Summary
Non-vitamin K antagonist oral anticoagulants are becoming increasingly important in the prophylaxis and treatment of thrombosis in atrial fibrillation and venous thromboembolism. Antiplatelets are widely prescribed in the primary and secondary prevention of cardiac and vascular diseases. There are potentially numerous situations where anticoagulants and antiplatelets may be combined; these combinations have been explored in coronary artery disease, and some have been included in updated recommendations. Is it legitimate to transpose these recommendations to the management of peripheral artery disease? The specific characteristics of the treated vessels, the stents used, the respective frequencies of stent thrombosis and its effect on the target organ are probably different, and explain why opinions differ. However, because of a lack of evidence, empirical behaviours are being established without scientific validation. This review of the literature details the situations in which combinations of an anticoagulant and an antiplatelet have been explored in peripheral artery disease. We discuss the issue of antithrombotic combinations in stable peripheral artery disease and for vascular or endovascular surgery.
Résumé
Les anticoagulants oraux directs ont pris une place essentielle dans la prophylaxie des embolies systémiques dans la fibrillation auriculaire et le traitement prophylactique et curatif de la thrombose et la maladie thromboembolique veineuse. Les antiplaquettaires sont largement prescrits en prévention primaire et secondaire de la maladie cardiovasculaire. Il existe de nombreuses situations où, potentiellement anticoagulants et antiplaquettaires peuvent être combinés. Les possibilités des associations intégrant les nouvelles molécules ont été étudiées dans la maladie coronarienne permettant la mise à jour des recommandations. Est-il cependant légitime de transposer ces recommandations à la gestion de l’artériopathie oblitérante des membres inférieurs ? Les caractéristiques spécifiques des vaisseaux traités, des stents utilisés, les fréquences respectives de thrombose de stent et leurs effets sur l’organe cible sont probablement différents et expliquent que les avis divergent. Cependant, faute de preuves, des comportements empiriques de prise en charge se sont mis en place sans validation scientifique. Cette revue de la littérature détaille les situations dans lesquelles des combinaisons d’un anticoagulant et un antiplaquettaire ont été explorés dans la maladie artérielle périphérique, abordant les anticoagulants oraux directs. Nous discuterons de la question de ces combinaisons dans la maladie périphérique artérielle stable et après chirurgie vasculaire ou endovasculaire.
Background
The effectiveness of a new class of anticoagulants, known as non-vitamin K antagonist oral anticoagulants (NOACs), in preventing stroke and systemic embolism in non-valvular atrial fibrillation (AF) and venous thromboembolism is not inferior to that of a standard anticoagulant, usually consisting of parenteral heparin followed by a vitamin K antagonist (VKA), titrated to a target international normalized ratio (INR) between 2 and 3 . The safety of NOACs has been demonstrated in all published clinical trials by a significant reduction in the incidence of major bleeding, including intracranial haemorrhage . Furthermore, the overall benefit of NOACs over standard anticoagulation has been unambiguously established by the findings of two meta-analyses . Finally, real-life studies have confirmed the clinical benefit of this pharmacological class in everyday use . In the field of anticoagulation, NOACs are the therapeutic revolution of this decade.
Antiplatelets are widely used in the primary and secondary prevention of cardiovascular disease . Since the discovery of the inhibitory properties of acetyl salicylic acid (ASA) on prostaglandins and thromboxane A2 synthesis by John Vain, low-dose aspirin has been prescribed to millions of patients . Later, thienopyridines – and clopidogrel, in particular – were validated in cardiovascular pathology. In peripheral artery disease (PAD), clopidogrel has been shown to be of interest in the secondary prevention of recurrent major cardiovascular events . Nowadays, prasugrel and ticagrelor – new, more specific and powerful antiplatelet molecules – are commonly used in cardiology, and their clinical development in peripheral vascular disease is ongoing .
Antiplatelets reduce the incidence of major cardiovascular events in patients with PAD , and it is therefore reasonable to assume that the addition of an anticoagulant to an antiplatelet would increase this benefit. This hypothesis was not supported by a study that found that the combination of a VKA (warfarin) and aspirin in patients with PAD resulted in a higher rate of bleeding without reducing the rate of cardiovascular events . However, NOACs cause fewer major bleeding events than VKAs, and their combination with aspirin has been shown to benefit patients with acute coronary syndromes (ACS) . Nonetheless, information about the efficacy and safety of oral anticoagulation, specifically NOACs, with or without antiplatelets, is limited in patients with PAD . We therefore conducted a review of clinical trials in patients with PAD that measured the effectiveness and safety of anticoagulant and antiplatelet combinations, with a particular interest in combinations of NOACs and antiplatelets.
Asymptomatic/intermittent claudication PAD
Antiplatelets
Antiplatelets are a cornerstone in the treatment of PAD . A meta-analysis of 9706 patients with intermittent claudication and/or peripheral artery bypass or angioplasty showed a 23% reduction in major cardiovascular events in those receiving an antiplatelet drug . According to the 2011 European Society of Cardiology guidelines on the diagnosis and treatment of PAD, long-term antiplatelet therapy using low-dose aspirin (75–150 mg) or clopidogrel (75 mg) is recommended in patients with symptomatic PAD . Low-dose aspirin has been validated in the secondary prevention of atherosclerosis in general, with a better cost/benefit than clopidogrel, but its effectiveness is less well documented than that of clopidogrel in patients with PAD. Indeed, in the CAPRIE study, which compared aspirin and clopidogrel for secondary prevention in patients with a history of vascular myocardial infarction, stroke or PAD, clopidogrel produced a significant 8.7% reduction in the combined primary endpoint (myocardial infarction, ischaemic stroke, or vascular death) in the whole population, and a relative risk reduction of 23.8% (95% confidence interval [CI] 8.9–36.2) in patients with symptomatic PAD . However, the CAPRIE trial was not powered to evaluate the efficacy of clopidogrel in subgroups. Dual antiplatelet therapy with clopidogrel and aspirin versus aspirin alone has been tested for the prevention of atherothrombotic events in high-risk cardiovascular patients in the CHARISMA trial . In this trial, the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of major cardiovascular events among patients with stable cardiovascular disease or multiple cardiovascular risk factors. Furthermore, the risk of moderate-to-severe bleeding was increased . To summarize, in stable PAD, there is no recommendation for dual antiplatelet therapy, which does not reduce the risk of cardiovascular events and increases the risk of bleeding .
Antiplatelets combined with VKAs
The combination of antiplatelet therapy and oral anticoagulation was evaluated in patients with PAD in the WAVE study . In this study, 2161 patients with PAD received either warfarin alone (target INR 2–3) or combined with an antiplatelet therapy (mainly ASA). The warfarin and antiplatelet combination had no beneficial effect on the cumulative incidence of the primary endpoint (myocardial infarction, stroke or severe ischaemia of the lower limb requiring urgent intervention or cardiovascular death) (relative risk 0.91, 95% CI 0.74–1.12; P = 0.37), but resulted in a significant cumulative increase in the incidence of life-threatening bleeding (relative risk 3.41, 95% CI 1.84–6.35; P < 0.001) . Thus, the warfarin/aspirin combination is complicated by a higher rate of bleeding without a reduction in the rate of cardiovascular events. The use of a combination of VKAs and antiplatelets confers a significantly high bleeding risk, and should probably be reserved for high-risk patients, such as those who develop atherothrombotic events despite adequate antiplatelet or anticoagulant therapy . Apart from the formal indication of an anticoagulant, it is not recommended to prescribe a VKA alone or in combination with antiplatelets in patients with stable PAD .
Antiplatelets combined with NOACs
Given the lower incidence of bleeding events with the use of NOACs, it seemed reasonable to study the possibility that the addition of a NOAC to an antiplatelet agent would be beneficial for patients with PAD. This hypothesis was supported by the positive effects of the combination of the NOAC rivaroxaban with antiplatelets in patients with ACS . An ongoing clinical trial, COMPASS, is evaluating rivaroxaban in the prevention of major cardiovascular events in coronary patients or patients with PAD . This clinical trial includes three treatment groups: rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg/day); rivaroxaban (5 mg twice daily); and aspirin (100 mg/day). Patients will be followed for 5 years, and the results are expected in 2018.
Key messages
In PAD, except for formal indications for anticoagulation, the use of oral anticoagulants alone or in combination with antiplatelets is not recommended because of an increased risk of bleeding associated with this combination. Antiplatelets (low-dose aspirin or clopidogrel) are indicated as first-line treatment. There is currently no evidence to support the combination of NOACs with antiplatelets in PAD ( Table 1 ).
| Low-dose aspirin | Clopidogrel (75 mg) | Aspirin and clopidogrel | Aspirin & VKAs | Aspirin & NOACs | |
|---|---|---|---|---|---|
| Asymptomatic/intermittent claudication | Yes | Yes | No | No | No |
| Endovascular surgery | Yes | Yes | Yes a (1 month) | No | No b |
| Vascular surgery | Yes | Yes | Yes a (1 month) | No | No b |
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