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Beraprost for Treatment of Intermittent Claudication - Beraprost for Treatment of Intermittent Claudication
Description:
The goal of the trial was to evaluate the effect of beraprost sodium, an orally active prostaglandin I2 analogue, on treadmill exercise performance, quality of life (QOL), and ischemic events in patients with intermittent claudication.
Hypothesis:
Beraprost will improve treadmill exercise performance and QOL, and will decrease rates of ischemic events in patients with intermittent claudication.
Study Design
Study Design:
Patients Enrolled: 762
Mean Follow Up: 12 months
Mean Patient Age: mean age 66 years
Female: 23%
Patient Populations:
Age 40-80 years, stable, intermittent claudication >6 months; rest ABI ≤0.90, with a 10 mm Hg decrease in ankle pressure one minute after completing the exercise treadmill test; PFWD on a standardized treadmill test ≥164 ft (50 m) but ≤984 ft (300 m) at screening; and PFWD variability <25% between the tests performed during the run-in phase
Exclusions:
Critical limb ischemia (defined as the presence of rest pain requiring analgesics >2 weeks or the presence of lower limb ulcers or gangrene); coronary artery or peripheral artery angioplasty or surgical limb arterial bypass within the last three months; anticipated to require surgical or percutaneous revascularization within six months of randomization; currently participating in a supervised exercise regimen; stroke, MI, or deep-vein thrombosis within the last three months; nonatherosclerotic peripheral arterial disease; known abdominal aortic aneurysm ≥4.5 cm; unstable angina pectoris within the last three months; heart failure (New York Heart Association class III or IV); severe, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >95 mm Hg); anemia or any clinically significant bleeding episode within the last year; an abnormal platelet count; type I diabetes mellitus; morbid obesity; severe renal or hepatic insufficiency; and any disorder that would affect the interpretation of treadmill test results
Primary Endpoints:
Maximum walking distance on treadmill at six months after randomization
Secondary Endpoints:
Distance walked before the onset of pain; subjective walking distance, as assessed by the Walking Impairment Questionnaire; health-related QOL questionnaire (short-form 36); change in the ankle-brachial index (ABI); and the incidence of critical cardiovascular events (defined as cardiovascular death, nonfatal MI, unstable angina, stroke or transient ischemic attack, critical leg ischemia, subacute critical ischemia, peripheral angioplasty, peripheral bypass surgery, or amputation at any level)
Drug/Procedures Used:
Following a single-blinded, placebo run-in phase, patients were randomized to beraprost sodium (40 μg three times per day; n=385) taken with meals or placebo (n=377) for six months.
Principal Findings:
The primary endpoint of maximum walking distance at six months did not differ in the beraprost group (16.7%) versus the placebo group (14.6%, p=NS). There was also no difference in the secondary endpoint of pain-free walking distance (19.2% and 15.4%, p=0.24). In addition, there was no difference in maximum or pain-free walking distance when data were analyzed as per protocol, rather than intent to treat. QOL measures did not differ between the treatment groups, including baseline and final SF-36-derived physical component score (47 vs. 50 for the beraprost arm and and 50 vs. 51 for the placebo arm, p=NS for both).
The frequency of critical cardiovascular events did not differ between arms (7.3% in the beraprost group and 11.4% in the placebo group, p=NS), but the combination of cardiovascular death and myocardial infarction (MI) was significantly lower in the beraprost group (n=1) than the placebo arm (n=9; p=0.01). Several adverse events occurred more frequently in the beraprost arm versus placebo, including headache (27.5% vs. 5.0%, p<0.001), vasodilation (13.5% vs. 4%, p<0.001), diarrhea (7.3% vs. 1.3%), pain (5.5% vs. 1.1%), and nausea (4.4% vs. 1.3%; p<0.02 for all).
Interpretation:
Among patients with intermittent claudication, treatment with beraprost sodium, an orally active prostaglandin I2 analogue, was not associated with a difference in the primary endpoint of maximum walking distance at six months. Despite the lack of benefit in the primary endpoint and many of the secondary endpoint measures of claudication symptoms, cardiovascular death or MI occurred less frequently in the beraprost arm, although the overall number of events was small (n=10). A larger trial would be required to conclude whether beraprost therapy was associated with a true reduction in cardiovascular events.
The results of the present trial are similar to an earlier 300-patient US trial, which showed no benefit associated with beraprost therapy. However, results differ in the European BERCI-1 and BERCI-2 studies, in which beraprost therapy was associated with significant improvements in both peak and maximum walking distance and QOL. The authors hypothesize that the short half-life of oral beraprost therapy may in part explain the lack of clinical efficacy.
References:
Mohler ER 3rd, Hiatt WR, Olin JW, Wade M, Jeffs R, Hirsch AT. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. J Am Coll Cardiol 2003;41:1679–86.
Keywords: Intermittent Claudication, Nausea, Myocardial Infarction, Epoprostenol, Vasodilation, Platelet Aggregation Inhibitors, Diarrhea, Headache, Vasodilator Agents, Peripheral Vascular Diseases, Walking, Half-Life, Quality of Life, Exercise Test
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