Methylphenidate and Short-Term Cardiovascular Risk.

Importance: There are concerns about the safety of medications for treatment of attention-deficit/hyperactivity disorder (ADHD), with mixed evidence on possible cardiovascular risk. Objective: To assess whether short-term methylphenidate use is associated with risk of cardiovascular events. Design, Setting, and Participants: This retrospective, population-based cohort study was based on national Swedish registry data. Participants were individuals with ADHD aged 12 to 60 years with dispensed prescriptions of methylphenidate between January 1, 2007, and June 30, 2012. Each person receiving methylphenidate (n = 26 710) was matched on birth date, sex, and county to up to 10 nonusers without ADHD (n = 225 672). Statistical analyses were performed from September 13, 2022, to May 16, 2023. Main Outcomes and Measures: Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias, 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a bayesian within-individual design. Analyses were stratified by history of cardiovascular events. Results: The cohort included 252 382 individuals (15 442 [57.8% men]; median age, 20 (IQR, 15-31) years). The overall incidence of cardiovascular events was 1.51 per 10 000 person-weeks (95% highest density interval [HDI], 1.35-1.69) for individuals receiving methylphenidate and 0.77 (95% HDI, 0.73-0.82) for the matched controls. Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41; 95% HDI, 1.09-1.88) compared with matched controls (IRR, 1.18; 95% HDI, 1.02-1.37). The posterior probabilities were 70% for at least a 10% increased risk of cardiovascular events in individuals receiving methylphenidate vs 49% in matched controls. No difference was found in this risk between individuals with and without a history of cardiovascular disease (IRR, 1.11; 95% HDI, 0.58-2.13). Conclusions and Relevance: In this cohort study, individuals receiving methylphenidate had a small increased cardiovascular risk vs matched controls in the 6 months after treatment initiation. However, there was little evidence for an increased risk of 20% or higher and for differences in risk increase between people with and without a history of cardiovascular disease. Therefore, before treatment initiation, careful consideration of the risk-benefit trade-off of methylphenidate would be useful, regardless of cardiovascular history.

Associations Between General and Specific Mental Health Conditions in Young Adulthood and Cardiometabolic Complications in Middle Adulthood: A 40-Year Longitudinal Familial Coaggregation Study of 672,823 Swedish Individuals.

OBJECTIVE: Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability to psychopathology or confounded by unmeasured familial factors. The authors investigated the association between psychiatric conditions in young adulthood and the risk of cardiometabolic complications in middle adulthood, up to 40 years later. METHODS: This cohort study (N=672,823) identified all individuals and their siblings born in Sweden between 1955 and 1962 and followed the cohort through 2013. Logistic regression models were used to estimate the bivariate associations between 10 psychiatric conditions or criminal convictions and five cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the comorbidity among psychiatric conditions and criminal convictions. The cardiometabolic complications were then regressed on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs. RESULTS: Each psychiatric condition significantly increased the risk of cardiometabolic complications. These associations appeared nonspecific, as multivariate models indicated that most were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals' general psychopathology and their siblings' cardiometabolic complications. The same pattern was evident for the specific internalizing and psychotic factors. CONCLUSIONS: Associations between mental disorders in early life and later long-term risk of cardiometabolic complications appeared to be attributable to a general liability to psychopathology. Familial coaggregation analyses suggested that the elevated risk could not be attributed to confounders shared within families. One possibility is that lifestyle-based interventions may reduce the risk of later cardiometabolic complications for patients with several mental disorders.

Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases.

Importance: Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear. Objective: To assess the association between long-term use of ADHD medication and the risk of CVD. Design, Setting, and Participants: This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up. Exposure: Cumulative duration of ADHD medication use up to 14 years. Main Outcomes and Measures: The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs. Results: Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years). Conclusions and Relevance: This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.

Psychiatric comorbidities in women with cardiometabolic conditions with and without ADHD: a population-based study.

BACKGROUND: Leveraging a large nationwide study of Icelandic women, we aimed to narrow the evidence gap around female attention-deficit/hyperactivity disorder (ADHD) and cardiometabolic comorbidities by determining the prevalence of obesity, hypertension, type 2 diabetes, and cardiovascular diseases among women with ADHD and examine the association between cardiometabolic conditions and co-occurring ADHD with anxiety and mood disorders, alcoholism/substance use disorder (SUD), self-harm, and suicide attempts. METHODS: We conducted a cross-sectional analysis of the nationwide, all-female, population-based SAGA Cohort Study (n = 26,668). To ascertain diagnoses and symptoms, we used self-reported history of ADHD diagnoses, selected cardiometabolic conditions and psychiatric disorders, and measured current depressive, anxiety, and PTSD symptoms through appropriate questionnaires (PHQ-9, GAD-7, and PCL-5). We calculated age-adjusted prevalences of cardiometabolic conditions by women's ADHD status and estimated adjusted prevalence ratios (PR) and 95% confidence intervals (CI), using modified Poisson regression models. Similarly, we assessed the association of cardiometabolic conditions and co-occurring ADHD with current psychiatric symptoms and psychiatric disorders, using adjusted PRs and 95% CIs. RESULTS: We identified 2299 (8.6%) women with a history of ADHD diagnosis. The age-adjusted prevalence of having at least one cardiometabolic condition was higher among women with ADHD (49.5%) than those without (41.7%), (PR = 1.19, 95% CI 1.14-1.25), with higher prevalence of all measured cardiometabolic conditions (myocardial infarctions (PR = 2.53, 95% CI 1.83--3.49), type 2 diabetes (PR = 2.08, 95% CI 1.66-2.61), hypertension (PR = 1.23, 95% CI 1.12-1.34), and obesity (PR = 1.18, 95% CI 1.11-1.25)). Women with cardiometabolic conditions and co-occurring ADHD had, compared with those without ADHD, substantially increased prevalence of (a) all measured mood and anxiety disorders, e.g., depression (PR = 2.38, 95% CI 2.19-2.58), bipolar disorder (PR = 4.81, 95% CI 3.65-6.35), posttraumatic stress disorder (PR = 2.78, 95% CI 2.52-3.07), social phobia (PR = 2.96, 95% CI 2.64-3.32); (b) moderate/severe depressive, anxiety, and PTSD symptoms with PR = 1.76 (95% CI 1.67-1.85), PR = 1.97 (95% CI 1.82-2.12), and PR = 2.01 (95% CI 1.88-2.15), respectively; (c) alcoholism/SUD, PR = 4.79 (95% CI 3.90-5.89); and (d) self-harm, PR = 1.47 (95% CI 1.29-1.67) and suicide attempts, PR = 2.37 (95% CI 2.05-2.73). CONCLUSIONS: ADHD is overrepresented among women with cardiometabolic conditions and contributes substantially to other psychiatric comorbidities among women with cardiometabolic conditions.

Prognostic importance of biomarkers associated with haemostatic, vascular and endothelial disturbances in acute coronary syndrome patients in relation to kidney function.

BACKGROUND: Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. METHODS: Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. RESULTS: Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44-2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. CONCLUSIONS: Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function.

Risk of Cardiovascular Diseases Associated With Medications Used in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis.

Importance: Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades, but there are concerns regarding their cardiovascular safety. Objective: To provide an updated synthesis of evidence on whether ADHD medications are associated with the risk of a broad range of cardiovascular diseases (CVDs). Data Sources: PubMed, Embase, PsycINFO, and Web of Science up to May 1, 2022. Study Selection: Observational studies investigating the association between ADHD medications (including stimulants and nonstimulants) and risk of CVD. Data Extraction and Synthesis: Independent reviewers extracted data and assessed study quality using the Good Research for Comparative Effectiveness (GRACE) checklist. Data were pooled using random-effects models. This study is reported according to the Meta-analyses of Observational Studies in Epidemiology guideline. Main Outcomes and Measures: The outcome was any type of cardiovascular event, including hypertension, ischemic heart disease, cerebrovascular disease, heart failure, venous thromboembolism, tachyarrhythmias, and cardiac arrest. Results: Nineteen studies (with 3 931 532 participants including children, adolescents, and adults; 60.9% male), of which 14 were cohort studies, from 6 countries or regions were included in the meta-analysis. Median follow-up time ranged from 0.25 to 9.5 years (median, 1.5 years). Pooled adjusted relative risk (RR) did not show a statistically significant association between ADHD medication use and any CVD among children and adolescents (RR, 1.18; 95% CI, 0.91-1.53), young or middle-aged adults (RR, 1.04; 95% CI, 0.43-2.48), or older adults (RR, 1.59; 95% CI, 0.62-4.05). No significant associations for stimulants (RR, 1.24; 95% CI, 0.84-1.83) or nonstimulants (RR, 1.22; 95% CI, 0.25-5.97) were observed. For specific cardiovascular outcomes, no statistically significant association was found in relation to cardiac arrest or arrhythmias (RR, 1.60; 95% CI, 0.94-2.72), cerebrovascular diseases (RR, 0.91; 95% CI, 0.72-1.15), or myocardial infarction (RR, 1.06; 95% CI, 0.68-1.65). There was no associations with any CVD in female patients (RR, 1.88; 95% CI, 0.43-8.24) and in those with preexisting CVD (RR, 1.31; 95% CI, 0.80-2.16). Heterogeneity between studies was high and significant except for the analysis on cerebrovascular diseases. Conclusions and Relevance: This meta-analysis suggests no statistically significant association between ADHD medications and the risk of CVD across age groups, although a modest risk increase could not be ruled out, especially for the risk of cardiac arrest or tachyarrhythmias. Further investigation is warranted for the cardiovascular risk in female patients and patients with preexisting CVD as well as long-term risks associated with ADHD medication use.

Outcomes After Acute Coronary Syndrome in Patients With Diabetes Mellitus and Peripheral Artery Disease (from the TRACER, TRILOGY-ACS, APPRAISE-2, and PLATO Clinical Trials).

Patients with acute coronary syndrome (ACS) are at risk for recurrent adverse events, and multiple reports suggest that this risk is increased in patients with concomitant diabetes mellitus (DM) and peripheral artery disease (PAD). The aim of this article was to investigate cardiovascular outcomes in patients with DM presenting with ACS, stratified by PAD status. Data were derived from 4 randomized post-ACS trials (PLATO [Platelet Inhibition and Patient Outcomes], APPRAISE-2 p Apixaban for Prevention of Acute Ischemic Events 2], TRILOGY [Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage], and TRACER [Thrombin Receptor Agonist for Clinical Event Reduction in Acute Coronary Syndrome]). Using Cox regression analysis, we investigated major adverse cardiovascular events (MACEs), a composite of cardiovascular mortality, myocardial infarction (MI), or stroke and the individual components of MACE and all-cause mortality in patients with DM, presenting with ACS, stratified by PAD status as the risk modifier. This study included 15,387 patients with a diagnosis of DM and ACS, of whom 1,751 had an additional diagnosis of PAD. PAD was associated with more than doubled rates of MACE (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.81 to 2.27), all-cause mortality (HR 2.48, 95% CI 2.14 to 2.87), cardiovascular mortality (HR 2.42, 95% CI 2.04 to 2.86), and MI (HR 2.07, 95% CI 1.79 to 2.38). Patients with both PAD and DM were also more optimally treated with antihypertensive, antidiabetic, and statin medication at baseline. In conclusion, this analysis of 4 major post-ACS trials showed that patients with DM and PAD had a substantially higher risk of MACE, cardiovascular mortality, all-cause mortality, and MI despite being optimally treated with guideline-based therapies.

Major adverse cardiovascular events following acute coronary syndrome in patients with bipolar disorder.

BACKGROUND: Persons with bipolar disorder (BD) have a higher cardiovascular mortality compared to the general population, partially explained by the increased burden of cardiovascular risk factors. Research regarding outcomes following acute coronary syndrome (ACS) in this population remains scarce. DESIGN: This Danish register-based study included patients diagnosed with BD and ACS in the period between January 1st, 1995, to December 31st, 2013. Study participants were matched 1:2 to patients without BD on sex, date of birth, time of ACS diagnosis and comorbidities. The primary outcome of interest was major adverse cardiovascular events (MACE) a composite of all-cause mortality, reinfarction or stroke. MACE and its individual components were compared between patients with and without BD. RESULTS: 796 patients with BD were compared to 1592 patients without BD, both groups had a mean age of first ACS of 66.5 years. MACE was 38% increased (HR 1.38 95% CI 1.25-1.54), all-cause mortality was 71% increased (HR 1.71 95% CI 1.52-1.92), stroke was 94% increased (HR 1.94 95% CI 1.56-2.41) and reinfarction rates were 17% lower (HR 0.83 95% CI 0.69-1.00) in the BD population compared to the population without BD. We also found higher prevalences of heart failure (9.1% vs. 6.5%), valve disease (5.3% vs. 3.5%), anemia (8.7% vs. 5.8%), chronic obstructive pulmonary disease (13.4% vs. 9.3%) and stroke (11.8% vs. 7.8%) in the population with BD at baseline, all p-values <0.05. CONCLUSION: Bipolar disorder was associated with a higher risk of composite MACE, all-cause mortality, and stroke, after ACS compared to patients without BD.

Associations between off-label low-dose olanzapine or quetiapine and cardiometabolic mortality.

Olanzapine and quetiapine are routinely used off-label at lower doses, though it remains unclear whether treatment is associated with mortality. Here, we examined the associations between low-dose olanzapine/quetiapine, defined as 5 mg/day of olanzapine equivalents (OE) with cardiometabolic mortality in a population-based, longitudinal cohort of individuals who sought specialized psychiatric services. Through cross-linked Swedish registries, 428,525 individuals without psychotic, bipolar, or cardiometabolic disorders, or previous treatment with antipsychotics or cardiometabolic-related drugs were followed for up to 10.5 years. Extended stratified Cox proportional hazards regressions were employed to estimate the hazard ratios (HR) of cardiometabolic mortality as a function of cumulative OE exposures, adjusted for age, sex, inpatient care, and time-dependent psychiatric diagnoses and treatments. Individuals were followed for a total of 2.1 million person-years. Treatment with olanzapine/quetiapine occurred in 18,317 of the cohort. In total, 2606 cardiometabolic-related deaths occurred. Treatment status (treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted HR 0.86, 95% CI 0.64-1.15, P = 0.307). However, compared to no treatment, treatment for <6 months was significantly associated with a reduced risk (adjusted HR 0.56, 95% CI 0.37-0.87, P = 0.010) whereas treatment for 6-12 months was significantly associated with an increased risk (adjusted HR 1.89, 95% CI 1.22-2.92, P = 0.004), but not significantly beyond 12 months. Among those treated, each year exposed to an average 5 mg/day was significantly associated with increased cardiometabolic mortality (adjusted HR 1.45, 95% CI 1.06-1.99, P = 0.019). Overall, low-dose olanzapine/quetiapine treatment was weakly associated with cardiometabolic mortality. Clinicians should consider potential cardiometabolic sequelae at lower doses.

Uninterrupted Oral Anticoagulant Therapy in Patients Undergoing Unplanned Percutaneous Coronary Intervention.

OBJECTIVES: This study sought to compare interrupted and uninterrupted oral anticoagulant therapy (I-OAC vs. U-OAC) in patients on OAC undergoing percutaneous coronary intervention. BACKGROUND: There is a paucity of data regarding the optimal peri-procedural management of OAC-treated patients. METHODS: In the SWEDEHEART registry, all patients on OAC who were admitted acutely and underwent percutaneous coronary intervention or coronary angiography with a diagnostic procedure, from 2005 to 2017, were included. Outcomes were major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, or stroke) and bleeds at 120 days. Propensity score was used to adjust for the nonrandomized treatment selection. RESULTS: The study included 6,485 patients: 3,322 in the I-OAC group and 3,163 in the U-OAC group. The cumulative incidence of MACCE was 8.2% (269 events) versus 8.2% (254 events) in the I-OAC and the U-OAC groups, respectively. The adjusted risk for MACCE did not differ between the groups (I-OAC vs. U-OAC hazard ratio: 0.89; 95% confidence interval: 0.71 to 1.12). Similarly, no difference was found in the risk for MACCE or bleeds (12.6% vs. 12.9%, adjusted hazard ratio: 0.87; 95% confidence interval: 0.70 to 1.07). The risk for major or minor in-hospital bleeds did not differ between the groups. However, U-OAC was associated with a significantly shorter duration of hospitalization: 4 (3 to 7) days versus 5 (3 to 8) days; p < 0.01. CONCLUSIONS: I-OAC and U-OAC were associated with equivalent risk for MACCE and bleeding complications. An U-OAC strategy was associated with shorter length of hospitalization. These data support U-OAC as the preferable strategy in patients on OAC undergoing coronary intervention.

Adherence to beta-blockers and long-term risk of heart failure and mortality after a myocardial infarction.

AIMS: The aim of this study is to investigate the association between adherence to beta-blocker treatment after a first acute myocardial infarction (AMI) and long-term risk of heart failure (HF) and death. METHODS AND RESULTS: All patients admitted for a first AMI included in the nationwide Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies register between 2005 and 2010 were eligible (n = 71 638). After exclusion of patients who died in-hospital, patients with previous HF, patients with unknown left ventricular ejection fraction (EF), and patients who died during the first year after the index event, 38 608 patients remained in the final analysis. Adherence to prescribed beta-blockers was determined for 1 year after the index event using the national registry for prescribed drugs and was measured as proportion of days covered, the ratio between the numbers of days covered by the dispensed prescriptions and number of days in the period. As customary, a threshold level for proportion of days covered ≥80% was used to classify patients as adherent or non-adherent. At discharge 90.6% (n = 36 869) of all patients were prescribed a beta-blocker. Among 38 608 1 year survivors, 31.1% (n = 12 013) were non-adherent to beta-blockers. Patients with reduced EF with and without HF were more likely to remain adherent to beta-blockers at 1-year compared with patients with normal EF without HF (NEF). Being married/cohabiting and having higher income level, hypertension, ST-elevation MI, and percutaneous coronary intervention were associated with better adherence. Adherence was independently associated with lower all-cause mortality [hazard ratio (HR) 0.77, 95% confidence interval [CI] 0.71-0.84] and a lower risk for the composite of HF readmission/death, (HR 0.83, 95% CI 0.78-0.89, P value <0.001) during the subsequent 4 years of follow up. These associations were favourable but less apparent in patients with HFNEF and NEF. CONCLUSIONS: Nearly one in three AMI patients was non-adherent to beta-blockers within the first year. Adherence was independently associated with improved long-term outcomes; however, uncertainty remains for patients with HFNEF and NEF.

Higher risk of major adverse cardiac events after acute myocardial infarction in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia are a high-risk population due to higher prevalences of cardiovascular risk factors and comorbidities that contribute to shorter life expectancy. PURPOSE: To investigate patients with and without schizophrenia experiencing an acute myocardial infarction (AMI) in relation to guideline recommended in-hospital management, discharge medications and 5-year major adverse cardiac events (MACE: composite of all-cause mortality, rehospitalisation for reinfarction, stroke or heart failure). METHODS: All patients with schizophrenia who experienced AMI during 2000-2018 were identified (n=1008) from the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry and compared with AMI patients without schizophrenia (n=2 85 325). Kaplan-Meier survival curves and multivariable Cox regression models were used to compare the populations. RESULTS: Patients with schizophrenia presented with AMI approximately 10 years earlier (median age 64 vs 73 years), and had higher prevalences of diabetes, heart failure and chronic obstructive pulmonary disease. They were less likely to be invasively investigated or discharged with aspirin, P2Y12 inhibitors, ACE inhibitors/angiotensin II receptor blockers, beta-blockers and statins (all p<0.005). AMI patients with schizophrenia had higher adjusted risk of MACE (aHR=2.05, 95% CI 1.63 to 2.58), mortality (aHR=2.38, 95% CI 1.84 to 3.09) and hospitalisation for heart failure (aHR=1.39, 95% CI 1.04 to 1.86) compared with AMI patients without schizophrenia. CONCLUSION: Patients with schizophrenia experienced an AMI almost 10 years earlier than patients without schizophrenia. They less often underwent invasive procedures and were less likely to be treated with guideline recommended medications at discharge, and had more than doubled risk of MACE and all-cause mortality. Improved primary and secondary preventive measures, including adherence to guideline recommendations, are warranted and may improve outcome.

Neighborhood socioeconomic status and aortic stenosis: A Swedish study based on nationwide registries and an echocardiographic screening cohort.

BACKGROUND: Aortic stenosis (AS) is the most common valvular heart disease in developed countries, confers high mortality in advanced cases, but can effectively be reversed using endovascular or open-heart surgery. We evaluated the association between AS and neighborhood socioeconomic status (NSES). METHODS: We used Swedish population-based nationwide registers and an echocardiography screening cohort during the study period 1997-2014. NSES was determined by an established neighborhood deprivation index composed of education, income, unemployment, and receipt of social welfare. Multilevel adjusted logistic regression models determined the association between NSES and incident AS (according to ICD-10 diagnostic codes). RESULTS: The study population of men and women (n=6,641,905) was divided into individuals living in high (n = 1,608,815 [24%]), moderate (n = 3,857,367 [58%]) and low (n = 1,175,723 [18%]) SES neighborhoods. There were 63,227 AS cases in total. Low NSES (versus high) was associated with a slightly increased risk of AS (OR 1.06 [95% CI 1.03-1.08]) in the nationwide study population. In the echocardiography screening cohort (n = 1586), the association between low NSES and AS was markedly stronger (OR: 2.73 [1.05-7.12]). There were more previously undiagnosed AS cases in low compared to high SES neighborhoods (3.1% versus 1.0%). CONCLUSIONS: In this nationwide Swedish register study, low NSES was associated with a slightly increased risk of incident AS. However, the association was markedly stronger in the echocardiography screening cohort, which revealed an almost three-fold increase of AS among individuals living in low SES neighborhoods, possibly indicating an underdiagnosis of AS among these individuals.

Time Trends in the Use of Coronary Procedures, Guideline-Based Therapy, and All-Cause Mortality following the Acute Coronary Syndrome in Patients with Schizophrenia.

AIM: Schizophrenia is associated with high cardiovascular mortality predominantly as a result of acute coronary syndrome (ACS). The aim of this study is to analyze time trends of coronary procedures, guideline-based therapy, and all-cause mortality in patients diagnosed with schizophrenia. METHODS AND RESULTS: This Danish nationwide register-based study analyzed 734 patients with a baseline diagnosis of schizophrenia and an incident diagnosis of ACS in the period between January 1, 1996, and December 31, 2015. The 734 patients with schizophrenia were matched to 2,202 psychiatric healthy controls (PHC). No change over time was seen in the relative difference between the population with schizophrenia and the PHC in the use of coronary angiography, percutaneous coronary intervention, and coronary bypass grafting, nor in 1-year mortality or guideline-based therapy following ACS. Patients with schizophrenia had higher prevalence rates of diabetes, chronic obstructive pulmonary disease, and stroke, and a lower prevalence of hypertension (p < 0.05). CONCLUSION: The gap in the use of coronary procedures, guideline-based therapy, and all-cause mortality following ACS in patients with schizophrenia compared to those without has remained constant over the past 2 decades.

Risk of Stroke in Patients With Atrial Fibrillation Is Associated With Stroke in Siblings: A Nationwide Study.

Background It remains unclear whether heritable factors can contribute to risk stratification for ischemic stroke in patients with atrial fibrillation (AF). We examined whether having a sibling with ischemic stroke was associated with increased risk of ischemic stroke and mortality in patients with AF. Methods and Results In this nationwide study of the Swedish population, patients with AF and their siblings were identified from the Swedish patient registers and the Swedish MGR (Multi-Generation Register). Ischemic stroke events were retrieved from the Swedish patient registers and CDR (Cause of Death Register). Risk of ischemic stroke was compared between patients with AF with and without a sibling affected by ischemic stroke, AF, or both ischemic stroke and AF. The total study population comprised 113 988 subjects (mean age, 60±12 years) diagnosed with AF between 1989 and 2012. In total, 11 709 of them were diagnosed with a first ischemic stroke and 20 097 died during a mean follow-up time of 5.5 years for ischemic stroke and 5.9 years for mortality. After adjustment for covariates having a sibling with ischemic stroke, or both ischemic stroke and AF, was associated with increased risk of ischemic stroke (hazard ratio, 1.31; 95% CI, 1.23-1.40 or hazard ratio, 1.36; 95% CI, 1.24-1.49, respectively). Furthermore, ischemic stroke in a sibling was associated with all-cause mortality (hazard ratio, 1.09; 95% CI, 1.05-1.14). In contrast, the risk of stroke was only marginally increased for patients with AF with a spouse affected by ischemic stroke. Conclusions Having a sibling affected by ischemic stroke confers an increased risk of ischemic stroke and death independently of traditional risk factors in patients with AF.

Beta-blockeRs tO patieNts with CHronIc Obstructive puLmonary diseasE (BRONCHIOLE) - Study protocol from a randomized controlled trial.

BACKGROUND: Observational studies indicate that beta-blockers are associated with a reduced risk of exacerbation and mortality in patients with chronic obstructive pulmonary disease (COPD) even without overt cardiovascular disease, but data from randomized controlled trials (RCT) are lacking. The aim of this RCT is to investigate whether beta-blocker therapy in patients with COPD without diagnosed cardiovascular disease is associated with a decreased 1-year risk of the composite endpoint of death, exacerbations, or cardiovascular events. METHODS: The Beta-blockeRs tO patieNts with CHronIc Obstructive puLmonary diseasE (BRONCHIOLE) study is an open-label, multicentre, prospective RCT. A total of 1700 patients with COPD will be randomly assigned to either standard COPD care and metoprolol at a target dose of 100 mg per day or to standard COPD care only. The primary endpoint is a composite of death, COPD exacerbations, and cardiovascular events. Major exclusion criteria are ischemic heart disease, left-sided heart failure, cerebrovascular disease, critical limb ischemia, and atrial fibrillation/flutter. Study visits are an inclusion visit, a metoprolol titration visit at 1 month, follow-up by telephone at 6 months, and a final study visit after 1 year. Outcome data are obtained from medical history and record review during study visits, as well as from national registries. DISCUSSION: BRONCHIOLE is a pragmatic randomized trial addressing the potential of beta-blockers in patients with COPD. The trial is expected to provide relevant clinical data on the efficacy of this treatment on patient-related outcomes in patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03566667. Registered on 25 June 2018.

Oxygen therapy in suspected acute myocardial infarction and concurrent normoxemic chronic obstructive pulmonary disease: a prespecified subgroup analysis from the DETO2X-AMI trial.

BACKGROUND: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial did not find any benefit of oxygen therapy compared to ambient air in normoxemic patients with suspected acute myocardial infarction. Patients with chronic obstructive pulmonary disease may both benefit and be harmed by supplemental oxygen. Thus we evaluated the effect of routine oxygen therapy compared to ambient air in normoxemic chronic obstructive pulmonary disease patients with suspected acute myocardial infarction. METHODS AND RESULTS: A total of 6629 patients with suspected acute myocardial infarction were randomly assigned in the DETO2X-AMI trial to oxygen or ambient air. In the oxygen group (n=3311) and the ambient air group (n=3318), 155 and 141 patients, respectively, had chronic obstructive pulmonary disease (prevalence of 4.5%). Patients with chronic obstructive pulmonary disease were older, had more comorbid conditions and experienced a twofold higher risk of death at one year (chronic obstructive pulmonary disease: 32/296 (10.8%) vs. non-chronic obstructive pulmonary disease: 302/6333 (4.8%)). Oxygen therapy compared to ambient air was not associated with improved outcomes at 365 days (chronic obstructive pulmonary disease: all-cause mortality hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.50-1.99, Pinteraction=0.96); cardiovascular death HR 0.80, 95% CI 0.32-2.04, Pinteraction=0.59); rehospitalisation with acute myocardial infarction or death HR 1.27, 95% CI 0.71-2.28, Pinteraction=0.46); hospitalisation for heart failure or death HR 1.08, 95% CI 0.61-1.91, Pinteraction=0.77]); there were no significant treatment-by-chronic obstructive pulmonary disease interactions. CONCLUSIONS: Although chronic obstructive pulmonary disease patients had twice the mortality rate compared to non-chronic obstructive pulmonary disease patients, this prespecified subgroup analysis from the DETO2X-AMI trial on oxygen therapy versus ambient air in normoxemic chronic obstructive pulmonary disease patients with suspected acute myocardial infarction revealed no evidence for benefit of routine oxygen therapy consistent with the main trial's findings. CLINICAL TRIALS REGISTRATION: NCT02290080.

Smokeless tobacco, snus, at admission for percutaneous coronary intervention and future risk for cardiac events.

Objective: To assess the risk of future death and cardiac events following percutaneous coronary intervention (PCI) in patients using smokeless tobacco, snus, compared with patients not using snus at admission for a first PCI. Methods: The Swedish Coronary Angiography and Angioplasty Registry is a prospective registry on coronary diagnostic procedures and interventions. A total of 74 958 patients admitted for a first PCI were enrolled between 2009 and 2018, 6790 snus users and 68 168 not using snus. We used Cox proportional hazards regression for statistical modelling on imputed datasets as well as complete-case datasets. Results: Patients using snus were younger (mean (SD) age 61.0 (±10.2) years) than patients not using snus (67.6 (±11.1), p<0.001) and more often male (95.4% vs 67.4%, p<0.001). After multivariable adjustment, snus use was not associated with the primary composite outcome of all-cause mortality, new coronary revascularisation or new hospitalisation for heart failure at 1 year (HR 0.98, 95% CI 0.91 to 1.05). In patients using snus at baseline who underwent a second PCI (n=1443), the duration from the index intervention was shorter for subjects who continued using snus (n=921, 63.8%) compared with subjects who had stopped (mean number of days 285 vs 406, p value=0.001). Conclusions: Snus use at admission for a first PCI was not associated with a higher occurrence of all-cause mortality, new revascularisation or heart failure hospitalisation. Discontinuing snus after a first PCI was associated with a significantly longer duration to a subsequent PCI.

Impact of Baseline Anemia in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: A Prespecified Analysis From the VALIDATE-SWEDEHEART Trial.

Background The impact of baseline anemia in a contemporary acute coronary syndrome (ACS) population undergoing percutaneous coronary intervention in the era of predominant radial artery access, potent P2Y12 inhibition, and rare use of glycoprotein IIb/IIIa inhibitors has not been adequately studied. Methods and Results ACS patients who underwent percutaneous coronary intervention between 2014 and 2016 in the VALIDATE-SWEDEHEART (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies Registry) trial without missing values for hemoglobin were included (n=5482). Mortality, myocardial reinfarction, and major bleeding at 180 days were assessed using Cox regression models and propensity score matching. All studied comorbidities were more common in ACS patients who had anemia (n=792). ACS patients with anemia had higher rates of 180-day mortality (6.9% versus 2.1%; hazard ratio, 1.9; 95% CI, 1.3-2.7; P<0.001), myocardial reinfarction (4.3% versus 1.9%; hazard ratio, 1.7; 95% CI, 1.1-2.7; P=0.013), and major bleeding (13.4% versus 8.2%; hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.041). The results were most evident in patients with a hemoglobin value <100 g/L, who had a nearly 10 times higher mortality rate. Conclusions Baseline anemia in ACS patients undergoing percutaneous coronary intervention, treated according to current practice including routine radial artery access, constitutes a high-risk feature for both ischemic events, bleeding events, and mortality. A multidisciplinary approach is warranted to maximize benefit and minimize patient risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02311231.

Peripheral artery disease and outcomes in patients with acute myocardial infarction.

Aim: To describe the population of patients with previously diagnosed peripheral artery disease (PAD) experiencing a myocardial infarction (MI) and to investigate 1-year major adverse cardiac events (MACE: all-cause mortality, reinfarction, stroke and heart failure hospitalisation) following MI. Background: MI patients with PAD constitute a high-risk population with adverse cardiac outcomes. Contemporary real-life data regarding the clinical characteristics of this patient population and clinical event rates following MI remain scarce. Methods: This observational study included all MI patients presenting with ST-elevation MI or non-ST-elevation MI between 01 January 2005 and 31 December 2014 with (n=4213) and without (n=106 763) a concurrent PAD diagnosis, identified in the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry and the National Patient Registry (PAD prevalence: 3.8%). Cox proportional hazard models were applied to compare the outcome between the two populations. Results: MI patients with PAD were older and more often burdened with comorbidities, such as diabetes, hypertension and previous MI. After adjustments, PAD was significantly associated with higher rates of MACE (HR 1.35, 95% CI 1.27 to 1.44), mortality (HR 1.59, 95% CI 1.43 to 1.76), reinfarction (HR 1.48, 95% CI 1.32 to 1.66), stroke (HR 1.27, 95% CI 1.05 to 1.53), heart failure (HR 1.29, 95% CI 1.20 to 1.40) and bleeding (HR 1.26, 95% CI 1.09 to 1.47) at 1 year. Conclusion: A concurrent PAD diagnosis was independently significantly associated with higher rates of adverse outcomes following MI in a nationwide real-life MI population. The low prevalence of PAD compared with previous studies suggests significant underdiagnosing. Future studies should investigate if PAD screening with ankle-brachial index may increase diagnosing and subsequently lead to improved treatment of polyvascular disease.