NSAIDs are a largely used class of drugs, maybe the most widely used in the world, because of implicated to treat pain in many different diseases. In many countries (i.e., the United States, Germany, Sweden, Spain, and others), some of them (most often ibuprofen, naproxen, and diclofenac) can also be purchased as over-the-counter medicines in supermarkets, at gas stations, and convenience stores without any expert advice on their use or potential side-effects.1 In patients with systemic inflammatory diseases, NSAIDs play an important role as analgesics and anti-inflammatory effects.2,3 Nevertheless, today NSAIDs are less used in systemic inflammatory diseases patients as first-line treatment because of their inability to control disease progression and several side-effects, particular at gastrointestinal4 and cardiac5 level. Aim of this document is to review side-effects profile of NSAIDs and, specifically, to investigate cardiovascular consequences of NSAIDs use in clinical practice.
Mechanisms of action and side-effects profile
NSAIDs inhibit the two recognized forms of cyclooxygenase, namely COX-1 and COX-2, blocking prostaglandin and prostacyclin biosynthesis.6 By inhibiting COX-1, NSAIDs as aspirin, reduce thromboxane production, and this contributes to their antiplatelet effect. By more effectively inhibiting COX-2, other NSAIDs, as ibuprofen, naproxen, diclofenac, and COX-2 selective inhibitors, known as coxibs, have relatively greater anti-inflammatory, antipyretic, and analgesic effects.7 The adverse effect profile of nonselective NSAIDs primarily includes bleeding, particularly gastrointestinal bleeding, which is thought to result from gastric irritation, antiplatelet effects, and the loss of prostaglandin-mediated mucosal repair.8
COX-1 is expressed constitutively in most tissues, whereas COX-2 is induced primarily by inflammation and in response to shear stress on endothelial tissues.9 Thus, the largest part of gastrointestinal side-effects of NSAIDs is because of COX-1 inhibition, whereas NSAIDs, which selectively inhibit COX-2, might reduce the risk of gastrointestinal toxicity. Coxibs were developed in the 1990s, and early trials comparing coxibs vs. traditional NSAIDs seemed to confirm similar analgesic efficacy and less gastrointestinal toxicity.10,11 Unfortunately, subsequent placebo-controlled trials showed unequivocally that coxibs are associated with an increased risk of atherothrombotic vascular events.
Cardiovascular safety on NSAIDs is highly controversial. For several coxibs, randomized placebo-controlled clinical trials have demonstrated an increased risk of serious cardiovascular disease.12–15 However, there is considerable uncertainty with regard to cardiovascular safety of the older traditional NSAIDs.16 Meta-analyses of observational studies17,18 suggested that cardiovascular risk varies for individual drugs in this class, with diclofenac associated with greater risk than naproxen. Otherwise, meta-analysis of clinical trials16 reported a greater risk of both diclofenac and ibuprofen over naproxen (Table 1). Subsequent observational studies demonstrated an association between ischemic cardiovascular events and the use of nonselective and more commonly available NSAIDs, such as ibuprofen and diclofenac, especially when taken at higher doses and by patients with known cardiovascular disease.16,19
Many proposed pathophysiological mechanisms have been raised to explain the cardiovascular side-effects of NSAIDs. One possible explanation that has been recently validated in animal models is that the imbalance of vasodilatory prostacyclin and prostaglandin E2 vs. vasoconstrictive thromboxane A2, created in the endothelium with NSAIDs use, leads to thrombosis.20,21 It has also been well established that COX-2 inhibition promotes sodium and water retention, exacerbates heart failure and hypertension, and increases adverse ventricular remodeling.22–24 Indeed, NSAIDs use in patients with chronic heart failure has been associated with a significant increase in cardiovascular morbidity and mortality.25 Furthermore, the beneficial effect of aspirin may be attenuated by concomitant administration of NSAIDs.26,27
An increase in thrombotic events, ischemic hospitalizations, and heart failure is expected consistent with the clinical and physiologic effects of NSAIDs. First, there is evidence that the homeostatic mechanisms that exist between prostacyclin-mediated vasodilation (blocked by COX-2 inhibitors) and tromboxane A2-mediated vasoconstriction is perturbed when (selective or nonselective) COX-2 inhibitors are used.20 Second, NSAIDs may increase salt and water retention, blood pressure,20,24,28 and afterload, which also can result in increased myocardial infarction (MI), stroke, and heart failure risk. Third, as already mentioned, these drugs have been shown to possibly attenuate the action of aspirin.26,27
NSAIDs and cardiovascular side-effects
The rate of NSAIDs cardiovascular side-effects has been widely investigated in several studies.
Olsen et al.29 in a cohort of 61 971 patients admitted for first-time MI, showed an increased rate of combined cardiovascular events (cardiovascular death, nonfatal recurrent MI, ischemic stroke, transient ischemic attack, and systemic arterial emboli) in patients treated with NSAIDs, than in patients without NSAIDs treatment [hazard ratio, 1.40 (95% CI, 1.30–1.49)] during a median follow-up of 3.5 years. Lamberts et al.30 studied 150 900 patients with atrial fibrillation, of which 69.8% were treated with an antiplatelet or an oral anticoagulant, whereas only 5% of the whole population were treated with a concomitant NSAID. This study showed an increased absolute risk of serious bleeding (described as gastrointestinal and intracranial) and thromboembolism with NSAIDs treatment compared with no NSAIDs treatment [hazard ratio, 2.27 (95% CI, 2.15–2.40), hazard ratio, 1.36 (95% CI, 1.27–1.45), respectively]. In an analysis from the REduction of Atherothrombosis for Continued Health registry, a multinational registry of outpatients with stable atherothrombotic disease, Kohli et al.9 examined 44 095 patients and reported the relationship between NSAIDs use and several cardiovascular endpoints at 4 years. These included the occurrence of the composite of cardiovascular death, nonfatal MI, nonfatal stroke and ischemic hospitalizations, the composite of cardiovascular death, MI and stroke, heart failure, and each individual component of composite endpoints. When analyzed in a univariate fashion, there were significantly higher rates of the composite of cardiovascular death/MI/stroke/hospitalization (32.6 vs. 30.3%), hospitalization for heart failure (11.4 vs. 8.2%), and hospitalization for ischemic events (25.3 vs. 22.3%) in individuals who used NSAIDs (P ≤ 0.001 for all). Olsen et al.31 in another study, considered a cohort of 99 187 patients with first time MI. They showed a consistently increased risk of composite outcome (all-cause death, coronary death, readmission for nonfatal MI) among patients receiving any NSAIDs during the 5-year follow-up. The risk remained virtually unchanged throughout all 5 years. Use of diclofenac was associated with the highest risk compared with ibuprofen, rofecoxib, celecoxib, and particularly naproxen that was the drug with the lowest relative risk of cardiovascular events.
According to these data, much attention has been given to the cardiovascular safety of NSAIDs. It is widely accepted that the use of common agents, including diclofenac, high doses of celecoxib, and ibuprofen, increase the risk of thrombotic events, whereas naproxen has not been associated with this reported increased risk (Table 1).18,19,32,33
Ray et al.34 in a cohort of 48 566 patient, admitted for acute MI (40%), coronary revascularization procedures (40%), or unstable angina (20%), found the lowest adjusted rates of both serious coronary heart disease and serious cardiovascular disease/death from any cause in current users of naproxen compared with other NSAIDs, and no differences with nonusers. In particular, when compared with current users of naproxen, users of diclofenac showed an increased risk of serious coronary heart disease [1.44 (0.96 to 2.15), P = 0.076] and serious cardiovascular disease/death [1.52 (1.22 to 1.89), P = 0.0002], whereas ibuprofen users exhibited increased risk only of the latter endpoint [1.25 (1.02 to 1.53), P = 0.032]. The most commonly prescribed dose of naproxen was 1000 mg or greater, accounting for 77% of current use. Compared with nonusers of any NSAID, current users of naproxen showed no increased risk of either serious coronary heart disease [incidence rate ratio (IRR)_0.78 (0.55 to 1.10)] or serious cardiovascular disease/death [IRR_0.85 (0.71 to 1.03)]. Relative to high-dose naproxen, current users of high-dose celecoxib (>200 mg) and rofecoxib (>25 mg) showed increased risk of serious coronary heart disease [IRRs of 1.61 (1.01 to 2.57) and 2.29 (1.24 to 4.22), respectively]. Similarly, Fosbøl et al.1 studied 1 028 427 healthy persons, showing that the use of ibuprofen was associated with a significant increase in risk of coronary death or nonfatal MI and fatal or nonfatal stroke (only in high doses). Use of diclofenac was associated with a significant increase in risk of cardiovascular death, coronary death, or nonfatal MI, as well as fatal or nonfatal stroke (high doses). The results showed a clear dose-dependent relationship. The selective COX-2 inhibitor rofecoxib was significantly related to an increased risk of cardiovascular death and the composite of coronary death or nonfatal MI. Celecoxib was not related to excess cardiovascular death or fatal/nonfatal stroke, and the results showed no trend for a dose-dependent relationship. Finally, use of naproxen was neutral in terms of outcome except for fatal or nonfatal stroke, which showed a trend for increased risk.
Finally, a meta-analysis of clinical trials33 showed that, compared with placebo, the risk of major vascular events was increased by about a third in patients allocated to a coxib compared with placebo (307 [1.15% per annum] vs 175 [0.82% per annum], respectively; rate ratio [RR] 1.37, 95% CI 1.14–1.66, P = 0.0009) or diclofenac (1.41, 1.12–1.78, P = 0.0036), chiefly because of an increase of about three-quarters in the risk of major coronary events (coxibs 1.76, 1.31–2.37, P = 0.0001; diclofenac 1.70, 1.19–2.41, P = 0.0032). Ibuprofen also significantly increased major coronary events (2.22, 1.10–4.48, P = 0.0253), but not major vascular events (1.44, 0.89–2.33, P = 0.14). By contrast with other traditional NSAIDs (heterogeneity P = 0.04), high-dose naproxen was not associated with any significant excess risk of major vascular events (0.93, 0.69–1.27), and nor was there an increase in major coronary events (0.84, 0.52–1.35). There was no evidence that any NSAID significantly increased the risk of stroke. The risk of hospitalization because of heart failure was roughly doubled by all NSAIDs regimens studied (coxib 2.28, 95% CI 1.62–3.20, P < 0.0001; diclofenac 1.85, 1.17–2.94, P = 0.0088; ibuprofen 2.49, 1.19–5.20, P = 0.0155; naproxen 1.87, 1.10–3.16, P = 0.0197). The risk of vascular death was significantly increased by coxibs (1.58, 99% CI 1.00–2.49, P = 0.0103) and diclofenac (1.65, 0.95–2.85, P = 0.0187), nonsignificantly increased by ibuprofen (1.90, 0.56–6.41, P = 0.17) and by naproxen (1.08, 0.48–2.47, P = 0.80). The risk of death from any cause was significantly increased by around a quarter by allocation to a coxib (1.22, 1.04–1.44, P = 0.0139), but despite a clear excess of vascular deaths, the corresponding excess was not significant for diclofenac (1.20, 0.94–1.54, P = 0.15), and nor were there significant excesses of death from any cause for ibuprofen (1.61, 0.90–2.88, P = 0.11) or naproxen (1.03, 0.71–1.49, P = 0.88).
In conclusion, NSAIDs use exhibits a great risk of major cardiovascular events occurrence and the safest drug in terms of cardiovascular side-effects is naproxen. Nevertheless, the adverse effects profile of NSAIDs and concern about the relationship between NSAIDs and higher rates of ischemic cardiovascular events, prompted clinical guidelines to recommend caution on the use of these agents in patients with a previous history of cardiovascular disease.35,36
However, because these medications are readily available, generally well tolerated, and often an alternative treatment in patients with severe or functionally impairing arthritis, physicians are often pushed to use them, despite their cardiovascular risk profile.37 Thus, an accurate selection of patients and an adequate drugs’ choice should be always advised and performed to minimize the risk of serious adverse events.
F.M. has been supported by a research grant provided by the Cardiovascular Pathophysiology and Therapeutics PhD program.
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