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Study Question: What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)?, Methods: This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models., Study Answer and Limitations: The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82,955 post-myocardial infarction patients (mean age 67.4 years, 64% (n=53,070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35,233) filled at least one prescription for NSAIDs and 45.5% (n=37,771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding., What This Study Adds: In post-myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used., Funding, Competing Interests, Data Sharing: AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation., (© Schjerning Olsen et al 2015.)

Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with increased risk of cardiovascular disease. Yet, the risk of atrial fibrillation (AF) associated with NSAIDs among patients with prior myocardial infarction (MI) has not been examined, and such data could contribute considerably to the risk-benefit assessment of NSAID use in this clinical context., Methods and Results: Using nationwide administrative registries in Denmark, we studied patients aged ≥30 years admitted with first-time MI and without prior AF in the period of 1997-2011. Risk of AF associated with NSAID use vs. no NSAID use was analysed by multivariable time-dependent Cox proportional hazard models. Of the 86 496 patients [mean age 66 (SD 13) years; 64% men] included in this study, 44.1% filled at least one NSAID prescription after discharge from MI. During a mean follow-up of 5.3 years, 7831 (8.9%) developed AF. The confidence intervals rate (95% CI) of AF per 100 person-years with NSAID treatment was 2.2 (2.0-2.4) compared with 1.7 (1.6-1.7) without NSAIDs. In the adjusted model, the risk of AF after NSAID treatment increased [Hazard ratio (HR) 1.27 (1.14-1.40)]. An increased risk of AF was seen regardless of the type of NSAID or with short-term (0-14 days) treatment [HR 1.45 (1.24-1.69)]. When the risk of death in patients exposed [crude rate 23.3 (19.7-27.5)] vs. not exposed [crude rate 17.4 (95% CI 16.8-18.1)] to NSAIDs at the time of AF was compared, NSAID use was associated with a poorer prognosis [HR 1.35 (1.14-1.60)]., Conclusion: Our study suggests that the use of NSAIDs might be associated with the increased risk of AF in post-MI patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Importance: Antithrombotic treatment is indicated for use in patients after myocardial infarction (MI); however, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) could pose safety concerns., Objective: To examine the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed., Design, Setting, and Participants: Using nationwide administrative registries in Denmark (2002-2011), we studied patients 30 years or older admitted with first-time MI and alive 30 days after discharge. Subsequent treatment with aspirin, clopidogrel, or oral anticoagulants and their combinations, as well as ongoing concomitant NSAID use, was determined., Exposures: Use of NSAIDs with ongoing antithrombotic treatment after first-time MI., Main Outcomes and Measures: Risk of bleeding (requiring hospitalization) or a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke) according to ongoing NSAID and antithrombotic therapy, calculated using adjusted time-dependent Cox regression models., Results: We included 61,971 patients (mean age, 67.7 [SD, 13.6] years; 63% men); of these, 34% filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2%). A total of 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%) occurred. The crude incidence rates of bleeding (events per 100 person-years) were 4.2 (95% CI, 3.8-4.6) with concomitant NSAID treatment and 2.2 (95% CI, 2.1-2.3) without NSAID treatment, whereas the rates of cardiovascular events were 11.2 (95% CI, 10.5-11.9) and 8.3 (95% CI, 8.2-8.4). The multivariate-adjusted Cox regression analysis found increased risk of bleeding with NSAID treatment compared with no NSAID treatment (hazard ratio, 2.02 [95% CI, 1.81-2.26]), and the cardiovascular risk was also increased (hazard ratio, 1.40 [95% CI, 1.30-1.49]). An increased risk of bleeding and cardiovascular events was evident with concomitant use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use., Conclusions and Relevance: Among patients receiving antithrombotic therapy after MI, the use of NSAIDs was associated with increased risk of bleeding and excess thrombotic events, even after short-term treatment. More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assumed to increase bleeding risk, but their actual relation to serious bleeding in patients with atrial fibrillation (AF) who are receiving antithrombotic medication is unknown., Objective: To investigate the risk for serious bleeding and thromboembolism associated with ongoing NSAID and antithrombotic therapy., Design: Observational cohort study., Setting: Nationwide registries., Patients: Danish patients with AF hospitalized between 1997 and 2011., Measurements: Absolute risk for serious bleeding and thromboembolism with ongoing NSAID and antithrombotic therapy, assessed by using Cox models., Results: Of 150 900 patients with AF (median age, 75 years [interquartile range, 65 to 83 years]; 47% female), 53 732 (35.6%) were prescribed an NSAID during a median follow-up of 6.2 years (interquartile range, 2.1 to 14.0 years). There were 17 187 (11.4%) and 19 561 (13.0%) occurrences of serious bleeding and thromboembolism, respectively. At 3 months, the absolute risk for serious bleeding within 14 days of NSAID exposure was 3.5 events per 1000 patients compared with 1.5 events per 1000 patients without NSAID exposure. The risk difference was 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients. Use of NSAIDs was associated with increased absolute risks for serious bleeding and thromboembolism across all antithrombotic regimens and NSAID types. An NSAID dosage above the recommended minimum was associated with a substantially increased hazard ratio for bleeding., Limitation: Observational design and unmeasured confounders., Conclusion: Use of NSAIDs was associated with an independent risk for serious bleeding and thromboembolism in patients with AF. Short-term NSAID exposure was associated with increased bleeding risk. Physicians should exercise caution with NSAIDs in patients with AF., Primary Funding Source: None.

Background: Nonsteroidal anti-inflammatory drugs can increase bleeding and thrombosis, but little is known about the cerebrovascular safety of these drugs, especially among healthy people., Aims: The aim of this study was to examine the risk of ischemic and hemorrhagic stroke associated with the use of nonsteroidal anti-inflammatory drugs in healthy people., Methods: By individual-level linkage of nationwide administrative registers in Denmark, information on hospital admissions, prescription claims, vital status, and cause of death were obtained. A cohort of healthy people without hospital admissions for five-years and no important prescription claims for two-years was selected. Case crossover and Cox proportional hazard models were used to analyze the relationship between nonsteroidal anti-inflammatory drug utilization and specific cerebrovascular risk (fatal or non-fatal ischemic or hemorrhagic stroke)., Results: We selected 1,028,437 healthy individuals (median age 39 years). At least one nonsteroidal anti-inflammatory drug was claimed by 44·7% of the study population, and the drugs were generally used for a short period of time and in low doses. High-dose ibuprofen and diclofenac were associated with increased risk of ischemic stroke [hazard ratio 2·15 (95% confidence interval 1·66-2·79) and 2·37 (confidence interval 1·99-2·81), respectively]. Diclofenac was also associated with increased risk of hemorrhagic stroke and so was naproxen [hazard ratio 2·15 (confidence interval 1·35-3·42)]., Conclusions: In healthy individuals, use of commonly available nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, and naproxen was associated with increased risk of stroke., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

This MiniReview describes the present evidence for the relationship between cardiovascular risk and use of non-steroidal anti-inflammatory drugs (NSAIDs) with special focus using Danish register-based data. NSAIDs are among the most widely used drugs worldwide and mainly used for management of pain and inflammatory conditions. Through the past decade, much attention has been given to the cardiovascular safety of these drugs, and several studies have shown increased risk of adverse cardiovascular effects associated with NSAID use. Current guidelines discourage any use of NSAIDs in patients with cardiovascular disease, yet over a period of 8-10 years, 35-44% of patients with myocardial infarction or heart failure were exposed to NSAIDs in Denmark. Furthermore, NSAID use was associated with an increased risk of death or myocardial infarction by up to 5 times that of non-users. There was also a clear indication for a dose-related response in risk associated with NSAID therapy, supporting a causal association. Notably, the cardiovascular risk associated with NSAID treatment was prevalent at start of treatment, suggesting no safe treatment window for NSAIDs in patients with cardiovascular disease. Thus, evidence from observational studies is accumulating, suggesting that NSAIDs are a major public health concern due to the widespread use of these drugs. Although it seems unlikely that we can completely avoid use of NSAIDs, even among high-risk patients, these results highlight the importance of balancing the benefit versus the risk of treatment before initiating NSAID treatment., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose of Review: Despite the fact that NSAIDs are not recommended among patients with established cardiovascular disease, many patients receive NSAID treatment for a short period of time. However, up until recently, data on the relationship between treatment duration and associated cardiovascular risk were sparse and have not been summarized., Recent Findings: A series of recent studies of patients with prior myocardial infarction (MI) demonstrated that short-term treatment with most NSAIDs is associated with an increased cardiovascular risk relative to no NSAID treatment. These studies furthermore 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 for at least 5 years thereafter., Summary: The present review indicates that there is no apparent well-tolerated therapeutic window for associated cardiovascular risk and NSAID use in patients with prior MI. Further randomized studies are warranted to evaluate the cardiovascular safety of NSAIDs, but, at this point, the overall evidence suggests advising caution in using NSAIDs at all times after MI. Legislation bodies need to address this issue of public health proportions, as studies have shown that utilization rates of NSAID keep increasing.

Background: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with increased cardiovascular morbidity and mortality. The purpose of this study was to examine the effect of ongoing NSAID treatment at time of admission for myocardial infarction (MI) on prognosis., Methods: All patients admitted with first-time MI in 1997-2006 were included by use of individual-level linkage of nationwide registries. By claimed prescription of NSAIDs, availability of tablets was estimated within 14 days prior to inclusion and defined ongoing use. Risk of death within 30 days and risk of death or MI within 1 year was analyzed by logistic regression and Cox proportional-hazard models, respectively., Results: A total of 97,458 patients were included (mean age 69.9 [SD 13.2] years and 62% males); the 30 day and 1 year mortality rates were 18.1% and 27.7%, respectively. Ongoing NSAID treatment was identified in 12,156 (12.5%) patients and 30-day mortality was significantly increased in patients receiving rofecoxib (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.22-1.68) and celecoxib (OR 1.23; CI 1.03-1.47) relative to no use of NSAIDs. Correspondingly, the 1-year rate of death or recurrent MI was significantly increased in patients receiving rofecoxib (hazard ratio [HR] 1.15; CI 1.04-1.27), celecoxib (HR 1.13; CI 1.01-1.26), diclofenac (HR 1.12; CI 1.04-1.20) or any NSAID use (HR 1.05; CI 1.02-1.09). No association was found for naproxen or ibuprofen., Conclusion: Ongoing treatment with NSAIDs and in particular the cyclooxygenase-2-selective inhibitors rofecoxib, celecoxib, and diclofenac is associated with worsened prognosis in patients admitted with first-time MI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients., Methods and Results: By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997-2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36-1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79-2.15] and HR1.66 [1.44-1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26-1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01-1.59]., Conclusion: Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.

Background: The cardiovascular risk after the first myocardial infarction (MI) declines rapidly during the first year. We analyzed whether the cardiovascular risk associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with the time elapsed following first-time MI., Methods and Results: We identified patients aged 30 years or older admitted with first-time MI in 1997 to 2009 and subsequent NSAID use by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. We calculated the incidence rates of death and a composite end point of coronary death or nonfatal recurrent MIs associated with NSAID use in 1-year time intervals up to 5 years after inclusion and analyzed risk by using multivariable adjusted time-dependent Cox proportional hazards models. Of the 99 187 patients included, 43 608 (44%) were prescribed NSAIDs after the index MI. There were 36 747 deaths and 28 693 coronary deaths or nonfatal recurrent MIs during the 5 years of follow-up. Relative to noncurrent treatment with NSAIDs, the use of any NSAID in the years following MI was persistently associated with an increased risk of death (hazard ratio 1.59 [95% confidence interval, 1.49-1.69]) after 1 year and hazard ratio 1.63 [95% confidence interval, 1.52-1.74] after 5 years) and coronary death or nonfatal recurrent MI (hazard ratio, 1.30 [95% confidence interval,l 1.22-1.39] and hazard ratio, 1.41 [95% confidence interval, 1.28-1.55])., Conclusions: The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in the use of NSAIDs for patients after MI.

Background: Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI)., Methods and Results: Patients ≥30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment)., Conclusions: Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.