Editor's Note
The late-breaking presentation of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial by Eikelboom et al. at the European Society of Cardiology Congress 2017 stimulated a discussion by Escarcega Alarcon, Baker, and Lipinski on the relative risk benefit of anticoagulation strategies. Their succinct summary follows.
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

Study Hypothesis

Rivaroxaban alone or rivaroxaban in addition to aspirin therapy will lead to a significant reduction in cardiovascular (CV) events compared with aspirin therapy alone for patients with stable atherosclerotic vascular disease

Study Methodology

This was a multicenter double-blind, double-dummy trial in which patients with coronary artery disease, peripheral arterial disease, or both were randomized to receive rivaroxaban alone (5 mg twice daily) with an aspirin-matched placebo, rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily), or aspirin (100 mg daily) with a rivaroxaban-matched placebo (twice daily). There was a further randomization to pantoprazole 40 mg daily or placebo in eligible patients. The primary efficacy outcome was a composite of CV death, stroke, or myocardial infarction (MI). The main safety outcomes were International Society on Thrombosis and Haemostasis criteria for major bleeding, including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization or acute care facility. There were a variety of pre-specified secondary outcomes.

Results

In this study, 9,152 patients were randomized to rivaroxaban plus aspirin, 9,117 patients were randomized to rivaroxaban alone, and 9,126 patients were randomized to aspirin alone. Patient groups were evenly matched for CV risk factors, though only 22% of patients were female. Regarding the primary outcome of CV death, stroke, or MI, the combination of rivaroxaban and aspirin had a significant reduction of events compared with aspirin alone (379 [4.3%] vs. 496 [5.4%], hazard ratio [HR] 0.76 [0.66-0.86], p < 0.001). As expected, rivaroxaban alone compared with aspirin alone significantly reduced the risk of ischemic stroke (HR 0.69 [0.53-0.90], p = 0.006) but led to a significant increase in hemorrhagic stroke (HR 2.70 [1.31-5.58], p = 0.005). Importantly, the combination of lower dose rivaroxaban and aspirin significantly reduced ischemic stroke (HR 0.51 [0.38-0.68], p < 0.001) without significantly increasing hemorrhagic stroke (HR 1.49 [0.67-3.31], p = 0.33) when compared with aspirin. The combination of rivaroxaban and aspirin also significantly reduced the risk of all-cause mortality and CV death compared with aspirin alone.

The combination of rivaroxaban and aspirin significantly increased the risk of major bleeding compared with aspirin alone (288 [3.1%] vs. 170 [1.9%], HR 1.70 [1.40-2.05], p < 0.001), largely due to acute bleeding leading to presentation to an acute care facility or hospitalization. This difference in major bleeding was largely driven by an increased risk of gastrointestinal bleeding (HR 2.15 [1.60-2.89], p < 0.001). Rivaroxaban alone compared with aspirin alone also had an increased risk of major bleeding (HR 1.51 [1.25-1.84], p < 0.001). This was associated with a slight increase in risk of both gastrointestinal and intracranial bleeding.

Commentary

We read with interest the COMPASS trial,¹ which was a large trial that aimed to reduce the composite of CV death, stroke, and MI in patients with stable atherosclerotic CV disease through the addition of rivaroxaban. The results show a significant reduction in the primary outcome compared with aspirin alone. Without a doubt, this is a very well conducted clinical trial with good science and exciting results. However, its clinical application in the real world may be challenging. In the current era, cost and cost-effectiveness are of critical importance. Rivaroxaban has proven to be cost-effective in different settings such as for patients with thromboembolic diseases such as pulmonary embolus.² Rivaroxaban is an expensive drug, particularly for patients using Medicare who traditionally have fixed incomes. In our day-to-day clinical practice, we face cost issues with multiple drugs. In this trial, not surprisingly, reducing clinical events came at the cost of increased bleeding. This is a phenomenon that is familiar to the field of cardiology and adds to the growing literature supporting this trend with new antithrombotic and anticoagulant drugs (Table 1). At first glance, this trial shows us a dramatic reduction in the primary endpoint (0.76, 95% confidence interval [0.66-0.86), p < 0.001). However, this led to only a 1.3% absolute risk reduction of the composite endpoint. Similar small reductions were seen in all-cause death (0.7%), MI (0.3%), and CV death (0.5%). To completely justify the addition of yet another pill that will increase cost, we must look critically at adverse events. Again, if we look at the HR, the risk of bleeding was increased by 70% (1.70, 95% confidence interval [1.4-2.05)], p < 0.001), though this was associated with an absolute difference of 1.2%. Rivaroxaban increased transfusion within 48 hours by 0.5% (which was double the rates on aspirin alone) and increased minor bleeding by 3.7%. Despite the efforts to show the net clinical benefit still favoring the rivaroxaban-plus-aspirin strategy, the numbers show that the tradeoff on the primary endpoint and major bleeding is almost a wash. Although the study is very exciting by showing a further decrease in major events with the addition of rivaroxaban, we believe that the clinical application of this study will face major challenges, particularly justifying the addition of a drug with substantial cost for a small benefit. Thus, a cost-effectiveness analysis is greatly needed, particularly in the current fiscal climate.

Table 1: Comparison of Primary Endpoint Reduction With Bleeding Risk for a Variety of Antithrombotic and Anticoagulant Medications

Trial	Groups Studied	Primary Outcome (efficacy)	Bleeding Risk (safety)
CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events)	Clopidogrel vs. placebo for acute coronary syndromes (ACS)	MI, stroke, or CV death reduced (0.80 [0.72-0.90])	Increased major bleeding
CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance)	Clopidogrel vs. clopidogrel + aspirin for secondary prevention	MI, stroke, or CV death no difference (0.93 [0.83-1.05])	No difference in major bleeding Increased moderate bleeding
PLATO (A Comparison of Ticagrelor and Clopidogrel in Patients With Acute Coronary Syndrome)	Ticagrelor + aspirin vs. clopidogrel + aspirin for ACS	Death from vascular causes, MI, or stoke reduced (0.84 [0.77-0.92])	No difference in major bleeding (study or Thrombolysis In Myocardial Infarction [TIMI] criteria) Increased non- coronary artery bypass graft (CABG) related major bleeding Increased fatal intracranial bleeding
TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38)	Prasugrel + aspirin vs. clopidogrel + aspirin for ACS	MI, stroke, or CV death reduced (0.81 [0.73-0.90])	Increased non-CABG-related TIMI major bleeding Increased life-threatening bleeding
ATLAS ACS 2- TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51)	Rivaroxaban + dual antiplatelet therapy (DAPT) vs. DAPT for secondary prevention following ACS	MI, stroke or CV reduced (0.84 [0.72-0.96])	Increased TIMI major bleeding Increased minor bleeding Increased intracranial bleeding
APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2)	Apixaban + DAPT vs. DAPT for secondary prevention following ACS	MI, stroke or CV death no difference (0.95 [0.80-1.110])	Increased TIMI major bleeding Increased intracranial bleeding
TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50)	Vorapaxar + antiplatelet agent(s) vs. antiplatelet agent(s) for secondary prevention	MI, stroke or CV death reduced (0.87 [0.80-0.94])	Increased Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding Increased TIMI clinically significant bleeding
PEGASUS TIMI 54 (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)	Ticagrelor + aspirin vs. clopidogrel + aspirin for long-term secondary prevention following ACS	MI, stroke or CV death reduced (0.84 [0.74-0.95])	Increased TIMI major bleeding Increased TIMI minor bleeding
COMPASS	Rivaroxaban + aspirin vs. rivaroxaban alone	MI, stroke or CV death reduced (0.76 [0.66-0.86])	Increased major bleeding

References

1. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30.
2. Wang L, Baser O, Wells P, et al. Overall Effectiveness of Rivaroxaban in Patients with Pulmonary Embolism. Clin Ther 2017;39:1426-36e2.

Keywords: ESC Congress, ESC2017, Anticoagulants, Aspirin, Coronary Artery Disease, Peripheral Arterial Disease, Hemorrhage, Stroke, Intracranial Hemorrhages, Myocardial Infarction, Thrombosis, Hemostasis, Embolism, Angiography, Angina, Stable

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