart Failure), 2,737 patients with mild heart failure were randomized to receive 20 to 50 mg eplerenone or placebo in addi-tion to standard heart failure therapy. There were 249 deaths from cardio-vascular causes or hospitalizations for heart failure among patients taking eplerenone, compared with 356 in the placebo group.
Eplerenone works by blocking the action of aldosterone, a naturally occur-ring hormone that can cause serious harm to the cardiovascular system. Aldosterone concentrations are typi-cally high in people with heart failure, but current treatment guidelines recom-mend aldosterone antagonists only for patients with moderate to severe heart failure and reduced heart function or for patients with heart failure following a heart attack.
“This treatment is certainly going to change the guidelines for mild heart failure,” said lead author Faiez Zannad, MD, PhD, Professor of Therapeutics and Director of the Clinical Investigation Center at the Nancy University Hospital Center in Nancy, France. “Now patients with all kinds of severity of systolic heart failure, whether it is post–myocardial infarction [or] with mild or severe symp-toms, are potentially eligible for some kind of aldosterone blockade, and, cer-tainly, for eplerenone.”
In addition to reducing the risk of heart failure hospitalization and cardio-vascular death, eplerenone decreased the rate of other complications. The drug reduced the number of deaths due to any cause and hospitalizations for any rea-son by one-third, Zannad said. “What was impressive was that we also hit all the secondary endpoints, including mortality from all causes,” he said.
—James Hataway, MAContributing writer
Moving forward in the fight against strokeRecent news from the National Center for Health Statistics sug-gests that health professionals have made positive steps in the fight against stroke. In a December 9 report, stroke was officially moved from the third leading cause of death in the United States to the fourth. The change in ranks is driven mostly by a decrease in the numbers of deaths from stroke, from 167,661 in 2000 to 133,750 in 2008, but also by an increase in the number of deaths from chronic lower respiratory diseases (CLRD).
CLRD’s new place as the third leading cause of death must be interpreted with caution, however, researchers warned. The World Health Organization recently changed the way CLRDs are coded and classified, which may have contributed to the increase in recorded CLRD deaths.
Nevertheless, the reduction in the number of stroke-related deaths should serve as a reminder that positive steps are being made in the fight against cardiovascular and cerebrovascular disease.
www.pharmacytoday.org58 PHARMACY TODAY • JANUARY 2011
REVIEWS
Anticoagulant therapies: Review of available and upcoming agentsMaria G. Tanzi
Maria G. Tanzi, PharmD, is Clinical Assistant Professor, Department of Pharmacy Prac-tice, College of Pharmacy, University of Illi-nois at Chicago.
Correspondence: Maria G. Tanzi, PharmD, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., Room B12, Chicago, IL 60612-7230. Fax: 312-996-0448. E-mail [email protected]
Disclosure: The author declares no con-flicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria.
Abstract
Objectives: To identify clinical issues with warfarin therapy, differentiate be-tween unfractionated heparin (UFH) and low–molecular weight heparin (LMWH) and their respective advantages and disadvantages, explain the place in therapy for indi-rect and direct factor Xa inhibitors and direct thrombin inhibitors, and describe the role new oral anticoagulants will have in the future of anticoagulation therapy.
Data sources: PubMed was searched using the following terms: warfarin, un-fractionated heparin, low molecular weight heparin, factor Xa inhibitors, direct thrombin inhibitors, and new oral anticoagulants. Limits on publication dates were not applied.
Data synthesis: In recent years, major advances have occurred in the field of anticoagulation, with new data emerging related to pharmacogenomic issues and warfarin dosing, the expanded use of LMWHs, approval of the first oral direct throm-bin inhibitor, and a robust pipeline with more oral agents expected to be available in the coming years. Information related to these topics is reviewed with an empha-sis on practical considerations to help the pharmacist understand the specific place in therapy of these anticoagulation agents. Agents within a class and comparisons across the various classes were performed as appropriate. In addition, an expanded discussion on two oral agents in the pipeline, rivaroxaban and apixaban, is included.
Conclusion: Many issues need to be considered when initiating and maintain-ing a patient on anticoagulation therapy. Newer agents in the pipeline have been designed to reduce complex dosing regimens and have minimal monitoring require-ments. These agents are poised to have a substantial impact on the future of antico-agulation therapy.
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AGENTS FOR ANTICOAGULANT THERAPY REVIEWS
Assess your knowledgeTake a moment to assess your current knowledge by reviewing the case study and answering the following questions. The answers to case study questions appear later in the article.
P.S. is a 65-year-old man with a history of atrial fibrillation (AF) cur-rently on warfarin therapy for the prevention of stroke. He had been nonadherent with his international normalized ratio (INR) monitoring visits, and when he does come to clinic, his INR is not at goal because of a sporadic diet with varying amounts of vitamin K.1. Which medication may be a good alternative to warfarin for P.S. at
this time?2. How would you initiate this medication?
Anticoagulation therapy was much simpler in years past, with clinicians primarily treating patients with unfrac-tionated heparin (UFH) for acute thrombosis and/or
warfarin for long-term treatment.1 However, in recent years, this area has expanded to include a variety of other agents, such as low–molecular weight heparins (LMWHs), factor Xa inhibitors, and parenteral and oral direct thrombin inhibitors. These medications work at various points in the anticoagula-tion cascade1 and are used for different indications. This review will highlight the key nuances for these various agents to help pharmacists understand their specific place in therapy and any special dosing, monitoring, and safety considerations. In addi-tion, the anticoagulation pipeline is filled with agents that are currently in Phase II and III clinical trials and poised to reach the market in the coming years; a brief review of the efficacy and safety of these agents will also be presented. Antiplatelet therapies and fibrinolytics are beyond the scope of this review.
ObjectivesThe current work seeks to identify clinical issues with warfa-rin therapy, differentiate between UFH and LMWH and their respective advantages and disadvantages, explain the place in therapy for indirect and direct factor Xa inhibitors and direct thrombin inhibitors, and describe the role new oral anticoagu-lants will have in the future of anticoagulation therapy.
Vitamin K antagonists: Focusing on warfarinWarfarin, a vitamin K antagonist, has been the main oral anti-coagulant used in the United States for more than half a century to treat a variety of conditions, including primary and second-ary prevention of venous thromboembolism (VTE), prevention of systemic VTE in patients with atrial fibrillation (AF) or pros-thetic heart valves, prevention of thromboembolic stroke, and primary and secondary prevention of acute myocardial infarc-tion (MI).1 This agent works by inhibiting the liver enzyme epox-ide reductase, which results in inhibition of four vitamin K–de-pendent clotting factors (II, VII, IX, and X), as well as proteins C and S.1,2 The full therapeutic effect of warfarin is attained after a few days because of the extended half-life of some of the clot-ting factors. Because protein C and S are inhibited more rapidly and may lead to a procoagulant state, patients must be initi-ated on a parenteral anticoagulant, generally UFH or LMWH, for a few days until warfarin reaches its therapeutic effect.1
The primary problem with warfarin is that it is challenging
to dose and monitor because of its narrow therapeutic index; interindividual variability in patient response; dietary (i.e., foods with vitamin K), drug, and disease interactions; and po-tentially serious adverse effects such as hemorrhage.2 Warfa-rin is monitored using the international normalized ratio (INR), which is a standardized prothrombin time used to measure the level of anticoagulation, with an INR between 2.0 and 3.0 be-ing the goal for most patients. Patients with mechanical heart values require higher INRs between 2.5 and 3.5. Because of all the factors affecting warfarin dosing, frequent INR follow-up is required and several dose adjustments often are needed.1 In recent years, FDA has updated warfarin’s labeling to highlight how pharmacogenomic differences can affect the initial dos-ing of warfarin.3 Specifically, single nucleotide polymorphisms in the cytochrome P450 (CYP) complex 2C9 can affect war-farin’s metabolism. Patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated INR. In addition, patients with single polymorphisms in vitamin K epoxide reductase (VKORC1) may be more sensitive to warfarin therapy and require lower doses. Estimates indicate that 30% of warfarin’s dose variation re-sults from variants of both VKORC1 and CYP2C9.2
Dosing algorithms incorporating clinical, demographic, and genetic information have been developed to help select a starting warfarin dose; however, the most recent antithrom-botic guidelines from 2008 recommend starting most patients on doses between 5 and 10 mg for the first 1 to 2 days, with subsequent dosing based on INR.4,5 Lower starting doses (≤5 mg) are recommended for patients who are elderly, debili-tated, malnourished, or have certain comorbidities or taking interacting medications (e.g., amiodarone).5 The guidelines specifically recommend against the use of pharmacogenetic-based initial dosing of warfarin. For follow-up, monitoring of INRs is recommended at least once every 4 weeks, and ele-vated INRs can be managed by omitting doses of warfarin or giving vitamin K. Anticoagulation services, with many staffed by pharmacists, have traditionally monitored INRs, but some patients have are self-monitoring and self-adjusting their war-farin therapy using guided dosing algorithms at home.5,6
Heparins
UFH versus LMWHsBoth UFH and LMWH are indirect thrombin inhibitors derived from biologic sources; however, these agents have key pharma-cologic differences.1 LMWHs are derived from heparin and, in a simplistic sense, are smaller fragments of the same drug. UFH exerts its anticoagulant effect via a plasma cofactor, antithrom-bin, inhibiting thrombin (factor IIa) and factor Xa in a one-to-one ratio. Unfortunately, UFH also binds to a variety of plasma and cellular proteins, resulting in decreased bioavailability and variable patient response. Therefore, frequent monitoring of the activated partial thromboplastin time (aPTT) is required and dosage adjustments are needed to ensure that adequate antico-agulation is achieved. In contrast, LMWH has enhanced affinity for factor Xa compared with factor IIa and has less binding to
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plasma and cellular proteins. These differences result in greater bioavailability and a more predictable anticoagulant response compared with UFH, and routine monitoring of its anticoagulant effect via anti-Xa levels generally is not recommended except for special patient groups.1,5,7 Some experts have suggested that the anticoagulant effects of LMWH should be monitored in patients with morbid obesity (weight > 190 kg), those with severe renal impairment, and those with moderate renal impairment on pro-longed therapy (>10 days).7 The current antithrombotic guide-lines recommend monitoring anti-Xa levels in pregnant women who require therapeutic doses of LMWH.5
At lower doses, UFH and LMWH have been used for prevent-ing VTE, and at higher doeses, they have been used for treating VTE and pulmonary embolism and treating patients with acute myocardial ischemia.1,2,8 UFH is primarily given intravenously to hospitalized patients but also can be given subcutaneously (two to three times daily), whereas LMWHs are primarily adminis-tered once- or twice-daily subcutaneously.1 The half-life of UFH is very short (i.e., 1 hour) compared with that of LMWH (i.e., 4 hours), and the antidote protamine sulfate is completely effec-tive at reversing the effects of UFH but only partially effective for LMWHs.1,8 Other differences include a lower incidence of osteo-penia and heparin-induced thrombocytopenia (HIT) with LMWH, but these agents are associated with a higher acquisition cost, have less data in special populations, and must be dose adjusted in patients with renal impairment.1 Key differences between UFH and LMWH are summarized in Table 1.
The FDA-approved LMWH agents are dalteparin (Frag-min—Eisai; Pfizer), enoxaparin (Lovenox—sanofi-aventis), and tinzaparin (Innohep—Leo), and these agents vary with respect to their labeled indications (Table 2).9 Enoxaparin has more la-beled indications and has been studied more extensively than the other two agents. Tinzaparin has the least amount of available data and is only indicated for treatment of deep-vein thrombosis (DVT) with or without pulmonary embolism. These three agents are not interchangeable (unit for unit), and all have a boxed warning for spinal/epidural hematomas if given to patients who are receiving neuraxial anesthesia or spinal puncture. Until recently, none of these agents were available generically; how-ever, in July 2010, FDA approved a generic version of enoxapa-rin by Sandoz.10 Before approval, FDA received a citizen’s pe-tition questioning the approval criteria for enoxaparin because
it is a biologic product with a complex manufacturing process. FDA responded by releasing a detailed document summarizing the steps Sandoz had to go through to obtain approval of its AP-rated, bioequivalent enoxaparin product.11 These steps included showing documentation of equivalence of the following: heparin source material and mode of depolymerization, physiochemical properties, biological and biochemical assays, and in vivo phar-macodynamic profile.
Factor Xa inhibitors
IndirectFondaparinux (Arixtra—GlaxoSmithKline) is the only available indirect factor Xa inhibitor currently on the market.1 It exerts its mechanism of action by binding to antithrombin with high affinity, causing a permanent conformational change and thus increasing the rate of factor Xa inhibition. Fondaparinux is in-dicated for the prophylaxis of DVT in patients undergoing hip fracture surgery, hip replacement surgery, knee replacement surgery, and abdominal surgery who are at risk for thrombo-embolic complications.12 It is also indicated for treating acute DVT and pulmonary embolism, in conjunction with warfarin. Fondaparinux differs from UFH and LMWH in that it is a syn-thetic version of the five-sugar sequence of heparin and thus
Table 1. Comparison of UFH with LMWHs1,8
UFH LMWHsMolecular weight 15,000 5,000Bioavailability 30% 90%Half-life 1 hour 4 hoursRenal excretion No YesRoute of adminis-tration
Table 2. FDA-approved indications of available low-molecular weight heparins9
Condition Dalteparin Enoxaparin TinzaparinProphylaxis of DVT that may lead to PE: Abdominal surgery √ √Hip replacement surgery √ √Knee replacement surgery √In patients with severely restricted mobility during acute illness √ √
Treatment of DVT with or without PE √ √Prophylaxis of ischemic complications in unstable angina and non–Q-wave MI √ √Acute STEMI √Extended treatment of symptomatic VTE in cancer patients to reduce recurrence √Abbreviations used: DVT, deep-vein thrombosis; MI, myocardial infarction; PE, pulmonary embolism; STEMI, ST-elevation myocardial infarction; VTE, venous thromboembolism.
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referred to as a pentasaccharide.1 Because it is a synthetic product, fondaparinux offers the advantages of no risk of ani-mal pathogen transmission, batch-to-batch consistency, and unlimited sourcing materials. Other favorable attributes of fondaparinux include its long half-life (17–21 hours), allowing for once-daily administration (subcutaneously) and a predict-able anticoagulant effect; therefore, routine monitoring and dosage adjustments are not required. In addition, fondaparinux does not affect platelet function or appear to react with hepa-rin/platelet factor 4 antibodies, so it has emerged as a favor-able treatment option for use in patients with a history of HIT.
Clinical concerns with fondaparinux include the current lack of an antidote; thus, its anticoagulant effect cannot be reversed easily in patients who have uncontrolled bleeding or require urgent surgery.1 In addition, it is renally eliminated and therefore contraindicated in patients with severe renal impair-ment (defined as creatinine clearance [CrCl] <30 mL/min).12 Fondaparinux also is contraindicated in patients who weigh less than 50 kg, when used for thromboembolism prophylaxis, because of the increased risk of bleeding that occurs in this patient population.
Other indirect factor Xa inhibitors have been devel-oped, such as idraparinux (sanofi-aventis) and biotinyl-ated idraparinux (idrabiotaparinux—sanofi-aventis).13,14 Idraparinux is a hypermethylated derivative of fondaparinux with a plasma half-life of 80 hours, allowing for once-weekly subcutaneous administration. Numerous clinical trials were conducted with idraparinux for treatment of DVT and pulmo-nary embolism and for prevention of thromboembolism in pa-tients with AF.13,15 Although shown to be effective compared with warfarin for some of these indications (DVT and AF), this agent was associated with more major bleeding events, in-cluding fatal intracranial bleeding when given for more than 6 months. Based on these data, sanofi-aventis halted the de-velopment of this compound and switched its focus to idrab-iotaparinux.16,17 This compound has an attached biotin moiety that allows its affects to be rapidly neutralized by avidin, an intravenously administered egg-derived protein with low anti-genicity. Currently, idrabiotaparinux, given as a 3.5-mg once-weekly subcutaneous injection, is being investigated for pre-vention of recurrent events in patients with acute VTE and AF. The fate of this compound will depend on the safety and efficacy data from these trials, as well as the safety and efficacy of in-travenous avidin to reverse its effects in emergent situations.17
DirectNumerous oral direct factor Xa inhibitors are being developed currently (Table 3). Rivaroxaban (Xarelto—Bayer; Ortho-Mc-Neil Janssen) and apixaban (Pfizer; Bristol-Myers Squibb) are both in Phase III testing and have the most published clinical data to date.18–20
Rivaroxaban is highly bioavailable (60–80%), reaches peak levels within 2 to 3 hours, and has a terminal half-life of 7 to 11 hours.21 It is administered once daily and does not require any special monitoring or ongoing dose adjustments; however, some clinical considerations for this novel agent include dos-
age adjustments for patients with renal impairment and drug interactions with agents that strongly inhibit or induce the CYP3A4 enzyme, as rivaroxaban is a CYP3A4 substrate. In ad-dition, no antidote exists currently to reverse the anticoagulant effect of rivaroxaban.
Rivaroxaban has been studied for prevention of VTE, treat-ment of VTE, and stroke prevention in AF patients; ongoing studies for patients with acute coronary syndromes also are under way.21 For preventing VTE, rivaroxaban 10 mg once dai-ly was compared with enoxaparin, either in hip replacement or knee replacement surgery, in four Phase III clinical trials known as RECORD (Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Em-bolism) 1 through 4.18,19 In RECORD 1, 3, and 4, rivaroxaban 10 mg daily had greater effectiveness compared with enoxapa-rin with respect to the primary endpoint of total VTE, and RE-CORD 2 showed that prolonged administration of rivaroxaban conferred additional clinical benefits compared with short-term enoxaparin therapy.19
Based on the results of these trials, a New Drug Applica-tion for rivaroxaban was submitted to FDA in July 2008, and in March 2009, FDA’s advisory committee agreed by a vote of 15 to 2 that the clinical data for rivaroxaban demonstrated a favorable risk–benefit profile.22 FDA did not approve rivar-oxaban at that time; instead, the agency asked for additional data from completed and ongoing studies, market surveillance data from countries in which rivaroxaban is already approved, and information about the RECORD study sites. Since 2009, results from additional studies such as the EINSTEIN-DVT and ROCKET AF (Rivaroxaban Once Daily Oral Direct Inhibi-tion Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) have been re-leased.23,24 The EINSTEIN-DVT trial showed that rivaroxaban 15 mg twice daily for the first 3 weeks, followed by rivaroxaban 20 mg once daily thereafter, demonstrated noninferiority to the standard of care (i.e., initial enoxaparin treatment followed by an oral vitamin K antagonist) for prevention of recurrent VTE in patients with acute symptomatic DVTs.23 In addition, the two regimens had comparable safety profiles. The ROCKET AF trial showed superiority of rivaroxaban 20 mg for patients with nor-mal renal function or 15 mg daily for patients with moderate renal impairment, compared with dose-adjusted warfarin, in reducing the risk of stroke and non–central nervous system
Table 3. Oral direct factor Xa inhibitors in the pipeline20
Compound name Company PhaseRivaroxaban Bayer, Ortho-
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systemic embolism in patients with AF.24 Rates of bleeding in this trial also were similar to warfarin; however, bleeding events such as intracranial hemorrhage, critical organ bleed, and bleeding-related death occurred more frequently in the warfarin group.
Apixaban is more than 50% bioavailable, reaches peak levels within 3 to 4 hours, and has a terminal half-life of 10 to 14 hours.20 Compared with rivaroxaban, it is administered twice daily but also does not require any special monitoring or ongoing dose adjustments and does not have an antidote to re-verse its effects. It is partially eliminated by the kidneys (25%) and is metabolized in part by the CYP3A4 enzyme. Apixaban is expected to have a low likelihood of drug–drug interactions; however, its safe use in patients with hepatic or renal impair-ment remains to be determined.
Apixaban also has been extensively studied for prevent-ing VTE (ADVANCE 1–3 trials), for treating VTE (AMPLIFY [Apixaban After the Initial Management of Pulmonary Em-bolism and Deep Vein Thrombosis with First-line Therapy]), for stroke prevention in AF patients (ARISTOTLE [Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrilla-tion] and AVERROES [Apixaban Versus Acetylsalicylic Acid to Prevent Strokes]), and for patients with acute coronary syndromes (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events 2]).20 The three ADVANCE trials evaluated the efficacy of apixaban 2.5 mg twice daily compared with enoxa-parin in patients undergoing major orthopedic surgery. In AD-VANCE-1, the predetermined noninferiority endpoint was not met for apixaban20; however, a recent combined analysis of data from the ADVANCE-2 and -3 trials showed that apixaban was more effective than enoxaparin in preventing major VTE without increasing the rate of bleeding.25
As of December 2010, the results of the AMPLIFY and AR-ISTOTLE trials have not been released; however, both AVER-ROES and APPRAISE-2 were terminated earlier that year for different reasons.26,27 In June 2010, AVERROES was halted early because a predefined interim analysis revealed clear evidence of a clinically important reduction in stroke and sys-temic embolism in patients with AF considered intolerant of or unsuitable for warfarin who received apixaban 5 mg twice
daily compared with aspirin 81 to 324 mg once daily.26 In No-vember 2010, APPRAISE-2 was halted early because of an increased risk of bleeding among patients with acute coro-nary syndromes randomized to apixaban 5 mg twice daily in addition to mono- or dual-antiplatelet therapy compared with those given placebo plus antiplatelet therapy.27
Direct thrombin inhibitorsDirect thrombin inhibitors bind directly to thrombin; thereby inhibiting its activity.1 Advantages of these agents include their ability to inactivate clot-bound thrombin and an absence of plasma protein and platelet interactions, which can lead to complications such as HIT. Currently, four parenterally ad-ministered (one subcutaneous and three intravenous) and one oral direct thrombin inhibitor are available on the market.9,28
ParenteralDesirudin (Iprivask—Canyon) is the only fixed-dose direct thrombin inhibitor administered subcutaneously and is indi-cated for the prophylaxis of DVT, which may lead to pulmonary embolism, in patients undergoing hip replacement surgery.9 The agent recently became commercially available for use in the United States (March 2010) and offers clinicians an al-ternative to UFH or LMWH for preventing DVT, especially for patients at risk for HIT.29 In two head-to-head clinical trials, one with UFH and one with LMWH, desirudin was shown to be superior to these agents for preventing proximal DVT and for major VTE events after elective hip surgery. The drug must be renally dose adjusted and is monitored using aPTT.9
Lepirudin (Refludan—Hoechst-Marion Roussel), bivaliru-din (Angiomax—Medicines Company), and argatroban (Glax-oSmithKline) are administered intravenously, and all have a relatively short half-life. Lepirudin’s half-life is approximately 80 minutes, and the agent is used primarily as an anticoagulant in patients with HIT and associated thromboembolic disease to prevent further thromboembolic complications.1,9 Dosages of lepirudin are adjusted according to a patient’s renal func-tion and the aPTT ratio, with a target aPTT ratio of 1.5 to 2.5. Argatroban has a half-life of 40 to 50 minutes and is approved as an anticoagulant for patients with HIT and those with or at
Table 4. Dabigatran dosing considerations28
Converting from warfarin Discontinue warfarin and start dabigatran once INR <2.0Converting to warfarin CrCl >50 mL/min: start warfarin 3 days before stopping dabigatran
CrCl 31–50 mL/min: start warfarin 2 days before stopping dabigatran CrCl 15–30 mL/min: start warfarin 1 day before stopping dabigatran CrCl <15 mL/min: no recommendations can be made
Converting to parenteral anticoagulation
Wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of dabigatran before starting parenteral anticoagulation
Converting from parenteral anticoagulation
Start dabigatran 0 to 2 hours before the time that the next dose of parenteral drug was to be given or at the time of discontinuation of a continuously administered parenteral drug (e.g., I.V. UFH)
Surgical/invasive interventions Discontinue dabigatran 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before an invasive procedure; longer times should be considered for patients undergoing major surgery or those receiving spinal puncture/epidural catheter
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risk for HIT undergoing a percutaneous coronary intervention (PCI). Argatroban dosing is not affected by renal function; how-ever, this agent must be dose adjusted for patients with hepatic dysfunction. Bivalirudin has a half-life of approximately 25 minutes and is indicated as an anticoagulant for patients with HIT and those with or at risk for HIT undergoing PCI. In addi-tion, bivalirudin is used in a broader patient population than lepirudin and argatroban because it also is indicated for pa-tients with unstable angina undergoing angioplasty and with the provisional use of glycoprotein IIb/IIIa inhibitors in patients undergoing PCI.9 Bivalirudin must be dose adjusted in patients with moderate to severe renal impairment and is monitored primarily by using activated clotting time (ACT). Argatroban is monitored using both aPTT and ACT.30 Currently, no antidotes are available for any of these direct thrombin inhibitors.
OralIn October 2009, the first oral direct thrombin inhibitor, dabi-gatran (Pradaxa—Boehringer Ingelheim) was approved by FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.28 This approval was a milestone because warfarin was the only other available oral anticoagulant ap-proved in more than half a century for AF patients at high risk for stroke. Dabigatran is a prodrug that is rapidly absorbed and converted to its active moiety by esterase-catalyzed hydrolysis in the plasma and liver. It does not require any special monitor-ing and is dosed as 150 mg twice daily for patients with a CrCl greater than 30 mL/min. Because it is primarily eliminated re-nally (80%), dabigatran must be dose adjusted to 75 mg twice daily for patients with a CrCl between 15 and 30 mL/min. It is not a substrate, inhibitor, or inducer of the CYP450 system; there-fore, drug interactions via this pathway do not appear to be an issue. However, dabigatran is an efflux P-glycoprotein substrate, so agents that affect this pathway may be of concern. The label-ing also has information on switching patients from warfarin to dabigatran and vice versa, to and from parenteral anticoagula-tion, and considerations for surgical interventions (Table 4). As with the parenteral direct thrombin inhibitors, no antidote for dabigatran is available currently.
The efficacy of dabigatran for patients with AF was proven in the RELY (Randomized Evaluation of Long-Term Antico-agulation Therapy) trial, in which dabigatran 150 mg twice daily was superior to dose-adjusted warfarin for the primary outcome of stroke or systemic embolism with a similar rate of major bleeding.31 Dabigatran has been evaluated in numer-ous trials for prevention of VTE after orthopedic surgery and in a trial for treatment of acute VTE in addition to AF.32–35 The data showed that dabigatran was noninferior to enoxaparin in two prevention trials (RE-MODEL and RE-NOVATE) but infe-rior in a third trial (RE-MOBILIZE).32–34 For treatment of acute VTE, dabigatran was found to be as effective as warfarin with a similar safety profile (RE-COVER).35
While the cost of dabigatran ($6 to $7 per day) has been a concern, a cost-effectiveness model that used the RE-LY data showed that the agent compares favorably with warfarin therapy when costs of monitoring and clinic visits are factored
in. Incremental cost-effectiveness ratios were $51,229 and $45,372 per quality-adjusted life–year for low- and high-dose dabigatran therapy, respectively, compared with warfarin.36
Pulling it all togetherEstablished anticoagulants such as warfarin, UFH, and LMWHs are still in widespread use despite their identified shortcom-ings. The main disadvantages of UFH and warfarin are unpre-dictable anticoagulant response and the need for continuous monitoring. LMWHs were developed to overcome some of the issues seen with UFH; however, these agents are far from ideal because of the need for parenteral administration, high acquisi-tion cost, and the need to monitor in special populations. In ad-dition, protamine sulfate is only partially effective at reversing the effects of LMWHs. Fondaparinux is a synthetic anticoagu-lant that is useful in patients with or at risk for HIT; however, it also is given parenterally, is contraindicated in patients with severe renal impairment, and has no available antidote.
The search for an ideal oral anticoagulant that can be used easily in the outpatient setting has been under way for years. The approval of dabigatran for preventing stroke and systemic embolism in patients with nonvalvular AF offers clinicians an alternative to warfarin that has straightforward dosing, does not require continuous monitoring, and appears to have mini-mal drug interactions. Data regarding the efficacy of dabiga-tran for preventing VTE (compared with enoxaparin) and treat-ing acute VTE (compared with warfarin) have been favorable, and the agent likely will be approved for these indications.
Rivaroxaban and apixaban also should reach the market-place soon and be used for a variety of indications (e.g., pre-vention and treatment of VTE) and for patients with AF. As with dabigatran, these oral agents also have straightforward dosing and do not require continuous monitoring. The primary issues with these new oral anticoagulants are that antidotes are un-available currently and that nonadherent patients will be more difficult to identify. Currently, clinicians can easily determine whether patients are adequately anticoagulated with warfarin based on their monthly INR readings.
The advantages of new oral anticoagulants over older thera-pies are changing the way patients needing anticoagulatiion are managed and are sure to have substantial impact on the daily functions of anticoagulation clinics. Anticoagulation clinicians may be able to move away from routine INR monitoring and into greater roles of patient and physician education.
Assess your knowledge case study responses1. Dabigatran is a good alternative to warfarin for P.S. because it is
indicated for managing AF patients, it does not require patients to adhere to routine monitoring visits, and its anticoagulant affects are not affected by dietary vitamin K.
2. Warfarin should be discontinued and dabigatran should be initi-ated after the INR is less than 2.0. P.S.’s creatinine clearance (CrCl) should be calculated, and if it is greater than 30 mL/min, dabigatran can be given at a dose of 150 mg twice daily. If CrCl is between 15 and 30 mL/min, then 75 mg twice daily should be given.
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