Myocardial infarction naproxen

However, already in an early clinical trial, rofecoxib was found to produce four times the number of myocardial infarctions than its comparator drug, naproxen. A subsequent trial of rofecoxib compared to placebo in colorectal cancer prevention demonstrated, after 18 months of study, that a greater number of myocardial infarctions occulted in the rofecoxib group. In 2004 the manufacturers of rofecoxib withdrew the diug from the market. A similar study of celecoxib compared to placebo in cancer prevention, showed that celecoxib also increased the risk of cardiovascular embolisms [3]. 

In VIGOR, rofecoxib 50 mg/day was associated with a higher rate of non-fatal myocardial infarction (0.4%) than the non-selective COX-2 inhibitor naproxen 500 mg bd (0.1%) (RR = 0.2 Cl = 0.1, 0.7) (33). In CLASS there was no difference in the rates of myocardial infarction in patients taking celecoxib (0.5%) and those taking ibuprofen or diclofenac (0.4%). However, the protocols of the two studies differed substantially with respect to the use of aspirin. In VIGOR, the patients were not allowed to take aspirin or any other antiplatelet drug, while in... 

Some data may help to answer the important question of whether the relative difference in the incidence of myocardial infarction in VIGOR was due to a harmful effect of rofecoxib or a beneficial effect of naproxen. Although contrasting data have been published (48), the hypothesis that naproxen has a cardioprotective effect has gained wider support (49). Only one of the four most recently published studies negated a potential cardioprotective effect of naproxen. 

Opposite evidence has emerged from three case-control studies from the USA, Canada, and the UK, which showed that the rates of myocardial infarction in patients taking naproxen were lower than in patients not taking any NSAIDs (51,52) and those taking other NSAIDs (53). 

In the first study, 4425 patients hospitalized with acute myocardial infarction who used NSAIDs were compared with 17 700 controls in a large health-care database in the USA (51). Multivariate models were constructed to control for potential confounders. A quarter of the cases and controls had also filled a prescription for an NSAID in the 6 months before the study. Overall, the NSAID users had the same risk of acute myocardial infarction as non-users, but naproxen users had a significantly lower risk of acute myocardial infarction compared with those who were not taking NSAIDs (adjusted OR = 0.84 95% Cl = 0.72, 0.98). The cardioprotective effect of naproxen was very modest compared with aspirin (a 44% reduction in the risk of acute myocardial infarction in the Physician Health Study (54)). 

In conclusion, although these three studies suggest that patients who take naproxen have a lower incidence of myocardial infarction than those who take other NSAIDs or who do not take NSAIDs, the data do not provide definitive evidence that naproxen is cardioprotective. The data therefore raise a cautionary flag about the risk of severe cardiovascular events with COX-2 inhibitors and again call for more studies. 

Information on the effect of COX-2-selective inhibitors on arterial blood pressure is scanty. In VIGOR, more patients developed hypertension with rofecoxib than naproxen. For rofecoxib, the mean increase in blood pressure was 4.6/1.7 mmHg compared with a l.O/O.l mmHg increase with naproxen (34). Previous work has shown that a 2 mmHg reduction in diastolic blood pressure can result in about a 40% reduction in the rate of stroke and a 25% reduction in the rate of myocardial infarction (57). The effect of celecoxib on blood pressure was evaluated in a post hoc analysis... 

Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002 162(10) llll-lk... 

Mamdani M, Rochon P, Juurlink DN et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Archives of Internal Medicine 2003,163 481 -486. 

Initially this increased risk of myocardial infarction was attributed to the myocardial protective properties of the nonselective COX inhibitors. COX-2 selective inhibitors may lack this protective capability. Later meta analysis suggested that the degree of myoprotection associated with naproxen could not account for the difference in the incidence of myocardial infarction. Merck, the maker of rofecoxib, withdrew the drug from the market because of this association. The other two coxibs, celecoxib and lumiracoxib, remain on the market as no similar increase in myocardial infarction has been associated with these drugs. It must be stated here that there is controversy regarding this issue and only time will provide the ultimate answer regarding the car-diotoxic potential of these two coxibs. 

Patients with osteoarthritis or rheumatoid arthritis are randomized to one of three treatments, celecoxib, ibuprofen, or naproxen, and the primary endpoint is the occurrence of a cardiovascular endpoint a nonfatal myocardial infarction, a nonfatal stroke, or any cardiovascular death. Non-inferiority will be assessed for three different pairwise comparisons celecoxib versus ibuprofen, celecoxib versus naproxen, and ibuprofen versus naproxen. The definition of non-inferiority differs somewhat from the fixed margin approach describe earlier in that there are separate criteria for the confidence interval and the point estimate. The hazard ratio for each comparison will be calculated, and non-inferiority will be concluded if the upper end of the... 

Several studies have suggested that regular use of coxibs increases the risk of myocardial infarction. New analyses have confirmed this view. In a retrospective cohort study (n = 38 258 patients 26 376 patient-years), the odds of acute myocardial infarction during exposure to etodolac, naproxen, celecoxib, or rofecoxib were reported. Compared with naproxen, there was no significantly increased risk with etodolac, whereas with celecoxib (OR = 2.18 95% Cl = 1.09, 4.35) and rofecoxib (OR = 2.16 95% Cl = 1.04, 4.46) there was an increased risk [8 ]. 

In a case-control study using drug-dispensing and hospitalization data from more than 2 million residents in The Netherlands, subjects with a first hospitalization for acute myocardial infarction, cardiovascular and gastrointestinal events were identified [14 J. Use of coxibs and non-selective NSAIDs was classified into remote, recent, and current use. Compared with remote use, the risk of acute myocardial infarction was increased in current users of all coxibs (adjusted OR = 1.73 95% Cl = 1.37, 2.19) and all non-selective NSAIDs (adjusted OR = 1.41 95% Cl = 1.23, 1.61). Analysis by separate agents showed that the risk of acute myocardial infarction was increased with celecoxib (OR = 2.53 95% Cl = 1.53, 4.18), rofecoxib (OR = 1.60 95% Cl = 1.22, 2.10), ibuprofen (OR = 1.56 95% Cl — 1.19, 2.05), and diclofenac (OR = 1.51 95% Cl = 1.22, 1.87), but not with naproxen (OR = 1.21 95% Cl = 0.87,1.68). 

In a retrospective cohort study patients with osteoarthritis (6580 patients chronically exposed to celecoxib, 9800 to rofecoxib, 2907 to naproxen, and 51 539 non-chroni-cally exposed controls, either non-chronic users or non-users) were investigated. Comparing the risk of hospitalization for acute myocardial infarction or ischemic stroke with the non-chronic users as the reference group, there was an increased risk with rofecoxib (adjusted HR = 1.25 95% Cl = 1.04, 1.50) but no significantly increased risk with celecoxib or naproxen. Furthermore, the risk of hospitalization for acute myocardial infarction or ischemic stroke varied considerably with patient characteristics the excess risk attributable to rofecoxib... 

Warner JJ, Weideman RA, Kelly KC, Brilakis ES, Baneijee S, Cunningham F, Harford WV, Kazi S, Little BB, Cryer B. The risk of acute myocardial infarction with etodolac is not increased compared to naproxen a historical cohort analysis of a generic COX-2 selective inhibitor. J Cardiovasc Pharmacol Ther 2008 13(4) 252-60. 

The first suggestions of adverse effects with rofecoxib came from the Vioxx GI Outcomes Research (VIGOR) trial in 2000, where the effects were compared with those of the non-selective drug naproxen, in a relatively large group of patients. This showed a 5-fold increased risk of myocardial infarctions, some with fatal consequences, in patients treated with rofecoxib when compared with those treated with naproxen. Other studies have since confirmed these results and demonstrated increased morbidity and mortality in patients treated with this dmg. " The Vioxx episode has become a modern study in how not to deal with a drug withdrawal and a developing crisis, and how to avoid bad publicity when action needs to be taken. 

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