97th Meeting of the Cardiovascular and Renal Drugs Advisory Committee
July 18th and 19th, 2002
The Committee was asked to assess the request of AstraZeneca for a proposed change in the labeling of candesartan cilextil, a selective angiotensin I subtype receptor antagonist initially approved for use in 1998 for hypertension. The sponsor proposed a labeling change to support a claim of greater antihypertensive efficacy for candesartan than losartan as monotherapy. The application was based on 2 identically designed and concurrently conducted randomized, double-blind trials that used a forced titration approach comparing candesartan started at 16 mg once daily and forced titrated to 32 mg at 2 weeks, with losartan started at 50 mg and forced titrated to 100 mg once daily. The 2 studies were conducted in 1265 subjects with essential hypertension who had mean diastolic blood pressures between 95 and 114 mm Hg. At the end of 8 weeks, candesartan lowered systolic and diastolic pressure by ≈3 and 2 mm Hg, respectively, at trough, when compared with losartan.
The Committee noted that the present labels for losartan and candesartan include the recommendation that twice-daily dosing might have a greater antihypertensive effect in some patients, and hence that any claim for superiority must be restricted to once-daily dosing. Additional discussion unfolded on the likelihood that clinical benefits would be associated with the demonstrated average blood pressure decline and it was agreed that, given the similar pharmacology of the 2 agents (both angiotensin I subtype receptor antagonists), this was a reasonable supposition. It was also agreed that such a claim would be more difficult to support for agents from different classes, in which differences in adverse event profiles, metabolism, and other clinical effects could vary significantly. Finally, in light of the recently published International Conference on Harmonization guidelines, the Committee was asked whether the comparison was fair. The fairness conditions considered related to dose, patient population, and the selection and timing of end points. It was agreed that these had been satisfied. The Committee voted unanimously to support the label change.
Pravastatin and Aspirin
Bristol-Myers Squibb (BMS) resubmitted a New Drug Application for packaging pravastatin and aspirin together for secondary reduction of cardiovascular events. The resubmission aimed at providing greater dosing flexibility for the proposed combination product over that originally proposed. Thus, instead of the originally proposed unit doses of pravastatin 40 mg plus aspirin 81 mg and pravastatin 40 mg plus aspirin 325-mg, BMS now proposes to provide a wide range of dose options, including pravastatin 20 mg, 40 mg, and 80 mg, each with aspirin at either the 81 mg or the 325 mg dose, for a total of 6 dose options. The rationale for this approach is the provision of sufficient options so that physicians’ decisions about optimal dosing to reach cholesterol goals consistent with present guidelines are not sacrificed to gain the convenience (and, possibly, improved patient adherence) of the combination preparation. In addition, it is believed that the dose of aspirin intended by the physician may be more likely to be used when it is part of a prescription medication than when the patient obtains aspirin over the counter at the physician’s suggestion; in the latter situation, a wide and possibly confusing array of doses, preparations, and product trade names is available.
Data from 5 secondary prevention studies involving pravastatin were provided to support the use of acetylsalicylic acid (ASA) with pravastatin. Some patients in these studies used aspirin and some did not. Even though aspirin use or nonuse was not prescribed by the study protocols, the information was captured in care report froms and, thus, post hoc analyses were performed to assess the relative impact of the combination versus pravastatin alone. These analyses indicated incremental risk reduction from the combination without increased risk of gastrointestinal bleeding or other complications. It was also noted that a recently published metaanalysis of ASA use suggested no loss of benefit for the lower proposed aspirin dose compared with higher doses, as well as an increased frequency of side effects at higher doses.
Substantial discussion focused on the labeling of the proposed new combination and the need to alert patients and physicians about the ASA content of the product, as well as the potential need to discontinue it before certain procedures, especially those involving surgery in a confined space (eg, neurosurgery).
In a 7-to-1 vote, the Committee supported the copackaging of 20 mg, 40 mg, and 80 mg pravastatin with 81-mg and 325-mg doses of ASA. It was recognized that, should this product be approved, it would differ importantly from other approved cardiovascular combination products (like antihypertensives) in that the combination product comprises agents affecting different pathophysiological processes impacting on the same clinical end point. Although it was appreciated that such an approval would set a precedent that might lead to other combinations to simplify patient adherence to increasingly complex multidrug therapy, the Committee noted that any applications for other drug combinations would need to be judged individually.
The Committee reviewed data submitted by Bristol-Myers Squibb on omapatrilat, a vasopeptidase inhibitor that simultaneously inhibits angiotensin-converting enzymes (ACEs) and neutral endopeptidase. This agent is the first antihypertensive to combine these actions in one molecule. BMS originally submitted an NDA in 1999, but the NDA was withdrawn on the basis of discussions with the Food and Drug Administration in the first quarter of 2000 and concerns about severe angioedema in initial clinical trials. Subsequently, BMS sponsored the Omapatrilat Cardiovascular Treatment Versus Enalapril (OCTAVE) study, a large double-blind trial (n=25 302) comparing omapatrilat with enalapril over 24 weeks in hypertensive patients. The study population comprised 3 subcohorts: patients with (1) untreated or (2) previously treated mild or moderate hypertension and (3) patients with moderate to severe hypertension (≤180/110 mm Hg on prior therapy).
Each drug was titrated to the highest dose suggested in its respective label, or to a maximally tolerated dose if lower: The omapatrilat starting dose was 10 mg once daily, uptitrated to 20 mg, 40 mg, and 80 mg at 2 week intervals; enalapril was started at 5 mg once daily and titrated to 40 mg once daily. The trial demonstrated that, compared with the 40 mg daily peak dose of enalapril, omapatrilat 80 mg PO daily lowered blood pressure further, by approximately 3 mm Hg (systolic) and 2 mm Hg (diastolic). During 2 protocol-defined follow-up visits, patients on omapatrilat required additional antihypertensive therapy to achieve the target of 140/90 mm Hg less frequently than patients receiving enalapril.
Because of concerns raised by the findings of earlier studies with omapatrilat, this large trial was powered to define the frequency (as well as the range of severity) of angioedema with omapatrilat versus the ACE inhibitor. Angioedema was observed in 274 (2.17%) patients receiving omapatrilat versus 86 (0.68%) patients receiving enalapril (risk ratio 3.17 [95% CI 2.52-4.12]). The individual episodes with omapatrilat were more severe and their timing was earlier than with enalapril—the majority occurred within the first few hours after the initial dose. Risk factors for angioedema with omapatrilat were identified, most prominently including race (African Americans had higher risk) and smoking history, but no factors were identified that conferred risks as low as those associated with enalapril.
The Committee generally accepted the suggestion that omapatrilat is a particularly potent antihypertensive relative to ACE inhibitors and other comparator drugs within the dose ranges tested. Furthermore, the Committee generally accepted the likelihood that a population could be found in which control of hypertension could not be achieved with presently available regimens and for which, therefore, the addition of omapatrilat would provide putative clinical benefits (prevention of cardiovascular events) that exceed the risks associated with angioedema of the frequency and severity reported in OCTAVE. However, the Committee was concerned that the sponsor had not defined that population with adequate precision for labeling and had not specifically assessed the efficacy and safety of the drug in that population. Finally, the Committee was concerned that the sponsor’s plan for a patient education program to minimize the risks associated with angioedema was unlikely to provide a substantial safety margin.
The Committee voted 5-to-1 to reject BMS’s application for approval of omapatrilat to treat hypertension.