medwireNews: Older patients with atrial fibrillation (AF) who are taking rivaroxaban or apixaban are at greater risk for serious bleeding when concurrently treated with diltiazem rather than metoprolol for ventricular rate control, study findings indicate.
Writing in JAMA, Wayne Ray (Vanderbilt University School of Medicine, Tennessee, Nashville, USA) and colleagues say: “The absolute risk of serious bleeding associated with diltiazem treatment increased with diltiazem doses higher than 120 mg/d; increased HAS-BLED score, which summarizes common risk factors for anticoagulant-related hemorrhage; and rivaroxaban use, which has been consistently associated with rates of serious bleeding greater than those for other direct oral anticoagulants.”
They suggest that “measures to reduce the clinical impact of the interaction of diltiazem with study anticoagulants should target high-risk patients, including those with advanced age, history of bleeding, pro-hemorrhagic medication use, or rivaroxaban use.”
For the study, the researchers analyzed data from 204,155 Medicare beneficiaries with AF, who initiated treatment with either apixaban 1.5–5.0 mg twice daily or rivaroxaban 15–20 mg daily to prevent blood clots and who also began treatment with diltiazem (n=53,275) or metoprolol (n=150,880) for ventricular rate control. The mean age of the patients was 76.9 years, and 52.7% were women.
Over a median follow-up of 120 days, the primary outcome of serious bleeding events – a composite of bleeding-related hospitalization or death with recent evidence of bleeding – occurred in significantly more patients receiving diltiazem than those receiving metoprolol, at rates of 60.3 versus 49.7 events per 1000 person–years. The risk for serious bleeding was a significant 21% greater with diltiazem and a significant difference compared with metoprolol was evident within the first 180 days.
The bleeding risk associated with diltiazem increased with higher doses, Ray et al point out. Patients treated with a dose of 120 mg/day or less were 13% more likely to have a serious bleeding event than those receiving metoprolol, with 6.7 more serious bleeding events per 1000 person–years.
By comparison, those taking diltiazem at a dose above 120 mg/day had a 29% increased risk, with 15.1 additional serious bleeding events per 1000 person–years. At the higher dose, the greatest difference in serious bleeding events was seen for patients taking rivaroxaban and those with worse HAS-BLED scores of 4 or more, with 21.2 and 22.0 additional events per 1000 person–years, compared with their counterparts taking metoprolol.
There was no increased risk for ischemic stroke, systemic embolism, or death without recent evidence of bleeding with either dose of diltiazem versus metoprolol, although the higher diltiazem dose was associated with a significant 14% increased risk for major ischemic or hemorrhagic events.
Ray et al say that “many patients with atrial fibrillation and elevated risk of hemorrhage will continue to be treated with diltiazem and direct factor Xa inhibitors,” because diltiazem is “relatively contraindicated for those with chronic obstructive pulmonary disease and bronchospasm, may provide better rate control and reduction of arrhythmia symptoms, and is preferred for hypertension.”
They continue: “If, as postulated, elevated anticoagulant plasma concentrations mediate the increased risk of serious bleeding associated with diltiazem, therapeutic drug monitoring could be studied in patients for whom diltiazem is indicated.”
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