Long QT syndrome is associated with an increased burden of diabetes, psychiatric and neurological comorbidities: a nationwide cohort study.

Objective: Studies have suggested a shared genetic aetiology between congenital long QT syndrome (LQTS) and diabetes, epilepsy and mental disorders. We investigated the prevalence of metabolic, neurological and psychiatric comorbidities in LQTS patients. Methods: This retrospective cohort study was based on data from nationwide Danish registries, 2003-2017. LQTS patients were matched 1:5 with controls on sex and age. Results: We matched 463 LQTS patients with 2315 controls from the background population. Mean age was 35.7 (SD 21.0) years, and 38% were males in both groups. LQTS patients had a higher prevalence of atrial fibrillation (6.5% vs 2.3%, p<0.001), diabetes (3.7% vs 1.8 %, p=0.011) and hearing loss (3.2% vs 1.7%, p=0.027). LQTS patients had a higher prevalence of psychiatric disorders overall (13.0% vs 9.1%, p=0.01) but the difference could not be attributed to a specific psychiatric disease subgroup. LQTS patients had a higher prevalence of neurological disorders (22.0% vs 13.2%, p<0.001), largely driven by epilepsy (6.7% vs 1.6%, p<0.001). In 20/27 (74%) of the LQTS patients, the epilepsy diagnosis did not reappear in the registries after the LQTS diagnosis was established. Conclusions: In this nationwide cohort, patients with LQTS had a significantly increased burden of diabetes, neurological and psychiatric comorbidities, compared with the background population. The higher prevalence of neurological comorbidities was largely driven by epilepsy, despite a high rate of potentially misdiagnosed patients prior to LQTS diagnosis. Our data support that LQTS may be considered a multiorgan disease and suggest that patient management should be adjusted accordingly.

Characteristics and prognosis of heart failure with improved compared with persistently reduced ejection fraction: A systematic review and meta-analyses.

Aims We assessed the clinical characteristics and prognosis of chronic heart failure patients with improved ejection fraction (HFIEF) compared with persistently reduced ejection fraction (HFpREF) after evidence-based therapy. Methods and results We performed a meta-analysis including 24 eligible observational studies comparing 2663 HFIEF (≥5% left ventricular ejection fraction (LVEF) improvement) versus 8355 HFpREF patients who received recommended drug therapy, cardiac resynchronization therapy and/or intracardiac defibrillator. LVEF was assessed at baseline and reassessed after 19 ± 19 months. The primary endpoints were all-cause mortality and appropriate shocks. The mean duration of follow-up was 39 ± 12 months. Among HFIEF patients, LVEF improved 16.3 percentage points (95% confidence interval 15.9-16.6, p < 0.0001). Compared with HFpREF patients, HFIEF patients had a comparable mean age (60.9 years vs. 62.4 years, p = 0.11), were more often women (33% vs. 25%), had a higher prevalence of non-ischaemic heart failure (58% vs. 53%), less diabetes (27% vs. 28%), higher systolic blood pressure (127.5 ± 9 vs. 122 ± 12 mmHg) and lower left ventricle end-diastolic diameter (64.1 ± 3.7 vs. 67.4 ± 4.9 mmHg), all p-values < 0.05. Absolute risk of all-cause mortality was lower in HFIEF (5.8%) compared with HFpREF (17.5%) with a risk ratio of 0.34 (95% confidence interval 0.28-0.41), p < 0.001. Risk of appropriate shocks was significantly lower in HFIEF versus HFpREF (risk ratio 0.58 (95% confidence interval 0.46-0.74), p < 0.001). Conclusion In heart failure patients, we identified several baseline characteristics in favour of an improved LVEF, in response to evidence based therapy. Patients with improved LVEF had significantly lower risks of mortality and appropriate shocks compared with patients with persistently reduced LVEF.

Beta-blocker subtype and risks of perioperative adverse events following non-cardiac surgery: a nationwide cohort study.

AIMS: Beta-blockers vary in pharmacodynamics and pharmacokinetic properties. It is unknown whether specific types are associated with increased perioperative risks. We evaluated perioperative risks associated with beta-blocker subtypes, overall and in patient subgroups. METHODS AND RESULTS: We performed a Danish Nationwide cohort study, 2005-2011, of patients treated chronically with beta blocker (atenolol, bisoprolol, carvedilol, metoprolol, propranolol, or other) prior to non-cardiac surgery. Risks of 30-day all-cause mortality (ACM) and 30-day major adverse cardiovascular events (MACE) were estimated using adjusted logistic regression models and odds ratios with 95% confidence intervals. We identified 61 660 patients, most frequently treated with metoprolol (67% of patients, mean age 69 years, 49% males), atenolol (10% of patients, mean age 68 years, 36% males), or carvedilol (9% of patients, mean age 68 years, 60% males). The crude incidences of ACM and MACE were 4.1 and 3.5% in patients with metoprolol, 3.0 and 2.3% with atenolol, and 4.8 and 4.6% with carvedilol. In adjusted models, risks were not significantly different with atenolol (ACM; 1.10 [0.92-1.32], MACE; 1.08 [0.90-1.31]) or carvedilol (ACM; 0.99 [0.85-1.16], MACE; 1.07 [0.92-1.25]), compared with metoprolol. Risks of ACM were significantly lower in prior myocardial infarction patients treated with carvedilol (0.62 [0.43-0.87]) and no different in patients with uncomplicated hypertension (1.41 [0.83-2.40]). Risks did not differ in analyses stratified by age, surgery priority, duration of anaesthesia or surgery risk (all P for interaction >0.05). CONCLUSION: Risks of ACM and MACE did not systematically differ by beta-blocker subtype. Findings may guide clinical practice and future trials.

Risks of Cardiovascular Adverse Events and Death in Patients with Previous Stroke Undergoing Emergency Noncardiac, Nonintracranial Surgery: The Importance of Operative Timing.

BACKGROUND: The outcomes of emergent noncardiac, nonintracranial surgery in patients with previous stroke remain unknown. METHODS: All emergency surgeries performed in Denmark (2005 to 2011) were analyzed according to time elapsed between previous ischemic stroke and surgery. The risks of 30-day mortality and major adverse cardiovascular events were estimated as odds ratios (ORs) and 95% CIs using adjusted logistic regression models in a priori defined groups (reference was no previous stroke). In patients undergoing surgery immediately (within 1 to 3 days) or early after stroke (within 4 to 14 days), propensity-score matching was performed. RESULTS: Of 146,694 nonvascular surgeries (composing 98% of all emergency surgeries), 5.3% had previous stroke (mean age, 75 yr [SD = 13]; 53% women, 50% major orthopedic surgery). Antithrombotic treatment and atrial fibrillation were more frequent and general anesthesia less frequent in patients with previous stroke (all P < 0.001). Risks of major adverse cardiovascular events and mortality were high for patients with stroke less than 3 months (20.7 and 16.4% events; OR = 4.71 [95% CI, 4.18 to 5.32] and 1.65 [95% CI, 1.45 to 1.88]), and remained increased for stroke within 3 to 9 months (10.3 and 12.3%; OR = 1.93 [95% CI, 1.55 to 2.40] and 1.20 [95% CI, 0.98 to 1.47]) and stroke more than 9 months (8.8 and 11.7%; OR = 1.62 [95% CI, 1.43 to 1.84] and 1.20 [95% CI, 1.08 to 1.34]) compared with no previous stroke (2.3 and 4.8% events). Major adverse cardiovascular events were significantly lower in 323 patients undergoing immediate surgery (21%) compared with 323 successfully propensity-matched early surgery patients (29%; P = 0.029). CONCLUSIONS: Adverse cardiovascular outcomes and mortality were greatly increased among patients with recent stroke. However, events were higher 4 to 14 days after stroke compared with 1 to 3 days after stroke.

Functional Testing or Coronary Computed Tomography Angiography in Patients With Stable Coronary Artery Disease.

BACKGROUND: The choice of either anatomical or functional noninvasive testing to evaluate suspected coronary artery disease might affect subsequent clinical management and outcomes. OBJECTIVES: This study analyzed the association of initial noninvasive cardiac testing in outpatients with stable symptoms, with subsequent use of medications, invasive procedures, and clinical outcomes. METHODS: We studied patients enrolled in a Danish nationwide register who underwent initial noninvasive cardiac testing with either coronary computed tomography angiography (CTA) or functional testing (exercise electrocardiography or nuclear stress testing) from 2009 to 2015. Further use of noninvasive testing, invasive procedures, medications, and medical costs within 120 days were evaluated. Risks of long-term mortality and myocardial infarction (MI) were analyzed using adjusted Cox proportional hazard models. RESULTS: A total of 86,705 patients underwent either functional testing (n = 53,744, mean age 57.4 years, 49% males) or coronary CTA (n = 32,961, mean age 57.4 years, 45% males), and were followed for a median of 3.6 years. Compared with functional testing, there was significantly higher use of statins (15.9% vs. 9.1%), aspirin (12.7% vs. 8.5%), invasive coronary angiography (14.7% vs. 10.1%), and percutaneous coronary intervention (3.8% vs. 2.1%); all p < 0.001 after coronary CTA. The mean costs of subsequent testing, invasive procedures, and medications were higher after coronary CTA ($995 vs. $718; p < 0.001). Unadjusted rates of mortality (2.1% vs. 4.0%) and MI hospitalization (0.8% vs. 1.5%) were lower after coronary CTA than functional testing (both p < 0.001). After adjustment, coronary CTA was associated with a comparable all-cause mortality (hazard ratio: 0.96; 95% confidence interval: 0.88 to 1.05), and a lower risk of MI (hazard ratio: 0.71; 95% confidence interval: 0.61 to 0.82). CONCLUSIONS: In stable patients undergoing initial evaluation for suspected coronary artery disease, coronary CTA was associated with greater use of statins, aspirin, and invasive procedures, and higher costs than functional testing. Coronary CTA was associated with a lower risk of MI, but a similar risk of all-cause mortality.

ß-Blocker-Associated Risks in Patients With Uncomplicated Hypertension Undergoing Noncardiac Surgery.

IMPORTANCE: Perioperative ß-blocker strategies are important to reduce risks of adverse events. Effectiveness and safety may differ according to patients' baseline risk. OBJECTIVE: To determine the risk of major adverse cardiovascular events (MACEs) associated with long-term ß-blocker therapy in patients with uncomplicated hypertension undergoing noncardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Association study based on in-hospital records and out-of-hospital pharmacotherapy use using a Danish nationwide cohort of patients with uncomplicated hypertension treated with at least 2 antihypertensive drugs (ß-blockers, thiazides, calcium antagonists, or renin-angiotensin system [RAS] inhibitors) undergoing noncardiac surgery between 2005 and 2011. INTERVENTIONS: Various antihypertensive treatment regimens, chosen as part of usual care. MAIN OUTCOMES AND MEASURES: Thirty-day risk of MACEs (cardiovascular death, nonfatal ischemic stroke, nonfatal myocardial infarction) and all-cause mortality, assessed using multivariable logistic regression models and adjusted numbers needed to harm (NNH). RESULTS: The baseline characteristics of the 14,644 patients who received ß-blockers (65% female, mean [SD] age, 66.1 [12.0] years) were similar to those of the 40,676 patients who received other antihypertensive drugs (57% female, mean [SD] age, 65.9 [11.8] years). Thirty-day MACEs occurred in 1.3% of patients treated with ß-blockers compared with 0.8% of patients not treated with ß-blockers (P < .001). ß-Blocker use was associated with increased risks of MACEs in 2-drug combinations with RAS inhibitors (odds ratio [OR], 2.16 [95% CI, 1.54-3.04]), calcium antagonists (OR, 2.17 [95% CI, 1.48-3.17]), and thiazides (OR, 1.56 [95% CI, 1.10-2.22]), compared with the reference combination of RAS inhibitors and thiazides. Results were similar for all-cause mortality. Risk of MACEs associated with ß-blocker use seemed especially pronounced for patients at least 70 years old (number needed to harm [NNH], 140 [95% CI, 86-364]), for men (NNH, 142 [95% CI, 93-195]), and for patients undergoing acute surgery (NNH, 97 [95% CI, 57-331]), compared with patients younger than 70 years, women, and patients undergoing elective surgery, respectively. CONCLUSIONS AND RELEVANCE: Antihypertensive treatment with a ß-blocker may be associated with increased risks of perioperative MACEs and all-cause mortality in patients with uncomplicated hypertension.

Use of quinine and mortality-risk in patients with heart failure--a Danish nationwide observational study.

PURPOSE: Leg cramps are common in patients with heart failure. Quinine is frequently prescribed in low doses to these patients, but safety of this practice is unknown. We studied the outcomes associated with use of quinine in a nationwide cohort of patients with heart failure. METHODS: Through individual-level-linkage of Danish national registries, we identified patients discharged from first-time hospitalization for heart failure in 1997-2010. We estimated the risk of mortality associated with quinine treatment by time-dependent Poisson regression models. RESULTS: A total of 135 529 patients were included, with 14 510 patients (11%) using quinine at some point. During a median time of follow-up of 989 days (interquartile range 350-2004) 88 878 patients (66%) died. Patients receiving quinine had slightly increased mortality risk, adjusted incidence rate ratio (IRR) 1.04 (95% confidence interval [CI] 1.01 to 1.07). The risks differed according to concomitant ß-blocker treatment. For patients treated with both quinine and ß-blockers IRR was 1.15 (95% CI 1.09 to 1.21) vs. 0.99 (95% CI 0.96 to 1.03) for patients treated with quinine but not ß-blockers. The risks were highest shortly after initiation of therapy: for the first 14 days of treatment IRR was 2.12 (95% CI 1.54 to 2.93) for patients in treatment with ß-blockers and 1.17 (95% CI 0.86 to 1.59) for patients not treated with ß-blockers. CONCLUSIONS: Use of quinine was common and associated with increased mortality in heart failure, especially if administered together with ß-blockers and shortly after treatment initiation. Mechanisms underlying the findings remain to be established.

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.

Time elapsed after ischemic stroke and risk of adverse cardiovascular events and mortality following elective noncardiac surgery.

IMPORTANCE: The timing of surgery in patients with recent ischemic stroke is an important and inadequately addressed issue. OBJECTIVE: To assess the safety and importance of time elapsed between stroke and surgery in the risk of perioperative cardiovascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS: Danish nationwide cohort study (2005-2011) including all patients aged 20 years or older undergoing elective noncardiac surgeries (n=481,183 surgeries). EXPOSURES: Time elapsed between stroke and surgery in categories and as a continuous measure. MAIN OUTCOMES AND MEASURES: Risk of major adverse cardiovascular events (MACE; including ischemic stroke, acute myocardial infarction, and cardiovascular mortality) and all-cause mortality up to 30 days after surgery. Odds ratios (ORs) were calculated by multivariable logistic regression models. RESULTS: Crude incidence rates of MACE among patients with (n = 7137) and without (n = 474,046) prior stroke were 54.4 (95% CI, 49.1-59.9) vs 4.1 (95% CI, 3.9-4.2) per 1000 patients. Compared with patients without stroke, ORs for MACE were 14.23 (95% CI, 11.61-17.45) for stroke less than 3 months prior to surgery, 4.85 (95% CI, 3.32-7.08) for stroke 3 to less than 6 months prior, 3.04 (95% CI, 2.13-4.34) for stroke 6 to less than 12 months prior, and 2.47 (95% CI, 2.07-2.95) for stroke 12 months or more prior. MACE risks were at least as high for low-risk (OR, 9.96; 95% CI, 5.49-18.07 for stroke <3 months) and intermediate-risk (OR, 17.12; 95% CI, 13.68-21.42 for stroke <3 months) surgery compared with high-risk surgery (OR, 2.97; 95% CI, 0.98-9.01 for stroke <3 months) (P = .003 for interaction). Similar patterns were found for 30-day mortality: ORs were 3.07 (95% CI, 2.30-4.09) for stroke less than 3 months prior, 1.97 (95% CI, 1.22-3.19) for stroke 3 to less than 6 months prior, 1.45 (95% CI, 0.95-2.20) for stroke 6 to less than 12 months prior, and 1.46 (95% CI, 1.21-1.77) for stroke 12 months or more prior to surgery compared with patients without stroke. Cubic regression splines performed on the stroke subgroup supported that risk leveled off after 9 months. CONCLUSIONS AND RELEVANCE: A history of stroke was associated with adverse outcomes following surgery, in particular if time between stroke and surgery was less than 9 months. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke. The time dependency of risk may warrant attention in future guidelines.