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Cilostazol (Pletal) is a drug for the treatment of intermittent claudication. It allows people with this condition to exercise longer before developing their characteristic leg pain and to walk longer before they must stop because of the pain. Cilostazol’s mechanism of action is not clear. It is an inhibitor of phosphodiesterase III (PDE III), which causes it to be a vasodilator and inhibitor of platelet aggregation, these actions may contribute to its effect, but other drugs with those properties are not known to be useful in intermittent claudication. This brief summary of the basis for approval should be read with the approved labeling, which considers the clinical pharmacology of the drug and the adverse effects seen during testing.
Cilostazol was studied in 8 large controlled trials, involving over 2000 patients, comparing it to placebo and, in two studies, to pentoxifylline, the only other drug approved for intermittent claudication. In some studies two different doses of cilostazol were included. The studies were of 3-6 months duration and included male and female patients with chronic (at least 6 months) stable disease and exercise limited by claudication. Patients with pain at rest, leg ulcers, or gangrene were excluded. Patients also had to have a demonstrated fall in ankle blood pressure on exercise. In addition, patients could not have had symptomatic heart failure. In general, people with severe (New York Heart Association Class III or IV) heart failure would not have exercise limited by claudication, nor would patients with severe angina pectoris. Patients with cardiac dysfunction (e.g., decreased cardiac output or ejection fraction) that was not symptomatic were not excluded but were not specifically identified.
The primary endpoints of the studies were the distances patients could walk on a treadmill before the onset of claudication pain (initial claudication distance, ICD) and before pain became intolerable (absolute claudication distance, ACD). In addition, patients responded in 6 of the studies to a questionnaire, the Walking Improvement Questionnaire, which asked about the patients’ ability to walk during normal activities. The treadmill tests were all performed at constant speed with a grade that was constant (usually 12.5%) in 4 studies, and increased in 4 studies (at 3 minute intervals in 3 of the studies).
In 6 of the 8 studies ICD and ACD were significantly improved on cilostazol compared to placebo. One of the other two studies, showed a strong trend favoring cilostazol while the other numerically favored the drug. In one study cilostazol was superior to pentoxifylline; in the other comparison with pentoxifylline neither drug was superior to placebo. In general, 100 mg twice daily was superior to 50 mg twice daily. The 100 mg twice daily dose is recommended except for people who would have higher than usual blood levels on that dose. The results of all 8 of the studies are shown in Table I for ACD (ICD results are similar). The effectiveness of cilostazol in the symptomatic treatment of claudication is well-established by the results of six adequate and well-controlled studies. There are no data bearing on longer term aspects of treatment, such as limb preservation, rate of progression, etc.
Cilostazol was evaluated in over 2100 patients, with more than 600 treated for more than 6 months. Although acutely ill patients were excluded, 25% of patients were diabetic, 22% were post-infarction, 12% had a past history of heart failure, and 17% had a history of angina; 40% of patients were smokers.
The adverse effects seen in clinical studies are enumerated in labeling; effects notably different from placebo include headache, severe enough to cause discontinuation of treatment in 3% of patients, palpitation, tachycardia, and diarrhea.
There were, however, two important safety concerns considered by the Agency and by FDA’s Cardio-Renal Advisory Committee:
Cilostazol is a PDE III inhibitor. Other drugs with that pharmacologic property, notably milrinone, vesnarinone, enoximone, and pimobendan, have been studied for their effectiveness as inotropic agents in severe (NYHA class III and IV) heart failure and have shown increased mortality in well controlled studies. In the two largest studies with published data, of milrinone [The Promise Study, New England Journal of Medicine 1991; 325: 1468-75] and of vesnarinone [Vesnarinone Study, New England Journal of Medicine 1998; 339: 1810-16], there was an approximately 20-30% increased mortality; this was attributed to an increased risk of sudden death in the Vesnarinone Study. Flosequinan (PROFILE study, not yet published) a vasodilator with PDE III activity showed an approximately 50% increase in mortality. Results with pimobendan and enoximone in smaller studies were less clear but trended in the same direction, with the increased mortality attributed to sudden death and to progression of heart failure. A beta-agonist, xamoterol, which, like PDE III inhibitors, would increase intracellular cyclic AMP, also caused increased mortality in patients with severe heart failure; again due to sudden death and progressive heart failure. There are no data on the effects of PDE III inhibitors on people without severe congestive heart failure. The critical question therefore is whether cilostazol could have adverse effects on survival in people with claudication but without heart failure.
Clopidogrel is an anti-platelet drug indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease. Unlike aspirin, which is effective in patients with a previous heart attack or stroke but does not appear active in patients with claudication, clopidogrel appears effective in all three groups. It is therefore a potentially important drug for people with claudication and might be expected to be used by them. As both cilostazol and clopidogrel inhibit platelet aggregation, there was concern that their concomitant use could lead to excessive bleeding.
These issues were the principal concerns about which the agency sought advice at the Cardio-Renal Advisory Committee on July 9, 1998.
It is clear that available data from controlled trials of cilostazol, although relatively extensive (about 1300 cilostazol, about 1000 placebo), cannot adequately determine whether there is an increased risk of death or sudden death in the claudication population because there were far too few events in the trials to detect such an effect.
In the PROMISE study (of milrinone), for example, there were 295 deaths during a median follow-up of 6 months in about 1100 patients. In the Vesnarinone Trial there were 534 deaths in the placebo and high dose groups among 2500 patients, almost all sudden death or death due to pump failure. The increased mortality in the treated group in that study appeared entirely related to increased sudden death. Trials of cilostazol, in contrast, with an average follow up of about 4 months, had just 19 total deaths, 12 on cilostazol, 7 on placebo, for crude rates of 0.83% cilostazol and 0.68% for placebo. This gives no signal of an adverse effect, but confidence intervals are very wide. Examination of the likely cause of these deaths reveals that none represented progressive heart failure and just five plausibly could be described as sudden death (2 cilostazol, 3 placebo), for rates of 0.14% cilostazol and 0.29% placebo, again certainly not suggesting an adverse effect of cilostazol but with too little data to provide a clear answer.
Cilostazol appears to inhibit PDE III at clinical doses, causes a modest increase in heart rate (about 7 beats/minute) and a small increase in VPB rates (from 1/hour to 4/hour); patients on cilostazol were also more likely to complain of palpitations. Cilostazol is a positive inotrope in animals at doses that inhibit platelet aggregation. Cilostazol would thus be expected to have the PDE III class effect in patients with severe heart failure. The effects of a PDE inhibitor, in a non-heart failure population, on the other hand, are not known, the available data with cilostazol in that population show no adverse effect but are not adequate to rule one out.
Concern about effects of cilostazol on mortality thus does not arise from the cilostazol data themselves but from the history of the class of PDE inhibitor inotropes. Despite the absence of a signal of increased mortality, in the Cilostazol data, the Advisory Committee expressed concern about a drug that is a PDE III inhibitor. They discussed at length whether cilostazol could be approved based on its clear benefit in a debilitating, albeit not life-threatening, disease, before the mortality effect was addressed in a much larger study, and, if so, with what labeling and commitment to further study. The Committee was aware that there was no alternative therapy for many claudication patients and also knew that there were no long-term mortality data for the only alternative drug therapy, pentoxifylline. The Committee concluded, by a vote of 7-3, that properly informed patients with claudication, but without heart failure, could decide to accept the incompletely characterized risk of cilostazol. It was critical to this conclusion that there be patient and physician labeling warning against use of cilostazol by patients with heart failure and also explaining candidly to patients that the risk of a PDE III inhibitor like cilostazol in them was not fully evaluated and that there could be such a risk. The agency agreed with the Committee’s recommendation. Cilostazol will be marketed in unit-of-use packaging with attached patient labeling that will insure that patients receive a complete patient package insert each time they have a prescription filled or refilled (physician labeling and patient labeling attached.)
Both the physicians’ labeling and the patient directed labeling explicitly state that patients with congestive heart failure should not receive cilostazol (it is contraindicated), that in congestive heart failure the effects of PDE III inhibitors are known to adversely affect mortality, and that in patients with intermittent claudication the effects on mortality are not yet fully described could be adverse. In addition, the manufacturer of cilostazol (Otsuka) has agreed to conduct a Phase 4 controlled clinical trial that will enroll all patients with intermittent claudication, a sicker population than the stable patients in earlier trials. The trial will involve over 1800 patients and will be of about one year duration. It will involve a comparison of placebo, pentoxifylline and cilostazol. Morbid and mortal end-points will be measured. It should be appreciated that if that population still has a low risk of sudden death and heart failure, a still larger study (tens of thousands) would be needed to rule out the 20-30% increased risk seen in the PROMISE and Vesnarinone trials.
As clopidogrel is a potentially important drug for patients with claudication, concomitant use of the two drugs must be studied. The question asked of the Advisory Committee was whether cilostazol could be approved before these data were available. The Committee concluded that it could be approved. They were reassured by data on concomitant use of cilostazol with aspirin, showing no excess bleeding, and wide experience with multiple platelet aggregation inhibitors in patients with coronary artery disease.. Otsuka has agreed to study the interactions as a phase 4 commitment. Meanwhile, labeling will point out that there is no experience with concomitant use.
Because clopidogrel was not approved for marketing until after the cilostazol NDA had been submitted, there was no real opportunity to obtain information on combined administration of clopidogrel and cilostazol. Use with aspirin thus represented the best available assessment of the combination of cilostazol with another anti-platelet drug. There are situations in which interaction data with a marketed drug would be so critical that a new drug could not be approved without it, but this was not, in the view of the Committee or FDA, such a case. Routine decisions to require such data on interactions with newly approved drugs prior to approval of a new drug would have important implications; no development program, after all, can anticipate approvals that have not occurred and study interactions with these new agents. Nonetheless, in this case, the Committee’s advice was sought; the Committee concluded 7-3 that the interaction data should be collected after approval and its absence noted in labeling, but that its lack should not bar approval.
Consideration of cilostazol raised complex benefit/risk considerations. Clearly effective for a debilitating condition whose current treatment is often inadequate, cilostazol is a member of a pharmacologic class that is dangerous to people with severe heart failure and unstudied in other people. Cilostazol has been studied in people without heart failure, without evidence of harm, but much more data would be needed to determine that there is no risk at all. Although cilostazol would not be approvable for a trivial condition the Cardio-Renal Advisory Committee and FDA concluded that fully informed patients and physicians should be able to choose to use it to treat intermittent claudication. Patient and physician labeling will describe the basis for concern and the incomplete information available.
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