Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality--a retrospective nationwide study.

AIMS: Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs. METHODS: Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference. RESULTS: A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005). CONCLUSION: Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.

AIMS: The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study. METHODS AND RESULTS: All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint. CONCLUSION: Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.

Use and discontinuation of hormone replacement therapy in women with myocardial infarction: a nationwide study.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: General use of hormone replacement therapy (HRT) dropped drastically after 2002 when pivotal randomized trials showed increased risk of coronary artery disease and other complications with HRT. HRT is not recommended for primary or secondary prevention of coronary heart disease and guidelines recommend discontinuation of HRT after myocardial infarction (MI). It is unknown whether women actually discontinue HRT after MI. WHAT THIS STUDY ADDS: Women who use HRT when they experience their MI generally continue using HRT. We found a remarkably low increase in discontinuation after 2002, in contrast to the general drop in use of HRT. AIM: To characterize the pattern of use and discontinuation of postmenopausal hormone replacement therapy (HRT) in women with myocardial infarction (MI) before and after 2002, where the general use of HRT dropped drastically subsequent to the results of the Women's Health Initiative trial. METHODS: All Danish women aged ≥40 years hospitalized with MI in the period 1997 to 2005 and their use of HRT were identified by individual-level-linkage of nationwide registers of hospitalization and drug dispensing from pharmacies. Characteristics associated with HRT use at time of MI and subsequent HRT discontinuation were analysed by multivariable logistic regression. RESULTS: In the study period, 34,778 women were discharged after MI. Of these, 3979 (11.4%) received HRT at the time of MI and their most used categories of HRT were vaginal oestrogen and oral oestrogen alone (46.6% and 28.7%, respectively). The percentage of women who continued HRT during the first year after discharge was 85.0% in the period 2000-2002 and had decreased to 79.6% in the period 2003-2005. Vaginal oestrogen use was associated with overall discontinuation of HRT (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.10, 1.72), whereas use of oral oestrogen alone and use of oral cyclic combined oestrogen/progestogen were associated with change of HRT after MI (OR 2.33, 95% CI 1.10, 4.93 and OR 2.94, 95% CI 1.35, 6.39, respectively). CONCLUSION: The majority of women experiencing an MI during ongoing HRT continued HRT after discharge and this pattern of HRT use did not change markedly after 2002.

Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals.

BACKGROUND: Studies have raised concern on the cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs). We studied safety of NSAID therapy in a nationwide cohort of healthy individuals. METHODS AND RESULTS: With the use of individual-level linkage of nationwide administrative registers, we identified a cohort of individuals without hospitalizations 5 years before first prescription claim of NSAIDs and without claimed drug prescriptions for selected concomitant medication 2 years previously. The risk of cardiovascular death, a composite of coronary death or nonfatal myocardial infarction, and fatal or nonfatal stroke associated with the use of NSAIDs was estimated by case-crossover and Cox proportional hazard analyses. The entire Danish population age 10 years or more consisted of 4,614,807 individuals on January 1, 1997, of which 2,663,706 (57.8%) claimed at least 1 prescription for NSAIDs during 1997 to 2005. Of these; 1,028,437 individuals were included in the study after applying selection criteria regarding comorbidity and concomitant pharmacotherapy. Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk. There was a trend for increased risk of fatal or nonfatal stroke associated with ibuprofen treatment (odds ratio, 1.29; 95% confidence interval, 1.02 to 1.63), but naproxen was not associated with increased cardiovascular risk (odds ratio for cardiovascular death, 0.84; 95% confidence interval, 0.50 to 1.42). CONCLUSIONS: Individual NSAIDs have different degrees of cardiovascular safety, which must be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals, whereas our results suggest that naproxen has a safer cardiovascular risk-profile.

Increased mortality associated with low use of clopidogrel in patients with heart failure and acute myocardial infarction not undergoing percutaneous coronary intervention: a nationwide study.

OBJECTIVES: We studied the association of clopidogrel with mortality in acute myocardial infarction (AMI) patients with heart failure (HF) not receiving percutaneous coronary intervention (PCI). BACKGROUND: Use of clopidogrel after AMI is low in patients with HF, despite the fact that clopidogrel is associated with absolute mortality reduction in AMI patients. METHODS: All patients hospitalized with first-time AMI (2000 through 2005) and not undergoing PCI within 30 days from discharge were identified in national registers. Patients with HF treated with clopidogrel were matched by propensity score with patients not treated with clopidogrel. Similarly, 2 groups without HF were identified. Risks of all-cause death were obtained by the Kaplan-Meier method and Cox regression analyses. RESULTS: We identified 56,944 patients with first-time AMI. In the matched cohort with HF (n = 5,050) and a mean follow-up of 1.50 years (SD = 1.2), 709 (28.1%) and 812 (32.2%) deaths occurred in patients receiving and not receiving clopidogrel treatment, respectively (p = 0.002). The corresponding numbers for patients without HF (n = 6,092), with a mean follow-up of 2.05 years (SD = 1.3), were 285 (9.4%) and 294 (9.7%), respectively (p = 0.83). Patients with HF receiving clopidogrel demonstrated reduced mortality (hazard ratio: 0.86; 95% confidence interval: 0.78 to 0.95) compared with patients with HF not receiving clopidogrel. No difference was observed among patients without HF (hazard ratio: 0.98; 95% confidence interval: 0.83 to 1.16). CONCLUSIONS: Clopidogrel was associated with reduced mortality in patients with HF who do not undergo PCI after their first-time AMI, whereas this association was not apparent in patients without HF. Further studies of the benefit of clopidogrel in patients with HF and AMI are warranted.

Prognosis in heart failure and the value of {beta}-blockers are altered by the use of antidepressants and depend on the type of antidepressants used.

BACKGROUND: Depression worsens the prognosis in patients with cardiac disease, and treatment with antidepressants may improve survival. Guidelines recommend use of selective serotonin reuptake inhibitors (SSRIs), but knowledge of the prognostic effect of different classes of antidepressants is sparse. METHODS AND RESULTS: We studied 99 335 patients surviving first hospitalization for heart failure (HF) from 1997 to 2005. Use of HF medication and antidepressants (divided into tricyclic antidepressants [TCA] and SSRI) was determined by prescription claims. Risk of overall and cardiovascular death associated with antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due to cardiovascular causes (median follow-up, 1.9 years; 5, 95% fractiles, 0.04 to 7.06 years). Use of beta-blockers was associated with decreased risk of cardiovascular death (hazard ratio [HR], 0.77; 95% CI, 0.75 to 0.79). Antidepressants were prescribed to 19 411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and beta-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of beta-blockers and TCA (P for interaction <0.01). CONCLUSIONS: Use of antidepressants in patients with HF was associated with worse prognosis. Coadministration of SSRIs and beta-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and beta-blockers. To further clarify this, clinical trials testing the optimal antidepressant strategy in patients with HF are warranted.

Location of cardiac arrest in a city center: strategic placement of automated external defibrillators in public locations.

BACKGROUND: Public-access defibrillation with automated external defibrillators (AEDs) is being implemented in many countries worldwide with considerable financial implications. The potential benefit and economic consequences of focused or unfocused AED deployment are unknown. METHODS AND RESULTS: All cardiac arrests in public in Copenhagen, Denmark, from 1994 through 2005 were geographically located, as were 104 public AEDs placed by local initiatives. In accordance with European Resuscitation Council and American Heart Association (AHA) guidelines, areas with a high incidence of cardiac arrests were defined as those with 1 cardiac arrest every 2 or 5 years, respectively. There were 1274 cardiac arrests in public locations. According to the European Resuscitation Council or AHA guidelines, AEDs needed to be deployed in 1.2% and 10.6% of the city area, providing coverage for 19.5% (n=249) and 66.8% (n=851) of all cardiac arrests, respectively. The excessive cost of such AED deployments was estimated to be $33 100 or $41 000 per additional quality-adjusted life year, whereas unguided AED placement covering the entire city had an estimated cost of $108 700 per quality-adjusted life year. Areas with major train stations (1.8 arrests every 5 years per area), large public squares, and pedestrianized areas (0.6 arrests every 5 years per area) were main predictors of frequent cardiac arrests. CONCLUSIONS: To achieve wide AED coverage, AEDs need to be more widely distributed than recommended by the European Resuscitation Council guidelines but consistent with the American Heart Association guidelines. Strategic placement of AEDs is pivotal for public-access defibrillation, whereas with unguided initiatives, AEDs are likely to be placed inappropriately.

Antiarrhythmic therapy and risk of death in patients with atrial fibrillation: a nationwide study.

AIMS: To examine the risk of death associated with antiarrhythmic drug (AAD) therapy in a nationwide unselected cohort of patients with atrial fibrillation (AF). METHODS AND RESULTS: All patients admitted with AF in Denmark from 1995 to 2004 and their subsequent use of AADs were identified by individual-level linkage of nationwide registries. Multivariable Cox proportional-hazard models with time-dependent covariates were used to analyse the risk of death associated with AAD therapy. A total of 141,500 patients were included in the study; of these 3356 (2.4%) patients received treatment with flecainide, 3745 (2.6%) propafenone, 23,346 (16.5%) sotalol, and 10,376 (7.3%) amiodarone. Annualized mortality rates were 2.54, 4.25, 5.29, and 7.42 per year per 100 person years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariable Cox proportional-hazard models did not show increased risk of death associated with any of the AADs. Hazard ratio (95% confidence interval) for flecainide 0.38 (0.32-0.44), propafenone 0.65 (0.58-0.71), sotalol 0.65 (0.63-0.67), and amiodarone 0.94 (0.89-1.00). CONCLUSION: In an unselected cohort of patients with AF, antiarrhythmic treatment with flecainide, propafenone, sotalol, or amiodarone was not associated with increased risk of death. From a safety perspective, this indicates appropriate selection of patients for AAD therapy.

Mortality and reinfarction among patients using different beta-blockers for secondary prevention after a myocardial infarction.

OBJECTIVES: To study differences in the clinical efficacy of various brands of beta-blocker in secondary prevention after a myocardial infarction (MI). METHODS: All patients hospitalized with a first MI between 1995 and 2002 who were still alive 30 days after discharge and had had at least one prescription for a beta-blocker filled were identified by individual-level linkage of nationwide registries of hospitalizations and drugs dispensed from pharmacies. A total of 32,259 MI patients were included in the study. Multivariable Cox proportional hazard models were used to analyze the risks of death and recurrent MI related to treatment with different beta-blockers. RESULTS: The risks for death and recurrent MI were similar in patients using different beta-blockers, except that mortality from all causes among patients with a prescription for sotalol was higher. Subgroup analyses of high-risk patients with diabetes or congestive heart failure and of patients using comparable dosages of beta-blockers did not show effects on the risk of death or recurrent MI. CONCLUSION: Except for sotalol, the different types of beta-blocker had similar clinical efficacy in reducing mortality and the recurrence of MI. The equivalent efficacy remained when high-risk patients were analyzed separately.

Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people.

BACKGROUND: Previous studies reveal major differences in the estimated cardiovascular risk in diabetes mellitus, including uncertainty about the risk in young patients. Therefore, large studies of well-defined populations are needed. METHODS AND RESULTS: All residents in Denmark > or = 30 years of age were followed up for 5 years (1997 to 2002) by individual-level linkage of nationwide registers. Diabetes patients receiving glucose-lowering medications and nondiabetics with and without a prior myocardial infarction were compared. At baseline, 71 801 (2.2%) had diabetes mellitus and 79 575 (2.4%) had a prior myocardial infarction. Regardless of age, age-adjusted Cox proportional-hazard ratios for cardiovascular death were 2.42 (95% confidence interval [CI], 2.35 to 2.49) in men with diabetes mellitus without a prior myocardial infarction and 2.44 (95% CI, 2.39 to 2.49) in nondiabetic men with a prior myocardial infarction (P=0.60), with nondiabetics without a prior myocardial infarction as the reference. Results for women were 2.45 (95% CI, 2.38 to 2.51) and 2.62 (95% CI, 2.55 to 2.69) (P=0.001), respectively. For the composite of myocardial infarction, stroke, and cardiovascular death, the hazard ratios in men with diabetes only were 2.32 (95% CI, 2.27 to 2.38) and 2.48 (95% CI, 2.43 to 2.54) in those with a prior myocardial infarction only (P=0.001). Results for women were 2.48 (95% CI, 2.43 to 2.54) and 2.71 (95% CI, 2.65 to 2.78) (P=0.001), respectively. Risks were similar for both diabetes types. Analyses with adjustments for comorbidity, socioeconomic status, and prophylactic medical treatment showed similar results, and propensity score-based matched-pair analyses supported these findings. CONCLUSIONS: Patients requiring glucose-lowering therapy who were > or = 30 years of age exhibited a cardiovascular risk comparable to nondiabetics with a prior myocardial infarction, regardless of sex and diabetes type. Therefore, requirement for glucose-lowering therapy should prompt intensive prophylactic treatment for cardiovascular diseases.

The pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) from 1997 to 2005: a nationwide study on 4.6 million people.

PURPOSE: To describe the nationwide pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) in the Danish population. METHODS: All Danish citizens aged 10 or above 1 January 1997 were included in the study. The national prescription registry was used to identify all claimed prescriptions for NSAIDs by the cohort until 2005. By individual-level-linkage of nationwide registries, information was acquired concerning hospitalizations, comorbidity, concomitant pharmacotherapy and socioeconomic factors. RESULTS: The population consisted of 4,614,807 individuals, of which 2,663,706 (57.8%) claimed at least one prescription for NSAID from 1997 to 2005. Ibuprofen and diclofenac were the most frequently used non-selective NSAIDs, whereas rofecoxib and celecoxib were the most frequently used selective cyclooxygenase-2 (COX-2) inhibitors. The usage was similar across all age groups. Female sex and increasing age was associated with increased use of NSAID. Factors predicting extensive NSAID use were: rheumatic disease (odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.69-1.90), gout agents (allopurinol) (OR = 2.54, CI: 2.44-2.64) and other pain medication (OR = 3.27, CI: 3.23-3.31). NSAIDs were most often prescribed for use for one distinct treatment interval and for a short period (overall inter-quartile range [IQR]: 9-66 days). High doses were used in a relatively large proportion of the population (8.9% for etodolac to 19.5% for celecoxib) and 54,373 (2.0%) claimed prescriptions for more than one NSAID at the same time. CONCLUSION: NSAIDs were commonly used in the Danish population. Since NSAIDs have been associated with increased cardiovascular risk, further research on the overall risk associated with these drugs on a national scale is needed.

Different angiotensin-converting enzyme inhibitors have similar clinical efficacy after myocardial infarction.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Treatment with an angiotensin-converting enzyme (ACE) inhibitor benefits many patients with cardiovascular disease. ACE inhibitors are generally assumed to be equally effective, but this has never been fully verified in clinical trials. WHAT THIS STUDY ADDS: Studying the association among ACE inhibitors after myocardial infarction demonstrated similarity in clinical outcome and supports a dosage-response relationship. Therefore, for long-term benefits for patients who need treatment with an ACE inhibitor, a focus of treatment at the recommended dosage is most important and not which ACE inhibitor is used. AIM: Therapy with angiotensin-converting enzyme (ACE) inhibitors is common after myocardial infarction (MI). Given the lack of randomized trials comparing different ACE inhibitors, the association among ACE inhibitors after MI in risk for mortality and reinfarction was studied. METHODS: Patients hospitalized with first-time MI (n = 16,068) between 1995 and 2002, who survived at least 30 days after discharge and claimed at least one prescription of ACE inhibitor, were identified using nationwide administrative registries in Denmark. RESULTS: Adjusted Cox regression analysis demonstrated no differences in risk for all-cause mortality, but patients using captopril had higher risk of reinfarction (hazard ratio 1.18, 95% confidence interval 1.05, 1.34). However, following adjustment for differences in used dosages, all ACE inhibitors had similar clinical efficacy. Risk of all-cause mortality: trandolapril (reference) 1.00, ramipril 0.97 (0.89, 1.05), enalapril 1.04 (0.95, 1.150), captopril 0.95 (0.83, 1.08), perindopril 0.98 (0.84, 1.15) and other ACE inhibitors or angiotensin II receptor blockers (ARB) 1.06 (0.94, 1.19). Reinfarction: trandolapril (reference) 1.00, ramipril 0.98 (0.89, 1.08), enalapril 1.04 (0.92, 1.17), captopril 1.05 (0.89, 1.25), perindopril 0.96 (0.81, 1.14) and other ACE inhibitors or ARB 0.99 (0.86, 1.14). Furthermore, the association between ARBs and clinical events was similar to ACE inhibitors (trandolapril reference): all-cause mortality 0.99 (0.84, 1.16) and recurrent MI 0.99 (0.83, 1.19). CONCLUSIONS: Our results suggest a class effect among ACE inhibitors when used in comparable dosages. Focus on treatment at the recommended dosage is therefore most important, and not which ACE inhibitor is used.

Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes.

BACKGROUND: Undertreatment with recommended pharmacotherapy is a common problem in heart failure and may influence prognosis. We studied initiation and persistence of evidence-based pharmacotherapy in 107,092 patients discharged after first hospitalization for heart failure in Denmark from 1995 to 2004. METHODS AND RESULTS: Prescriptions of dispensed medication and mortality were identified by an individual-level linkage of nationwide registers. Inclusion was irrespective of left ventricular function. Treatment with renin-angiotensin inhibitors (eg, angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers), beta-blockers, spironolactone, and statins was initiated in 43%, 27%, 19%, and 19% of patients, respectively. Patients who did not initiate treatment within 90 days of discharge had a low probability of later treatment initiation. Treatment dosages were in general only 50% of target dosages and were not increased during long-term treatment. Short breaks in therapy were common, but most patients reinitiated treatment. Five years after initiation of treatment, 79% patients were still on renin-angiotensin inhibitors, 65% on beta-blockers, 56% on spironolactone, and 83% on statins. Notably, multiple drug treatment and increased severity of heart failure was associated with persistence of treatment. Nonpersistence with renin-angiotensin inhibitors, beta-blockers, and statins was associated with increased mortality with hazard ratios for death of 1.37 (95% CI, 1.31 to 1.42), 1.25 (95% CI, 1.19 to 1.32), 1.88 (95% CI, 1.67 to 2.12), respectively. CONCLUSIONS: Persistence of treatment was high once medication was started, but treatment dosages were below recommended dosages. Increased severity of heart failure or increased number of concomitant medications did not worsen persistence, but nonpersistence identified a high-risk population of patients who required special attention. A focused effort on early treatment initiation, appropriate dosages, and persistence with the regimen is likely to provide long-term benefit.

Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.

BACKGROUND: The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. We analyzed the risk of rehospitalization for acute myocardial infarction (MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with prior MI. METHODS AND RESULTS: All patients with first-time MI between 1995 and 2002 as well as all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs. CONCLUSIONS: Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI and should therefore be used with particular caution in these patients.