Nonsteroidal anti-inflammatory drugs (NSAIDs) may almost double the risk for venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, according to an article published online September 24 in Rheumatology.
“[T]he results of our meta-analysis demonstrate a statistically significantly increased VTE risk among NSAID users. Physicians should be aware of this association and NSAIDs should be prescribed with caution, especially in patients at high baseline risk of VTE,” write Patompong Ungprasert, MD, from the Bassett Medical Center and Columbia University College of Physicians and Surgeons, New York City, and colleagues.
The investigators note that this is first systematic review and meta-analysis of published observational studies to examine the association between NSAID use and VTE. They used observational studies for their analysis because the complication is too rare to show up reliably in most randomized clinical trials.
Of 597 potential published studies, the researchers included 6, representing 21,401 VTE events, in their final analysis. The studies reported odds ratios, relative risks, hazard ratios, or standardized incidence ratios for VTEs among NSAID users compared with nonusers.
The studies, 1 cohort (n= 19,293; 215 events) and 5 case-control studies (cases, 21,186; controls, 110,824), were conducted in the United Kingdom, France, the Netherlands, Denmark, and Sweden between 2007 and 2013.
The pooled risk ratio among NSAID users was 1.8-fold for VTE (95% confidence interval, 1.28 – 2.52). Among participants who used selective cyclooxygenase 2 (COX-2) inhibitors, the pooled risk ratio was 1.99 (95% confidence interval, 1.44 – 2.75). Both measures reached statistical significance.
Increased VTE risk may come primarily from COX-2 inhibitors, the researchers write, because aspirin, a COX-1 inhibitor, has been shown to be effective in VTE prevention.
The mechanism for risk for VTE remains unclear, however.
“Inhibition of the COX-2 enzyme has been shown to inhibit the synthesis of prostacyclins, potent platelet activation inhibitors, while stimulating the release of thromboxane, a potent platelet aggregation facilitator, from the activated platelets. The activation and aggregation of platelets might, in turn, induce a coagulation cascade and clotting,” the researchers write.
Limitations of the results include a possible publication bias, heterogeneity among the studies, and an inability to show cause and effect from observational studies.
Nevertheless, the researchers write “With the widespread use of these medicines, this increased risk may have important public health implications.”
The authors have disclosed no relevant financial relationships.
Rheumatology. Published online September 24, 2014. Abstract