American Heart Association (AHA)/American College of Cardiology (ACC)/American Diabetes Association (ADA) [22]
1. Aspirin is reasonable in diabetic patient whose 10 year risk of events is >10 % and who are not at increased risk of bleeding
2. Aspirin may be considered for diabetic patients with intermediate risk of cardiovascular events (younger patients with at least risk factor, older patients with no risk factors, or patients with a 10-year risk of 5–10 %)
Aspirin (75–100 mg daily) for persons age 50 years or older without symptomatic CVD (Grade 2B)
US Preventative Services Task Force [23]
Low dose Aspirin for men 45–79 years and women 55–79 years when the potential benefit due to reduction of MI outweighs the potential harm due to increase in gastrointestinal hemorrhage (Grade A). Risk factor calculator for available at http://cvdrisk.nhlbi.nih.gov/calculator.asp
European Society of Cardiology [24]
Aspirin is not recommended in individuals without cardiovascular or cerebrovascular disease due to increased risk of major bleeding (Class III, Level of Evidence: B)
As there is already a concern of increased bleeding with aspirin alone for primary prevention, it is no surprise that combining with an anticoagulant in primary prevention leads to even further increases in bleeding. There are limited data that assess combination therapy in the primary prevention cohort. One meta-analysis of ten randomized controlled trials performed by Dentali et al. assessed the treatment of combination warfarin-ASA compared to warfarin alone primarily in patients where the indication for aspirin was the primary prevention of cardiovascular disease (both CAD and stroke) [25]). Six of the trials used low dose aspirin (<100 mg), and four of the trials had higher doses of aspirin. The risk for cardiovascular events was significantly reduced by combination warfarin-ASA therapy (OR = 0.66; 95 % CI: 0.52–0.84). However, this therapeutic benefit was driven by five studies involving patients with mechanical heart valves (OR = 0.27; 95 % CI: 0.15–0.49). There was no statistically significant cardiovascular event reduction in the other studies where the warfarin was given for other indications. The aforementioned meta-analysis also assessed the risk for major bleeding associated with combination warfarin-ASA compared with warfarin alone. There was an increased risk for major bleeding with warfarin-ASA over warfarin alone, with an annual risk of 2.3 % vs. 1.3 %, a difference that was clinically relevant, although it was of borderline statistical significance (OR = 1.43; 95 % CI: 1.00–2.02).
In the ORBIT AF registry, it was found that despite this known evidence, it is common in up to 35 % of patients in atrial fibrillation in modern practice to be on combination therapy with an antiplatelet on top of an anticoagulant [26]. A significant proportion of this population (39 %) was on the antiplatelet agent for primary prevention only. As this was a more modern study, most (89 %) patients were on an 81 mg dose of aspirin. This study also confirmed what was postulated in the prior meta-analysis: combination therapy was associated with more major bleeding (adjusted hazard ratio, 1.53; 95 % confidence interval, 1.20–1.96 p = 0.0006) with no benefit in preventing ischemic outcomes leading toward a trend in increased mortality in the dual therapy group (adjusted hazard ratio 1.26 (0.98–1.63) p = .08).
Overall, there does not appear to be compelling evidence that warfarin-ASA combination therapy is more effective than warfarin alone for the prevention of cardiovascular events in patients with atrial fibrillation. There is, however, consistent evidence that warfarin-ASA therapy increases serious bleeding, irrespective of the patient population studied. As stated above, the group of patients with mechanical heart valves should be considered separately as combination therapy has shown net clinical benefit. Patients with mechanical valve prostheses require long-term anticoagulation and aspirin administration due to the inherent risk of thromboembolism. This is primarily due to abnormal flow conditions (stagnation and shear stress flow) imposed by the prosthetic heart valves, increasing both the risk of thrombosis and thromboembolism [27]. In a Cochrane report, 13 studies involving 4122 patients were reviewed [28]. Compared with anticoagulation alone, the addition of an antiplatelet agent (either dipyridamole or ASA) reduced the risk of thromboembolic events (odds ratio (OR) 0.43, 95 % confidence interval (CI) 0.32–0.59; P < 0.00001). This came at the expense of an increase in major bleeding (OR 1.58, 95 % CI 1.14–2.18; P = 0.006), despite the fact that low dose aspirin (<100 mg) was used in a majority of the trials that included aspirin as the antiplatelet agent. However, the net clinical benefit favored the combination of an anticoagulant plus an antiplatelet, as there was shown to be decreased mortality (OR 0.57, 95 % CI 0.42–0.78; P = 0.0004). In summary, patients with mechanical heart valves derive a net therapeutic benefit with warfarin-ASA as the reduction in thromboembolic events outweighs the increase in the risk for serious bleeding and this combination is endorsed by the latest American College of Cardiology (ACC) 2014 guidelines on Valvular heart disease [29].
Secondary Prevention
While it is fairly clear from primary prevention that the risk of bleeding outweighs the benefit of a combination of antiplatelet therapy and anticoagulation, there is much more controversy in the realm of secondary prevention. There are many different secondary prevention scenarios (stable CAD, acute coronary syndromes, patients after recent coronary artery bypass surgery (CABG), and patients after recent stenting) each of which have different ischemic risk profiles in which to balance the bleeding risk. As we make our decision as to what regimen to give, we are always balancing a risk/benefit ratio of ischemic efficacy vs bleeding risk. The ischemic benefit of the antiplatelet therapy on top of the anticoagulants is quite different in each of those secondary prevention scenarios. Unfortunately, there are not enough data available to cover every different drug in every different clinical scenario. However, we must examine these clinical scenarios separately and review the data that are available and the subsequent guideline recommendations from the major medical societies.
Secondary Prevention of Stable CAD
The ACC guidelines on secondary prevention in stable ischemic heart disease state that aspirin monotherapy (or other antiplatelet if allergic) is a Class I indication to continue lifelong [30]. For a patient on anticoagulation for thrombotic disease, the anticoagulants are more efficacious as compared to antiplatelet agents in preventing a thrombotic event in the common clinical scenarios of deep vein thrombosis (DVT), pulmonary embolism (PE), and atrial fibrillation [31]. It is common in up to 11 % of the population with stable coronary artery to have an indication for anticoagulation [32]. In this situation, it is common for practitioners to combine an antiplatelet agent with an anticoagulant with the thought that they are treating two separate diseases with two separate targeted therapies. However, recent real world registries have shown that the combination can lead to serious bleeding which is an independent predictor of mortality [32, 33]. In the CORONOR trial, over 4000 patients with stable CAD (at least 1 year out from any acute coronary syndrome or revascularization procedure) were prospectively studied over a 2 year period [32]. Patients on an anticoagulant in addition to an antiplatelet had a 7.3 times increased risk of bleeding in comparison to antiplatelet monotherapy. This trial only assessed significant (Bleeding Academic Research Consortium (BARC) 3 or higher) bleeding, and indeed the bleeding events were an independent predictor of mortality in this stable CAD population. There was no downside (no increased ischemic stroke, myocardial infarction or cardiovascular death) to being on a single anticoagulant alone as compared to being on an anticoagulant plus an antiplatelet agent. Therefore, this study clearly shows the benefit of only taking anticoagulation alone (without the addition of any antiplatelet agent) in a stable coronary artery disease patient that is at least 1 year out from an acute coronary syndrome or any type of revascularization that has a definite indication for anticoagulation. One limitation of this study was that the dosing of aspirin was not reported. A larger observational cohort study of 8700 Danish patients with both atrial fibrillation and stable coronary artery disease backs up this hypothesis as well [33]. They showed that relative to warfarin monotherapy, there was no decrease in the risk of MI or coronary death associated with the use of warfarin plus an antiplatelet agent. In fact, if triple combination therapy was used, there was actually an increase in this ischemic risk. There was also comparative benefit in all of these groups in terms of preventing thromboembolism. On the flip side, bleeding risk hazard ratios were significantly (50–80 %) higher on dual therapy and up to 100 % higher with triple therapy as compared with monotherapy with warfarin alone. Bleeding was also shown to be an independent predictor of mortality in this study as well. What about trying antiplatelet therapy alone in this population? This population had over 95 % of the patients with a CHADS2VASC2 score of ≥2. Antiplatelet therapy alone did have decreased bleeding risks, but in exchange there was increased MI, cardiovascular death, thromboembolism and mortality. Therefore, this is not an acceptable alternative. One limitation of this large data set was that the exact aspirin dosing was not reported and broken down to the individual endpoints, although it was stated that all doses were <150 mg i.e. a relatively low dose. A second limitation was that there were no patients on NOACS or new antiplatelet agents in this trial. However, the combination of dual or single antiplatelet therapy in addition to NOACs has been shown to have a similarly increased bleeding risk without additional stroke prevention benefit [34, 35]. Current guidelines do not provide guidance on combination therapy in this stable ischemic heart disease population.
Secondary Prevention after Acute Coronary Syndrome (ACS) or Percutaneous Coronary Intervention (PCI)
Most ACS patients will undergo an early invasive strategy which frequently leads them to revascularization by CABG or stenting. It is clear from the early stent trials that antiplatelet therapy is more efficacious in preventing stent thrombosis than warfarin alone or with warfarin with a single antiplatelet agent [36–39]. However, these trials involved early generation bare metal stents that were not necessarily deployed appropriately and would be expected to be at a higher risk of thrombosis than current stent deployment techniques with thin strut bare metal stent systems or second /third generation drug eluting stent (DES) systems. On the other hand, it is also clear that dual antiplatelet therapy alone is not a substitute for anticoagulation in those patients at risk of stroke [40]. Therefore, it is important to assess newer trials in the DES area to see where the net clinical benefit of multiple pharmacologic regimens lie.
Initial registry data (n = 239) showed the combination of warfarin plus clopidogrel as having no stent thrombosis compared to a 15 % rate with warfarin plus aspirin, as well as a higher MI rate of 18.2 % vs 11 % [41]. This was followed by the large Danish registry assessing over 12,000 patients with atrial fibrillation that had a recent MI or PCI on various anticoagulant regimens [42]. This registry showed no increased risk of an ischemic coronary event in double therapy (anticoagulant plus single antiplatelet) vs triple therapy (dual antiplatelet plus anticoagulant). On the other hand, the bleeding risk was lower with dual therapy as compared to triple therapy. When clopidogrel was the antiplatelet agent, this lower bleeding risk was not statistically significant, compared to aspirin which did have statistically significant lower bleeding. One limitation of this trial was that aspirin dosing was not reported. All-cause mortality was statistically significantly lower with the combination of an oral anticoagulant plus clopidogrel in comparison to an oral anticoagulant plus aspirin. As a whole, these registry data are hypothesis-generating suggesting that a combination of clopidogrel plus an oral anticoagulant alone might be the best combination when a stent is placed and both an anticoagulant and an antiplatelet is needed.
The warfarin and clopidogrel combination was more definitively tested in the multicenter, randomized WOEST trial [43]. The WOEST trial studied 573 patients who were on long term anticoagulation for multiple clinical indications (majority of patient had atrial fibrillation) and who were undergoing PCI (25–30 % with acute coronary syndromes). Patients were randomized to receive triple therapy (aspirin at a dose of 80–100 mg, clopidogrel 75 mg, and warfarin) versus dual therapy with warfarin plus clopidogrel. The primary endpoint was any bleeding which occurred more in the triple therapy group (44.4 %) as compared to the double therapy group (19.4 % p < .0001). Severe bleeding (BARC 3) was twice as high with triple therapy as compared to double therapy and this was statistically significant. There was no difference in ischemic/thrombotic outcomes in either of the groups. However, there was lower mortality with double therapy (2.5 %) vs triple therapy (6.3 % p = .027). While these data are impressive, the study was not powered to consider the ischemic and mortality endpoints and must only be considered hypothesis-generating.
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