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The 2007 American Heart Association (AHA) Scientific Sessions took place November 3 to 7, 2007, in Orlando, Florida. Among the new data presented were the much anticipated results of a phase 3 trial of prasugrel versus clopidogrel in patients scheduled for percutaneous coronary intervention (PCI). Other clinical trials of note were the first prospective study of a statin in patients with ischemic heart disease and heart failure and a comparison of eptifibatide with abciximab on ST-segment resolution in patients with myocardial infarction (MI) who are undergoing primary PCI. This AHA Special Report details these and other trials.
Prasugrel superior to clopidogrel for reducing cardiac risk in patients with ACS undergoing PCI
TRITON-TIMI 38 included 13,608 patients with moderate-to-high risk ACS who were scheduled for PCI. Patients were randomized to prasugrel, administered as a 60-mg loading dose followed by a 10-mg/d maintenance dose, or clopidogrel, administered as a 300-mg loading dose followed by a 75-mg/d maintenance dose, for 6 to 15 months. The median duration of therapy was 14.5 months.
The primary end point was a composite of cardiovascular-related death, nonfatal myocardial infarction (MI), and nonfatal stroke. The end point was observed in 9.9% of patients randomized to prasugrel and in 12.1% of patients randomized to clopidogrel, representing a 19% relative risk reduction with prasugrel (P=.0004).
The number needed to treat (NNT) to prevent 1 occurrence of the primary end point within a 15-month period would be 46 for prasugrel vs clopidogrel.
Prasugrel use was associated with a favorable effect on stent thrombosis, a prespecified secondary end point: 1.1% of the prasugrel-treated patients and 2.4% of the clopidogrel-treated patients experienced stent thrombosis, representing a 52% reduction (HR=0.48; 95% CI, 0.36-0.64; P<.001) with prasugrel. Prasugrel was also associated with significant reductions in MI (7.4% vs 9.7%; P<.001) and urgent target-vessel revascularization (2.5% vs 3.7%; P<.001) compared with clopidogrel. There were no significant differences in mortality rates between the treatment groups.
Prasugrel demonstrated a benefit with regard to the primary end point by Day 3, and the benefit was maintained throughout the study, which, according to Dr Antman, provides evidence of efficacy with both the loading and maintenance doses of the drug.
Prasugrel was associated with a significant increase in major bleeding not associated with coronary artery bypass graft (CABG) compared with clopidogrel (2.4% vs 1.8%; HR=1.32; 95% CI, 1.03-1.68; P=.03). Prasugrel was also associated with significant increases in life-threatening (1.4% vs 0.9%; P=.01) and fatal (0.4% vs 0.1%; P=.002) bleeding compared with clopidogrel.
"We identified where most of the excess bleeding occurred," Dr Antman said. In a post-hoc subgroup analysis, patients with a prior stroke or transient ischemic attack (TIA) (approximately 4% of all patients enrolled in the trial) experienced an increase in major bleeding and worse outcomes with prasugrel than with clopidogrel. Subgroup analyses of patients aged ≥75 years and those who weighed <60 kg demonstrated no net benefit with prasugrel.
A prespecified analysis of net clinical benefit that included all-cause mortality, nonfatal MI, nonfatal stroke, and TIMI major hemorrhage demonstrated an overall benefit with prasugrel compared with clopidogrel (HR=0.87; 95% CI, 0.79-0.95; P=.004).
Compared with clopidogrel, treatment with prasugrel was associated with 23 fewer MIs per every 1,000 patients with an additional 6 major bleeding complications.
According to Dr Antman, a lower prasugrel maintenance dose may improve the risk:benefit ratio in older patients and in those with low body weight. The results of a pharmacokinetics substudy of TRITON-TIMI 38 are scheduled for publication in the journal Circulation. Dr Antman said these results should add greater clarity to the potential benefit of dose modifications in these subgroups.
Dr Antman said that in a study of inhibition of platelet aggregation with prasugrel compared with a higher-than-standard loading dose of clopidogrel, "prasugrel always had a higher inhibition of platelet aggregation, even when compared with a 600-mg loading dose of clopidogrel." He said the higher inhibition of platelet aggregation results in a reduction of ischemic events. According to Dr Antman, the same study demonstrated that the 10-mg maintenance dose of prasugrel was superior to a 150-mg maintenance dose of clopidogrel for the inhibition of platelet aggregation. These results will also be included in the Circulation article.
Eric Topol, MD, chief of genomic medicine and translational science at Scripps Health in La Jolla, California, summarized the impact of the TRITON-TIMI 38 results, saying that the risk of serious bleeding with prasugrel is approximately 1 in 100. Dr Topol said prasugrel could be expected to prevent approximately 2 deaths or MIs per 100 patients treated with the drug, with the entirety of its benefit being a reduction in the incidence of MI.
Daiichi-Sankyo and Lilly, which manufacture prasugrel, plan to submit an NDA by the end of 2007.
The results of TRITON-TIMI38 were published in the electronic version of the New England Journal of Medicine (NEJM) to coincide with the presentation at the AHA Scientific Sessions 2007 and are available at http://www.nejm.org/cgi/content/full/NEJMoa0706482 and in print (NEJM. 2007;357:2001-2015).
Rosuvastatin not associated with significant CV benefit among older patients with systolic heart failure
According to the results of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), the addition of rosuvastatin to standard optimized heart failure treatment among older patients with systolic heart failure had no significant effect on the incidence of a composite end point of cardiovascular-related death, nonfatal myocardial infarction (MI), or nonfatal stroke compared with placebo. Rosuvastatin use was associated with reductions in all-cause and cardiovascular-related hospitalizations.
Åke Hjalmarson, MD, PhD, Wallenberg Laboratory for Cardiovascular Research, Sählgrenska University Hospital, Goteberg, Sweden, said these results suggest that "the major etiology of cardiovascular deaths in this older, vulnerable category of otherwise well-treated patients with advanced systolic heart failure may be a primary electrical event related to ventricular dilatation and scarring, and not to an atherothrombotic event," and would therefore not be prevented by a statin.
CORONA included 5,011 patients with New York Heart Association (NYHA) class II, III, or IV systolic heart failure of ischemic etiology with an ejection fraction ≤40% (≤35% in patients with NYHA class II) who did not have an indication for lipid-lowering therapy. Patients were randomized to rosuvastatin 10 mg/d (n=2,514) or placebo (n=2,497) plus optimal heart failure medications. The mean patient age was 73 years; median follow-up was 33 months.
The primary outcome occurred in 692 patients who received rosuvastatin and in 732 patients who received placebo (HR=0.92; 95% CI, 0.83-1.02; P=.12). Rosuvastatin use was associated with a nonsignificant 8% reduction in the incidence of adverse coronary events.
There were significantly fewer hospitalizations for any cause (P=.007), for cardiovascular causes (P<.001), and for heart failure (P=.01) among patients treated with rosuvastatin versus placebo.
According to Dr Hjalmarson, rosuvastatin may have been initiated too late to modify the course of the disease in these patients with more advanced forms of heart failure. "It might well be that younger patients with less severe heart failure might have a benefit," he said. He stated that use of a statin in older patients with heart failure and a short life expectancy is not warranted.
Gordon Tomaselli, MD, chairman of the American Heart Association (AHA) Committee on Scientific Sessions Program, and chief of cardiology at Johns Hopkins University School of Medicine, Baltimore, Maryland, said that the study results "would not deter me from prescribing a statin in a patient who otherwise has an indication for a statin, and I certainly wouldn't stop a statin in a person who develops left ventricular dysfunction while on the drug."
Dr Hjalmarson said that rosuvastatin was demonstrated to be "extremely safe, even in these older, sick patients." Patients who received rosuvastatin did not experience an excess of significant elevations in liver transaminase levels, muscle-related symptoms, or elevations of creatine kinase levels.
The CORONA data were published in the electronic version of the New England Journal of Medicine to coincide with the presentation at the AHA Scientific Sessions 2007 and are available at http://www.nejm.org/cgi/content/full/NEJMoa0706201.
Ranolazine may be beneficial in treatment of type 2 diabetes
The results of a new analysis of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN)-Thrombolysis in Myocardial Infarction (TIMI) 36 study indicate that ranolazine may be useful to treat diabetes. As previously reported in Formulary (2007;42:221-232), ranolazine failed to demonstrate efficacy in reducing the incidence of the study's composite primary end point of cardiovascular-related death, myocardial infarction (MI), or recurrent ischemia. Ranolazine was associated with significant reductions in recurrent ischemia, worsening angina, arrhythmias on Holter monitoring, and the need for antianginal therapy compared with placebo.
In this most recent analysis, ranolazine was associated with significant reductions in hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes.
Ranolazine use was also associated with an increase in the proportion of patients who met current goals for the management of hyperglycemia and a reduction in the incidence of new hyperglycemia in patients without diabetes, said David Morrow, MD, MPH, associate physician in the cardiovascular division at Brigham and Women's Hospital, Boston, Massachusetts, and an assistant professor of medicine at Harvard Medical School, Boston.
The MERLIN-TIMI 36 trial included 6,560 patients with non-ST-elevation acute coronary syndromes (ACS) who had clinical indicators of moderate-to-high risk of recurrent ischemic events; 35% of enrolled patients had diabetes at baseline. Patients were treated with standard medical therapy and were randomized to ranolazine, initiated intravenously (IV) and followed by the oral extended-release formulation (1,000 mg BID), or to placebo for approximately 12 months.
The new analysis included 4,306 patients enrolled in the MERLIN-TIMI 36 trial for whom serial HbA1c data were available. All patients with diabetes were also receiving standard medical treatment for diabetes.
At Month 4, the use of ranolazine in the overall cohort resulted in a reduction in HbA1c from 6.2% to 5.9% versus no change in HbA1c among patients randomized to placebo. Among patients with diabetes, the use of ranolazine was associated with a significant reduction in HbA1c of –0.64% from baseline to Month 4 and –0.43% compared with placebo (P<.001) at Month 4, a difference that was sustained at Month 8.
Patients assigned to ranolazine were also significantly more likely (P<.001) to achieve the HbA1c target of <7.0%; 59% of patients with diabetes had achieved this target Month 4.
Patients without diabetes experienced a 32% reduction (P=.003) in the development of impaired fasting glucose or an HbA1c level >6.0%.
"If a significant hypoglycemic effect [of ranolazine] is supported by ongoing mechanistic studies, ranolazine would be extremely attractive for the treatment of patients with coronary artery disease and diabetes mellitus," Dr Morrow said. Preclinical studies have demonstrated that ranolazine increases glucose-stimulated insulin secretion in pancreatic islet cells and improves glucose homeostasis.
According to Dr Morrow, the mechanisms for reducing HbA1c levels must be further investigated, but if the efficacy is confirmed, the drug would offer significant advantages as an antianginal agent. "Physicians see so many patients with diabetes and coronary disease in whom it's a struggle to meet targets for HbA1c. It would be a great clinical advantage to hit two birds with one stone," he said.
EVA-AMI and BRIEF-PCI
Eptifibatide noninferior to abciximab in patients undergoing PCI; length of infusion does not affect efficacy
The results of 2 major trials involving eptifibatide were presented at the 2007 AHA Scientific Sessions. The first trial, Eptifibatide Versus Abciximab in Primary PCI for Acute ST Elevation Myocardial Infarction (EVA-AMI), demonstrated that the eptifibatide is noninferior to abciximab in patients undergoing percutaneous coronary intervention (PCI) for ST-segment myocardial infarction (STEMI). The second trial, Brief Infusion of Eptifibatide Following Successful Percutaneous Coronary Intervention (BRIEF-PCI), demonstrated that a standard 18-hour infusion of eptifibatide offered no additional benefit compared with a brief (<2-h) infusion of the drug.
The EVA-AMI trial included 427 patients with STEMI who were scheduled for PCI. All patients were pretreated with aspirin, clopidogrel, and unfractionated heparin or enoxaparin and were randomized to either a double bolus of eptifibatide followed by a 24-hour infusion of the drug (n=226) or a single bolus of abciximab followed by a 12-hour infusion of the drug (n=201).
The primary end point was complete ST resolution (>70%) at 60 minutes after PCI compared with the baseline electrocardiograph (ECG). A noninferiority margin of 15% was selected. A total of 63.1% of patients treated with eptifibatide and 59.6% of patients treated with abciximab reached the primary end point, representing a nonsignificant difference that met the noninferiority standard.
"Eptifibatide, given as a double bolus, was equally effective as abciximab as an adjunct to primary PCI with respect to myocardial reperfusion," said Uwe Zeymer, MD, Herzzentrum Ludwigshafen, Germany.
The trial was not powered for clinical end points, but there were no significant differences in the occurrence of in-hospital clinical events between treatment groups. The incidence of death was 3.5% in each group, the rates of reinfarction were 1.5% in the eptifibatide group and 0 in the abciximab group, and heart failure occurred in 6.4% of patients in the eptifibatide group versus 8.5% of patients in the abciximab group. Treatment with eptifibatide was associated with a greater incidence of major bleeding compared with abciximab (1.8% vs 0).
According to Robert Wilcox, DM (doctor of medicine), FRCP, professor of cardiovascular medicine, University of Nottingham, UK, the excess bleeding associated with eptifibatide use suggests that the drug was overdosed; however, the higher reinfarction rate with the agent's use suggests underdosing. Dr Wilcox said that ST resolution would be a reasonable surrogate marker to compare the drugs because the degree of ST resolution at 90 minutes has been demonstrated to correlate with 30-day mortality. "Although comparable surrogacy prevailed, a formal clinical outcome comparison would be preferable," Dr Wilcox said.
The BRIEF-PCI trial was a noninferiority trial of a brief (<2-h) infusion (n=312) versus a standard 18-hour infusion (n=312) of eptifibatide in patients who had successful nonemergent PCI. The primary end point was the incidence of periprocedural ischemic myocardial injury, defined as a postprocedure elevation of troponin-I >0.26 mcg/L. This end point was observed in 30.1% of patients who received the brief infusion and in 28.3% of patients who received the standard infusion (P<.012 for noninferiority), according to Anthony ung, MD, director of cardiac catheterization laboratories, Vancouver General Hospital, British Columbia, Canada.
The standard infusion of eptifibatide was associated with a greater incidence of major bleeding compared with the brief infusion (4.2% vs 1.0%; P=.02).
The 30-day incidence of MI was 4.8% among patients randomized to brief infusion and 4.5% among patients randomized to standard infusion, representing a nonsignificant difference. The need for target vessel revascularization was 0.6% in each group.