key: cord-0851874-nfo65vqn
authors: Siegal, Deborah M.; Anand, Sonia S.
title: Considerations for use of direct oral anticoagulants in arterial disease
date: 2021-05-28
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12502
sha: 5c0b81d2cfd6c6ba0168cf7fedb52e65c6be73ea
doc_id: 851874
cord_uid: nfo65vqn

Cardiovascular diseases including coronary heart disease, stroke, and peripheral arterial disease were responsible for an estimated 18 million deaths in 2017. Despite advances in management over the past several decades, these patients continue to have substantial risk of subsequent cardiovascular events. We provide a narrative review of randomized clinical trials evaluating direct oral anticoagulants (DOACs) for the treatment of acute coronary syndromes, noncardioembolic ischemic stroke, embolic stroke of undetermined source, and peripheral arterial disease. In these conditions, considerations for use of single antiplatelet therapy, dual antiplatelet therapy, or low‐dose DOACs used together with antiplatelet therapy are presented.

Cardiovascular diseases including coronary heart disease, stroke, and peripheral arterial disease (PAD) were responsible for an estimated 18 million deaths in 2017. 1 These arterial vascular diseases arise from atherosclerosis, a pathologic process that results in the formation of plaques within the inner lining of coronary, cerebral, and peripheral arteries and the aorta. 2 Atherothrombosis arises from atherosclerotic plaque rupture, which (i) exposes tissue factor, thereby triggering coagulation; and (ii) activates platelets, upon which coagulation is amplified. 3 Because of the central role of platelets in the pathogenesis of atherothrombosis, antiplatelet therapy remains a cornerstone of prevention and treatment. However, the modest benefit of antiplatelet therapies and the role of coagulation in the pathophysiology of atherothrombosis have led to the evaluation of anticoagulant drugs for the prevention and treatment of arterial diseases. The purpose of this review is to summarize recent randomized clinical trials (RCTs) evaluating the use of direct oral anticoagulants (DOACs) for patients with atherosclerosis-based arterial diseases. In particular, we review acute coronary syndromes, noncardioembolic ischemic stroke, embolic stroke of undetermined source (ESUS), and PAD. Table 1 provides a summary of phase III randomized trials of DOACs for arterial thrombosis.

Despite advances in reperfusion and antithrombotic strategies over the past several decades, patients with acute coronary syndrome (ACS) remain at high risk of cardiovascular events (9%-11% within 1 year of ACS) even since the widespread use of potent P2Y 12 inhibitors. [4] [5] [6] Increasing the intensity of antithrombotic effects with the addition of anticoagulants to antiplatelet therapies after ACS is predicated on the observation that elevation in thrombin levels and coagulation activity persist after ACS. 7, 8 Enhanced risk reduction in cardiovascular events can indeed be achieved with anticoagulants, but this effect is counterbalanced by an increased risk of bleeding.

Warfarin, when used alone or in combination with aspirin, may reduce the risk of ischemic events compared to aspirin alone, but this benefit is dependent on anticoagulation intensity and is counterbalanced by an increased risk of bleeding. In a meta-analysis of 14 RCTs including 25 307 patients, warfarin (irrespective of international normalized ratio [INR] ) in combination with aspirin did not reduce the risk of all-cause death, nonfatal myocardial infarction (MI), or nonfatal thromboembolic stroke compared to aspirin alone (odds ratio

[OR], 0.96; 95% confidence interval [CI], 0.90-1.03) but increased the risk of major bleeding (OR, 1.77; 95% CI, 1.47-2.13). 9 When limited to studies with INR maintained between 2 and 3, combination therapy was associated with a reduced risk of all-cause death, nonfatal MI, or nonfatal thromboembolic stroke (OR, 0.73; 95% CI, 0.63-0.84) but also increased the risk of major bleeding (OR, 2.32; 95% CI, 1.63-3.29) compared to aspirin alone, suggesting that anticoagulant dose intensity influences cardiovascular morbidity and mortality. 9

DOACs are a potentially attractive option for increasing antithrombotic effect while minimizing bleeding in patients with ACS. They have been shown to reduce the risk of major, fatal, and intracranial bleeding compared to warfarin in patients with nonvalvular atrial fibrillation and are administered in fixed doses without routine monitoring. 10 However, despite their favorable characteristics and reduced risk of bleeding compared to warfarin in atrial fibrillation, the addition of DOACs to standard antiplatelet therapy following ACS is largely limited by an increased risk of major bleeding. A recent meta-analysis of 6 RCTs (29 667 patients) evaluated the efficacy and safety of DOACs in addition to antiplatelet therapy after ACS. 11 A range of DOAC dose intensities were studied, including apixaban (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily), rivaroxaban (5, 10, 15 , and 20 mg once daily), and dabigatran (50, 75, 110 , and 150 mg twice daily). The study population included mostly young men (mean age, 62.5 years), of whom the majority received dual antiplatelet therapy (DAPT). When added to antiplatelet therapy, DOACs reduced the risk of cardiovascular death, MI, and stroke after ACS compared to antiplatelet therapy alone (OR, 0.85; 95% CI, 0.77-0.93) corresponding to a number needed to treat of 84 (95% CI, 55-176) or an absolute risk reduction of 1.2%. 11 It is important to note, however, that the pooled estimates described above are derived from studies that evaluated a heterogeneous mix of dose intensities and do not specifically exclude the possibility that very-low-dose DOACs may provide benefit for some patients with an acceptable risk of bleeding, particularly those considered to be at high thrombotic risk and low bleeding risk. For example, in the anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndromethrombolysis in myocardial Infarction 51 study (ATLAS ACS-2-TIMI 51) , very-low-dose rivaroxaban (2.5 mg twice daily) but not rivaroxaban 5 mg twice daily added to DAPT (eg, aspirin and clopidogrel) reduced the rates of death from cardiovascular causes (2.7% vs 4.1%; hazard ratio [HR], 0.66; 95% CI, 0.51-0.86; P = .002) and death from any cause (2.9% vs 4.5%; HR, 0.68; 95% CI, 0.53-0.87; P = .002) compared to placebo in patients with recent ACS. 12 However, the rate of major bleeding not related to coronary artery bypass grafting (CABG) was higher with both rivaroxaban 2.5 mg (1.8% vs 0.6%; P < .001) and rivaroxaban 5 mg (2.4% vs 0.6%; P < .001) compared to placebo. The results of ATLAS ACS-2-TIMI-51 formed the rationale to investigate low-dose rivaroxaban and aspirin in patients with stable coronary and peripheral artery disease in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial. Among 27 395 patients, lower-dose rivaroxaban (2.5 mg twice daily) in combination with aspirin (100 mg) significantly reduced the primary major adverse cardiovascular events (MACEs) composite of cardiovascular death, MI, and stroke by 24% (95% CI, 14%-34%; P < .001) compared to aspirin alone. Although major bleeding was significantly increased (HR, 1.70; 95% CI, 1.40-2.05; P < .001), there was no increase in fatal or critical organ bleeding such that an 18% mortality reduction was observed (P = .01), and a favorable net clinical benefit (HR, 0.80; 95% CI, 0.70-0.91; P < .001) was apparent. 13 Moreover, in the recent study to compare the safety of rivaroxaban versus acetylsalicylic acid in addition to either clopidogrel or ticagrelor therapy in participants with acute coronary syndrome (GEMINI-ACS-1) the rate of Thrombolysis in Myocardial Infarction (TIMI) non-CABG clinically significant bleeding (primary outcome) was similar in patients with recent ACS receiving rivaroxaban 2.5 mg twice daily compared to low-dose aspirin in addition to either clopidogrel or ticagrelor (5.3% vs 4.9%; HR, 1.09; 95% CI, 0.80-1.50). 14 Although the study was not powered to evaluate differences in efficacy, the rates of all-cause mortality (1.4% vs 1.5%) and a composite of cardiovascular death, MI, stroke, and definite stent thrombosis (5.0% vs 4.7%) were similar between the rivaroxaban and aspirin groups. This trial suggests that adding very-low-dose rivaroxaban to a P2Y 12 inhibitor instead of aspirin mitigates the increased bleeding risk seen in other DOAC studies in ACS. However, net clinical benefit must be established in a larger randomized trial powered to evaluate thrombotic outcomes.

antiplatelet therapy after ACS in Europe but not in the United States.

Some notable uncertainty remains. The meta-analysis by Chiarito and colleagues 11 suggests that the balance of benefit and harm may be more favorable in patients with STEMI compared to those with NSTE-ACS, a hypothesis that requires confirmation in randomized trials.

Further, the findings above including the reduction in mortality seen with very-low-dose rivaroxaban may not be generalizable to women and patients of older age who were underrepresented in these trials.

Finally, these studies did not include patients receiving the more potent P2Y 12 inhibitors prasugrel and ticagrelor. In the GEMINI-ACS-1 trial, patients with ACS randomized to rivaroxaban 2.5 mg twice daily had a similar risk of TIMI non-CABG major bleeding compared to those receiving aspirin 100 mg daily (1% vs 1%; HR, 1.25; 95% CI, 0. 49-3.17) in addition to clopidogrel or ticagrelor, but a higher risk of ISTH major bleeding (2% vs 1%; HR, 1.83; 95% CI, 1.01-3.31; P = .042). 14 

Based on their enhanced safety and efficacy for preventing ischemic stroke and systemic embolism compared to warfarin in atrial fibrillation, DOACs are attractive options for enhancing antithrombotic benefit compared to aspirin in acute noncardioembolic ischemic stroke and ESUS.

Antiplatelet therapies are the mainstay of antithrombotic strategy for the acute treatment of noncardioembolic ischemic stroke or transient ischemic attack (TIA). However, high rates of recurrent ischemic stroke (up to 8% within 90 days) are seen even with early administration of DAPT. [15] [16] [17] The clopidogrel in high-risk patients with acute nondisabling cerebrovascular events (CHANCE) and platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trials demonstrated enhanced efficacy and safety of early DAPT initiation (within 12 hours and 24 hours, respectively) compared to aspirin alone in patients with acute minor stroke or high-risk TIA. A meta-analysis of these trials (n = 10 051 patients) showed that DAPT was associated with a lower risk of ischemic stroke, MI, or death from ischemic vascular causes at 90 days (6.5% vs 9.1%; HR, 0.70; 95% CI, 0.61-0.81) compared to aspirin. 18 Major bleeding was not statistically different between the treatments (0.6% vs 0.4%; HR, 1.59; 95% CI, 0.88-2.86).

Heparin, low-molecular-weight heparin, and warfarin have been evaluated as potential antithrombotic strategies. Evidence from numerous studies shows that anticoagulation with these agents reduces the risk of recurrent ischemic stroke compared to aspirin after acute noncardioembolic stroke, but this benefit is offset by an increase in symptomatic hemorrhagic transformation. 19, 20 More recently, in the thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events (TRA 2P)-TIMI-50 (TRA 2P-TIMI-50) trial, which evaluated a novel protease-activated receptor 1 (PAR-1) antagonist, vorapaxar (2.5 mg daily), or placebo in patients with a history of MI, ischemic stroke, or PAD, study treatment was discontinued in patients with a history of stroke due to an increased risk of intracranial hemorrhage. 21 

Dabigatran is the only DOAC to have been evaluated in RCTs for the treatment of acute noncardioembolic ischemic stroke. 22 The dabigatran treatment following transient ischemic attack and minor stroke II (DATAS II) study suggested that dabigatran may be safe for treatment of acute ischemic stroke/TIA; there were no hemorrhagic transformation events in 154 patients randomized to dabigatran (n = 154; 150 mg twice daily, or 110 for individuals ≥80 years of age or creatinine clearance 30-50 mL/min) or aspirin (n = 151) within 90 days of acute minor noncardioembolic ischemic stroke or TIA. 23 However, the study was not powered to detect differences in the rates of clinically overt recurrent ischemic events in the dabigatran and aspirin groups ( 

Embolic stroke of undetermined source denotes nonlacunar cryptogenic ischemic strokes that occur without evidence of a cardioembolic source, stenosis (≥50%) of cervical or intracranial arteries proximal to the infarct and other causes of stroke identified. 24 Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CI, confidence interval; CV, cardiovascular; DSMB, Data Safety Monitoring Board; ESUS, embolic stroke of undetermined source; HR, hazard ratio; MI, myocardial infarction; NA, not available; RCT, randomized controlled trial; TIMI, Thrombolysis in Myocardial Infarction. a DOACs or placebo were given in addition to standard antiplatelet therapies. b Study treatments were given in addition to clopidogrel or ticagrelor (at investigator discretion before randomization). c Clopidogrel could be added up to 6 mo.

These large trials found no benefit and greater harm with DOACs compared to aspirin for secondary prevention of stroke in patients with ESUS. This may be explained, at least in part, by heterogeneous stroke mechanisms included within the ESUS construct (ie, embolism vs atherosclerosis). 27 Research directed at enhancing the characterization of stroke mechanisms in ESUS may help optimize antithrombotic treatment by identifying subgroups of patients that may benefit from different antithrombotic strategies (eg, anticoagulation for occult embolic causes and antiplatelet therapies for atherosclerosis).

Dual pathway inhibition strategies with low-dose DOACs in combination with antiplatelet therapy may offer enhanced efficacy in patients with ESUS. For example, in the COMPASS trial, rivaroxaban (2.5 mg twice daily) in combination with aspirin (100 mg daily) compared to aspirin alone, the relative risk reduction of all stroke was 42%, and ischemic stroke was 31% in patients with stable coronary artery disease, PAD, or both. 13 The rate of disabling or fatal stroke (modified Rankin Scale scores, 3-6) was lower in patients receiving rivaroxaban and aspirin compared to those receiving aspirin alone (0.2% vs 0.3%;

Apixaban 5 mg twice daily 

There 

As noted above in the TRA 2P trial, vorapaxar was compared to placebo in patients with a history of MI, ischemic stroke, or symptomatic PAD, with a substantial proportion of patients taking DAPT.

This therapy was effective in reducing MACEs and MALEs, including urgent hospitalization for a peripheral artery cause. 39 However, there was an excess of major bleeding with this therapy, and although approved by regulatory bodies, vorapaxar has not been widely used by clinicians.

More recently, the examining use of ticagrelor in peripheral artery disease (EUCLID) trial evaluated a more potent P2Y 12 antagonist, ticagrelor (90 mg twice daily), as compared to clopidogrel in 13 885 patients with PAD. 33 However, no differences in MACE or MALE outcomes were observed.

A number of RCTS in which patients with PAD were enrolled as part of larger randomized trials in a broad range of vascular patients, patients following MI, or patients with coronary artery disease with diabetes, including Charisma (clopidogrel and aspirin vs aspirin), 40 prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin-thrombolysis in myocardial infarction 54 (PEGASUS-TIMI 54; ticagrelor and aspirin vs aspirin) 39 ; and the effect of ticagrelor on health outcomes in diabetes mellitus patients intervention study (THEMIS) 41 (ticagrelor and aspirin vs aspirin). Each demonstrated reduced ischemic events with DAPT compared to aspirin. However, these trials also demonstrated increased risks of major bleeding with DAPT versus SAPT. Thus, a careful risk-benefit assessment is required before using one of these DAPT regimens when more potent therapies than SAPT are desired.

Oral anticoagulants have been used to treat patients with PAD for the past 50 years. Contemporary trials have been evaluated vitamin K antagonists with or without antiplatelet agents in RCTs in outpatients with stable PAD, 36 a Veterans Affairs patient population, 42 and after lower extremity revascularization. 43 Overall, in patients with PAD, vitamin K antagonists when tested at moderate to high intensity with or without antiplatelet agents, show no clear reduction in ischemic events and a significant excess in life-threatening bleeding, such that vitamin K antagonists are not recommended for long-term use in patients with PAD.

The use of full-dose DOACs in PAD is increasing, yet there are limited data directing their widespread use. However, the outcomes of patients with PAD with atrial fibrillation treated with full-dose DOACs in large databases have been reported. 44 An adjusted indirect comparison meta-analysis between DOACs for prevention of acute limb ischemia in patients with atrial fibrillation was conducted. 

Several abstracts related to the use of DOACs for the prevention and treatment of arterial thrombosis were presented at the ISTH 2020 Congress. 

Single or dual antiplatelet therapy is used as first line among patients with coronary artery disease, cerebrovascular disease, and PAD.

However, there is increasing evidence of the efficacy and safety of low-dose DOACs used together with aspirin in preventing atherothrombosis, demonstrating a new management option through dual pathway inhibition.

We thank Natalie Williams for her assistance in formatting and submitting the article. 

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