VTE May Not Be Significant Driver of Death

July 30, 2020

A new systematic review and meta-analysis challenges the notion that preventing VTE is associated reduced mortality risk.

Investigators have challenged the belief that venous thromboembolism (VTE) is a common cause of mortality, based on their new findings from a systematic review and meta-analysis of trials which observed the causal effect of VTE reduction on patient mortality.

In new findings from an analysis of large-scale, randomized, controlled trials, a team of US-based investigators reported an insignificant evidence of VTE effect on overall mortality.

The team, led by Nicholas D. Klemen, MD, of the Memorial Sloan Kettering Cancer Center, also challenged the utility of composite endpoints in VTE prevention assessments based on their findings.

Their systematic review and meta-analysis included research into randomized, controlled trials published in 1 of 4 databases from January 1993- March 2018. Eligible studies included patients who were at elevated VTE risk, and were assigned randomly to either anticoagulant or antiplatelet therapy versus placebo or no therapy.

Trials including an active control agent were excluded, as they may mitigate the understood lethality of VTE. Investigators also excluded trials for which mortality data were unavailable.

Meta-analysis heterogeneity was modeled via Bayesian framework. Overall mortality served as the primary endpoint; pulmonary embolism, fatal pulmonary embolism, and major patient bleeding were secondary endpoints.

“We focused our analyses on studies reporting statistically significant effects of prevention on venous thromboembolism endpoints,” Klemen and colleagues wrote.

Of the screened 4229 studies, 86 were identified as eligible randomized, controlled trials. From those, 52 were positive—and showed through data from 70,000-plus patients a significantly increased risk of VTE in control patients versus treatment arms (RR, 2.74; 95 CI%, 2.32-3.31; P <.0001).

Through the meta-analysis, Klemen and colleagues observed a non-impactful causal effect of VTE prevention mortality: control group mortality included 3391 (9.8%) patients, while treatment arm mortality included 3498 (9.8%) (RR, 1.01; 95% CI, 0.97-1.06; P = .58). Investigators additionally observed low heterogeneity.

Regarding secondary endpoints, control patients were actually less likely to report major bleeding than treated patients (RR, 0.60; 95% CI, 0.47-0.75; P <.0001).

However, investigators did observe a greater rate of overall pulmonary embolism (RR, 2.22; 95% CI 1.78-2.89; P <.0001) and fatal pulmonary embolism (RR, 1.58; 95% CI, 1.14-2.19; P = .01) in control patients versus treatment arms.

The team’s meta-analysis of the additional 34 negative trials showed similar results across all endpoints, though fatal pulmonary embolism’s effect on control versus treated patients was observed to be weaker.

The new findings come at a time when major organizations including the American Heart Association (AHA) and International Society on Thrombosis and Hemostasis (ISTH) just recently called for the advancement of preventive VTE research—noting a 2008 Surgeon General’s Call to Action for improved VTE care that went largely unanswered more than a decade ago.

In a recent interview with HCPLive® regarding the AHA and ISTH statement, Maja Zaric, MD, interventional cardiologist and assistant professor at Zucker Medical School, discussed the complicated network of morbidities associated with VTE—including pulmonary embolisms and bleeding risks.

In some instances, more than 50% of patients are at risk of such additional burdens.

“I don’t think we’ve moved an iota since 2008 in terms of dropping those numbers down to a measurable level,” Zaric said. “The research has been done…we can’t say there hasn’t been any effort to do so.”

Given the new findings from Klemen and colleagues, there may be reason to look more closely into these conflicting comorbidities than VTE itself.

“The perception that venous thromboembolism is a common cause of mortality should be revised considering the null effect of venous thromboembolism prevention on mortality,” they concluded. “Our findings call into question the use of composite endpoints in venous thromboembolism-prevention trials and provide rationale for de-escalation trials.”

The study, “Mortality risk associated with venous thromboembolism: a systematic review and Bayesian meta-analysis,” was published online in The Lancet Haematology.


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