Development of New Antithrombotic Regimens for Patients with Acute Coronary Syndrome
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Patients with acute coronary syndrome (ACS) require long-term antithrombotic intervention to reduce the risk of further ischemic events; dual antiplatelet therapy with a P2Y12 inhibitor and acetylsalicylic acid (ASA) is the current standard of care. However, pivotal clinical trials report that patients receiving this treatment have a residual risk of approximately 10% for further ischemic events. The development of non-vitamin K antagonist oral anticoagulants (NOACs) has renewed interest in a ‘dual pathway’ strategy, targeting both the coagulation cascade and platelet component of thrombus formation. In the phase III ATLAS ACS 2 TIMI 51 trial, a ‘triple therapy’ approach (NOAC plus dual antiplatelet therapy) showed reduced ischemic events with rivaroxaban 2.5 mg twice daily, albeit at an increased risk of bleeding. Two studies have investigated the role of NOACs in combination with a P2Y12 inhibitor, with or without ASA, in reducing bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention; two further studies are underway. Although these trials will help to inform optimal treatment protocols for secondary prevention of ACS, an individualized approach to treatment will be needed, taking account of the high frequency of co-morbid conditions found in this patient population.
Dual antiplatelet therapy with a P2Y12 inhibitor and acetylsalicylic acid is the current standard of care for patients with acute coronary syndrome; however, a residual risk of approximately 10% for recurrent ischemic events and death persists.
Triple therapy with a non-vitamin K antagonist oral anticoagulant (NOAC) plus dual antiplatelet therapy reduces the risk of ischemic events, albeit at an increased risk of bleeding.
Studies are now focused on dual targeting of platelet and thrombin activation pathways with a NOAC plus single antiplatelet therapy.
Admissions for acute coronary syndrome (ACS) in the USA accounted for > 1.3 million unique hospitalizations in 2006, with annual costs estimated at US$54,821 per patient . Rehospitalization with a cardiovascular diagnosis cost an average of US$9510 per patient, with 30% of patients rehospitalized at least once within the first 12 months after index ACS admission. In Europe, hospital discharge rates for coronary heart disease per 100,000 population increased from 532 in 2001 to 608 in 2012 , and the estimated annual cost (2004) per patient with ACS ranges from €7009 (UK) to €12,086 (Italy). The largest contributor to total costs was hospital stay .
Despite optimal standard care and secondary prevention, patients remain at high risk of further ischemic coronary events and death in the months and years after an index ACS event [4, 5]. This article examines a ‘dual antiplatelet’ approach for secondary prevention in patients with ACS and explores the evidence base for a ‘dual strategy’ approach in this setting.
2 Antithrombotic Approaches to Secondary Prevention
Historical data confirm the efficacy of targeting the dual pathway in reducing ischemic events after ACS . Meta-analysis data show that, versus acetylsalicylic acid (ASA) alone, ASA plus warfarin significantly reduced the risk of death, myocardial infarction (MI), or stroke in patients with an international normalized ratio of 2–3 (p < 0.0001). However, major bleeding risk was increased  and led to the restriction of combined anticoagulant and antiplatelet therapy to patients with ACS and a firm indication for oral anticoagulation, such as paroxysmal, persistent, or permanent atrial fibrillation (AF), and a CHA2DS2–VASc (Cardiac failure, Hypertension, Age ≥ 75 [2 points], Diabetes, Stroke [2 points]–Vascular disease, Age 65–74, Sex category) score ≥ 2 . The long-term standard of care for antithrombotic treatment after ACS remains ‘dual antiplatelet therapy’ with potent P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) plus ASA [12, 13], based on trial data showing clinical benefit when added to ASA.
The first trial demonstrating clinical benefit was the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, where addition of clopidogrel to various doses of ASA reduced the rate of cardiovascular death, MI, or stroke versus ASA alone. As might be expected, bleeding risk increased with increasing ASA dose .
Subsequent trials have demonstrated the superiority of prasugrel and ticagrelor over clopidogrel in reducing ischemic events, albeit with increased bleeding. The TRITON–TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial of > 13,000 patients with ACS undergoing percutaneous coronary intervention (PCI) compared prasugrel and ASA with clopidogrel and ASA. The composite of cardiovascular death, non-fatal MI, or non-fatal stroke occurred in 9.9% of patients receiving prasugrel and in 12.1% receiving clopidogrel (p < 0.001). Non-coronary artery bypass graft (CABG)-related Thrombosis in MI (TIMI) major bleeding was more frequent with prasugrel (2.4% vs. 1.8%, respectively; p = 0.03), as was fatal bleeding .
Vascular death, MI, or stroke occurred in 9.8% of > 18,000 patients with ACS in the PLATO (PLATelet inhibition and patient Outcome) trial administered ticagrelor plus ASA versus 11.7% treated with clopidogrel plus ASA (p < 0.001). Major bleeding rates between the groups were similar. However, non-CABG-related TIMI major bleeding was more frequent with ticagrelor (2.8% vs. 2.2%, respectively; p = 0.03), as was fatal intracranial bleeding .
These studies established the role of P2Y12 inhibitors as the mainstay of antithrombotic therapy in ACS. However, although TRITON–TIMI 38 and PLATO showed superiority over clopidogrel in reducing post-ACS ischemic events, they revealed a residual risk of recurrent cardiovascular events and death of ~ 10% despite ‘optimal’ dual antiplatelet therapy . Therefore, new approaches to further reduce the residual risk of subsequent ischemic events, while minimizing bleeding risk, are required.
More recently, studies have explored novel therapeutic agents targeting different pathways of the coagulation cascade and adding a new agent to a dual antiplatelet regimen.
Vorapaxar, a protease-activated receptor-1 antagonist, inhibits thrombin-induced platelet aggregation. In the phase III TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial, 12,944 patients with ACS received vorapaxar or placebo plus standard antiplatelet therapy, predominantly clopidogrel plus ASA . Vorapaxar increased moderate or severe bleeding (7.2% vs. 5.2%; p < 0.001) and intracranial bleeding (1.1% vs. 0.2%; p < 0.001) in GUSTO (Global Utilization of Streptokinase and t-PA [tissue plasminogen activator] for Occluded Coronary Arteries), without improving ischemic outcomes. The composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization was not significantly reduced with vorapaxar (18.5% vs. 19.9%; p = 0.07) .
Endpoints of the ATLAS ACS 2 TIMI 51, APPRAISE-2, RE-DEEM, RUBY-1, and AXIOM-ACS trials
ATLAS ACS 2 TIMI 51 
CV death, MI, or stroke: 9.1% with rivaroxaban 2.5 mg bid vs. 10.7% with placebo (p = 0.02)a
Non-CABG-related bleeding: 1.8% with rivaroxaban 2.5 mg bid vs. 0.6% with placebo (p < 0.001)a
Intracranial hemorrhage: 0.4% with rivaroxaban 2.5 mg bid vs. 0.2% with placebo (p = 0.04)a
CV death, MI, or ischemic stroke: 7.5% with apixaban vs. 7.9% with placebo (p = NS)
Major bleeding: 1.3% with apixaban vs. 0.5% with placebo (p = 0.001)
CV death, non-fatal MI, or non-hemorrhagic stroke: 4.6, 4.9, 3.0, and 3.5% with dabigatran 50, 75, 110, and 150 mg bid, respectively, vs. 3.8% with placebo
Major or clinically relevant minor bleeding: 3.5, 4.3, 7.9, and 7.8% with dabigatran 50, 75, 110, and 150 mg bid, respectively, vs. 2.2% with placebo (p < 0.001 for dabigatran 110 and 150 mg bid vs. placebo)a
All-cause death, non-fatal MI, non-fatal stroke, or severe recurrent ischemia: 6.5% with darexaban vs. 5.2% with placeboa
Major or clinically relevant non-major bleeding: 5.6–7.3% (od) and 6.8–11.3% (bid) with darexaban 10–60 mg/day vs. 3.1% with placebo (overall p = 0.02)a
CV death, non-fatal MI, non-fatal stroke, or myocardial ischemia requiring hospitalization: 4.8% with letaxaban 20–240 mg/day vs. 4.4% with placebo (p = NS)
TIMI major bleeding: 0.9% with letaxaban 20–240 mg/day vs. 0.5% with placebo (p = NS)
The phase III ATLAS ACS 2 TIMI 51 trial  randomized over 15,500 patients with ACS to receive rivaroxaban 2.5 or 5 mg twice daily (doses based on phase II ATLAS ACS TIMI 46 trial ) or placebo in addition to ASA with or without clopidogrel or ticlopidine in accordance with local guidelines. The findings led to approval of rivaroxaban in Europe in combination with ASA alone or ASA and clopidogrel (or ticlopidine) in selected patients with ACS at low risk of bleeding; rivaroxaban remains the only NOAC currently approved for this indication .
In contrast, other trials [19, 20, 21, 23] with NOACs in a triple therapy regimen failed to show net clinical benefit. The phase III APPRAISE-2 trial aimed to investigate the efficacy and safety of apixaban in addition to standard antiplatelet therapy in patients with a recent ACS and at least two additional risk factors for ischemic events. The trial was terminated early because apixaban 5 mg twice daily plus antiplatelet therapy led to an increase in the number of major bleeding events in this patient population, without a significant reduction in recurrent ischemic events . These NOAC trials demonstrate the need for ‘optimal balance’ between reducing ischemic events and increasing bleeding risk when combining anticoagulant and antiplatelet therapies in patients with ACS.
The phase II GEMINI-ACS-1 trial took a different approach to secondary prevention and compared rivaroxaban 2.5 mg twice daily plus a P2Y12 inhibitor with ASA plus a P2Y12 inhibitor in patients with ACS . The risk of TIMI non-CABG clinically significant bleeding was similar in both trial arms. The rate of the exploratory endpoint of the composite of cardiovascular death, MI, stroke, or definite stent thrombosis was also similar between the treatment arms.
The role of ASA has been questioned because of concerns over increased bleeding with triple therapy. WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing), a small-scale, open-label study , compared clopidogrel alone (dual therapy) with clopidogrel plus ASA (triple therapy) in patients already receiving long-term oral anticoagulation who had undergone PCI . Compared with triple therapy, dual therapy had a lower rate of any bleeding (19.4% vs. 44.4%; p < 0.0001) and a lower rate of death, MI, stroke, target vessel revascularization, or stent thrombosis (11.1% vs. 17.6%; p = 0.025) . A large meta-analysis was conducted to compare the safety and efficacy of dual therapy with triple therapy in patients on oral anticoagulants undergoing PCI, and obtained similar findings to the WOEST study; there was an increased risk of major bleeding events with triple therapy compared with dual therapy . The WOEST 2 registry (ClinicalTrials.gov identifier NCT02635230) plans to recruit 2200 patients with AF undergoing coronary revascularization, treated with an oral anticoagulant and a P2Y12 inhibitor with or without ASA, with completion scheduled for 2019. Despite its limitations, WOEST was the first study to suggest that combining an anticoagulant with a P2Y12 inhibitor alone may be suitable for long-term secondary prevention after an ACS event in patients with no prior indication for long-term anticoagulant therapy such as AF.
Ongoing trials in patients with atrial fibrillation undergoing percutaneous coronary intervention
AF + ACS or PCI with stenting
AF + PCI with stenting
Apixaban 2.5 or 5 mg bid + P2Y12 inhibitor ± ASA
Edoxaban 60 mg (or 30 mg) od + P2Y12 inhibitor
VKA + P2Y12 inhibitor ± ASA
VKA + P2Y12 inhibitor + ASAa
Major or CRNM bleeding
Major or CRNM bleeding
Death, ischemic events
Death, ischemic events
Target enrollment (n)
3 Discussion and Future Perspectives
The development of NOACs, which have demonstrated fewer intracranial bleeding events and deaths than VKAs in AF trials , has renewed interest in a dual pathway strategy for the secondary prevention of ACS, targeting both the coagulation cascade and the platelet component of thrombus formation [7, 33].
The disparate outcomes of the only two phase III trials (ATLAS ACS 2 TIMI 51 and APPRAISE-2) conducted to date in patients with ACS deserve further discussion. The apixaban dose in APPRAISE-2 was the same as that recommended for use in patients with AF, whereas the rivaroxaban dose in ATLAS ACS 2 TIMI 51 was adjusted to 25–50% of the AF dose . The lower rivaroxaban dose (2.5 mg twice daily) exhibited the best efficacy and safety profile .
The importance of dose selection for patients with ACS may be partly explained by the ‘dual property’ of thrombin. Thrombin is anticoagulatory at low concentrations but a procoagulant at high concentrations, a scenario known as the ‘thrombin paradox’ . The GUSTO IIb trial of patients with ACS showed elevated thrombin generation in the 12 months post index event . However, the correlation between thrombin generation and clinical events was non-linear, with higher rates of cardiac death or MI seen at both very low and very high thrombin levels, complicating the search for an optimal post-ACS anticoagulant dose .
In addition, compared with ATLAS ACS 2 TIMI 51, APPRAISE-2 patients were older and more likely to have diabetes mellitus and/or renal dysfunction, and non-ST-elevation MI versus ST-elevation MI as their index event [19, 22, 33]. Furthermore, ATLAS ACS 2 TIMI 51 excluded patients with prior stroke or transient ischemic attack who were already receiving ASA plus a P2Y12 inhibitor [22, 33]. The higher-risk population of APPRAISE-2 may have been less responsive to anticoagulant therapy than the ATLAS ACS 2 TIMI 51 population [22, 33].
The benefit–risk profile of dabigatran in patients with ACS can only be determined in an adequately powered phase III trial. To date, no such trial has been scheduled; however, the two highest dabigatran doses used in the phase II RE-DEEM trial significantly increased major and clinically relevant minor bleeding, and were identical to those used in patients with AF [23, 33].
The recently completed PIONEER AF-PCI  and RE-DUAL PCI  trials and the ongoing AUGUSTUS (NCT02415400) and ENTRUST AF-PCI (NCT02866175) trials should help to determine the treatment regimens with the optimal benefit–risk profile in patients with ACS and AF. The trials will also provide additional information on the appropriate duration of antiplatelet therapy and intensity of oral anticoagulation in patients with ACS and AF , and on the feasibility of removing ASA from the treatment regimen .
Most patients with ACS have co-morbidities and risk factors that put them at increased risk of ischemic or bleeding events . Therefore, individualized assessment of bleeding risk and risk of coronary stent thrombosis are important considerations in guiding the duration of triple therapy [12, 31, 37, 38] and stent type in patients requiring PCI.
Renal impairment occurs in approximately 30–40% of patients with ACS and is an independent predictor of increased mortality and major bleeding . Although the same antiplatelet regimens are recommended regardless of renal function status, dose adjustments of oral anticoagulants are usually recommended for those with moderate renal impairment [12, 37]. Dabigatran is unlikely to be the first-choice NOAC in patients with moderate renal impairment because it is primarily excreted via the kidneys . Minimal data are available in patients with severe renal impairment, and no prospective data exist for patients with end-stage renal disease or who are on hemodialysis .
Diabetes is present in 20–30% of patients with ACS and is an independent predictor of mortality [12, 36]. Although guidelines recommend that patients with diabetes receive the same antithrombotic regimens as those without diabetes , treatment of this patient population remains suboptimal . In a subanalysis, TRITON–TIMI 38, patients with diabetes received a greater net clinical benefit from prasugrel versus clopidogrel than non-diabetic patients . However, no such interaction with diabetic status was found in the PLATO trial with ticagrelor  or ATLAS ACS 2 TIMI 51 with rivaroxaban .
Female sex is a predictor of major bleeding in ACS, and women have an increased risk of recurrence of ischemic events at 6 months . Current guidelines recommend that men and women with ACS are managed similarly; however, some studies have suggested that women are less likely to receive evidence-based care .
Patients aged ≥ 75 years with ACS have an increased risk of recurrent ischemic events, bleeding, and mortality, with 60% of all ACS-related deaths occurring in this age group . However, again, they are less likely to receive evidence-based therapies . Although prasugrel is generally not recommended in elderly patients after TRITON–TIMI 38 did not find a net clinical benefit in this age group , the PLATO trial  did not find significant differences in efficacy and safety in elderly patients receiving ticagrelor. Guidelines recommend that close attention be paid to specific contraindications in elderly patients, as well as renal function. Individualized benefit–risk assessments in this age group should take account of estimated life expectancy, co-morbidities, quality of life, and patient preferences .
Despite optimal secondary prevention after ACS, a residual ongoing risk of recurrent ischemic events remains up to and beyond 12 months. Trials of triple therapy (oral anticoagulant plus dual antiplatelet therapy) targeting the dual pathway have shown reduced ischemic events, albeit at an increased risk of bleeding. Ongoing studies are focusing on dual therapy (oral anticoagulant plus single antiplatelet therapy) to target the platelet- and fibrin-mediated pathways of thrombus formation for ACS secondary prevention. Several trials are underway, particularly in patients with concomitant AF, and will provide important data on the optimal intensity of oral anticoagulation, the optimal antiplatelet therapy regimen, the use of oral anticoagulation combined with new P2Y12 inhibitors, and the efficacy and safety of NOACs versus VKAs. Many patients with ACS have co-morbidities, which require consideration to enable optimal treatment and long-term outcomes. The addition of anticoagulation may enable an individualized approach to the use of antithrombotic agents for secondary prevention of ACS. Algorithms to simplify choice between the increased treatment options may help clinicians assess benefits and risks of each treatment strategy and balance the risk of thrombotic events with the risk of bleeding .
The authors would like to acknowledge Ngaire White (Chameleon Communications Ltd), who provided editorial support with funding from Bayer AG.
Compliance with Ethical Standards
Editorial assistance for the preparation of this manuscript was funded by Bayer AG.
Conflict of interest
Sudhakar George, Eunice NC Onwordi, Amr Gamal, and Azfar Zaman declare that they have no conflicts of interest.
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