Late breaking results presented as part of a Clinical Trial Updates from the COMPASS Trial (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) suggest that bleeding in patients treated with anticoagulants should stimulate a search for cancer.[1] The data was presented at the annual congress if the European Society of Cardiology (ESC) being held August 25 – 29, 2018 in Munich, Germany.
The primary purpose of the trial, sponsored by Bayer AG, is to evaluate whether treatment with rivaroxaban (Xarelto? | BAY59-7939; Janssen Pharmaceuticals, licensed from Bayer HealthCare AG) and aspirin or rivaroxaban alone is better than aspirin alone in prevention of heart attacks, stroke or cardiovascular death in patients with coronary or peripheral artery disease.
Rivaroxaban is a selective direct factor Xa inhibitor that is used a prevention for and treatment of venous thromboembolism. The drug is also used to prevent stroke or systemic embolism in atrial fibrillation.
Substantial increase
“In patients with stable coronary artery disease or peripheral artery disease, the occurrence of major gastrointestinal bleeding predicts a substantial increase in new gastrointestinal cancer diagnoses, while major genitourinary bleeding predicts a substantial increase in new genitourinary tract cancer diagnoses,” explained Professor John Eikelboom, principal investigator, of the Population Health Research Institute, McMaster University, Hamilton, Canada.
Up to one in ten patients with cardiovascular disease have recurrent events each year. As previously reported, the COMPASS trial found that in patients with coronary artery disease or peripheral artery disease, the combination of rivaroxaban (2.5 mg twice daily) and aspirin reduced cardiovascular events compared to aspirin alone, but there were more major bleeding events in the combined drug group.[2]
Cancer diagnosis
For the first time today, the investigators report details on the effect of bleeding on subsequent cancer diagnoses.
Trial design
Briefly, the trial enrolled 27,395 patients with chronic stable coronary or peripheral artery disease from 602 centers in 33 countries. Patients were randomly allocated to one of three groups: 1) rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily 2) rivaroxaban 5 mg twice daily, or 3) aspirin 100 mg once daily. Results in each of the rivaroxaban groups were compared with the aspirin alone group. The mean duration of follow up was 23 months.
The combination increased major bleeding, as defined by the International Society on Thrombosis and Haemostasis (ISTH), compared with aspirin (3.1% versus 1.9%, hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.40-2.05, p<0.0001), but did not significantly increase intracranial (0.3% versus 0.3%, HR 1.16, 95% CI 0.67-2.00, p=0.60) or fatal bleeding (0.2% versus 0.1%, HR 1.49, 95% CI 0.67-3.33, p=0.32).
Major gastrointestinal bleeding was associated with a 20-fold increase in new diagnoses of gastrointestinal cancer (9.3% versus 0.7%, HR 22.6, 95% CI 14.9-34.3, p<0.0001) and a two-fold increase in non-gastrointestinal cancer (4.6% versus 3.1%, HR 2.55, 95% CI 1.47-4.42, p<0.0001).
Major non-gastrointestinal bleeding was associated with a five-fold increase in new non-gastrointestinal cancers (9.4% versus 3.0%, HR 5.49, 95% CI 3.95-7.62, p<0.0001), but not with new gastrointestinal cancer (0.5% versus 0.8%, HR 0.85, 95% CI 0.21-3.45, p=0.82).
“More than one in ten patients with major bleeding were subsequently diagnosed with cancer, and more than 20% of new cancer diagnoses were in patients who experienced bleeding. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and if bleeding unmasks cancer it could potentially lead to the added benefit of improved cancer outcomes,” Eikelboom said.
Reference
[1] Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial – NCT01776424.
[2] Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377:1319-1330. doi: 10.1056/NEJMoa1709118.
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