Comparative Efficacy and Safety of Different Antiplatelet Agents for Prevention of Major Cardiovascular Events and Leg Amputations in Patients with Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis

Abstract

There is a lack of consensus regarding which type of antiplatelet agent should be used in patients with peripheral arterial disease (PAD) and little is known on the advantages and disadvantages of dual antiplatelet therapy. We conducted a systematic review and network meta-analysis of available randomized controlled trials (RCT) comparing different antiplatelet drugs (Aspirin, Ticlopidine, Clopidogrel, Ticagrelor, Cilostazol, Picotamide and Vorapaxar as monotherapies or in combination with aspirin) in PAD patients (PROSPERO public database; CRD42014010299).We collated evidence from previous relevant meta-analyses and searched online databases. Primary efficacy endpoints were: (1) the composite rate of major adverse cardiovascular events (MACE; including vascular deaths, non-fatal myocardial infarction and non-fatal stroke), and (2) the rate of major leg amputations. The primary safety endpoint was the rate of severe bleeding events. Bayesian models were employed for multiple treatment comparisons and risk-stratified hierarchies of comparative efficacy were produced to aid medical decision making. Number-Needed-to-Treat (NNT) and Number-Needed-to-Harm (NNH) are reported in case of significant results. We analyzed 49 RCTs comprising 34,518 patients with 88,358 person-years of follow-up with placebo as reference treatment. Aspirin, Cilostazol, Vorapaxar and Picotamide were ineffective in reducing MACE. A significant MACE reduction was noted with Ticagrelor plus aspirin (RR: 0.67; 95%CrI: 0.46-0.96, NNT = 66), Clopidogrel (RR: 0.72; 95%CrI: 0.58-0.91, NNT = 80), Ticlopidine (RR: 0.75; 95%CrI: 0.58-0.96, NNT = 87), and Clopidogrel plus aspirin (RR: 0.78; 95%CrI: 0.61-0.99, NNT = 98). Dual antiplatelet therapy with Clopidogrel plus aspirin significantly reduced major amputations following leg revascularization (RR: 0.68; 95%CrI: 0.46-0.99 compared to aspirin, NNT = 94). The risk of severe bleeding was significantly higher with Ticlopidine (RR: 5.03; 95%CrI: 1.23-39.6, NNH = 25), Vorapaxar (RR: 1.80; 95%CrI: 1.22-2.69, NNH = 130), and Clopidogrel plus aspirin (RR: 1.48; 95%CrI: 1.05-2.10, NNH = 215). Clopidogrel monotherapy showed the most favourable benefit-harm profile (79% cumulative rank probability best and 77% cumulative rank probability safest). In conclusion, Clopidogrel should be the indicated antiplatelet agent in PAD patients. Dual antiplatelet therapy with aspirin and Clopidogrel can reduce the rate of major leg amputations following revascularization, but carries a slightly higher risk of severe bleeding.

Fig 1. PRISMA flowchart.

Trial selection process according to the PRISMA statement.

Fig 2. Network of evidence.

Straight lines denote direct head-to-head comparisons and dotted lines denote indirect comparisons where direct comparison data is missing. Numbers refer to the number of RCTs with direct comparisons available for each link and the size of circles is proportional to the pooled sample size (person-years) available for each direct comparison.

Fig 3. Observed risk of events in control and active arms of included RCTs.

Aggregate risks of events are reported for each node and expressed as percent person-years. ^# In case of the Cilostazol versus placebo trials the numbers of cardiovascular deaths were not available separately, but fatal and no-fatal MIs and strokes were reported. * The PLATO trial included patients with acute coronary syndrome (ACS) at baseline.

Fig 4. Pooled estimates for the MACE composite endpoint, major leg amputations and severe bleeding (Fixed effects forest plot).

Antiplatelets are reported in order of efficacy or safety ranking. Black circles denote the posterior median and the black lines denote the associated 95% CrI. Numbers represent rate ratios (RR) and 95% CrIs. P values were approximated by the two-tailed posterior probabilities.

Fig 5. Pooled estimates for cardiovascular deaths, non-fatal MI and non-fatal stroke (Fixed effects forest plot).

Antiplatelets are reported in order of efficacy ranking. Black circles denote the posterior median and the black lines denote the associated 95% CrI. Numbers represent rate ratios (RR) and 95% CrIs. P values were approximated by the two-tailed posterior probabilities.

Fig 6. Benefit-harm profile of different antiplatelet agents.

Two-dimensional ranking of antiplatelet agents according to safety (y axis) and efficacy (x axis) based on the cumulative rank probabilities (SUCRA; %). The top right corner denotes therapies with the most favourable benefit-harm profile (safe and effective).

Fig 7. Class-level network fixed effects forest plots.

Classes of antiplatelet agents are reported in order of efficacy or safety ranking. Black circles denote the posterior median and the black lines denote the associated 95% CrI. Numbers represent rate ratios (RR) and 95% CrIs. P values were approximated by the two-tailed posterior probabilities.

Fig 8. Icon arrays of absolute event rates.

Icon arrays showing composite absolute event rates of MACE (blue) and severe bleeding (red) for different classes of antiplatelet agents in PAD patients. Results based on Bayesian fixed effects modelling of the secondary condensed class-level network of evidence.

Fig 9. Hierarchical risk stratification analysis.

Meta-regression was employed to address baseline risk variability and produce risk stratified hierarchies of antiplatelet comparative efficacy. Coefficients of baseline risk meta-regression analysis were combined with the uncertainty surrounding the posterior medians of the rate ratios of events for each treatment to calculate the level of risk where each treatment is projected to reach statistical significance (97.5% CrI of the posterior median crosses unity). Numbers refer to percent person-years of baseline risk of events (low risk: <1%, intermediate risk: 1–2%, high risk: >2%).