News from the 2007 Scientific Sessions of the American Heart Association, Orlando, Fla, Nov. 10-14, 2007

Anti-ischemic agent also reduces HbA1c levels

An added benefit to the antianginal/anti-ischemic agent ranolazine appears to be a reduction in hemoglobin A1c (A1C) levels in patients with diabetes. This property allowed a significant proportion of ranolazine recipients in a large clinical trial to reach their A1C treatment target, said David Morrow, MD, MPH.

"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," said Dr Morrow, lead investigator of the study. Studies in animal models and in pancreatic cells have shown that ranolazine increases glucose-stimulated insulin secretion in pancreatic islet cells and improves glucose homeostasis. The exact mechanism behind the A1C decrease requires further investigation, he said.

"Physicians see so many patients with diabetes and coronary disease in whom it's a struggle to meet targets for A1C. It would be a great clinical advantage to hit 2 birds with 1 stone," said Dr Morrow, associate physician in the cardiovascular division at Brigham and Women's Hospital, Boston, and assistant professor of medicine at Harvard Medical School, Boston.

The A1C findings come from a subanalysis of a trial known as MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes), the principal result from which were released last year.

MERLIN enrolled 6560 patients with non—ST-elevation acute coronary syndromes who were at moderate to high risk of recurrent ischemic events. Thirty-five percent of the study population had diabetes at baseline. Patients were randomized to ranolazine, initiated intravenously followed by its oral extended-release formulation (1000 mg twice daily), or placebo for approximately 12 months in addition to standard medical therapy.

The primary end point—a composite of cardiovascular death, myocardial infarction, or recurrent ischemia—occurred in approximately the same proportion of patients randomized to ranolazine and placebo.

In the patients randomized to ranolazine, however, there were significant reductions in the incidence of recurrent ischemia (13% reduction; P = .03), worsening angina (23% reduction; P = .023), and the need for antianginal therapy (19% reduction; P = .006) compared with placebo.

The new analysis presented here looked at the 4306 patients in MERLIN for whom serial A1C data were available.

All patients with diabetes were on a background of standard treatments for diabetes. In the overall cohort, randomization to ranolazine resulted in a decrease of A1C from 6.2% to 5.9% at month 4, whereas there was no change in A1C in those randomized to placebo.

In the patients with diabetes, ranolazine was associated with a significant reduction in A1C of 0.64% compared with placebo at 4 months (P < .001), a difference that was sustained at 8-month follow- up. (There were too few patients followed to 16 months to show a significant difference at a 16-month follow-up.)

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Patients assigned to ranolazine were also significantly more likely ( < .001) to achieve their A1C target of less than 7.0%, with 59% of the diabetic cohort achieving this target at 4 months. Patients without diabetes had a 32% reduction ( = .03) in developing impaired fasting glucose or an A1C level greater than 6.0%.

A safe option to help patients with coronary disease and diabetes achieve their A1C target is attractive, given the safety concerns discovered recently with some hypoglycemic drugs, said Dr Morrow. "It's nice to have a large outcomes trial like MERLIN that establishes the safety of ranolazine in a high-risk group of patients," he said.

Investigational antiplatelet reduces risk of ischemic events compared with current standard

An investigational antiplatelet, prasugrel, was superior to clopidogrel in a Phase 3 trial in preventing major adverse cardiovascular events in patients in whom a percutaneous coronary intervention (PCI) was planned, said Elliott M. Antman, MD.

The reduction in ischemic events with prasugrel was accompanied by an increase in major bleeding. Still, the net clinical effect is one of significant benefit with prasugrel—23 fewer myocardial infarctions (MIs) at a cost of 6 major bleeding complications per 1000 patients treated with prasugrel instead of clopidogrel.

Based on the results of the study, Dr Antman said that, in his opinion, prasugrel is "definitely an approvable drug."

The study included 13,608 patients with acute coronary syndromes in whom PCI was planned. They were randomized to a 60-mg loading dose of prasugrel followed by a 10-mg/day maintenance dose, or a 300-mg loading dose of clopidogrel followed by a 75-mg/day maintenance dose for 6 to 15 months. The median duration of therapy was 12 months.

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The primary end point was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke. This end point was reached by 9.9% of patients randomized to prasugrel and 12.1% randomized to clopidogrel, which amounts to a 19% relative reduction in risk ( = .0004) with prasugrel.

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Stent thrombosis, a prespecified secondary end point, was also favorably affected by prasugrel. Less than half as many patients randomized to prasugrel compared with clopidogrel experienced stent thromobosis (1.1% vs 2.4%; <.001).

The benefit on the primary outcome with prasugrel was apparent as early as the 30-day follow-up. "There was benefit with both the loading phase and the maintenance phase with prasugrel," said Dr Antman, director, Samuel A. Levine Cardiac Unit, Brigham and Women's Hospital, Boston. Mortality was not significantly different between the 2 groups.

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Noncoronary artery bypass graft major bleeding events occurred in 2.4% of patients randomized to prasugrel vs 1.8% randomized to clopidogrel; a 32% increase ( = .03) associated with prasugrel. Fatal bleeding was rare in the study but did occur more frequently with prasugrel (0.4%) than with colpidogrel (0.1%); a difference that was significant ( = .002).

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On a net clinical benefit end point that included all-cause mortality, nonfatal MI, nonfatal stroke, or nonfatal major bleed, prasugrel was associated with a 13% reduction in risk ( = .004).

"We identified where most of the excess bleeding occurred," said Dr Antman. Patients with a prior stroke or transient ischemic attack (TIA), who constituted about 4% of the study population, had an increase in major bleeding and worse outcomes with prasugrel than clopidogrel. Two other subgroups—patients 75 years or older and patients weighing less than 60 kg&mdash;experienced an increase in bleeding with prasugrel but had a tendency toward better outcomes.

Although prasugrel should be avoided in patients with prior stroke or TIA, a lower prasugrel maintenance dose may improve the benefit:risk ratio in older patients and those with low body weight, said Dr Antman. The results of a pharmacokinetic substudy should clarify the potential benefit of dose modifications in these subgroups.

In responding to concerns over the bleeding risk with prasugrel, he said that every advance in antiplatelet therapy has been accompanied by an excess risk of bleeding, "but the net clinical benefit has always favored more potent antiplatelet therapy."

Pharmacogenetic-guided dosing of warfarin is promising but trial fails to meet its primary end point

In the first trial to explore the clinical utility of genomic medicine, real-time pharmacogenetic-based dosing of warfarin failed to decrease the proportion of prothrombin time International Normalized Ratios (INRs) out of the therapeutic range, but it did result in the need for fewer and smaller dosage adjustments, said Jeffrey L. Anderson, MD.

Previous research had identified variants in CYP2C9 and VKORC1 genes that partly influence response to warfarin. As a result, the US Food and Drug Administration—labeling of warfarin was recently changed to recognize the genetic effects on dosing. However, the impact of pharmacogenetic-guided dosing had not been adequately tested in prospective trials.

In the study presented here, 206 patients with an indication for warfarin were randomized in a double-blind fashion to genotype-based warfarin dose initiation and maintenance or to a standard, empiric-dosing algorithm.

DNA was extracted from a buccal swab to identify polymorphisms in the CYP2CP*2 and *3 and the VKORC1 genes, using rapid profiling. The primary end point was the proportion of INRs outside the therapeutic window, defined in this study as an INR < 1.8 or > 3.2.

Rapid genotyping to guide anticoagulation therapy was shown to be feasible.

"Pharmacogenetic-guided dosing much more closely predicted the average final dose against standard therapy," said Dr Anderson, associate chief of cardiology at LDS Hospital, University of Utah, Salt Lake City.

For example, among the group randomized to standard warfarin dosing, patients with the wild-type variant required an average increase in their dose of 13.6 mg/wk, compared with an average dose decrease of 0.5 mg/wk in those randomized to pharmacogenetic-guided dosing. Patients with multiple variants required an average dose reduction of 10 mg/wk when standard dosing was used, but only a 0.6 mg/wk reduction when pharmacogenetic-guided dosing was used.

"Despite the good predictive value, the percentage of out-of-range INRs was not significantly different," he said. The percentage of out-of-range INRs was 30.7% with pharmacogenetic-based dosing and 33.1% with standard dosing.

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In a subset analysis of the primary end point, the percentage of INRs that were out of range was significantly less ( = .03) when confined to the patients with wildtype or multiple variant carriers (pharmacogenetic = 29.3%; standard = 39.1%).

According to Dr Anderson, rapid genotyping deserves further investigation based on the promising data from this study. The precise setting and patient groups in which it will be most helpful still need to be determined.

He noted that outcomes were better than expected in the standard dosing arm because most of this group had careful management of their dosing by a dedicated anticoagulation service, with initial daily INR measurement being common. As a result, the actual proportion of out-of-range INRs was much lower than anticipated (40%) in the standard dosing arm.