薬 剤 疫 学 JPn J pharmacoepidemiol, 9 (2) Dec 2004:45
●Original Article
Oral Beraprost Sodium as a Prostaglandin 12 Analogue for Vascular Events in Patients with Peripheral Arterial Disease : Meta-Analysis of Two Placebo-Controlled Randomized Trials
Hideki ORIGASA*1, Yasuo IKEDA*2, Kazuyuki SHIMADA*3, Hiroshi SHIGEMATSU*4
Key words : prostacyclin, beraprost sodium, meta-analysis, intermittent claudication, vascular event
improvement of endothelial function3). Bera- Introduction prost was launched in the Japanese market in Beraprost sodium (beraprost) is an orally 1992 and is currently marketed in 3 Asian active prostaglandin I2 (PGI2) analogue, with counties to treat ischemic symptoms in chronic antiplatelet1), and vasodilating properties2) and arterial occlusion and primary pulmonary
*1 Division of Biostatistics , Faculty of Medicine, Toyama Medical and Pharmaceutical University, Japan *2 Division of Hematology , Department of Internal Medicine, Keio University School of Medicine, Japan *3 Department of Cardiology , Jichi Medical School, Japan *4 Department of Surgery , Faculty of Medicine, the University of Tokyo, Japan Address for correspondence : Hideki ORIGASA, Faculty of Medicine , Toyama Medical and Pharmaceuti- cal University, 2630 Sugitani, Toyama 930-0194, Japan 46 Original Article hypertension. Ilprost is also known to be a PGI, analogue. It is administered intravascularly (iv) and is targeted for more severe (Fontane stages III and IV) patients. The efficacy of ilprost has also been demonstrated by a meta-analysis4). There- fore, this study is limited to the efficacy of beraprost for more mild (Fontane stages II ) patients. Although PGI, analogues were expected to be clinically applied in various ways due to their physiological activities5'6), there are only a few reported placebo-controlled double-blind trials with PAD as the target disease to demon- strate efficacy in the treatment of arterioscler- otic disease). Likewise, all reported trials of beraprost have only targeted PAD among arter- iosclerotic diseases. For beraprost, there have been four reported placebo-controlled, randomized, double-blind trials in patients with intermittent claudication (IC) due to PAD8-11). Of these four, two phase 3 trials'") had claudication and cardiovascular events as outcome measures. A BERCI-2 tria110) Fig. 1 Literature search process (1966-2003) conducted in France and Italy demonstrated a significant improvement in claudication, while a study conducted in the United States11) Methods showed no statistically significant difference. Noteworthy was that the drug's tendency to 1. Trial selection improve cardiovascular events was observed in As shown in Figure 1, for the time period of both studies ; however, a statistically signifi- 1966 to 2003, a total of 224 articles were cant difference was absent, which indicates that retrieved by the Medline database using the beraprost has not been fully proved to be effec- keyword "beraprost". Limiting the search to tive for cardio/cerebrovascular events includ- the publication type of randomized controlled ing myocardial infarction, cardiovascular trial resulted in 13 articles. Among these 13 death, and stroke as endpoints. articles, 3 articles (Phase I trial) and 7 articles A meta-analysis of the two phase 3 trials was (other target diseases) were excluded as being performed to evaluate the effect of beraprost unrelated to our study purpose. The remaining on vascular events in more than 1,000 patients. 3 articles8,10,11)were thus regarded as candidates The present meta-analysis not only assesses the for evaluation. In addition, a single study9) was value of beraprost in reducing vascular events selected by a hand-search method. Since two of but also provides important information for the studies") did not deal with the endpoint of conducting clinical trials with cardio/cere- vascular events, the remaining two studies1011) brovascular events as a primary outcome mea- were evaluated for the preventive effect of sure. beraprost on vascular events. Of these two studies, one was the BERCI-2 trial10) involving 薬 剤 疫 学 JPn JPharmacoepldemiol, 9 (2) Dec 2004:47
549 patients in France and Italy, while the other events include lower limb deterioration and involved 897 patients in the United States (US cardio/cerebrovascular events, which were as- trial")) . The primary outcome measure in these sessed separately. Lower limb deterioration two trials was walking distance as evaluated by was regarded as a measure of PAD progression, the treadmill test. In addition, vascular events while cardio/cerebrovascular events were were assessed as a secondary outcome measure. evaluated to focus on ischemic heart disease 2 . General protocol and ischemic stroke. Both trials consisted of patients who met the 6 . Statistical analysis inclusion criteria after a single-blind placebo Statistical analysis was performed according run-in-phase and who were randomly assigned to the intention-to-treat population for the pri- to receive either beraprost (40 ,ug t.i.d.) or a mary studies. P-values were computed using the placebo (t.i.d.) for six months. Mante1-Haenszel chi-square test based on a 2× 3. Outcome assessments 2contingency table. A fixed effects model was The present analysis used vascular events as used to estimate the pooled risk ratio based on outcome measures. Since the US trial") and the a 2×2 table and its 95% confidence interval BERCI-2 trial") were conducted according to (CI) according to Mantel-Haenszel method. similar protocols, these two trials had the same Heterogeneity between the trials was examined definition of cardiovascular events including : using the Cochran's Q-test12®. A two-sided p- death of cardiovascular origin (confirmed or value of less than 0.05 was considered to be sudden death) , nonfatal myocardial infarction, statistically significant. Statistical analyses unstable angina, stroke or transient ischemic were performed by using Comprehensive Meta- attack, critical leg ischemia (rest pain neces- Analysis® software version 1.0.23. sitating an urgent medical intervention or a Results surgical procedure to avoid amputation) , subacute critical ischemia (continuous rest pain 1. Baseline characteristics for > 2 weeks requiring analgesics) , peripheral At randomization after the run-in-period, the angioplasty, peripheral bypass surgery, and BERCI-2 trial consisted of 209 patients in the amputation at any level. beraprost group and 213 patients in the placebo To avoid any potential bias by the investiga- group, while the US trial had 385 and 377 in the tor in event evaluation, in the US trial"), all beraprost and placebo groups, respectively. vascular events were adjudicated by an in- Baseline characteristics are shown in Table 1. dependent Critical Cardiovascular Events Com- As compared with the patients in the BERCI-2 mittee, while, in the BERCI-2 trial"), every trial, those in the US trial had slightly lower potential vascular event was fully documented ankle-brachial indices (ABIs) and shorter maxi- and evaluated blindly by three experienced mum walking distances (MWDs) . In addition, cardiologists. they were more likely to have hypertension, 4 . Study patients diabetes mellitus, or dyslipidemia. In the US Both trials had similar inclusion criteria with trial, 65%, 6.3%, and 0.5% of the patients the exception of patient age (BERCI-210), 35-75 concomitantly used aspirin, clopidogrel, and years ; US trial"), 40-80 years) and concomitant ticlopidine, respectively. medication (aspirin, clopidogrel, and ticlopidine 2 Incidence of vascular events were allowed in the US trial" but not in the Vascular events occurred in 29 patients BERCI-2 trial")) (6.9%) in the BERCI-2 trial and 71 patients 5. Endpoints (9.3%) in the US trial. Cardio/cerebrovascular The primary endpoint was defined as all events other than lower limb events were vascular events for this meta-analysis. These documented in 7 patients (1.7%) in the BERCI- 48 Original Article
Table 1 Baseline characteristics by treatment group for US trial and BERCI-2 trial
ABI : ankle-brachial index, MWD : maximum walking distance, PFWD : pain-free walking distance
2 trial and 45 patients (5.9%) in the US trial. p = 0.079) and the pooled risk ratio for cardio/ Overall, the incidence was higher in the US cerebrovascular events was 0.619 (95%CI : trial. 0.36 to 1.09, p = 0.085) ; these were statisti- Comparison between beraprost and the cally insignificant but similar to that for all placebo revealed that beraprost was associated vascular events. Heterogeneity among the two with a reduced incidence of vascular events in studies was not found in the risk ratio for any both trials ; events occurred in 10 beraprost- of these endpoints. treated patients (4.8%) and 19 placebo-treated Discussion patients (8.9%) in the BERCI-2 trial while 28 beraprost-treated patients (7.3%) and 43 1 Risk of vascular events in patients with PAD placebo-treated patients (11.4%) were reported The incidence of cardio/cerebrovascular to have had events in the US trial (Table 2). events was 1.7% in the BERCI-2 trial10) and Both trials showed similar risk reductions for 5.9% in the US trial11), a finding that highlights vascular events with 46.4% in the BERCI-2 an increased risk of cardio/cerebrovascular trial and 36.2% in the US trial. The number events in patients with PAD. The incidence of needed to treat was also quite similar, 24 for the nonfatal cardiovascular events in patients with US trial and 25 for the BERCI-2 trial. IC has been reported to be 2-4% annually13). 3. Meta-analysis The value for BERCI-2 was similar to the Figure 2 shows the results of the meta- previously reported one ; however, the US trial analysis of the two trials examining vascular gave a higher incidence only for six months. events. The pooled risk ratio was 0.608, indicat- In the Cardiovascular Health Study14), ABIs ing a significant risk reduction of beraprost on was closely correlated to the number of all vascular events (95%CI : 0.41 to 0.90, p= patients with myocardial infarction, angina, 0.012). The pooled risk ratio for lower limb and congestive heart disease. ABIs, smoking, deterioration was 0.598 (95%CI : 0.34 to 1.06, diabetes, hypertension, white cell count, 薬 剤 疫 学 JPn J pharmacoepidemio1, 9 (2) Dec 2004:49
Table 2 Summary of the vascular events in intention-to-treat population
Fig. 2 Meta-analysis of two randomized trials of beraprost sodium therapy for vascular events 50 Original Article asymptomatic carotid disease and fibrinogen elderly in Amami Island, Japan"). The three- have all been reported as predictors of mortal- year survival rate was 66.3% for patients with ity13). arteriosclerosis obliterans (ASO) and 74.3% for The US trial included patients with lower non-ASO individuals (p= NS) . ASO was fre- ABIs and a high number of patients with quently associated with cardiovascular deaths, diabetes mellitus, hypertension, or dys- with the most common cause of death being lipidemia. These factors may have affected the acute myocardial infarction (p < 0.05) . As in difference between the two trials. other countries, ASO is a disease with a poor 2. Risk reduction of beraprost on cardio/cere- life prognosis in Japan. brovascular events and limb deterioraion For the life prognosis of patients with ASO, In both trials, the total number of vascular Miyazaki et al. reported a retrospective study events was not statistically significant, but it of pharmacologic interventions17). In patients was relatively low in the beraprost group. In with ASO receiving various antiplatelet agents the US trial, there was a significant reduction after undergoing femoral-peripheral artery by- in the combination of cardiovascular death and pass graft, a multiple logistic regression analy- myocardial infarction in the beraprost group. sis including potential prognostic factors As expected, the meta-analysis of two trials has revealed that only beraprost significantly im- demonstrated the significant risk reduction of proved lifelong prognosis among antiplatelet beraprost in vascular events. Analyses showed agents such as aspirin and ticlopidine. This similar risk reductions of 39% (p=0.012) for report suggests that beraprost also reduces overall events, 40% (p= 0.079) for lower limb vascular events in Japanese PAD patients. events, and 38% (p=0.085) for cardio/cere- These promising effects should be evaluated brovascular events. Since stratification reduced prospectively in future trials of beraprost with the number of events and statistical power, vascular events as the primary outcome. Six these figures failed to reach significant levels. months is a widely accepted period for evaluat- Taken together, the results suggest that bera- ing treadmill walking distance as a primary prost may prevent the progression of arterio- outcome. However, periods of a year or longer sclerosis not only in peripheral arterial disease are suggested in such prevention trials to obtain but also in "systemic arterial disease". clinical relevance. A report by Antithrombotic Trialists' Collab- 4 Methodological limitation oration") described 26 trials of antiplatelet The two selected studies10,11)have utilized the agents in patients with IC due to PAD, estimat- log-rank test for comparison between groups. ing a 23% odds reduction for antiplatelet ther- They also presented the p-value obtained by a apy. The present analysis with beraprost also log-rank test. However, they did not show a gave a similar result. The goal of treatment in hazard ratio and have just shown the number of patients with intermittent claudication is to events per total number of patients. Thus, the extend walking distance, and the prevention of information obtained from articles was nothing the progression of lower limb disease is a thera- but several 2×2 contingency tables. The pres- peutic goal of PAD medications. The present ent meta-analysis should combine the hazard meta-analysis showed promising effects of ber- ratio across the studies since the time to event aprost in preventing the progression of lower was a primary outcome. However, their limb arteriosclerosis. detailed data was not presented in the articles. 3. Relevance of these findings to PAD treat- So that, there was only a way to combine the ment in Japan risk ratios computed by 2×2 contingency Ojiro and Yamazumi reported an tables. The bias caused by using a risk ratio epidemiological study of nursing homes for the rather than a hazard ratio is considered to be 薬 剤 疫 学 JPn J pharmacoepidemiol, 9 (2) Dec 2004:51 quite small since the two studies had a common diovasc Pharmacol 1996 ; 27 : 788-93. 6-month follow-up and the hazard is considered 9) Labs KH, Nehler MR, Roessner M, Jaeger KA, Hiatt WR. Reliability of treadmill testing in to be constant during this period. peripheral arterial disease : a comparison of a constant load with a graded load treadmill Acknowledgements protocol. Vasc Med 1999 ; 4 : 239-46. This study was partly supported by a grant-in- 10) Lievre M, Morand S, Besse B, Fiessinger JN, aid for scientific research from the Japanese Boissel JP. Oral Beraprost sodium, a prostaglan- Health and Labour Science (H15-Medicine-032) . din 12 analogue, for intermittent claudication : a double-blind, randomized, multicenter controlled trial. Beraprost et Claudication Inter- References mittente (BERCI) Research Group. Circulation 2000 ; 102 : 426-31. 1) Yang L, Yatomi Y, Satoh K, Ozaki Y. Inhibitory 11) Mohler ER 3rd, Hiatt WR, Olin JW, Wade M, effects of beraprost on platelet aggregation. Jeffs R, Hirsch AT. Treatment of intermittent Comparative study utilizing two methods of claudication with beraprost sodium, an orally aggregometry. 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Med J Kagoshima Univ treatment of peripheral arterial disease and 2000 ; 52 : 1-6. (In Japanese) pulmonary arterial hypertension. Drugs 2002 ; 17) Miyazaki K, Nishibe T, Sata F, et al. Prosthetic 62 : 107-33. grafts for above-knee femoropopliteal bypass. A 7) Reiter M, Bucek RA, Stumpflen A, Dirisamer A, multicenter retrospective study of 564 grafts. Int Minar E. Prostanoids in the treatment of inter- Angiol 2002 ; 21 : 145-51. mittent claudication : a meta-analysis. Vasa 2002 ; 31 : 219-24. 8) Lievre M, Azoulay S, Lion L, Morand S, Girre Manuscript recieved November 29, 2004 ; JP, Boissel JP. A dose-effect study of beraprost revised January 21, 2005 ; sodium in intermittent claudication. J Car- accepted January 31, 2005