Increased long-term risk of heart failure and other adverse cardiac outcomes in dermatomyositis and polymyositis: Insights from a nationwide cohort.

BACKGROUND: Mounting evidence suggests that dermatomyositis/polymyositis (DM/PM) are associated with increased risk of atherosclerotic events and venous thromboembolism. However, data on the association between DM/PM and other cardiac outcomes, especially heart failure (HF), are scarce. OBJECTIVES: To examine the long-term risk and prognosis associated with adverse cardiac outcomes in patients with DM/PM. METHODS: Using Danish administrative registries, we included all patients ≥18 years with newly diagnosed DM/PM (1996-2018). Risks of incident outcomes were compared with non-DM/PM controls from the background population (matched 1:4 by age, sex, and comorbidity). In a secondary analysis, we compared mortality following HF diagnosis between DM/PM patients with HF and non-DM/PM patients with HF (matched 1:4 by age and sex). RESULTS: The study population included 936 DM/PM patients (median age 58.5 years, 59.0% women) and 3744 matched non-DM/PM controls. The median follow-up was 6.9 years. Absolute 10-year risks of incident outcomes for DM/PM patients vs matched controls were as follows: HF, 6.98% (CI, 5.16-9.16%) vs 4.58% (3.79-5.47%) (P = 0.002); atrial fibrillation, 10.17% (7.94-12.71%) vs 7.07% (6.09-8.15%) (P = 0.005); the composite of ICD implantation/ventricular arrhythmias/cardiac arrest, 1.99% (1.12-3.27%) vs 0.64% (0.40-0.98%) (P = 0.02); and all-cause mortality, 35.42% (31.64-39.21%) vs 16.57% (15.10-18.10%) (P < 0.0001). DM/PM with subsequent HF was associated with higher mortality compared with HF without DM/PM (adjusted hazard ratio 1.58 [CI, 1.01-2.47]). CONCLUSION: Patients with DM/PM had a higher associated risk of HF and other adverse cardiac outcomes compared with matched controls. Among patients developing HF, a history of DM/PM was associated with higher mortality.

Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction.

BACKGROUND: Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. METHODS: All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. RESULTS: Amongst 214 998 individuals, during a median follow-up of 5.8 years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. CONCLUSION: Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.

BACKGROUND: Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). OBJECTIVE: We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. METHODS: Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). RESULTS: Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). CONCLUSIONS: Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban.

Initiation of anticoagulation in atrial fibrillation: which factors are associated with choice of anticoagulant?

BACKGROUND: The use of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prophylaxis in atrial fibrillation (AF) is increasing rapidly. We compared characteristics of AF patients initiated on NOACs versus vitamin K antagonists (VKAs). METHODS: Using Danish nationwide registry data, we identified AF patients initiating either a VKA or a NOAC from 22 August 2011 until 30 September 2016. We compared patient characteristics including age, gender, comorbidities, concomitant pharmacotherapy and CHA2 DS2 -VASc and HAS-BLED scores in patients initiated on a VKA, dabigatran, rivaroxaban or apixaban. Differences were examined using multivariable logistic regression models. RESULTS: The study population comprised 51 981 AF patients of whom 19 989 (38.5%) were initiated on a VKA, 13 242 (25.5%) on dabigatran, 8475 (16.3%) on rivaroxaban and 10 275 (19.8%) on apixaban. Those patients initiated on apixaban had higher mean ± SD CHA2 DS2 -VASc scores than those initiated on a VKA (3.1 ± 1.6 vs. 2.9 ± 1.6). Those initiated on dabigatran had lower mean CHA2 DS2 -VASc scores (2.7 ± 1.6) than all other groups. Patients with a history of a prior stroke were significantly more likely to be initiated on a NOAC compared with a VKA [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.28-1.43]. By contrast, patients with a history of myocardial infarction were less likely to be initiated on a NOAC compared with a VKA (OR 0.72, 95% CI 0.67-0.77). CONCLUSIONS: Atrial fibrillation patients who were initiated on apixaban had higher stroke risk scores than patients initiated on VKAs. Interestingly, opposite results were found for dabigatran.

Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus--a retrospective nationwide study.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited. METHODS: Danish individuals without prior myocardial infarction or stroke that initiated combinations of metformin with sulphonylurea (SU), DPP-4 inhibitors, GLP-1 agonists or insulin between 9 May 2007 and 31 December 2011 were followed up for the risk of all-cause mortality, cardiovascular (CV) mortality or a combined end point of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis. RESULTS: A total of 40 028 patients (59% men, mean age 60 ± 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345) or insulin (n = 6858). Crude incidence rates per 1000 patient years for the combined end point were 18 (SU), 10 (DPP-4 inhibitor), 8 (GLP-1 agonist) and 21 (insulin). In adjusted analyses with metformin + SU as reference, metformin + DPP-4 inhibitor was associated with an RR of 0.65 (0.54-0.80) for mortality, an RR of 0.57 (0.40-0.80) for CV mortality and an RR of 0.70 (0.57-0.85) for the combined end point. For metformin + GLP-1 agonist, the RR for mortality was 0.77 (0.51-1.17), for CV mortality 0.89 (0.47-1.68), and for the combined end point 0.82 (0.55-1.21). CONCLUSION: Incretin-based drugs combined with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline differences.

Incidence of acute myocardial infarction-related cardiogenic shock during corona virus disease 19 (COVID-19) pandemic.

AIMS: The hospitalization of patients with MI has decreased during global lockdown due to the COVID-19 pandemic. Whether this decrease is associated with more severe MI, e.g. MI-CS, is unknown. We aimed to examine the association of Corona virus disease (COVID-19) pandemic and incidence of acute myocardial infarction with cardiogenic shock (MI-CS). METHODS: On March 11, 2020, the Danish government announced national lock-down. Using Danish nationwide registries, we identified patients hospitalized with MI-CS. Incidence rates (IR) and incidence rate ratios (IRR) were used to compare MI-CS before and after March 11 in 2015-2019 and in 2020. RESULTS: We identified 11,769 patients with MI of whom 696 (5.9%) had cardiogenic shock in 2015-2019. In 2020, 2132 MI patients were identified of whom 119 had cardiogenic shock (5.6%). The IR per 100,000 person years before March 11 in 2015-2019 was 9.2 (95% CI: 8.3-10.2) and after 8.9 (95% CI: 8.0-9.9). In 2020, the IR was 7.5 (95% CI: 5.8-9.7) before March 11 and 7.7 (95% CI: 6.0-9.9) after. The IRRs comparing the 2020-period with the 2015-2019 period before and after March 11 (lockdown) were 0.81 (95% CI: 0.59-1.12) and 0.87 (95% CI: 0.57-1.32), respectively. The IRR comparing the 2020-period during and before lockdown was 1.02 (95% CI: 0.74-1.41). No difference in 7-day mortality or in-hospital management was observed between study periods. CONCLUSION: We could not identify a significant association of the national lockdown on the incidence of MI-CS, along with similar in-hospital management and mortality in patients with MI-CS.

Clinical consequences of hospital variation in use of oral anticoagulant therapy after first-time admission for atrial fibrillation.

OBJECTIVE: To analyse how hospital factors influence the use of oral anticoagulants (OAC) in atrial fibrillation (AF) patients and address the clinical consequences of hospital variation in OAC use. DESIGN AND SUBJECTS: By linkage of nationwide Danish administrative registers we conducted an observational study including all patients with a first-time hospitalization for AF between 1995 and 2004 as well as prescription claims for OAC. Multivariable logistic regression analysis was used to evaluate hospital factors associated with prescription of OAC therapy. Cox proportional-hazard models were used to estimate the risk of re-hospitalization for thromboembolism and haemorrhagic stroke with respect to discharge from a low, intermediate, or high OAC use hospital. RESULTS: Overall 40,133 (37%) out of 108,504 patients received OAC; ranging from 17% to 50% between the hospitals with the lowest and highest OAC use, respectively. Cardiology departments had the highest use of OAC, but neither tertiary university hospitals nor high volume hospitals had higher OAC use than local community hospitals and low volume hospitals. Risk of a thromboembolic event was significantly increased amongst patients from hospitals with a low OAC use (hazard ratio 1.16, confidence interval 1.10-1.22). Notably, higher OAC use was not associated with a higher risk of haemorrhagic stroke. CONCLUSION: In Denmark between 1995 and 2004, there was a major hospital variation in AF patients receiving OAC, and consequently, more thromboembolic events were observed amongst patients from low OAC use hospitals. Our study emphasizes the need for a continued vigilance on implementation of international AF management guidelines.

Initiation and persistence with clopidogrel treatment after acute myocardial infarction: a nationwide study.

AIMS: To identify possible underuse by analysing initiation and persistence with clopidogrel treatment in an unselected population of patients admitted with myocardial infarction (MI) with or without subsequent percutaneous coronary intervention (PCI). METHODS: Patients admitted with first-time MI from 2000 to 2005 and subsequent prescription claims of clopidogrel were identified by individual-level linkage of nationwide administrative registries in Denmark. Independent factors affecting initiation and persistence with treatment were analysed by multivariable logistic regression models and Cox proportional hazard models. RESULTS: A total of 46,190 MI patients were included in the study, of whom 14,939 were treated with PCI. From 2000 to 2005 initiation of clopidogrel increased from 80.4 to 93.7% among MI patients with PCI and from 2.8 to 39.3% among MI patients without PCI. MI patients with concomitant heart failure received less treatment [odds ratio (OR) 0.49, confidence interval (CI) 0.43, 0.56 among patients with PCI and OR 0.90, CI 0.81, 0.99 among patients without PCI in 2002-2003, and OR 0.89, CI 0.80, 1.00 in 2004-2005, respectively]. Of MI patients with PCI, 77.5% completed 9 months' clopidogrel treatment in 2004-2005, the corresponding figures for MI patients without PCI being 53.9%. CONCLUSIONS: Initiation and persistence with clopidogrel treatment is high in MI patients with PCI. However, we found substantial underuse among MI patients without PCI and in MI patients with heart failure.

Antipsychotics and associated risk of out-of-hospital cardiac arrest.

Antipsychotic drugs have been associated with sudden cardiac death, but differences in the risk of out-of-hospital cardiac arrest (OHCA) associated with different antipsychotic drug classes are not clear. We identified all OHCAs in Denmark (2001-2010). The risk of OHCA associated with antipsychotic drug use was evaluated by conditional logistic regression analysis in case-time-control models. In total, 2,205 (7.6%) of 28,947 OHCA patients received treatment with an antipsychotic drug at the time of the event. Overall, treatment with any antipsychotic drug was associated with OHCA (odds ratio (OR) = 1.53, 95% confidence interval (CI): 1.23-1.89), as was use with typical antipsychotics (OR = 1.66, CI: 1.27-2.17). By contrast, overall, atypical antipsychotic drug use was not (OR = 1.29, CI: 0.90-1.85). Two individual typical antipsychotic drugs, haloperidol (OR = 2.43, CI: 1.20-4.93) and levomepromazine (OR = 2.05, CI: 1.18-3.56), were associated with OHCA, as was one atypical antipsychotic drug, quetiapine (OR = 3.64, CI: 1.59-8.30).

Antidepressant use and risk of out-of-hospital cardiac arrest: a nationwide case-time-control study.

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were identified (2001-2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case-time-control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14-2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00-1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin-norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81-1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02-1.63) and nortriptyline (OR = 5.14, CI: 2.17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study.

Use of some nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased cardiovascular risk in several patient groups, but whether this excess risk exists in apparently healthy individuals has not been clarified. Using a historical cohort design, we estimated the risk of death and myocardial infarction associated with the use of NSAIDs. Participants in the study were selected from the Danish population and were defined as healthy according to a history of no hospital admissions and no concomitant selected pharmacotherapy. The source population consisted of 4,614,807 individuals, of whom 1,028,437 were included in the study after applying selection criteria. Compared to no NSAID use, hazard ratios (95% confidence limits) for death/myocardial infarction were 1.01 (0.96-1.07) for ibuprofen, 1.63 (1.52-1.76) for diclofenac, 0.97 (0.83-1.12) for naproxen, 2.13 (1.89-2.41) for rofecoxib, and 2.01 (1.78-2.27) for celecoxib. A dose-dependent increase in cardiovascular risk was seen for selective COX-2 inhibitors and diclofenac. Caution should be exercised in NSAID use in all individuals, and particularly high doses should be avoided if possible.