Talip Emre Eroglu - Academia.edu (original) (raw)

Papers by Talip Emre Eroglu

Research paper thumbnail of Sodium-glucose cotransporter-2 inhibitors compared with glucagon-like-peptide-1 receptor agonists and out-of-hospital cardiac arrest in type 2 diabetes: a nationwide nested case-control study

European Heart Journal - Cardiovascular Pharmacotherapy, May 12, 2023

Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have benefi... more Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes. Methods Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference). Results The study population consisted of 3618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58–0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (P-value interaction: 0.461), pre-existing cardiac disease (P-value interaction: 0.762), heart failure (P-value interaction: 0.891), diabetes duration (P-value interaction: 0.101), and chronic kidney disease (P-value interaction: 0.894). Conclusion Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.

Research paper thumbnail of Beta-blockers and initial heart rhythm in out-of-hospital cardiac arrest: A multi-country case-control study

Research paper thumbnail of Opioid use is associated with increased out‐of‐hospital cardiac arrest risk among 40,000‐cases across two countries

British Journal of Clinical Pharmacology, Dec 23, 2021

Opioid use has substantially increased in the last decade and is associated with overdose mortali... more Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA-risk of opioids in the community. Methods: We conducted 2 population-based case-control studies separately in the Netherlands (2009-2018) and Denmark (2001-2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non-OHCA-controls according to age, sex and OHCA-date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Research paper thumbnail of Association of beta-blockers and first-registered heart rhythm in out-of-hospital cardiac arrest: real-world data from population-based cohorts across two European countries

Europace, Jun 28, 2020

Conflicting results have been reported regarding the effect of beta-blockers on first-registered ... more Conflicting results have been reported regarding the effect of beta-blockers on first-registered heart rhythm in out-of-hospital cardiac arrest (OHCA). We aimed to establish whether the use of beta-blockers influences firstregistered rhythm in OHCA.

Research paper thumbnail of Sulfonylurea antidiabetics are associated with lower risk of out‐of‐hospital cardiac arrest: Real‐world data from a population‐based study

British Journal of Clinical Pharmacology, Apr 25, 2021

Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fib... more Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fibrillation (VT/VF), often triggered by acute myocardial infarction (AMI). Sulfonylurea (SU) antidiabetics can block myocardial ATP-regulated K + channels (K ATP channels), activated during AMI, thereby modulating action potential duration (APD). We studied whether SU drugs impact on OHCA risk, and whether these effects are related to APD changes. Methods: We conducted a population-based case-control study in 219 VT/VFdocumented OHCA cases with diabetes and 697 non-OHCA controls with diabetes. We studied the association of SU drugs (alone or in combination with metformin) with OHCA risk compared to metformin monotherapy, and of individual SU drugs compared to glimepiride, using multivariable logistic regression analysis. We studied the effects of these drugs on APD during simulated ischaemia using patch-clamp studies in human induced pluripotent stem cell-derived cardiomyocytes. Results: Compared to metformin, use of SU drugs alone or in combination with metformin was associated with reduced OHCA risk (OR SUdrugs-alone 0.6 [95% CI 0.4-0.9], OR SUdrugs + metformin 0.6 [95% CI 0.4-0.9]). We found no differences in OHCA risk between SU drug users who suffered OHCA inside or outside the context of AMI. Reduction of OHCA risk compared to glimepiride was found with gliclazide (OR adj 0.5 [95% CI 0.3-0.9]), but not glibenclamide (OR adj 1.3 [95% CI 0.6-2.7]); for tolbutamide, the association with reduced OHCA risk just failed to reach statistical significance (OR adj 0.6 [95% CI 0.3-1.002]). Glibenclamide attenuated simulated ischaemia-induced APD shortening, while the other SU drugs had no effect. Conclusions: SU drugs were associated with reduced OHCA risk compared to metformin monotherapy, with gliclazide having a lower risk than glimepiride. The differential effects of SU drugs are not explained by differential effects on APD.

Research paper thumbnail of Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries

European Heart Journal - Cardiovascular Pharmacotherapy, Aug 10, 2019

Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general populatio... more Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology.

Research paper thumbnail of Risk of out-of-hospital cardiac arrest in patients with rheumatoid arthritis: a nationwide study

Open heart, Jun 1, 2022

Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac ele... more Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac electrophysiology by inhibiting cardiac potassium currents, leading to delay of cardiac repolarisation and QT-prolongation. This may result in lethal arrhythmias. We studied whether RA increases the rate of out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case-control in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were OHCA patients from presumed cardiac causes, and were matched with non-OHCA-controls based on age, sex and OHCA date. Cox-regression with time-dependent covariates was conducted to assess the association between RA and OHCA by calculating the HR and 95% CI. Stratified analyses were performed according to sex and presence of cardiovascular diseases. Also, the association between OHCA and use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with RA was studied. Results We included 35 195 OHCA cases of whom 512 (1.45%) had RA, and 351 950 non-OHCA controls of whom 3867 (1.10%) had RA. We found that RA was associated with increased rate of OHCA after adjustment for cardiovascular comorbidities and use of QT-prolonging drugs (HR: 1.22, 95% CI: 1.11 to 1.34). Stratification by sex revealed that increased OHCA rate occurred in women (HR: 1.32, 95% CI: 1.16 to 1.50) but not in men (HR: 1.12, 95% CI: 0.97 to 1.28; P value interaction=0.046). OHCA rate of RA was not further increased in patients with cardiovascular disease. Finally, in patients with RA, use of NSAIDs was not associated with OHCA. Conclusion In the general population, RA is associated with increased rate of OHCA in women but not in men.

Research paper thumbnail of Out‐of‐hospital cardiac arrest and differential risk of cardiac and non‐cardiac QT‐prolonging drugs in 37 000 cases

British Journal of Clinical Pharmacology, Aug 28, 2021

AimsDrugs that prolong the QT interval, either by design (cardiac QT‐prolonging drugs: anti‐arrhy... more AimsDrugs that prolong the QT interval, either by design (cardiac QT‐prolonging drugs: anti‐arrhythmics) or as off‐target effect (non‐cardiac QT‐prolonging drugs), may increase the risk of ventricular arrhythmias and out‐of‐hospital cardiac arrest (OHCA). Risk mitigation measures were instituted, in particular, surrounding prescription of cardiac QT‐prolonging drugs. We studied OHCA risk of both drug types in current clinical practice.MethodsUsing data from large population‐based OHCA registries in the Netherlands and Denmark, we conducted two independent case–control studies. OHCA cases with presumed cardiac causes were matched on age/sex/index date with up to five non‐OHCA controls. We calculated odds ratios (ORs) for the association of cardiac or non‐cardiac QT‐prolonging drugs with OHCA risk using conditional logistic regression analyses.ResultsWe identified 2503 OHCA cases and 10 543 non‐OHCA controls in the Netherlands, and 35 017 OHCA cases and 175 085 non‐OHCA controls in Denmark. Compared to no use of QT‐prolonging drugs, use of non‐cardiac QT‐prolonging drugs (Netherlands: cases: 3.0%, controls: 1.9%; Denmark: cases: 14.9%, controls: 7.5%) was associated with increased OHCA risk (Netherlands: OR 1.37 [95% CI: 1.03–1.81]; Denmark: OR 1.63 [95% CI: 1.57–1.70]). The association between cardiac QT‐prolonging drugs (Netherlands: cases: 4.0%, controls: 2.5%; Denmark: cases: 2.1%, controls: 0.9%) and OHCA was weaker (Netherlands: OR 1.17 [95% CI: 0.92–1.50]; Denmark: OR 1.21 [95% CI: 1.09–1.33]), although users of cardiac QT‐prolonging drugs had more medication use and comorbidities associated with OHCA risk than users of non‐cardiac QT‐prolonging drugs.ConclusionIn clinical practice, cardiac QT‐prolonging drugs confer lower OHCA risk than non‐cardiac QT‐prolonging drugs, although users of the former have higher a priori risk. This is likely due to risk mitigation measures surrounding prescription of cardiac QT‐prolonging drugs.

Research paper thumbnail of Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current

Frontiers in Cell and Developmental Biology, Jun 3, 2022

Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (... more Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms. Methods: The SCA risk association with CBZ was studied in general population cohorts using a case-control design (n = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1-100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique. Results: CBZ use was associated with increased risk of SCA compared with no use (adjusted odds ratio 1.90 [95% confidence interval: 1.12-3.24]). CBZ reduced the AP upstroke velocity of rabbit and human cardiomyocytes, without prominent changes in other AP parameters. The reduction occurred at ≥30 µM and was frequency-dependent with a more pronounced reduction at high stimulus frequencies. The cardiac sodium current (I Na) was reduced at ≥30 μM; this was accompanied by a hyperpolarizing shift in the voltage-dependency of inactivation. The recovery from inactivation was slower, which is consistent with the more pronounced AP upstroke velocity reduction at high stimulus frequencies. The main cardiac K + and Ca 2+ currents were unaffected, except reduction of L-type Ca 2+ current by 100 µM CBZ. Conclusion: CBZ use is associated with an increased risk of SCA in the general population. At concentrations of 30 µM and above, CBZ reduces AP upstroke velocity and I Na in cardiomyocytes. Since the concentration of 30 µM is well within the therapeutic range (20-40 µM), we conclude that CBZ increases the risk of SCA by a reduction of the cardiac I Na .

Research paper thumbnail of The effect of discontinuing beta-blockers after different treatment durations following acute myocardial infarction in optimally treated, stable patients without heart failure - a Danish, nationwide cohort study

European Heart Journal - Cardiovascular Pharmacotherapy, Jun 30, 2023

Aims We studied the effect of discontinuing beta-blockers following myocardial infarction in comp... more Aims We studied the effect of discontinuing beta-blockers following myocardial infarction in comparison to continuous beta-blocker use in optimally treated, stable patients without heart failure. Methods and results Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography. The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21 220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; −4.19% [−8.95%; 0.57%], −1.18% [−4.11%; 1.75%], and −0.37% [−4.56%; 3.82%]). Further, beta-blocker discontinuation within 2 years after myocardial infarction was associated with an increased risk of the composite outcome (landmark year 2; absolute risk [95% confidence interval] 19.87% [17.29%; 22.46%]) compared with continued beta-blocker use (landmark year 2; absolute risk [95% confidence interval] 17.10% [16.34%; 17.87%]), which yielded an absolute risk difference [95% confidence interval] at −2.8% [−5.4%; −0.1%], however, there was no risk difference associated with discontinuation hereafter. Conclusion Discontinuation of beta-blockers 1 year or later after a myocardial infarction without heart failure was not associated with increased serious adverse events.

Research paper thumbnail of Risk of out-of-hospital cardiac arrest in patients with sarcoidosis: a Danish nationwide nested case–control study

Open heart, Feb 1, 2023

Objective Sarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish ... more Objective Sarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish whether sarcoidosis is associated with out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. OHCA cases from presumed cardiac causes were matched 1:10 by sex and age on OHCA date with non-OHCA controls from the general population. The association between sarcoidosis and OHCA was assessed using Cox regression by calculating HR and 95% CIs. Models were adjusted for cardiovascular disease. Finally, stratified analyses were performed according to sex, heart failure and ischaemic heart disease. Results We identified 35 195 OHCA cases and 351 950 matched controls without OHCA (median age 72 years and 66.8% male). Patients with sarcoidosis had higher rate of OHCA compared with the general population after adjustments for common OHCA risk factors (HR 1.51, 95% CI 1.19 to 1.92). This increased OHCA rate occurred in women (HR 2.11, 95% CI 1.42 to 3.12) but not in men (HR 1.27, 95% CI 0.93 to 1.72; p value interaction=0.033), and was larger in patients with than without heart failure (HR heart failure : 2.59, 95% CI 1.42 to 4.73; HR no heart failure : 1.33, 95% CI 1.01 to 1.74; p value interaction: 0.007). The HR associated with sarcoidosis did not vary by the presence of ischaemic heart disease. Conclusion Patients with sarcoidosis have a higher OHCA rate than the general population. This increased OHCA rate occurred in women but not in men, and was larger in patients with than without heart failure. ⇒ This study raises awareness of the higher risks of OHCA in patients with sarcoidosis. ⇒ Early risk monitoring is needed to prevent OHCA in sarcoidosis patients. ⇒ The mechanism(s) of sudden death in chronic inflammatory diseases need to be clarified.

Research paper thumbnail of Acetylsalicylic acid use is associated with reduced risk of out-of-hospital cardiac arrest in the general population: Real-world data from a population-based study

PLOS ONE, Jun 8, 2022

Aim Activated blood platelet products facilitate myocardial intracellular Ca 2+ overload, thereby... more Aim Activated blood platelet products facilitate myocardial intracellular Ca 2+ overload, thereby provoking afterdepolarizations and increasing susceptibility of ischemic myocardium to ventricular fibrillation (VF). These effects are counteracted in vitro by acetylsalicylic acid (ASA), but no prior study investigated whether ASA is associated with decreased out-of-hospital cardiac arrest (OHCA) risk on a population level. Therefore, we studied whether ASA and other antiplatelet drugs (carbasalate calcium, clopidogrel) are associated with decreased risk of OHCA. Methods We conducted a population-based case-control study among individuals (772 OHCA-cases with documented VT/VF, 2444 non-OHCA-controls) who had used antiplatelet drugs in the year before index-date (OHCA-date), and studied the association between current antiplatelet drug use and OHCA-risk with multivariable logistic regression analysis. Results ASA use was associated with reduced OHCA-risk (adjusted odds ratio (OR adj) 0.6 [0.5-0.8]), and more so in women (OR adj 0.3 [0.2-0.6]) than in men (OR adj 0.7 [0.5-0.95], P interaction 0.021). Carbasalate calcium was associated with decreased OHCA-risk in women (OR adj 0.5 [0.3-0.9]), but not in men (OR adj 1.3 [0.96-1.7], P interaction 0.005). Clopidogrel was not associated with reduction in OHCA-risk. Risk reduction associated with ASA in

Research paper thumbnail of Multiple categories of non-cardiac QT-prolonging drugs are associated with increased risk of out-of-hospital cardiac arrest: real-world data from a population-based study

Europace, Oct 18, 2021

Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] i... more Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] increase the risk of out-of-hospital cardiac arrest (OHCA). Such drugs are categorized in multiple clinically widely used CredibleMeds.org lists. Category 1 ('known risk of Torsade de Pointes') and category 2 ('possible risk of Torsade de Pointes') are of particular clinical relevance. However, a category-stratified analysis of OHCA-risk is presently unavailable.

Research paper thumbnail of Long-term stress conditions and out-of-hospital cardiac arrest risk: a nested case–control study

Open heart, May 1, 2023

Objective Patients with stress-related disorders and anxiety are at increased risk of developing ... more Objective Patients with stress-related disorders and anxiety are at increased risk of developing cardiovascular disease. However, the risk of out-of-hospital cardiac arrest (OHCA) is scarcely investigated. We aimed to establish whether long-term stress (post-traumatic stress disorder, adjustment disorder) or anxiety is associated with OHCA in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. Cases were OHCA patients with presumed cardiac causes. Each case was matched by age, sex and date of OHCA with 10 non-OHCA controls from the general population. HRs for OHCA were derived from Cox models after controlling for common OHCA risk factors. Stratified analyses were performed according to sex, age and pre-existing cardiovascular disease. Results We included 35 195 OHCAs and 351 950 matched controls (median age 72 years; 66.8% male). Long-term stress conditions were diagnosed in 324 (0.92%) OHCA cases and 1577 (0.45%) non-OHCA controls, and were associated with higher rate of OHCA (HR 1.44, 95% CI 1.27 to 1.64). Anxiety was diagnosed in 299 (0.85%) OHCA cases and 1298 (0.37%) controls, and was associated with increased rate of OHCA (HR 1.56, 95% CI1.37 to 1.79). We found no interaction with sex, age or history of cardiovascular diseases. Conclusion Patients with stress-related disorders or anxiety have an increased rate of OHCA. This association applies equally to men and women and is independent from the presence of cardiovascular disease. Awareness of the higher risks of OHCA in patients with stress-related disorders and anxiety is important when treating these patients. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ This study raises awareness of the higher risks of OHCA and early risk monitoring to prevent OHCA in patients with stress-related disorders and anxiety.

Research paper thumbnail of Risk of out‐of‐hospital cardiac arrest in antidepressant drug users

British Journal of Clinical Pharmacology, 2022

Conflicting results have been reported regarding the association between antidepressant use and o... more Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA.MethodsWe conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately.ResultsDuring the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (&gt...

Research paper thumbnail of High-dose nifedipine use is associated with increased risk of out-of-hospital cardiac arrest : Multi-country case-control study

Europace, Mar 1, 2019

Introduction Drugs that influence cardiac electrophysiological properties by impacting on cardiac... more Introduction Drugs that influence cardiac electrophysiological properties by impacting on cardiac ion channels have been associated with an increased risk of out-of-hospital cardiac arrest (OHCA) due to ventricular tachycardia/ventricular fibrillation (VT/VF). It is unknown whether dihydropyridines, which block L-type calcium channels, are associated with increased risk of OHCA. Purpose To determine whether the widely used dihydropyridines nifedipine and amlodipine are associated with increased OHCA risk. Methods We performed a multi-country case-control study using data from the Dutch Amsterdam Resuscitation Studies registry (ARREST, 2005-2011) and the Danish Cardiac Arrest Registry (DANCAR, 2001-2014). Both registries are community-based registries of all-cause OHCA and are part of the ESCAPE-NET consortium that studies OHCA across Europe. Cases were cardiac-caused OHCA patients with VT/VF, and controls (up to 5 per case) were non-OHCA individuals matched on age, sex and index (OHCA) date. Dutch controls were sampled from PHARMO Database Network and Danish controls from the general (Danish) population. We compared current use on the index date of the study drugs (prescription within 90 days before OHCA) to no use of any dihydropyridine, using conditional logistic regression analysis with adjustment for well-known risk factors of OHCA. Results We studied 2,503 cases and 10,543 controls in ARREST (median age 67.0 years, interquartile range [IQR] 57.0-77.0 years; 77.4% male), and 22,208 cases and 111,040 controls in DANCAR (median age 74 years, IQR 64-82 years; 62.9% male). In both registries, current use of high-dose nifedipine (≥60mg/day), but not low-dose nifedipine (

Research paper thumbnail of Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale

Drug Design, Development and Therapy, 2017

Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Alm... more Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM.

Research paper thumbnail of Use of methylphenidate is associated with increased risk of out-of-hospital cardiac arrest in the general population: a nationwide nested case-control study

European Heart Journal - Cardiovascular Pharmacotherapy

Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity d... more Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population. Methods and results Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate. The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62–81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of...

Research paper thumbnail of Use of sodium-glucose cotransporter-2 inhibitors and the risk for sudden cardiac arrest and for all-cause death in patients with type 2 diabetes mellitus

European Heart Journal - Cardiovascular Pharmacotherapy

Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have d... more Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. Methods Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥5 years), and the presence of cardiovascular disease. Results A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of...

Research paper thumbnail of Non-cardiac depolarization-blocking drugs are associated with increased risk of out-of-hospital cardiac arrest in the community

Aim Depolarization-blocking drugs (DB-drugs) used for cardiac disease increase the risk of cardia... more Aim Depolarization-blocking drugs (DB-drugs) used for cardiac disease increase the risk of cardiac arrhythmia (ventricular tachycardia/ventricular fibrillation[VT/VF]) and out-of-hospital cardiac arrest (OHCA) in specific patient groups. However, it is unknown whether drugs for non-cardiac disease that block cardiac depolarization as off-target effect increase the risk of OHCA on a population level. Therefore, we aimed to investigate OHCA-risk of non-cardiac DB-drugs in the community. Methods We conducted a population-based case-control study. We included OHCA-cases from an Emergency Medical Services attended OHCA-registry in the Netherlands (ARREST:2009-2018), and age/sex/OHCA-date matched non-OHCA-controls. We calculated adjusted odds ratios (ORadj) of use of non-cardiac DB-drugs for OHCA, using conditional logistic regression. Stratified analyses were performed according to first-registered rhythm (VT/VF or non-VT/VF), sex and age (≤50, 50-70, or ≥70 years). Results We included 5...

Research paper thumbnail of Sodium-glucose cotransporter-2 inhibitors compared with glucagon-like-peptide-1 receptor agonists and out-of-hospital cardiac arrest in type 2 diabetes: a nationwide nested case-control study

European Heart Journal - Cardiovascular Pharmacotherapy, May 12, 2023

Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have benefi... more Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes. Methods Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference). Results The study population consisted of 3618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58–0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (P-value interaction: 0.461), pre-existing cardiac disease (P-value interaction: 0.762), heart failure (P-value interaction: 0.891), diabetes duration (P-value interaction: 0.101), and chronic kidney disease (P-value interaction: 0.894). Conclusion Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.

Research paper thumbnail of Beta-blockers and initial heart rhythm in out-of-hospital cardiac arrest: A multi-country case-control study

Research paper thumbnail of Opioid use is associated with increased out‐of‐hospital cardiac arrest risk among 40,000‐cases across two countries

British Journal of Clinical Pharmacology, Dec 23, 2021

Opioid use has substantially increased in the last decade and is associated with overdose mortali... more Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA-risk of opioids in the community. Methods: We conducted 2 population-based case-control studies separately in the Netherlands (2009-2018) and Denmark (2001-2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non-OHCA-controls according to age, sex and OHCA-date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Research paper thumbnail of Association of beta-blockers and first-registered heart rhythm in out-of-hospital cardiac arrest: real-world data from population-based cohorts across two European countries

Europace, Jun 28, 2020

Conflicting results have been reported regarding the effect of beta-blockers on first-registered ... more Conflicting results have been reported regarding the effect of beta-blockers on first-registered heart rhythm in out-of-hospital cardiac arrest (OHCA). We aimed to establish whether the use of beta-blockers influences firstregistered rhythm in OHCA.

Research paper thumbnail of Sulfonylurea antidiabetics are associated with lower risk of out‐of‐hospital cardiac arrest: Real‐world data from a population‐based study

British Journal of Clinical Pharmacology, Apr 25, 2021

Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fib... more Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fibrillation (VT/VF), often triggered by acute myocardial infarction (AMI). Sulfonylurea (SU) antidiabetics can block myocardial ATP-regulated K + channels (K ATP channels), activated during AMI, thereby modulating action potential duration (APD). We studied whether SU drugs impact on OHCA risk, and whether these effects are related to APD changes. Methods: We conducted a population-based case-control study in 219 VT/VFdocumented OHCA cases with diabetes and 697 non-OHCA controls with diabetes. We studied the association of SU drugs (alone or in combination with metformin) with OHCA risk compared to metformin monotherapy, and of individual SU drugs compared to glimepiride, using multivariable logistic regression analysis. We studied the effects of these drugs on APD during simulated ischaemia using patch-clamp studies in human induced pluripotent stem cell-derived cardiomyocytes. Results: Compared to metformin, use of SU drugs alone or in combination with metformin was associated with reduced OHCA risk (OR SUdrugs-alone 0.6 [95% CI 0.4-0.9], OR SUdrugs + metformin 0.6 [95% CI 0.4-0.9]). We found no differences in OHCA risk between SU drug users who suffered OHCA inside or outside the context of AMI. Reduction of OHCA risk compared to glimepiride was found with gliclazide (OR adj 0.5 [95% CI 0.3-0.9]), but not glibenclamide (OR adj 1.3 [95% CI 0.6-2.7]); for tolbutamide, the association with reduced OHCA risk just failed to reach statistical significance (OR adj 0.6 [95% CI 0.3-1.002]). Glibenclamide attenuated simulated ischaemia-induced APD shortening, while the other SU drugs had no effect. Conclusions: SU drugs were associated with reduced OHCA risk compared to metformin monotherapy, with gliclazide having a lower risk than glimepiride. The differential effects of SU drugs are not explained by differential effects on APD.

Research paper thumbnail of Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries

European Heart Journal - Cardiovascular Pharmacotherapy, Aug 10, 2019

Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general populatio... more Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology.

Research paper thumbnail of Risk of out-of-hospital cardiac arrest in patients with rheumatoid arthritis: a nationwide study

Open heart, Jun 1, 2022

Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac ele... more Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac electrophysiology by inhibiting cardiac potassium currents, leading to delay of cardiac repolarisation and QT-prolongation. This may result in lethal arrhythmias. We studied whether RA increases the rate of out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case-control in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were OHCA patients from presumed cardiac causes, and were matched with non-OHCA-controls based on age, sex and OHCA date. Cox-regression with time-dependent covariates was conducted to assess the association between RA and OHCA by calculating the HR and 95% CI. Stratified analyses were performed according to sex and presence of cardiovascular diseases. Also, the association between OHCA and use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with RA was studied. Results We included 35 195 OHCA cases of whom 512 (1.45%) had RA, and 351 950 non-OHCA controls of whom 3867 (1.10%) had RA. We found that RA was associated with increased rate of OHCA after adjustment for cardiovascular comorbidities and use of QT-prolonging drugs (HR: 1.22, 95% CI: 1.11 to 1.34). Stratification by sex revealed that increased OHCA rate occurred in women (HR: 1.32, 95% CI: 1.16 to 1.50) but not in men (HR: 1.12, 95% CI: 0.97 to 1.28; P value interaction=0.046). OHCA rate of RA was not further increased in patients with cardiovascular disease. Finally, in patients with RA, use of NSAIDs was not associated with OHCA. Conclusion In the general population, RA is associated with increased rate of OHCA in women but not in men.

Research paper thumbnail of Out‐of‐hospital cardiac arrest and differential risk of cardiac and non‐cardiac QT‐prolonging drugs in 37 000 cases

British Journal of Clinical Pharmacology, Aug 28, 2021

AimsDrugs that prolong the QT interval, either by design (cardiac QT‐prolonging drugs: anti‐arrhy... more AimsDrugs that prolong the QT interval, either by design (cardiac QT‐prolonging drugs: anti‐arrhythmics) or as off‐target effect (non‐cardiac QT‐prolonging drugs), may increase the risk of ventricular arrhythmias and out‐of‐hospital cardiac arrest (OHCA). Risk mitigation measures were instituted, in particular, surrounding prescription of cardiac QT‐prolonging drugs. We studied OHCA risk of both drug types in current clinical practice.MethodsUsing data from large population‐based OHCA registries in the Netherlands and Denmark, we conducted two independent case–control studies. OHCA cases with presumed cardiac causes were matched on age/sex/index date with up to five non‐OHCA controls. We calculated odds ratios (ORs) for the association of cardiac or non‐cardiac QT‐prolonging drugs with OHCA risk using conditional logistic regression analyses.ResultsWe identified 2503 OHCA cases and 10 543 non‐OHCA controls in the Netherlands, and 35 017 OHCA cases and 175 085 non‐OHCA controls in Denmark. Compared to no use of QT‐prolonging drugs, use of non‐cardiac QT‐prolonging drugs (Netherlands: cases: 3.0%, controls: 1.9%; Denmark: cases: 14.9%, controls: 7.5%) was associated with increased OHCA risk (Netherlands: OR 1.37 [95% CI: 1.03–1.81]; Denmark: OR 1.63 [95% CI: 1.57–1.70]). The association between cardiac QT‐prolonging drugs (Netherlands: cases: 4.0%, controls: 2.5%; Denmark: cases: 2.1%, controls: 0.9%) and OHCA was weaker (Netherlands: OR 1.17 [95% CI: 0.92–1.50]; Denmark: OR 1.21 [95% CI: 1.09–1.33]), although users of cardiac QT‐prolonging drugs had more medication use and comorbidities associated with OHCA risk than users of non‐cardiac QT‐prolonging drugs.ConclusionIn clinical practice, cardiac QT‐prolonging drugs confer lower OHCA risk than non‐cardiac QT‐prolonging drugs, although users of the former have higher a priori risk. This is likely due to risk mitigation measures surrounding prescription of cardiac QT‐prolonging drugs.

Research paper thumbnail of Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current

Frontiers in Cell and Developmental Biology, Jun 3, 2022

Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (... more Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms. Methods: The SCA risk association with CBZ was studied in general population cohorts using a case-control design (n = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1-100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique. Results: CBZ use was associated with increased risk of SCA compared with no use (adjusted odds ratio 1.90 [95% confidence interval: 1.12-3.24]). CBZ reduced the AP upstroke velocity of rabbit and human cardiomyocytes, without prominent changes in other AP parameters. The reduction occurred at ≥30 µM and was frequency-dependent with a more pronounced reduction at high stimulus frequencies. The cardiac sodium current (I Na) was reduced at ≥30 μM; this was accompanied by a hyperpolarizing shift in the voltage-dependency of inactivation. The recovery from inactivation was slower, which is consistent with the more pronounced AP upstroke velocity reduction at high stimulus frequencies. The main cardiac K + and Ca 2+ currents were unaffected, except reduction of L-type Ca 2+ current by 100 µM CBZ. Conclusion: CBZ use is associated with an increased risk of SCA in the general population. At concentrations of 30 µM and above, CBZ reduces AP upstroke velocity and I Na in cardiomyocytes. Since the concentration of 30 µM is well within the therapeutic range (20-40 µM), we conclude that CBZ increases the risk of SCA by a reduction of the cardiac I Na .

Research paper thumbnail of The effect of discontinuing beta-blockers after different treatment durations following acute myocardial infarction in optimally treated, stable patients without heart failure - a Danish, nationwide cohort study

European Heart Journal - Cardiovascular Pharmacotherapy, Jun 30, 2023

Aims We studied the effect of discontinuing beta-blockers following myocardial infarction in comp... more Aims We studied the effect of discontinuing beta-blockers following myocardial infarction in comparison to continuous beta-blocker use in optimally treated, stable patients without heart failure. Methods and results Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography. The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21 220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; −4.19% [−8.95%; 0.57%], −1.18% [−4.11%; 1.75%], and −0.37% [−4.56%; 3.82%]). Further, beta-blocker discontinuation within 2 years after myocardial infarction was associated with an increased risk of the composite outcome (landmark year 2; absolute risk [95% confidence interval] 19.87% [17.29%; 22.46%]) compared with continued beta-blocker use (landmark year 2; absolute risk [95% confidence interval] 17.10% [16.34%; 17.87%]), which yielded an absolute risk difference [95% confidence interval] at −2.8% [−5.4%; −0.1%], however, there was no risk difference associated with discontinuation hereafter. Conclusion Discontinuation of beta-blockers 1 year or later after a myocardial infarction without heart failure was not associated with increased serious adverse events.

Research paper thumbnail of Risk of out-of-hospital cardiac arrest in patients with sarcoidosis: a Danish nationwide nested case–control study

Open heart, Feb 1, 2023

Objective Sarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish ... more Objective Sarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish whether sarcoidosis is associated with out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. OHCA cases from presumed cardiac causes were matched 1:10 by sex and age on OHCA date with non-OHCA controls from the general population. The association between sarcoidosis and OHCA was assessed using Cox regression by calculating HR and 95% CIs. Models were adjusted for cardiovascular disease. Finally, stratified analyses were performed according to sex, heart failure and ischaemic heart disease. Results We identified 35 195 OHCA cases and 351 950 matched controls without OHCA (median age 72 years and 66.8% male). Patients with sarcoidosis had higher rate of OHCA compared with the general population after adjustments for common OHCA risk factors (HR 1.51, 95% CI 1.19 to 1.92). This increased OHCA rate occurred in women (HR 2.11, 95% CI 1.42 to 3.12) but not in men (HR 1.27, 95% CI 0.93 to 1.72; p value interaction=0.033), and was larger in patients with than without heart failure (HR heart failure : 2.59, 95% CI 1.42 to 4.73; HR no heart failure : 1.33, 95% CI 1.01 to 1.74; p value interaction: 0.007). The HR associated with sarcoidosis did not vary by the presence of ischaemic heart disease. Conclusion Patients with sarcoidosis have a higher OHCA rate than the general population. This increased OHCA rate occurred in women but not in men, and was larger in patients with than without heart failure. ⇒ This study raises awareness of the higher risks of OHCA in patients with sarcoidosis. ⇒ Early risk monitoring is needed to prevent OHCA in sarcoidosis patients. ⇒ The mechanism(s) of sudden death in chronic inflammatory diseases need to be clarified.

Research paper thumbnail of Acetylsalicylic acid use is associated with reduced risk of out-of-hospital cardiac arrest in the general population: Real-world data from a population-based study

PLOS ONE, Jun 8, 2022

Aim Activated blood platelet products facilitate myocardial intracellular Ca 2+ overload, thereby... more Aim Activated blood platelet products facilitate myocardial intracellular Ca 2+ overload, thereby provoking afterdepolarizations and increasing susceptibility of ischemic myocardium to ventricular fibrillation (VF). These effects are counteracted in vitro by acetylsalicylic acid (ASA), but no prior study investigated whether ASA is associated with decreased out-of-hospital cardiac arrest (OHCA) risk on a population level. Therefore, we studied whether ASA and other antiplatelet drugs (carbasalate calcium, clopidogrel) are associated with decreased risk of OHCA. Methods We conducted a population-based case-control study among individuals (772 OHCA-cases with documented VT/VF, 2444 non-OHCA-controls) who had used antiplatelet drugs in the year before index-date (OHCA-date), and studied the association between current antiplatelet drug use and OHCA-risk with multivariable logistic regression analysis. Results ASA use was associated with reduced OHCA-risk (adjusted odds ratio (OR adj) 0.6 [0.5-0.8]), and more so in women (OR adj 0.3 [0.2-0.6]) than in men (OR adj 0.7 [0.5-0.95], P interaction 0.021). Carbasalate calcium was associated with decreased OHCA-risk in women (OR adj 0.5 [0.3-0.9]), but not in men (OR adj 1.3 [0.96-1.7], P interaction 0.005). Clopidogrel was not associated with reduction in OHCA-risk. Risk reduction associated with ASA in

Research paper thumbnail of Multiple categories of non-cardiac QT-prolonging drugs are associated with increased risk of out-of-hospital cardiac arrest: real-world data from a population-based study

Europace, Oct 18, 2021

Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] i... more Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] increase the risk of out-of-hospital cardiac arrest (OHCA). Such drugs are categorized in multiple clinically widely used CredibleMeds.org lists. Category 1 ('known risk of Torsade de Pointes') and category 2 ('possible risk of Torsade de Pointes') are of particular clinical relevance. However, a category-stratified analysis of OHCA-risk is presently unavailable.

Research paper thumbnail of Long-term stress conditions and out-of-hospital cardiac arrest risk: a nested case–control study

Open heart, May 1, 2023

Objective Patients with stress-related disorders and anxiety are at increased risk of developing ... more Objective Patients with stress-related disorders and anxiety are at increased risk of developing cardiovascular disease. However, the risk of out-of-hospital cardiac arrest (OHCA) is scarcely investigated. We aimed to establish whether long-term stress (post-traumatic stress disorder, adjustment disorder) or anxiety is associated with OHCA in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. Cases were OHCA patients with presumed cardiac causes. Each case was matched by age, sex and date of OHCA with 10 non-OHCA controls from the general population. HRs for OHCA were derived from Cox models after controlling for common OHCA risk factors. Stratified analyses were performed according to sex, age and pre-existing cardiovascular disease. Results We included 35 195 OHCAs and 351 950 matched controls (median age 72 years; 66.8% male). Long-term stress conditions were diagnosed in 324 (0.92%) OHCA cases and 1577 (0.45%) non-OHCA controls, and were associated with higher rate of OHCA (HR 1.44, 95% CI 1.27 to 1.64). Anxiety was diagnosed in 299 (0.85%) OHCA cases and 1298 (0.37%) controls, and was associated with increased rate of OHCA (HR 1.56, 95% CI1.37 to 1.79). We found no interaction with sex, age or history of cardiovascular diseases. Conclusion Patients with stress-related disorders or anxiety have an increased rate of OHCA. This association applies equally to men and women and is independent from the presence of cardiovascular disease. Awareness of the higher risks of OHCA in patients with stress-related disorders and anxiety is important when treating these patients. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ This study raises awareness of the higher risks of OHCA and early risk monitoring to prevent OHCA in patients with stress-related disorders and anxiety.

Research paper thumbnail of Risk of out‐of‐hospital cardiac arrest in antidepressant drug users

British Journal of Clinical Pharmacology, 2022

Conflicting results have been reported regarding the association between antidepressant use and o... more Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA.MethodsWe conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately.ResultsDuring the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (&gt...

Research paper thumbnail of High-dose nifedipine use is associated with increased risk of out-of-hospital cardiac arrest : Multi-country case-control study

Europace, Mar 1, 2019

Introduction Drugs that influence cardiac electrophysiological properties by impacting on cardiac... more Introduction Drugs that influence cardiac electrophysiological properties by impacting on cardiac ion channels have been associated with an increased risk of out-of-hospital cardiac arrest (OHCA) due to ventricular tachycardia/ventricular fibrillation (VT/VF). It is unknown whether dihydropyridines, which block L-type calcium channels, are associated with increased risk of OHCA. Purpose To determine whether the widely used dihydropyridines nifedipine and amlodipine are associated with increased OHCA risk. Methods We performed a multi-country case-control study using data from the Dutch Amsterdam Resuscitation Studies registry (ARREST, 2005-2011) and the Danish Cardiac Arrest Registry (DANCAR, 2001-2014). Both registries are community-based registries of all-cause OHCA and are part of the ESCAPE-NET consortium that studies OHCA across Europe. Cases were cardiac-caused OHCA patients with VT/VF, and controls (up to 5 per case) were non-OHCA individuals matched on age, sex and index (OHCA) date. Dutch controls were sampled from PHARMO Database Network and Danish controls from the general (Danish) population. We compared current use on the index date of the study drugs (prescription within 90 days before OHCA) to no use of any dihydropyridine, using conditional logistic regression analysis with adjustment for well-known risk factors of OHCA. Results We studied 2,503 cases and 10,543 controls in ARREST (median age 67.0 years, interquartile range [IQR] 57.0-77.0 years; 77.4% male), and 22,208 cases and 111,040 controls in DANCAR (median age 74 years, IQR 64-82 years; 62.9% male). In both registries, current use of high-dose nifedipine (≥60mg/day), but not low-dose nifedipine (

Research paper thumbnail of Sodium-glucose cotransporter 2 inhibitors combined with dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes: a review of current clinical evidence and rationale

Drug Design, Development and Therapy, 2017

Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Alm... more Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial cardiometabolic disorder. Almost half of adults with diabetes fail to achieve their recommended glucose control target. This has prompted some clinicians to advocate the use of more intensive initial therapy, including the use of combination therapy to target multiple physiologic defects in diabetes with the goal of achieving and sustaining glucose control. Numerous options exist for combining the various classes of glucose-lowering agents in the treatment of T2DM. This report reviews the mechanism, rationale, and evidence from clinical trials for combining two of the newer drug classes, namely, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors, and considers the possible role of such dual therapy in the management of T2DM.

Research paper thumbnail of Use of methylphenidate is associated with increased risk of out-of-hospital cardiac arrest in the general population: a nationwide nested case-control study

European Heart Journal - Cardiovascular Pharmacotherapy

Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity d... more Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population. Methods and results Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate. The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62–81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of...

Research paper thumbnail of Use of sodium-glucose cotransporter-2 inhibitors and the risk for sudden cardiac arrest and for all-cause death in patients with type 2 diabetes mellitus

European Heart Journal - Cardiovascular Pharmacotherapy

Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have d... more Aims Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. Methods Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥5 years), and the presence of cardiovascular disease. Results A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of...

Research paper thumbnail of Non-cardiac depolarization-blocking drugs are associated with increased risk of out-of-hospital cardiac arrest in the community

Aim Depolarization-blocking drugs (DB-drugs) used for cardiac disease increase the risk of cardia... more Aim Depolarization-blocking drugs (DB-drugs) used for cardiac disease increase the risk of cardiac arrhythmia (ventricular tachycardia/ventricular fibrillation[VT/VF]) and out-of-hospital cardiac arrest (OHCA) in specific patient groups. However, it is unknown whether drugs for non-cardiac disease that block cardiac depolarization as off-target effect increase the risk of OHCA on a population level. Therefore, we aimed to investigate OHCA-risk of non-cardiac DB-drugs in the community. Methods We conducted a population-based case-control study. We included OHCA-cases from an Emergency Medical Services attended OHCA-registry in the Netherlands (ARREST:2009-2018), and age/sex/OHCA-date matched non-OHCA-controls. We calculated adjusted odds ratios (ORadj) of use of non-cardiac DB-drugs for OHCA, using conditional logistic regression. Stratified analyses were performed according to first-registered rhythm (VT/VF or non-VT/VF), sex and age (≤50, 50-70, or ≥70 years). Results We included 5...