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American Heart Association 2010 Scientific Sessions and American Society of Nephrology: Renal Week 2010
Approximately 12,800 health care professionals, including 10,500 cardiologists, attended the AHA meeting in Chicago from November 13 to 17, 2010. Key among the several thousand abstract presentations were data supporting a long-awaited factor Xa inhibitor alternative to warfarin—rivaroxaban (Xarelto); evidence that high-dose clopidogrel (Plavix) does not reduce cardiovascular risks in patients whose platelets remain reactive; and studies confirming that risk-reducing statins remain underprescribed.
American Heart Association
Hold the Warfarin and Clopidogrel—But Not the Statins
Preventing Stroke with Rivaroxaban (Xarelto) The ROCKET–AF Trial
- Kenneth W. Mahaffey, MD, Duke University School of Medicine, Durham, N.C.
- Elaine M. Hylek, MD, MPH, Boston University School of Medicine, Boston, Mass.
- Robert M. Califf, MD, Vice Chancellor for Clinical Research, Duke University School of Medicine, Durham, N.C.
In reviewing ROCKET–AF (Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), the AHA-appointed discussant, Dr. Hylek, noted:
In October of 2006, the FDA issued a black-box warning for warfarin due to a growing appreciation of the hazards of this drug in routine clinical practice. The need for International Normalized Ratio (INR) monitoring has effectively relegated millions of individuals around the world to no therapy or ineffective therapy because of a lack of access to monitoring. Hence, there’s been an intense search for alternatives to warfarin with a predictable dose response that obviates the need for monitoring.
Rivaroxaban (Xarelto, Bayer/Ortho), Dr. Mahaffey said, is a first-in-class oral, once-daily, direct Xa inhibitor with a half-life of 5 to 13 hours. ROCKET–AF investigators compared rivaroxaban 20 mg daily with warfarin (Coumadin, Bristol-Myers Squibb) in patients with atrial fibrillation (AF) that was not related to valvular disease. For patients with a creatinine clearance of 30 to 49 mL/minute, the dose was 15 mg. The INR target was 2.5.
ROCKET–AF, which included 14,264 patients, was conducted in 45 countries and at 1,178 sites. The primary clinical endpoint was stroke or non–central nervous system (CNS) systemic embolism, and the primary safety outcome was major or non-major clinically relevant bleeding. Among the included patients, 62.5% had congestive heart failure, 90.5% had hypertension, 39.5% had diabetes, and 55% had a prior stroke or transient ischemic attack or an embolism.
In the primary analysis, participants taking rivaroxaban, compared with those taking warfarin, had fewer strokes and non-CNS emboli. With rivaroxaban, there were 1.71 events per 100 patient-years (188 patients); with warfarin, there were 2.16 events per 100 patient-years (241 patients) (P < 0.001 for non-inferiority). Superiority for rivaroxaban was shown in an on-treatment analysis (P = 0.015) but not in an intention-to-treat (ITT) analysis (P = 0.117).
Major bleeding complications were comparable in both treatment groups, occurring at rates of 3.60 per 100 patient-years (in 395 rivaroxaban patients) and 3.45 per 100 patient-years (in 386 warfarin patients) (P = 0.576). Intracranial hemorrhage and fatal bleeding rates were lower with rivaroxaban. Hemoglobin decreases of 2 g/dL or more were more frequent with rivaroxaban (P = 0.019), as was the need for transfusions (more than 2 units) (P = 0.044).
Dr. Mahaffey concluded, “Rivaroxaban is a proven alternative to warfarin for moderate- or high-risk patients with atrial fibrillation.”
Dr. Califf, co-principal investigator of the study, stated, “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.”
Dr. Hylek noted that the overall safety profile of rivaroxaban was made less clear by the fact that there were more hemorrhages requiring transfusions and more drops in hematocrit.
Platelet Reactivity: The GRAVITAS Trial
- Matthew J. Price, MD, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
- Jessica L. Mega, MD, MPH, Discussant, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
At least seven studies involving more than 3,000 patients have concluded that high residual platelet reactivity, as measured by the VerifyNow P2Y12 platelet function test (Accumetrics), is associated with poor clinical outcomes after percutaneous coronary intervention (PCI). Despite the potent inhibition of platelet reactivity by clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb), platelet reactivity varies widely among clopidogrel-treated patients. Attempts at further reducing platelet reactivity have not been tested in a large, randomized clinical trial. The purpose of GRAVITAS (Gauging Responsiveness With A VerifyNow Assay: Impact on Thrombosis And Safety) was to determine whether high-dose clopidogrel reduced cardiovascular events in patients with high residual platelet reactivity, as determined by the VerifyNow test.
GRAVITAS, an ongoing study, included 2,214 subjects with high residual platelet reactivity—with platelet reactivity units (PRUs) of 230 or more—who underwent PCI with drug-eluting stents for the treatment of stable or unstable coronary artery disease. After receiving a clopidogrel loading dose of 600 mg, the patients were then randomly assigned, in a 1:1 fashion, to receive a standard maintenance dose of 75 mg daily for six months or a doubled maintenance dose of 150 mg daily for six months. The primary endpoint was combined cardiovascular death, myocardial infarction (MI), and stent thrombosis.
Mean age was 64 years, and 65% of the patients were men. Mean PRUs in the high-dose and standard-dose groups were 282 and 283, respectively. Total stent length was comparable in both groups (30 mm and 29 mm, respectively).
After 30 days, persistently high platelet reactivity was found in 62% of patients in the standard-dose group and in 40% of those in the high-dose group (P < 0.001). Compared with the standard dose, the high dose of clopidogrel did not reduce the primary endpoint of incidence of death, heart attack, or stent thrombosis (high dose, 2.3%; standard dose, 2.3%) (P = 0.98).
Bleeding did not increase with the high-dose regimen. The endpoint rate of bleeding was similar to that found in 3,215 patients without high platelet reactivity, with PRUs below 230 (2.3% for the high-dose group vs. 1.4% for the standard-dose group, respectively) (P = 0.20).
Dr. Price concluded, “GRAVITAS does not support a treatment strategy of high-dose clopidogrel in low-risk patients with high residual reactivity identified by a single platelet function test after PCI.”
Dr. Mega commented that the study might have been under-powered:
It is very important to underscore that this study does not definitively rule out a benefit of tailoring antiplatelet therapy based on platelet function testing—or specifically testing more potent agents that achieve higher degrees of platelet reactivity inhibition, or maybe tailoring and using goal-directed therapies.
Type-2 Diabetes Is Undertreated with Statins
- Alex Z. Fu, PhD, Assistant Professor of Medicine, Cleveland Clinic, Cleveland, Ohio
Despite high cardiovascular risks in type-2 diabetic patients who take antihyperglycemic agents, more than one-third of patients are not being prescribed risk-lowering statin therapy, according to new research. The finding emerges from an analysis of 125,464 patients with type-2 diabetes who were at least 25 years of age.
Dr. Fu noted that individuals with type-2 diabetes are at an increased risk of cardiovascular disease (CVD) and death and that statins can reduce these risks in these patients. Treatment guidelines recommend initiating statins for most patients with type-2 diabetes regardless of their lipid levels.
Along with fellow investigators, Dr. Fu used GE Health-care’s electronic medical records database between July 2006 and June 2008 to estimate statin eligibility in patients with type-2 diabetes in clinical practice, based on American Diabetes Association (ADA) recommendations and actual statin use in this population. Mean patient age was 64 years, 48% were men, and 6.3% had cardiovascular conditions at baseline.
Although 98% of the patients satisfied ADA eligibility standards for statin therapy, only 63% received a statin prescription. The finding, according to Dr. Fu, implies that efforts should be made to increase statin use in patients with type-2 diabetes who are at an elevated risk of cardiovascular events.
An adjusted logistic regression showed that increasing age, male sex, smoking, and the use of antihypertensive and anticoagulant medications at baseline were associated with an increased likelihood of statin use (P < 0.001 for all).
Dr. Fu emphasized that the analysis did not exclude patients who might have been statin-intolerant or who had contraindications to statin use; this was a limitation of the study. In addition, data on a family history of premature coronary heart disease, which might have led to an underestimation of the cardiovascular risk and eligibility for statin therapy, were not available.