VTEs associated with risk category of hormonal contraception used
Results. The overall cohort included more than 2 million women who were followed for a median of 10 years. During 21.0 million person-years, 8,710 VTE events were diagnosed; almost one-third of these were pulmonary embolisms, with the remainder diagnosed as lower extremity VTE. Of these 8,710 women diagnosed with VTE, 7,043 (81%) were confirmed with either diagnostic imaging or prescription of an anticoagulant. Unfortunately, 228 women (2.6%) died within 30 days of the diagnosis of VTE.
The investigators identified concomitant use of hormonal contraception and NSAIDs in more than 500,000 women. Among women with such concomitant use, 58% were using contraceptives that were high risk while 23% used medium-risk and 19% used low/no-risk contraceptives. Ibuprofen (60%) was the most commonly used NSAID, followed by diclofenac (20%) and naproxen (6%). Between 97% and 98% of high-risk and medium-risk contraceptives were combination pills; 89% of low/no-risk contraceptives were progestin IUDs.
Compared with nonuse of both hormonal contraceptives and NSAIDs, incidence rate ratios of VTE adjusted for age, calendar year, and education were 8.1 (95% confidence interval [CI], 6.9–9.6) for use of NSAIDs only, 4.2 (95% CI, 4.0–4.4) for use of high-risk contraceptives only, 3.0 (95% CI, 2.8–3.2) for medium-risk contraceptive use, and 1.1 (95% CI, 1.0–1.3) for use of low/no-risk hormonal contraception. Risk of VTE was approximately twice as high with the use of diclofenac only compared with the risks associated with ibuprofen or naproxen use only.
With respect to concomitant use of NSAIDs and hormonal contraception, incidence rate ratios of VTE were 50.6 (95% CI, 44.2–57.8), 26.1 (95% CI, 19.6–34.7), and 5.7 (95% CI, 3.3–10.1), respectively, with use of high-risk, medium-risk, and low/no-risk hormonal contraceptives. Adjusting for time updated information on occurrences of migraine, connective tissue disorder, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension, and diabetes did not materially affect these associations.
When analysis was limited to women without these occurring conditions, rate ratios were somewhat higher (5.7 and 4.1) for use of high-risk and medium-risk contraceptives only. Incidence rate ratios in this subcohort of healthier women were substantially higher for NSAID use only (15.0), and 111.7, 43.2, and 13.0, respectively, for concomitant use of NSAIDs with high-risk, medium-risk, and low/no-risk contraceptives. In this analysis of healthier women, diclofenac continued to be associated with substantially higher risks of VTE than ibuprofen or naproxen. When the stricter definition of VTE (confirmed cases) was used, adjusted rate ratios remained similar.
Absolute risks of VTE
Although some of the elevated rate ratios noted in this study might appear alarming, it is important to keep in mind that the baseline incidence of VTE in healthy reproductive-age women is low. Accordingly, as the authors pointed out, even among women who used NSAIDs concomitantly with high-risk combination hormonal contraceptives, the absolute risk of VTE was 2/10,000.
Study strengths and limitations
Strengths of this analysis by Meaidi and colleagues include the use of large, essentially all-inclusive national registries. In addition, nationwide Danish registry data that indicate a diagnosis of VTE have been found to have a high positive predictive value.3 Another strength is the large number of potentially confounding factors that the authors controlled for.
One potential limitation of their analysis is that the use of only prescribed NSAIDs was considered. Fortunately, however, the prevalence of over-the-counter ibuprofen use in Denmark is not high enough to materially affect the authors’ findings.4 Another potential limitation was that information on smoking and body mass index was not available for most of the women included in the study cohort. The authors countered this limitation by pointing out that, in Denmark, smoking and obesity are highly correlated with educational status, and that all analyses were adjusted for educational status. ●
It is important for clinicians and our patients to recognize that pregnancy—the condition prevented by hormonal contraception— is associated with far higher risks of VTE (10–14 VTE events per 10,000 deliveries) than the use of any modern hormonal contraceptive.5 Although concomitant use of combination contraceptives and NSAIDs increases VTE risk, the absolute risk is modest, particularly when the NSAID is ibuprofen or naproxen (these are the non–aspirin NSAIDs most commonly used in the United States6). Women who regularly take NSAIDs can minimize VTE risk by choosing hormonal contraceptives with little or no impact on the risk of VTE: the progestin implant, progestin IUDs, and progestinonly pills.
ANDREW M. KAUNITZ, MD, MSCP