Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial

Deepak L Bhatt, John W Eikelboom, Stuart J Connolly, P Gabriel Steg, Sonia S Anand, Subodh Verma, Kelley R H Branch, Jeffrey Probstfield, Jackie Bosch, Olga Shestakovska, Michael Szarek, Aldo Pietro Maggioni, Petr Widimský, Alvaro Avezum, Rafael Diaz, Basil S Lewis, Scott D Berkowitz, Keith A A Fox, Lars Ryden, Salim Yusuf, COMPASS Steering Committee and Investigators, V Aboyans, M Alings, P Commerford, N Cook-Bruns, G Dagenais, A Dans, G Ertl, C Felix, T Guzik, R Hart, M Hori, A Kakkar, K Keltai, M Keltai, J Kim, A Lamy, F Lanas, Y Liang, L Liu, E Lonn, P Lopez-Jaramillo, K Metsarinne, P Moayyedi, M O'Donnell, A Parkhomenko, L Piegas, N Pogosova, M Sharma, S Stoerk, A Tonkin, C Torp-Pedersen, J Varigos, P Verhamme, D Vinereanu, K Yusoff, J Zhu, Deepak L Bhatt, John W Eikelboom, Stuart J Connolly, P Gabriel Steg, Sonia S Anand, Subodh Verma, Kelley R H Branch, Jeffrey Probstfield, Jackie Bosch, Olga Shestakovska, Michael Szarek, Aldo Pietro Maggioni, Petr Widimský, Alvaro Avezum, Rafael Diaz, Basil S Lewis, Scott D Berkowitz, Keith A A Fox, Lars Ryden, Salim Yusuf, COMPASS Steering Committee and Investigators, V Aboyans, M Alings, P Commerford, N Cook-Bruns, G Dagenais, A Dans, G Ertl, C Felix, T Guzik, R Hart, M Hori, A Kakkar, K Keltai, M Keltai, J Kim, A Lamy, F Lanas, Y Liang, L Liu, E Lonn, P Lopez-Jaramillo, K Metsarinne, P Moayyedi, M O'Donnell, A Parkhomenko, L Piegas, N Pogosova, M Sharma, S Stoerk, A Tonkin, C Torp-Pedersen, J Varigos, P Verhamme, D Vinereanu, K Yusoff, J Zhu

Abstract

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events.

Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding.

Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77, P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84, P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative Pinteraction<0.0001; 1.9% versus 0.6% for all-cause mortality, Pinteraction=0.02; 2.7% versus 1.7% for major vascular events, Pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative Pinteraction=0.001).

Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Keywords: anticoagulants; coronary artery disease; diabetes mellitus; peripheral artery disease; platelet aggregation inhibitors.

Figures

Figure 1.
Figure 1.
Cardiovascular death, myocardial infarction, or stroke. Kaplan-Meier event curves for patients with and without diabetes mellitus randomized to aspirin plus placebo or aspirin plus low-dose rivaroxaban. The primary end point of cardiovascular death, myocardial infarction, or stroke is shown. Percentages are Kaplan-Meier risks at 3 years. ARR indicates absolute risk reduction; and HR, hazard ratio.
Figure 2.
Figure 2.
All-cause death. Kaplan-Meier event curves for patients with and without diabetes mellitus randomized to aspirin plus placebo or aspirin plus low-dose rivaroxaban. The secondary end point of all-cause death is shown. Percentages are Kaplan-Meier risks at 3 years. ARR indicates absolute risk reduction; and HR, hazard ratio.
Figure 3.
Figure 3.
Major vascular events. Kaplan-Meier event curves for patients with and without diabetes mellitus randomized to aspirin plus placebo or aspirin plus low-dose rivaroxaban. The expanded end point of all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events [MALEs], including amputation) is shown. Percentages are Kaplan-Meier risks at 3 years. ARR indicates absolute risk reduction; and HR, hazard ratio.
Figure 4.
Figure 4.
Net clinical benefit. Kaplan-Meier event curves for patients with and without diabetes mellitus randomized to aspirin plus placebo or aspirin plus low-dose rivaroxaban. The net clinical benefit outcome (cardiovascular death, myocardial infarction [MI], stroke, fatal bleeding, or symptomatic bleeding into a critical organ) is shown. Percentages are Kaplan-Meier risks at 3 years. ARR indicates absolute risk reduction; and HR, hazard ratio.

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