This study examined cause-specific cardiovascular mortality and morbidity associated with NSAID treatment in a population of patients surviving to 30 days after their first-time MI. Utilization of all NSAIDs was associated with an increased risk of cardiovascular mortality and morbidity, yet only in high doses for ibuprofen and naproxen.The novel finding of this study is that we found different cause-specific cardiovascular risks associated with NSAID use among patients with prior MI.
In observational studies as ours one can not exclude the possibility that the high risk associated with use of NSAIDs was due to confounding by indication, i.e., patients taking NSAIDs may generally be sicker than those not treated with NSAIDs. However in the present study we found that deaths associated with NSAIDs were mainly due to cardiovascular cause. We found a clear relationship between the degree of COX-2 inhibition, and a dose dependent increase in risk, again indicating that the effect was associated with the drugs rather than with their therapeutic indications. This result further strengthens the known association between use of NSAID and cardiovascular risk. Rofecoxib, celecoxib, and diclofenac are all characterized by a high degree of COX-2 selectivity and our findings could therefore be suggestive of a detrimental COX-2 inhibitor class effect on cardiovascular outcomes 
. Various mechanisms, for instance hypertension, heart failure, renal failure and increased tendency for thrombosis have been proposed to explain an increased risk with COX-2 selective NSAIDs, with emphasis on their considerable inhibition of prostacyclin synthesis but failure to inhibit COX-1-mediated generation of thromboxane A2 in platelets (which are devoid of COX-2) 
Several studies have confirmed increased cardiovascular risk associated with rofecoxib and diclofenac, and general treatment recommendations include caution with NSAIDs and avoidance of selective COX2-inhibtors if possible 
Indeed, patients with established cardiovascular disease or patients at increased cardiovascular risk seem to be more vulnerable to the cardiovascular toxicity of NSAIDs. An interaction between previously cardiovascular event and NSAID use is found, however the effect size of this still remains unknown. In the present study we are looking at patients with first-time MI, and therefore we aren't able to analyze this interaction. However we have previously demonstrated that NSAID use among patients with first-time MI was associated with persistently increased risk of all-cause mortality and of a composite of coronary death or nonfatal recurrent MI, respectively, for at least 5 years thereafter. These results support previous findings that NSAIDs have no apparent safe treatment window among patients with MI. However even healthy people have increased risk of cardiovascular diseases taking NSAIDs in particular diclofenac. Fosbøl et al. have previously analyzed the cause-specified cardiovascular risk associated with NSAID in healthy individuals 
. In brief, they found that most NSAIDs were associated with increased cardiovascular risk and in particular, the use of the diclofenac and rofecoxib was associated with increased risk of cardiovascular mortality and morbidity. The present study compliments these findings in a high-risk population of post-MI patients where patients were generally more elderly, more frequently treated with NSAIDs, and with a high risk of subsequent cardiovascular events. The potential interaction between previously cardiovascular disease and NSAID needs further investigation, especially clarifying the effect size of this. Because treatment with NSAIDs is so prevalent in the general population, it is of great importance that the safest treatment alternative among the NSAID group is found when NSAID treatment cannot be avoided, and therefore further studies, specially randomized trials, are required. Of most concern may be the fact, that the traditional NSAID diclofenac, which is one of the most frequently used NSAIDs (available OCT in many countries), and where the considerable COX-2 selectivity may not be generally recognized, was associated with one of the highest risks of cardiovascular morbidity and mortality including fatal or nonfatal stroke and coronary death.
In our study, the NSAID with the least cause-specific cardiovascular risk was naproxen and this result is in accordance with previous studies 
. The cardiovascular safety of naproxen has been questioned, as a recent randomized study, designed to investigate the effect of the agent on Alzheimer dementia, was terminated due to a possible excess of adverse cardiovascular events with naproxen 
. Ibuprofen is widely sold OCT, which may lead to the assumption that this is a particularly safe NSAID. However in a recent meta-analysis by Trelle et al. the highest risk of stroke was associated with use of ibuprofen 
. The same trend was seen by Fosbøl et al, where use of ibuprofen treatment was associated with a trend for increased risk of fatal and nonfatal stroke 
. We found a non-significant trend for increased cardiovascular risk, with a dose-dependent relationship, associated with ibuprofen therapy. Thus, considering the current results and the accumulated evidence at this point, naproxen may be a safer alternative to ibuprofen in patients requiring NSAID treatment.
Strengths and limitations
This study's main strength was its completeness and size of data. This complete registration, including all citizens independent of race, socioeconomic status, age or participation in health insurance, also those outside the labour market, insured a minimum of selection bias. The Danish National Register as well as the national prescription register is known to be accurate 
. The data on mode of death were obtained from the Causes of Death Register, which is based on information from the death certificate filled out by the doctors declaring the individual's death or the individual's general practitioners with knowledge on the patient's comorbidities, if unknown by the doctors declaring the individual's death.
Complete registration was ensured as all Danish pharmacies are required to register all dispensed drug prescriptions 
. In Denmark, the only NSAID that was available as OTC drug during the study period, was ibuprofen (sine 2001), but only in low dosage (200 mg) and in limited quantity (100tablets). Furthermore in Denmark there is partial patient copayment of drug expenses and patients needing higher doses or long-term treatment would have a financial incentive to obtain a prescription from their physician to receive reimbursement. It is therefore unlikely that OTC use of NSAIDs had a major impact on this study.
The main limitation of our study was the observational nature of the study. We do not have any information about the precise indication for initiation of NSAID treatment and the calculations of dose and treatment duration represent approximations. The Cox models were used provide control of available confounders, but the control for confounding by indication may not have been complete. For this reason, we performed supplementary analyses investigating the risk of infectious disease, malignancies and deaths from other causes. We found low incidence rates of all these death causes associated with NSAID use. The observed dose-response effect, the different relative effects of different NSAIDs used for similar indications, and the clear relation between the degree of COX-2 inhibition as reported in the literature and risk of adverse cardiovascular outcomes observed here all support the importance of NSAIDs and not of the potential confounders. Furthermore, important cardiovascular risk factors such as lipid levels, smoking status, blood pressure, left ventricular ejection fraction, or obesity were lacking. Therefore we made a Schneeweiss analysis, which showed that if an unmeasured confounder or a combination of confounders was present in 20% of the cohort treated with NSAIDs, the confounder would have to elevate the risk by a factor 3.4 to 3.8 to explain the increased risk observed in our study. The existence of such a confounder or combination of confounders is highly unlikely, but not entirely impossible as we had no information on other important risk factors such as smoking, lipid levels, or body mass index.
Another limitation is the classification of death. The Causes of Death Register is based on information obtained from the death certificate filled out by the doctor declaring the individual's death. All deaths are registered in the Causes of Death Register and data are by legislation complete. In prior studies validation of coronary and cardiovascular events demonstrated acceptable levels of sensitivity, with a tendency to overestimate cardiovascular deaths, although this overestimation would occur in all risk groups in our study 
. The specific diagnosis of MI (combined validity of fatal and nonfatal MI) has proved to be valid, with a sensitivity of 91% and a positive predictive value of 93%. Through records on all hospital admissions to Danish hospitals the nonfatal events are obtained, whereas the fatal events are recorded in the Causes of Death Register based on information gathered from the death certificate. Nonfatal events, which did not result in hospital admission would not be recorded and this could in theory introduce bias; however, this is unlikely to influence the results, given the nature of the nonfatal events studied (i.e., MI and stroke). The stroke diagnoses (both fatal and nonfatal) used in this study has also been validated with a good result, and it was found that the diagnoses had positive predictive values of 74% to 97% 
Aspirin is available over the counter, which explains why the fraction of patients who fill prescriptions for aspirin is relatively low. Another consequence of this is that we do not have information on whether using NSAIDs may lead to prematurely discontinuing aspirin. We assume that most patients who did not fill a prescription for aspirin were treated with over-the-counter aspirin, since medication adherence has been documented to be high among patients in Denmark after MI 
. No study design can exclude the possibility that individuals do not take all prescribed medications and prescription data must therefore be viewed in the light of the possibility of non-adherence. However, non-adherence would influence the results towards the null and hence dilute the observed association between NSAID exposure and adverse cardiovascular outcomes. Another limitation is the effect of information bias. The patients don't necessarily take their medications consecutively leading to the fact that the prescription may run longer and the patients therefore are exposed later than the database might indicate. There would be no measurable consequences for the rest of the population since data from individuals taking therapy without being noted to be on a prescription would be diluted in the data from the much larger population not on therapy. However to control for this phenomenon, we examined if the increased risk with overall NSAID and with the individual NSAID persisted after stopping treatment. We divided the periods of not taking NSAID into time intervals of 14, 30, 90 days and used the Cox-proportional hazard models. For overall NSAID use the increased risk returned to baseline shortly after treatment was discontinued. For the individual NSAIDs the same trend was seen with diclofenac and ibuprofen, but for the selective Cox-2 inhibitor rofecoxib the risk was persistently increased after stopping treatment. This latter observation appears to strengthen our study conclusions even more as the same result with rofecoxib was very recently found in an analysis of data from a previous clinical trial