Report From the 100th Cardiovascular and Renal Drugs Advisory Committee Meeting
US Food and Drug Administration: December 8–9, 2003 Gaithersburg, Md
The Committee was asked, through a citizen petition filed by Bayer Healthcare, to evaluate amending the professional labeling for the use of aspirin (ASA) to include primary prevention of myocardial infarction (MI). They cited evidence from 5 studies germane to this issue. Specifically, the request was to expand the current cardiovascular indications for daily ASA (75 to 325 mg) to include asymptomatic individuals with a 10% or greater risk of coronary heart disease over 10 years.
The Food and Drug Administration (FDA) and the Advisory Committee considered the use of ASA in primary prevention in 1998, when the Physicians Health Study (PHS) and the British Doctors Study (BDS) were reviewed. At that time, the FDA concluded that the data were insufficient to warrant a change identical to that requested in the current application. Since then, 3 new studies have been conducted and were provided for the current review: (1) the Thrombosis Prevention Trial (TPT), (2) the Hypertension Optima Trial (HOT), and (3) the Primary Prevention Project (PPP).
Overall, these 5 trials represent data from more than 55 000 patients in placebo-controlled trials from heterogeneous patient populations, using differing doses and formulations of ASA, and aimed towards differing primary end points. The 2 previously reviewed studies in male doctors account for more than 27 000 patients within the new pooled analysis supporting the claim. TPT, conducted between 1984 and 1989 in 5085 British males, was a factorial study involving ASA and warfarin that revealed a 32% reduction in nonfatal MI (P=0.04). The PPP study enrolled 4495 patients (1912 females) >50 years of age with the primary intent to affect cardiovascular death and nonfatal MI; this trial was stopped prematurely because of ethical concerns about withholding ASA, and the primary end point was nonsignificant. The HOT study (the only trial for which the FDA had access to source data) was conducted in 18 790 men and women with mild to moderate hypertension and revealed a trend toward reduction in the primary end point of cardiovascular death, nonfatal MI, and stroke (RR 0.91, 95% CI 0.79–1.04, P=0.17). Of note was the fact that 3 of the trials were stopped before reaching their planned sample size, and 4 did not reach their primary end point. Notwithstanding this, pooled analysis of prevention of new MI for the trials revealed a reduction from 2.7% to 2.2% (RR 0.77, 95% CI 0.69–0.85, P<0.0001). The risk profiles for individual patients in the 5 trials were unavailable, but the TPT trial was the only trial that enrolled patients who were in the moderate-risk category to which the proposed label change was directed.
The Committee received an overview of ASA’s effects on patients from these 5 trials conducted by the Antithrombotic Trialists’ Collaboration, including an analysis of the small fraction (approximately 1/6) of the patients that comprised the moderate-risk group. Whereas these data supported a clear signal for prevention of nonfatal MI, there was a neutral effect on mortality and a trend toward increased stroke and major bleeding. This effect was estimated as a reduction of 5 nonfatal MIs among 1000 moderate-risk patients treated for 5 years and a risk of 1 excess disabling stroke and 2 to 4 serious gastrointestinal bleeds requiring transfusions. Factors that influenced the Committee’s decision included uncertainty about the overall risk-benefit ratio in certain relevant populations (eg, women and nonwhite populations), an incomplete understanding of the clinical significance of the MIs analyzed in most of the trials, the failure of an overall effect on mortality in the primary prevention setting, and a trend toward excess strokes in that population.
Finally, while acknowledging the importance of ASA’s role in prevention of cardiovascular disease, and recognizing new guidelines from the American Heart Association, American Diabetes Association, and the US Preventative Services Task Force supporting it, the Committee voted 11–3 against the proposed label change for primary prevention of MI in patients at moderate risk.
Ranolazine is a drug that is being developed by CV Therapeutics for the treatment of angina. After the FDA issued an approvable letter on the sponsor’s New Drug Application, the Advisory Committee was asked to give advice on additional data/studies that should be available to support approval. The Committee’s discussion focused primarily on data from 2 pivotal trials (MARISA [Monotherapy Assessment of Ranolazine In Stable Angina] and CARISA [Combination Assessment of Ranolazine In Stable Angina]), comprising a total of 1014 patients, which studied the sustained-release (SR) formulation. In each study, exercise time during standard treadmill exercise testing was the principal end point.
The MARISA trial was a double-blind, randomized crossover study of 191 patients receiving placebo or doses of 500, 1000, or 1500 mg BID of ranolazine SR as monotherapy. Each treatment period lasted for 1 week. There was a dose-related increase in exercise duration as well as in time to angina and 1-mm ST depression between the 500- and 1000-mg doses, but little further change was evident above the 1000-mg dose.
The CARISA trial was a double-blind, randomized, placebo-controlled study of 2 doses of ranolazine SR, 750 and 1000 mg BID, added to once-daily background antianginal therapy consisting of a dose of atenolol (50 mg), amlodipine (5 mg), or diltiazem CD (180 mg). At the end of 12 weeks, an increase in exercise duration, time to angina, and 1-mm ST depression was again demonstrated for both doses of ranolazine SR, although no dose response was evident. Both doses caused a decrease in the frequency of angina attacks and nitroglycerin consumption.
A principal safety issue related to QT prolongation, which was linearly related to ranolazine plasma concentrations and amounted to a mean effect of <5 ms at doses of 750 mg BID, corresponding to an increase in QT of 2.4 ms per increment of 1000 ng/mL in ranolazine blood concentration. Patients with hepatic disease had a significantly steeper slope for this relationship (ie, ≈7 ms/1000 ng/mL). The sponsor’s extensive preclinical work disassociating this QT prolongation with a propensity for torsade de pointes and its absence in any patients treated with ranolazine were reassuring to some Committee members. Side effects, most marked at doses above 1000 mg BID, included orthostatic hypotension, dizziness, and syncope, leading the sponsor to recommend use at or below this dose.
The Committee agreed that ranolazine was effective as an antianginal drug with genuine potential to fill an unmet need in the management of patients with chronic angina pectoris. Members also concluded that more long-term efficacy data were required in a broader population of patients with angina to include more females, elderly patients, and African Americans. Additional data were also deemed necessary in patients taking long-acting nitrates and other vasodilators. There was mixed opinion as to the appropriateness of immediate approval for use restricted to specific clinical circumstances. No formal vote was taken.