Author: Antje Schmidt (Klinik für Neurologie, Universitätsklinikum Münster, Germany)

What’s the most effective secondary prevention in cardiovascular disease? That’s what vascular neurologists, cardiologists, angiologists and general practitioners alike have been pondering about for years. Established prevention strategies include antihypertensives, statins, diabetes control, life style modification and antiplatelets. Until now, the standard antiplatelet drug for most indications has remained aspirin. But in spite of aspirin treatment, 5-10% of patients have a recurrent cardiovascular event.1 Therefore, various alternative treatments have been under investigation in large clinical trials, including different combinations of antiplatelets as well as warfarin. Aspirin in combination with clopidogrel, for instance, was not superior to aspirin alone in the prevention of atherothrombotic events in patients with either evident cardiovascular disease or multiple risk factors.2 The combination of aspirin and warfarin led to a reduction of recurrent cardiovascular events, but increased bleeding complications.3 More recently, low-dose rivaroxaban (2.5 mg or 5 mg twice daily) was successfully applied for secondary prevention in patients with an acute coronary syndrome,4 thus raising expectations for the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial.

The recently completed COMPASS trial included more than 27 000 patients with stable atherosclerotic vascular disease. Participants were randomized into the following three groups:

  • Rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily)
  • Rivaroxaban (5 mg twice daily)
  • Aspirin (100 mg once daily)

The primary efficacy endpoint was the composite of cardiovascular death, stroke, or myocardial infarction.

After a mean follow-up period of 23 months, the trial was stopped for superiority of the rivaroxaban-plus-aspirin group. Primary endpoint events occurred in 4,1% of patients in the rivaroxaban-plus-aspirin group and in 5,4% of patients in the aspirin group (hazard ratio: 0.76; 95% CI 0.66-0.86; p<0.001). The risk of stroke in particular was reduced by 42 % (hazard ratio: 0.58; 95% CI 0.44-0.76; p<0.001).

Should we worry about bleeding complications? The incidence of severe bleeding was indeed increased in the rivaroxaban-plus-aspirin group compared to aspirin alone. However, most bleeding events were controllable gastrointestinal bleedings, whereas intracranial bleedings and fatal bleedings were not significantly increased. Therefore, the net clinical benefit was clearly in favor of low-dose rivaroxaban plus aspirin.

Rivaroxaban (5 mg twice daily) alone did not reduce the composite endpoint of cardiovascular death, stroke, or myocardial infarction, but was associated with significantly increased bleeding rates.

Altogether, the COMPASS trial clearly demonstrates a clinical benefit of low-dose rivaroxaban plus aspirin – COMPASS literally shows us a new direction for secondary prevention in cardiovascular disease.

The results of the COMPASS trial were published on August 27, 2017 at NEJM.org.

References

  1. Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, Wilson PWF, Alberts MJ, D’Agostino R, Liau C-S, Mas J-L, Röther J, Smith SC, Salette G, Contant CF, Massaro JM, Steg PG, REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–1357.
  2. Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N. Engl. J. Med. 2006;354:1706–1717.
  3. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N. Engl. J. Med. 2002;347:969–974.
  4. Mega JL, Braunwald E, Wiviott SD, Bassand J-P, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KAA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FWA, Gibson CM, ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 2012;366:9–19.