Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study.

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.

Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study.

OBJECTIVE: To examine the risk of major cardiovascular disease associated with non-steroidal anti-inflammatory drugs (NSAIDs) in a large 'real-world' contemporary rheumatoid arthritis (RA) cohort. METHODS: A longitudinal cohort study was conducted with use of Danish nationwide individual-level registry data on inpatient and outpatient health care provision, pharmacotherapy and income during 1997-2009. 17 320 RA patients were identified and matched with 69 280 controls (4 : 1) by age and sex. NSAID-associated risk of major cardiovascular disease defined as the combined endpoint of myocardial infarction, stroke or cardiovascular mortality was assessed in multivariable survival models. RESULTS: During follow-up (median 4.9 years) 6283 events occurred. The cardiovascular risk associated with overall NSAID use was significantly lower in RA patients than in controls (HR 1.22 (95% CI 1.09 to 1.37) vs 1.51 (1.36 to 1.66), p<0.01). The pattern of lower NSAID-associated risk in RA patients was generally found with the individual NSAIDs investigated. While use of rofecoxib (HR 1.57 (1.16 to 2.12)) and diclofenac (HR 1.35 (1.11 to 1.64)) was associated with increased cardiovascular risk in RA patients, there was no significant risk increase associated with use of other NSAIDs in these patients. CONCLUSIONS: The cardiovascular risk associated with NSAID use in RA patients was modest and significantly lower than in non-RA individuals. Moreover, only a few of the individual NSAIDs were associated with increased cardiovascular risk. NSAID use should be assessed in the individual patient based on the indication for pain relief and risk factors for adverse effects, and not automatically be avoided due to concerns of severe cardiovascular outcomes alone.

Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study.

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.

Time-perspective in cardiovascular risk of NSAID use after first-time myocardial infarction.

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.

Accuracy of the ICD-10 discharge diagnosis for syncope.

AIMS: Administrative discharge codes are widely used in epidemiology, but the specificity and sensitivity of this coding is unknown and must be validated. We assessed the validity of the discharge diagnosis of syncope in administrative registers and reviewed the etiology of syncope after workup. METHODS AND RESULTS: Two samples were investigated. One sample consisted of 5262 randomly selected medical patients. The other sample consisted of 750 patients admitted or seen in the emergency department (ED) for syncope (ICD-10: R55.9) in three hospitals in Denmark. All charts were reviewed for baseline characteristics and to confirm the presence/absence of syncope and to compare with the administrative coding. In a sample of 600 admitted patients 570 (95%) and of 150 patients from ED 140 (93%) had syncope representing the positive predictive values. Median age of the population was 69 years (IQR: ± 14). In the second sample of 5262 randomly selected medical patients, 75 (1.4%) had syncope, of which 47 were coded as R55.9 yielding a sensitivity of 62.7%, a negative predictive value of 99.5%, and a specificity of 99.9%. CONCLUSION: ED and hospital discharge diagnostic coding for syncope has a positive predictive value of 95% and a sensitivity of 63%.

Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study.

AIMS: Non-vitamin K antagonist oral anticoagulants (NOACs) are displacing vitamin K antagonists (VKAs) for stroke prophylaxis in patients with atrial fibrillation (AF). Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) could increase gastrointestinal bleeding (GIB) risks among these patients. The aim of this study was to examine the risk of GIB among Danish AF patients taking oral anticoagulants (OACs) and NSAIDs. METHODS AND RESULTS: Using nationwide administrative registries, we determined concomitant NSAID use among anticoagulant-naïve patients with AF initiating OACs between August 2011 and June 2017. We calculated short-term absolute risks differences and hazard ratios (HRs) for GIB based on multiple adjusted cause-specific Cox regressions with time-dependent NSAID treatment. Among 41 183 patients [median age 70 years (interquartile range 64-78); 55% men], 21% of patients on NOACs and 18% on VKA were co-prescribed NSAIDs. The differences in absolute risk [95% confidence interval (CI)] of GIB within 14 days of commencing concomitant NSAID therapy (vs. no concomitant NSAID therapy) were 0.10% (0.04-0.18%) for NOACs and 0.13% (0.03-0.24%) for VKA. NOACs overall were associated with less GIB than VKA [HR 0.77 (95% CI 0.69-0.85)]. Compared with OACs alone, concomitant NSAIDs doubled the GIB risk associated with NOACs overall [HR 2.01 (95% CI 1.40-2.61)] and with VKA [HR 1.95 (95% CI 1.21-2.69)]. CONCLUSION: Among this nationwide AF population taking OACs, concomitant NSAID therapy increased the short-term absolute risk of GIB. Non-vitamin K antagonist oral anticoagulants alone were associated with lower GIB risks than VKA but concomitant NSAIDs abolished this advantage. The findings align with post hoc analyses from randomized studies. Physicians should exercise appropriate caution when prescribing NSAIDs for patients with AF taking NOACs or VKA.

Differences in cardiovascular safety with non-steroidal anti-inflammatory drug therapy-A nationwide study in patients with osteoarthritis.

Osteoarthritis (OA) and the non-steroidal anti-inflammatory drugs (NSAIDs) used to relieve OA-associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged ≥18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533 502 patients included, 64.3% received NSAIDs and 38 226 (7.2%) experienced a cardiovascular event during follow-up. Compared with non-use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 (95% confidence interval, 1.74-2.08); celecoxib, 1.47 (1.34-1.62); diclofenac, 1.44 (1.36-1.54); ibuprofen, 1.20 (1.15-1.25); and naproxen, 1.20 (1.04-1.39). Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs: 0.81 [CI: 0.74-0.90]) and naproxen (HRs: 0.81 [0.68-0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low-dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs: 1.12 (1.07-1.19) and 1.16 (0.92-1.42), respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief.

Long-Term Outcome in Patients With Heart Failure Treated With Levothyroxine: An Observational Nationwide Cohort Study.

CONTEXT: Hypothyroidism has detrimental effects on the cardiovascular system, but controversy remains concerning the benefits of levothyroxine (L-T4) substitution in patients with heart failure (HF). OBJECTIVE: Examining the effects of L-T4 in patients with HF. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: All Danish citizens aged ≥18 years diagnosed with HF between 1997 and 2012. L-T4 treatment was identified from nationwide registers. Incidence rate ratios (IRRs) were calculated with Poisson regression models. MAIN OUTCOME MEASURES: All-cause mortality, myocardial infarction (MI), cardiovascular death, and major adverse cardiovascular events (MACEs). RESULTS: A total of 224,670 patients were diagnosed with HF [mean age 70.7 (SD ± 14.7) years, 53% male]. Of these, 6560 patients were treated with L-T4 at baseline, and 9007 patients initiated L-T4 during follow-up. A total of 209,103 patients did not receive L-T4. During a median follow-up of 4.8 years [interquartile range (IQR) 9.2] 147,253 patients died. Increased risk of all-cause mortality (IRR 1.25; 95% CI, 1.21 to 1.29; IRR 1.13; 95% CI, 1.10 to 1.16), cardiovascular death (IRR 1.23; 95% CI, 1.18 to 1.27; IRR 1.11; 95% CI, 1.08 to 1.15), and MACE (IRR 1.26; 95% CI, 1.22 to 1.31; IRR 1.05; 95% CI, 1.02 to 1.09) was observed for treatment ongoing at baseline and initiated during follow-up, respectively. Increased risk of MI (IRR 1.32; 95% CI, 1.23 to 1.41) was observed for ongoing treatment, and reduced risk (IRR 0.87; 95% CI, 0.81 to 0.93) was observed for incident treatment. CONCLUSION: Ongoing and incident L-T4 treatment in patients with HF was associated with an increased risk of all-cause mortality, cardiovascular death, and MACE. Increased risk of MI was observed for ongoing treatment, and reduced risk was observed for incident treatment.

Thyroid dysfunction and electrocardiographic changes in subjects without arrhythmias: a cross-sectional study of primary healthcare subjects from Copenhagen.

OBJECTIVE: The objective of the present study was to investigate associations of both overt and subclinical thyroid dysfunction with common ECG parameters in a large primary healthcare population. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: The study population comprised of primary healthcare patients in Copenhagen, Denmark, who had a thyroid function test and an ECG recorded within 7 days of each other between 2001 and 2011. DATA SOURCES: The Danish National Patient Registry was used to collect information regarding baseline characteristics and important comorbidities. OUTCOME MEASURE AND STUDY GROUPS: Common ECG parameters were determined using Marquette 12SL software and were compared between the study groups. The study population was divided into five groups based on their thyroid status. Euthyroid subjects served as the reference group in all analyses. RESULTS: A total of 132 707 patients (age 52±17 years; 50% female) were included. Hyperthyroidism was significantly associated with higher heart rate and prolonged QTc interval with significant interaction with age (p<0.009) and sex (p<0.001). These associations were less pronounced for patients with higher age. Subclinical hyperthyroidism was associated with higher heart rate among females, and a similar trend was observed among males. Hypothyroidism was associated with slower heart rate and shorter QTc but only in women. Moreover, longer P-wave duration, longer PR interval and low voltage were observed in patients with both subclinical and overt hypothyroidism. However, the presence of low voltage was less pronounced with higher age (p=0.001). CONCLUSION: Both overt and subclinical thyroid disorders were associated with significant changes in important ECG parameters. Age and gender have significant impact on the association of thyroid dysfunction particularly on heart rate and QTc interval.

[Cardiovascular risks of non-steroidal anti-inflammatory drugs treatment].

Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Current evidence supports that all NSAIDs increase the risk of heart failure and elevate blood pressure, whereas the risk of thrombotic events varies with the type of drug. Use of newer selective cyclooxygenase-2 inhibitors has been associated with a substantial vascular risk but increasing concern also relates to traditional NSAIDs, in particular diclofenac. This review summarizes the current evidence regarding the cardiovascular safety of NSAIDs and presents recommendations for their use.

Long-Term Outcome in Levothyroxine Treated Patients With Subclinical Hypothyroidism and Concomitant Heart Disease.

CONTEXT: Subclinical hypothyroidism is a common condition that may lead to impaired cardiac function. OBJECTIVE: This study sought to examine the effects of levothyroxine treatment in patients with subclinical hypothyroidism and heart disease. DESIGN: This was a register-based historical cohort study. SETTING AND PARTICIPANTS: The study was composed of Danish primary care patients and hospital outpatients age 18 years and older with established heart disease who were diagnosed with subclinical hypothyroidism in 1997-2011. Patients were stratified according to whether they claimed a subsequent prescription of levothyroxine. Event rates and incidence rate ratios (IRR) were calculated by use of time-dependent multivariable Poisson regression models. MAIN OUTCOME MEASURES: Measures included all-cause mortality and major adverse cardiac events (MACEs), defined as cardiovascular death, fatal or nonfatal myocardial infaction and stroke, and all-cause hospital admissions. RESULTS: Of 61 611 patients with a diagnosis of cardiac disease having their first time thyroid function testing, 1192 patients with subclinical hypothyroidism (mean age 73.6 [SD ± 13.3] y, 63.8% female) were included, of whom 136 (11.4%) were treated with levothyroxine. During a median follow-up time of 5.6 y (interquartile range, 6.5 y), 694 (58.2%) patients died. Patients treated with levothyroxine displayed no significantly increased risk of all-cause mortality (adjusted IRR, 1.17; 95% confidence interval [CI], 0.90-1.52), MACE (adjusted IRR, 1.08; 95% CI, 0.80-1.45), or hospital admission (adjusted IRR, 0.94; 95% CI, 0.71-1.24), when compared with patients not treated with levothyroxine. CONCLUSION: Levothyroxine treatment in patients with subclinical hypothyroidism and heart disease was not associated with a significant benefit nor risk of all-cause mortality, MACE, or hospital admission in this large real-world cohort study.

Levothyroxine Substitution in Patients with Subclinical Hypothyroidism and the Risk of Myocardial Infarction and Mortality.

BACKGROUND: Subclinical hypothyroidism is associated with a number of cardiovascular risk factors, yet only limited data exist on long-term outcome of levothyroxine treatment of this condition with respect to hard end-points. The aim of this retrospective cohort study was to determine effects of levothyroxine treatment on myocardial infarction (MI), cardiovascular death and all-cause mortality, in patients with subclinical hypothyroidism. METHODS AND RESULTS: Primary care patients aged 18 years and older that underwent thyroid function tests between 2000 and 2009 were enrolled. Participants were identified by individual-level linkage of nationwide registers. Patients with subclinical hypothyroidism at baseline were included in the study. Exclusion criteria included a history of thyroid disease, related medication or medication affecting thyroid function. The total cohort comprised 628,953 patients of which 12,212 (1.9%) had subclinical hypothyroidism (mean age 55.2 [SD ± 18.8] years; 79.8% female). Within the first six months 2,483 (20.3%) patients claimed a prescription for levothyroxine. During a median follow-up of 5.0 (IQR: 5.2) years, 358 MI's and 1,566 (12.8%) deaths were observed. Out of these, 766 of the deaths were cardiovascular related. No beneficial effects were found in levothyroxine treated patients on MI (IRR 1.08 [95% CI: 0.81 to 1.44]), cardiovascular death (IRR 1.02 [95% CI: 0.83 to 1.25]) or all-cause mortality (IRR 1.03 [95% CI: 0.90 to 1.19]), except in patients under the age of 65 years (IRR 0.63 [95% CI: 0.40 to 0.99]). CONCLUSION: Levothyroxine substitution in subclinical hypothyroid patients does not indicate an association with lower mortality or decreased risk of MI.

Danish trends in pharmacotherapy, comorbidities, and demographics in patients referred for coronary angiography: what changed during a decade?

AIMS: Coronary angiography holds a central role in the diagnosis of coronary heart disease. We studied temporal trends in referral patterns 2000-09. METHODS AND RESULTS: We identified 156 496 first-time coronary angiographies in 2000-09 in nationwide registries. Trends were analyzed in 2-year intervals. Numbers of acute (5943-10 707) and elective (17 294-25 550) procedures increased between 2000-01 and 2008-09. Mean age increased from 61.8 to 63.9 years (P < 0.001) and the proportion of females increased from 33 to 37% (P < 0.001). An increase in the number of patients with prior chronic heart failure (2866 vs. 3197), cerebrovascular disease (1790 vs. 2906), diabetes (2527 vs. 4593), and arrhythmias (2985 vs. 4733) was observed. The proportion of acute patients examined the same day as hospitalized increased from 56.6 to 83.1%. Odds ratios (95% confidence interval) for treatment with statins [3.42(3.27;3.57)], RAS-inhibitors [1.85(1.77;1.93)], and acetylsalicylic acid [1.43(1.37;1.49)] at the time of coronary angiography increased towards 2008-09. Elective patients received medical treatment more often than acute patients (P < 0.001). CONCLUSION: During a 10-year period, there was an increase in the mean age of patients and the proportion of female patients, and a 56% increase in number of coronary angiographies performed. The use of prophylactic cardiovascular drugs among these high-risk patients increased during our study period.

Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study.

AIMS: Lower extremity peripheral artery disease (PAD) has been proposed as a 'coronary heart disease (CHD) risk equivalent'. We aimed to examine whether PAD confers similar risk for mortality as incident myocardial infarction (MI) and whether risk differs by gender. METHODS: Using nationwide Danish administrative registries (2000-2008), we identified patients aged ≥40 years with incident PAD (PAD only, n = 35,628), incident PAD with a history of MI (PAD + MI, n = 7029), and incident MI alone (MI alone, n = 71,115). RESULTS: Patients with PAD only tended to be younger, female, and have less comorbidity than the other groups. During follow up (median 1051 d, IQR 384-1938), we found that MI-alone patients had greater risk of adverse outcomes in the acute setting (first 90 d); however, the PAD-only and PAD + MI groups had higher long-term mortality at 7 years than those with MI alone (47.8 and 60.4 vs. 36.4%, respectively; p < 0.0001). After adjustment, the PAD-only and PAD + MI groups had a higher long-term risk for mortality [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.44-1.51; and HR 1.65, 95% CI 1.58-1.72, respectively], cardiovascular mortality (HR 1.30, 95% CI 1.26-1.34; and HR 1.71, 95% CI 1.62-1.80, respectively), and composite of death, MI, and ischaemic stroke, 95% CI HR, 1.38, 95% CI 1.36-1.42; and HR 1.68, 95% CI 1.61-1.75, respectively). The greater long-term risks of PAD were seen for both women and men. CONCLUSIONS: Both women and men with incident PAD have greater long-term risks of total and cardiovascular mortality vs. those with incident MI. PAD should be considered a CHD risk equivalent, warranting aggressive secondary prevention.

Nationwide trends in development of heart failure and mortality after first-time myocardial infarction 1997-2010: A Danish cohort study.

AIMS: Pharmacological and revascularization strategies following myocardial infarction (MI) have changed substantially during the last two decades. We investigated the temporal trends in heart failure (HF) incidence and mortality during the first 90 days following first-time MI between 1997 and 2010 in Denmark. METHODS AND RESULTS: Through administrative nationwide registers we identified 89,389 patients without prior HF hospitalized with first MI. The number of patients treated with percutaneous coronary intervention (PCI) days 0-1 after index MI increased from 2.5% in 1997-98 to 38.2% in 2009-10. Treatment with clopidogrel increased from 0.02% in 1997-98 to 68.1% in 2009-10 and statins from 8.1% in 1997-98 to 78.3% in 2009-10. The incidence of HF (defined as HF diagnosis or incident use of loop diuretics) decreased from 23.6% in 1997-98 to 19.6% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity, hazard ratio was 0.77 (95% confidence interval [CI] 0.74-0.79) for developing HF in 2009-10, compared with 1997-98. Adjusted for coronary interventions, and pharmacotherapy HR increased to 0.82 (95% confidence interval (CI) 0.79-0.85) compared with 1997-98. The 90-day mortality decreased from 19.6% in 1997-98 to 11.7% in 2009-10 (p<0.001). Adjusted for age, sex, and comorbidity HR was 0.59 (CI 0.55-0.64) in 2009-10 compared with 1997-98; upon additional adjustment for coronary interventions and pharmacotherapy the estimate was 0.75 (95% CI 0.69-0.81). CONCLUSION: We found a temporal decrease in HF incidence and mortality during the first 90 days after MI in 1997-2010. This could partly be explained by changes in interventional and pharmacological treatment strategies.

Use of nonsteroidal anti-inflammatory drugs among healthy people and specific cerebrovascular safety.

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.

Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study.

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.

New-onset atrial fibrillation is a predictor of subsequent hyperthyroidism: a nationwide cohort study.

AIMS: To examine the long-term risk of hyperthyroidism in patients admitted to hospital with new-onset AF. Hyperthyroidism is a well-known risk factor for atrial fibrillation (AF), but it is unknown whether new-onset AF predicts later-occurring hyperthyroidism. METHODS AND RESULTS: All patients admitted with new-onset AF in Denmark from 1997-2009, and their present and subsequent use of anti-thyroid medication was identified by individual-level linkage of nationwide registries. Patients with previous thyroid diagnosis or thyroid medication use were excluded. Development of hyperthyroidism was assessed as initiation of methimazole or propylthiouracil up to a 13-year period. Risk of hyperthyroidism was analysed by Poisson regression models adjusted for important confounders such as amiodarone treatment. Non-AF individuals from the general population served as reference. A total of 145,623 patients with new-onset AF were included (mean age 66.4 years [SD ±13.2] and 55.3% males) of whom 3% (4,620 events; 62.2% women) developed hyperthyroidism in the post-hospitalization period compared to 1% (48,609 events; 82% women) in the general population (n = 3,866,889). In both women and men we found a significantly increased risk of hyperthyroidism associated with new-onset AF compared to individuals in the general population. The highest risk was found in middle-aged men and was consistently increased throughout the 13-year period of observation. The results were confirmed in a substudy analysis of 527,352 patients who had thyroid screening done. CONCLUSION: New-onset AF seems to be a predictor of hyperthyroidism. Increased focus on subsequent risk of hyperthyroidism in patients with new-onset AF is warranted.