In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.
Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).
The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).
Morten Schmidt, MD, PhD
“Diclofenac is the most frequently used NSAID in low-, middle-, and high-income countries and is available over the counter in most countries; therefore, its cardiovascular risk profile is of major clinical and public health importance,” said Dr. Schmidt and his coauthors.
In all, the study included 1,370,832 individuals who initiated diclofenac, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, and 764,781 acetaminophen initiators. Those starting diclofenac were compared with those starting other medications and with 1,303,209 individuals who sought health care but did not start one of the medications.
Novel Methodology
The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.
For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.
The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.
Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.
Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.
“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.
Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.
Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.
Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.