Rivaroxaban and ASA: The new dream team of CHD prevention?

 COMPASS study on monotherapy vs. combination therapy

A combination therapy with aspirin and low-dose rivaroxaban appears to be more effective in the secondary prevention of cardiovascular events than aspirin monotherapy. This is shown by the COMPASS study recently presented in the Lancet Journal. Although gastrointestinal bleeding increased, all-cause mortality was lower than with aspirin.

Platelet inhibitor therapy is standard in the secondary prevention of cardiovascular events. In order to improve the survival of the patients, the therapy was extended to include anticoagulants. However, initial studies of vitamin K antagonists have been sobering. Although cardiovascular outcome improved, patients suffered more from severe intracranial bleeding. With the new direct anticoagulants, a new class of substances has emerged that might be more suitable. The multicenter, double-blind randomized COMPASS study presented here investigated rivaroxaban in this context.

27,000 patients in 3 treatment groups

The Bayer-funded study included around 27,400 patients from over 600 hospitals worldwide and was observed for an average of two years. Inclusion criteria were a known coronary artery disease (CHD) or symptomatic peripheral arterial occlusive disease (PAOD). The subjects were randomly divided into one of the three treatment arms: Acetylsalicylic acid (ASA) 100 mg + rivaroxaban 2.5 mg twice daily; rivaroxaban alone; ASA alone. 24,000 participants suffered from coronary heart disease, 7,500 from PAOD. The primary endpoint of the study was the occurrence of heart attack, stroke and cardiovascular death. The average study participant was a 69-year-old and slightly overweight man who had suffered a heart attack.

26% fewer cardiovascular events due to combination therapy

Looking at CHD patients, the combination of both blood thinners led to a significant reduction in cardiovascular events from 6% to 4% compared to ASA alone, which corresponds to a relative risk reduction of 26%. Furthermore, the incidence of stroke was reduced by 44% and the overall mortality of 23%. However, rivaroxaban alone did not improve these endpoints.

In the PAOD cohort, cardiovascular events were also significantly reduced from 7% to 5%, corresponding to a relative risk reduction of 28%. In addition, ischemia of the lower extremities was reduced by 46%. Rivaroxaban alone also showed a reduction in limb ischemia but did not improve the primary endpoint.

Disadvantage: Increased gastrointestinal bleeding

As usual in studies with anticoagulants, bleeding events were considered as important safety parameters. In the CHD cohort, 66% more bleeding events were recorded in the combination group compared to the ASA group, with gastrointestinal bleeding occurring most frequently. The deadly bleeding did not increase. Monotherapy with rivaroxaban also resulted in 51% more bleeding compared to ASA (especially more intracranial bleeding), but also no more fatal bleeding.

Similar results were obtained in the PAOD cohort. About 61% more bleeding occurred in combination therapy compared to ASA monotherapy, most of which was gastrointestinal bleeding. Deadly bleeding was rare and evenly distributed among the groups. Rivaroxaban alone led to 68% more bleeding events compared to ASA.

Since these data are relatively described, it should be noted that on average one in 30 patients suffered a bleeding event in the course of the study, but only one in 700 died from it.

A pioneering study on anticoagulants in CHD secondary prevention

While the ATLAS studies with apixaban 5 mg and rivaroxaban 5 mg did not yield promising results, the COMPASS study with the combination therapy of ASA and low-dose rivaroxaban 2.5 mg presented in November 2017 shows that optimized secondary prevention is possible for some patients without increasing the risk of severe bleeding. In the authors' opinion, this is also confirmed by the net consideration of positive and negative outcome: the reduced cardiovascular events would outweigh the increased bleeding tendency. The reduced all-cause mortality would also speak in favor of combination therapy. According to the authors, the cardiovascular benefit of two-year therapy with ASA and rivaroxaban can be compared to 5-year statin or ACE inhibitor therapy.

Combination therapy already used in certain cases

Numerous experts assume that the results of this study will soon also be applied in practice. A small non-representative survey of cardiologists at the Berlin, Germany-based university hospital Charité showed that the combination of ASA and rivaroxaban is already used, but is initially reserved for only a few patients with a high cardiovascular risk profile and a low risk of bleeding.

1. Connolly SJ et al. rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomized, double-blind, placebo-controlled trial. Lancet. 2017 Nov 10 pii: S0140-6736(17)32458-3. doi: 10.1016/S0140-6736(17)32458-3. [Epub ahead of print]
2. Anand SS et al. rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomized, double-blind, placebo-controlled trial. Lancet. 2017 Nov 10 pii: S0140-6736(17)32409-1. doi: 10.1016/S0140-6736(17)32409-1.[Epub ahead of print]

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