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The newer oral anticoagulants may increase the risk of gastrointestinal bleeding -- but it appears related to the choice of and indication for the drug, a large literature review found.

In a pooled analysis of 17 randomized controlled trials (RCT), there was a relative 55% risk of GI bleeding for patients receiving newer oral anticoagulants compared with those on standard care, according to I. Lisanne Holster, MD, of Erasmus MC University Medical Centre in Rotterdam, the Netherlands, and colleagues.

A subgroup analysis, however, revealed that much of the increased risk may be attributable to four trials -- two in patients with acute coronary syndrome (OR 5.21) and two in patients with acute venous thromboembolism (OR 1.59), they wrote in the study published in the July issue of Gastroenterology.

"Although not specifically stated in the manuscript, indication seemed to be a significant source of heterogeneity," wrote Steven J. Heitman, MD, of the University of Calgary in Alberta, and colleagues in an accompanying editorial.

Holster and colleagues found no increased risk of GI bleeds for these other indications:

• Prevention of stroke in nonvalvular atrial fibrillation
• Prevention of deep vein thrombosis (DVT) after orthopedic surgery
• Prevention of venous thromboembolism (VTE) in the medically ill

There was moderate to high heterogeneity in most of the analyses.

In another subgroup analysis, Holster and colleagues found that, individually, dabigatran (Pradaxa) was associated with a significant increased risk of GI bleeds (OR 1.58), as was rivaroxaban (Xarelto) (OR 1.49), compared with standard care -- which comprised either enoxaparin, warfarin, antiplatelet therapy, or no therapy (placebo).

Apixaban (Eliquis) and edoxaban did not show an increased risk.

The investigators initially identified 43 studies for inclusion in this meta-analysis and systematic review, but only the aforementioned 17 studies included data on GI bleeds.

All 43 studies, however, had data for the secondary outcome of clinically relevant bleeding (major and nonmajor). When pooled, these studies showed a modest increase in risk (OR 1.16) compared with standard care.

When the researchers pooled only the acute coronary syndrome (ACS) studies, the risk of clinically relevant bleeding was double that of prophylaxis during orthopedic surgery (OR 2.1 versus 1.05).

The other medical indications had no increased risk of clinically relevant bleeding, which is consistent with the literature, the authors noted.

Dabigatran, rivaroxaban, and apixaban are approved by the FDA; all three reduce the risk of stroke in nonvalvular atrial fibrillation. Rivaroxaban is also approved for prevention of VTE after knee and hip replacement and for treatment and reduction of recurrence of VTE.

All of the above mentioned oral anticoagulants plus betrixaban, which one trial examined, are factor Xa inhibitors, except dabigatran, which is a direct thrombin inhibitor.

The editorialists lamented the lack of antidotes for these new agents. "This is an alarming fact given the widespread use of new oral anticoagulants and the increased risk of bleeding that has now been demonstrated."

They called for clear and concise guidelines for managing acute GI bleeds in patients taking these drugs.

Holster and colleagues noted that other systematic reviews of these drugs have been limited by their focus on specific agents and indications, their lack of data on GI bleeds, and inconsistent results.

They therefore searched the literature and identified 43 RCTs encompassing 151,568 patients. Overall, they found a low rate (1.5%) of GI bleeds, but most of those that did occur (89%) were major.

They reported that the Egger regression test and funnel plots indicated no evidence of publication bias.

Trial characteristics varied when it came to allowing or disallowing medications, such as any co-medication that would affect coagulation, low-dose aspirin, short-acting nonsteroidal anti-inflammatory drugs (NSAIDs), and various combinations of NSAIDs with other drugs.

"The major strength of this meta-analysis was its focus on GI bleeds," the investigators said. They called for "better reporting of GI bleeding events in future trials [to] allow stratification of patients for therapy with gastroprotective agents."

The limitations, they acknowledged, included the inherent limitations of the available data, the relatively small number (less than half) of studies with GI bleeding data, and no data on the impact of concomitant use with other medications.

From the American Heart Association:

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