In patients with cardiovascular disease (CVD), resuming antithrombotic therapy within 4-30 days after gastrointestinal bleeding (GIB) was associated with lower odds of major cardiovascular events (MACEs) over 12 months — this vs discontinuation or no resumption within 60 days. And any post-GIB antithrombotic use was associated with lower all-cause death, according to results from the international INTERBLEED study.

While GIB is common in patients with CVD, outcomes have been unclear. To narrow that knowledge gap, INTERBLEED prospectively assessed outcomes in a large nine-country cohort from Argentina, Australia, Belgium, Brazil, Canada, China, Ireland, Netherlands, and Türkiye. Reporting in Gastroenterology, Nauzer Forbes, MD, MSc, a clinical associate professor of medicine in the Division of Gastroenterology and Hepatology at University of Calgary, in Calgary, Alberta, Canada, and colleagues evaluated almost 4000 adults CVD with GIB and without.

“Patients with cardiovascular disease are at increased risk of gastrointestinal bleeding for several reasons, the most important being that many are treated with antithrombotic medications such as antiplatelet agents, anticoagulants, or both, all of which increase bleeding risk,” Forbes told Medscape Medical News. “We expected that patients with established CVD who experienced GIB would have worse subsequent outcomes than comparable patients without bleeding, and that antithrombotic management after the bleed might be an important contributor.”

The cohort of 3814 patients consisted of 1612 patients with GIB and 2202 without. About 38% of patients in both cohorts were female, and the mean ages were 74 years (GIB) and about 66 years (no GIB). The majority in both were on antithrombotic therapy ranging from single or dual antiplatelets to a vitamin K antagonist and an injectable anticoagulant.

Baseline conditions included coronary or peripheral arterial disease, heart failure, atrial fibrillation, cerebrovascular disease, or venous thromboembolic disease. Adverse outcomes ranged from MACEs such as myocardial infarction, stroke, or CVD-related death to all-cause death to recurrent GIB at 12 months.

“In our cohort, patients with GIB were older and had a greater burden of comorbidity, which likely also contributed to bleeding risk,” Forbes noted.

Multivariable analyses revealed that patients with CVD-GIB were more likely to die within 12 months (odds ratio [OR], 2.29; 95% CI, 1.24-4.19). GIB was associated with recurrent GIB (OR, 4.28; 95% CI, 2.80-6.53) but not with MACE.

However, prompt post-GIB resumption of antithrombotic therapy within either 4-7days (OR, 0.37; 95% CI, 0.17-0.83) or 8-30 days (OR, 0.37; 95% CI, 0.17-0.81) was associated with lower odds of MACE within 12 months vs discontinuation or no resumption within 60 days. Any antithrombotic use following enrolment in the study was associated with lower all-cause death (OR, 0.45; 95% CI, 0.28-0.71). Neither antithrombotic use nor early resumption of it was associated with higher odds of recurrent GIB.

“That is clinically important because many physicians are understandably concerned that restarting treatment too soon will simply provoke another bleed,” said Forbes. “We were also reassured that several well-established predictors of poor cardiovascular outcomes, such as older age, atrial fibrillation, chronic kidney disease, and impaired functional status, behaved as expected in our models, which supports the internal consistency of the findings.”

“What was particularly notable was that among patients with GIB, resumption of antithrombotic therapy was so clearly associated with a reduced risk of adverse outcomes,” Forbes said. “This suggests that interruption of antithrombotic therapy may be the most important potentially modifiable mechanism behind adverse cardiovascular outcomes after GIB, although our observational design means we cannot prove causality.”

According to co-author John W. Eikelboom, MBBS, MSc, a professor in the Department of Medicine at McMaster University and a hematologist at Hamilton General Hospital, both in Hamilton, Ontario, Canada, this study addresses more than a bleeding management issue. “It’s also a cardiovascular risk management issue. Gastroenterologists are central to the early phase of care because endoscopic control of bleeding, risk stratification, and clear communication about when antithrombotic therapy can be restarted may have consequences well beyond the GI tract.”

Offering his perspective, Zachary L. Smith, DO, MSc, an associate professor of medicine and director of clinical research in the Division of Gastroenterology and Hepatology at Medical College of Wisconsin in Milwaukee, told Medscape Medical News, “INTERBLEED is a landmark study that changes how we think about this problem. Now we have strong evidence from thousands of patients worldwide that restarting anticoagulants sooner is safer than waiting.”

Smith, who did not participate in the study, added that “going forward, the conversation between cardiologists and gastroenterologists needs to happen at the bedside, not weeks later. Researchers must now design clinical trials to determine the exact right time to restart these medications.”

Forbes agreed. “The most important is the optimal timing and strategy for restarting antithrombotic therapy after GIB in patients with cardiovascular disease. We also need better data on whether management should differ by bleeding source, severity, etiology, or by the specific antithrombotic agent involved,” he added.

Another key unanswered question is whether dose reduction or de-escalation strategies could preserve cardiovascular benefit while lowering the risk for rebleeding, Forbes added. “More broadly, newer agents targeting [the clotting protein] factor XI are of considerable interest because in early studies they may reduce bleeding compared with conventional anticoagulants, with potential future applications in patients with previous GIB.”

And for patients, the takeaway is simple, said Smith: the risk of not restarting may be greater than the risk of restarting. “Time matters. Every day off anticoagulants carries real consequences. So the question has shifted — it’s no longer if we restart, but how soon.”

The practical message, Forbes stressed, “is that, once hemostasis is achieved and the individual bleeding situation has been assessed, clinicians should have an explicit, individualized plan for antithrombotic resumption and close follow-up rather than allowing treatment interruption to drift indefinitely.”

This study was supported by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Daiichi Sankyo, Hamilton Health Sciences, and the Canadian Institutes of Health Research.

The study authors and Smith had no relevant conflicts to declare.