For patients with unstable angina or non–ST elevation myocardial infarction (UA/NSTEMI), antiplatelet and anticoagulant medications are prescribed to reduce and prevent ischemic events and mortality. There is uncertainty about the optimal dosing and timing of these medications to balance ischemic risk and bleeding risk across different treatment strategies (early invasive, initial conservative, and postdischarge).
We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies.
Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded evidence. When possible, random-effects meta-analysis was used to compute summary estimates of effects.
Our review included 175 studies (302 articles); 87 studies were relevant to early invasive management, 33 were relevant to initial conservative management, and 71 were relevant to the postdischarge setting.
Patients undergoing an early invasive approach
Upstream (precatheterization) treatment using glycoprotein IIb/IIIa inhibitors (GPIs) was associated with lower rates of revascularization (odds ratio [OR] 0.77; 95% confidence interval [CI], 0.65 to 0.92) but higher risk of major bleeding events (OR 1.24; 95% CI, 1.08 to 1.43) at 30 days compared with deferred (periprocedural) GPI treatment (high strength of evidence [SOE]). This higher risk of bleeding from upstream GPI administration also occurred with either pretreatment (OR 1.49; 95% CI, 1.10 to 2.01; moderate SOE) or deferred clopidogrel administration (OR 1.27; 95% CI, 1.08 to 1.50; high SOE). Compared with clopidogrel, prasugrel reduced rates of cardiovascular death, myocardial infarction, or stroke at 30 days (5.7% prasugrel vs. 7.4% clopidogrel; moderate SOE). After 1 year, in a subgroup of patients who all had UA/NSTEMI, prasugrel reduced rates of the same composite endpoint compared with clopidogrel (9.9% prasugrel vs. 12.1% clopidogrel), as did ticagrelor (10.6% ticagrelor vs. 12.6% clopidogrel) (moderate SOE). Bivalirudin reduced major bleeding events at 30 days compared with heparin in several clinical scenarios: with planned GPI use (OR 0.52; 95% CI, 0.43 to 0.63); without planned GPI use (OR 0.63; 95% CI, 0.47 to 0.85; both high SOE); and in patients treated with clopidogrel before undergoing percutaneous coronary intervention (OR 0.64; 95% CI, 0.49 to 0.85; moderate SOE). Bivalirudin also reduced minor bleeding events at 30 days compared with heparin plus GPI (OR 0.49; 95% CI, 0.42 to 0.59; high SOE).
Patients undergoing an initial conservative approach
In randomized trials, enoxaparin reduced composite ischemic events (OR 0.84; 95% CI, 0.76 to 0.93; high SOE) and myocardial infarction (OR 0.85; 95% CI, 0.76 to 0.95; moderate SOE) at around 30 days compared with unfractionated heparin. The addition of GPIs to unfractionated heparin reduced the rate of mortality up to 30 days (OR 0.80; 95% CI, 0.67 to 0.96), but minor bleeding rates were increased (OR 1.62; 95% CI, 1.20 to 2.19; both high SOE).
Dual antiplatelet therapy (DAPT) reduced the rates of composite ischemic outcomes (ORs/relative risks ranging from 0.69 to 0.80; in-hospital, 9 months, and 1 year) and nonfatal myocardial infarction (DAPT 2.3% to 5.8% vs. aspirin 3.0% to 8.5%; 9 months and 1 year) compared with single antiplatelet therapy (high SOE). Meta-analyses using adjusted or propensity-scored hazard ratios from observational studies showed an association between proton pump inhibitor (PPI) use (any type with dual antiplatelet use) and increased rates of composite ischemic endpoints, death, nonfatal myocardial infarction, stroke, revascularization, stent thrombosis, and major bleeding. (Most outcomes were measured around 1 year and rated low SOE, and ratings were downgraded since the findings conflicted with the few randomized trials of omeprazole.) However PPIs with DAPT use reduced rates of upper gastrointestinal bleeding (moderate SOE).
This review was limited to comparative studies of antiplatelet and anticoagulant treatments, many of which did not separate findings by treatment approach (invasive, conservative, postdischarge) and included a mix of UA/NSTEMI and acute coronary syndrome populations. Also, different definitions of composite endpoints made quantitative analysis less feasible. Few trials of percutaneous coronary intervention reported long-term outcomes, and very few studies reported findings in the subpopulations of interest.
The number of studies available for each comparison was relatively small, and the preponderance of observational studies made the findings for some comparisons inconclusive. Further study is needed to determine the effectiveness and safety of newer agents in combination with other antiplatelet and anticoagulant strategies. Uncertainty remains about the optimal dosing, timing, duration, and combinations of these options, especially in subpopulations of interest (e.g., the elderly, patients with diabetes, women, obese patients, and people with comorbid illness).
Washam JB, Dolor RJ, Jones WS, et al. Dual antiplatelet therapy with or without oral anticoagulation in the postdischarge management of acute coronary syndrome patients with an indication for long term anticoagulation: a systematic review. J Thromb Thrombolysis. 2014 Jun 3. [Epub ahead of print] PMID: 24891133.
Melloni C, Washam JB, Jones WS, et.al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes. 2015 Jan;8(1):47-55. PMID: 25587094.