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Diclofenac use may increase risk of major adverse cardiovascular events

Stephen Padilla
11 Sep 2018
The study showed an increased of cardiac arrest linked to over-the-counter NSAIDs such as ibuprofen and diclofenac.

Use of diclofenac, a traditional nonsteroidal anti-inflammatory drug (NSAID) with cyclo-oxygenase-2 (COX-2) selectivity similar to COX-2 inhibitors, is associated with higher cardiovascular health risk compared with nonuse, paracetamol use and use of other traditional NSAIDs, a recent study has shown.

“It is time to acknowledge the potential health risk of diclofenac and to reduce its use,” researchers said. “Diclofenac should not be available over the counter, and when prescribed, should be accompanied by an appropriate front package warning about its potential risks.”

The increase in adverse event rate among Initiators of diclofenac was 50 percent compared with noninitiators (incidence rate ratio [IRR], 1.5; 95 percent CI, 1.4–1.7), 20 percent compared with paracetamol or ibuprofen initiators (IRR for both, 1.2; 1.1–1.3), and 30 percent compared with naproxen initiators (IRR, 1.3; 1.1–1.5). [BMJ 2018;362:k3426]

Compared with nonuse, diclofenac use increased the event rate for each component of the combined endpoint (atrial fibrillation/flutter: IRR, 1.2; 1.1–1.4; ischaemic stroke: IRR, 1.6; 1.3–2.0; heart failure: IRR, 1.7; 1.4–2.0; myocardial infarction: 1.9; 1.6–2.2; cardiac death: IRR, 1.7; 1.4–2.1). These increases were also observed with low doses of diclofenac.

Individuals with low or moderate baseline risk (ie, diabetes mellitus) showed the highest relative risk of major adverse cardiovascular events, but those with high baseline risk (ie, previous myocardial infarction or heart failure) demonstrated the highest absolute risk.

The risk of upper gastrointestinal bleeding at 30 days also increased by approximately 4.5-fold with diclofenac use vs nonuse, 2.5-fold vs ibuprofen or paracetamol initiation, and to a similar extent as naproxen initiation.

“Owing to its short half life of 1–2 hours, diclofenac is prescribed at doses high enough for effective analgesia throughout the dosing interval,” researchers said. “The plasma concentration of diclofenac therefore greatly exceeds that necessary to inhibit COX-2 early in the dosing interval, and coincidently inhibits COX-1 (attained selectivity).” [Annu Rev Med 2010;61:17-33]

Additionally, the following factors contribute to the cardiovascular toxicity of COX-2 inhibitors: acceleration of atherogenesis, elevation or destabilization of blood pressure, and risk of heart failure decompensation. [Science 2004;306:1954-1957; Arch Intern Med 2005;165:490-496; Proc Natl Acad Sci U S A 2009;106:7548-7552; Eur J Heart Fail 2008;10:1102-1107]

In this series of 252 nationwide cohort studies, each mimicked the strict design criteria of a clinical trial (emulated trial design). Participants included were all adults without malignancy, schizophrenia, dementia, or cardiovascular, kidney, liver or ulcer diseases (ie, low baseline risk): 1,370,832 diclofenac initiators, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, 764,781 healthcare-seeking paracetamol initiators matched by propensity score and 1,303,209 healthcare-seeking noninitiators also matched by propensity score.

“[T]he choice to use diclofenac as the reference group to provide evidence of safety of selective COX-2 inhibitors represents a potential flaw in safety trials. Future trials should instead use low-dose ibuprofen (≤1,200 mg/day) or naproxen (≤500 mg/day) as comparators. [Eur Heart J 2016;37:1015-1023; JAMA 2000;284:1247-1255; Eur Heart J 2017;38:1843-1850; Lancet 2006;368:1771-1781]

In a response, Siddharth Kumar Das, a rheumatologist and professor at K.G. Medical University in India, said that this study yet again hammers “a nail in the coffin of NSAIDs and particularly COX-2 inhibitors. However, unfortunately, I find it difficult to understand that this increase in risk is because of NSAIDs, till I understand the reasons for initiation [of] NSAIDs.” [BMJ 2018;362:k3426]

Boon Beng Goh, a general practitioner at Sri Rampai Mediviron Clinic in Malaysia, said that the study would be more complete if meloxicam and tramadol were included, “as the use of these analgesics is relatively common in [general practice] and hospital setting.” [BMJ 2018;362:k3426]

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