This study investigated the impact of chronic kidney disease on all-causes and cardiovascular mortality in patients with atrial fibrillation treated with digoxin.

Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients.

Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes.

There is no consensus on the preferred method for defining the non-inferiority margin in non-inferiority trials, and previous studies showed that the rationale for its choice is often not reported. This study investigated how the non-inferiority margin is defined in the published literature, and whether its reporting has changed over time.

Psychiatric patients have excess mortality compared to the general population, and several potential mechanisms may explain this increased risk. This study examined the relationship between serum potassium levels and risk of all-cause mortality in patients co-treated with antipsychotic and diuretic drugs. Using a register-based cohort design, we identified patients between 1995 and 2012 who received a combination of an antipsychotic and a diuretic drug and who further had a serum potassium measurement within 90 days. During the study period, we included the most frequently redeemed antipsychotic drugs with regard to the propensity of corrected QT (QTc) prolongation: zuclopenthixol (unknown/mild), flupentixol (mild), levomepromazine (moderate), and quetiapine (moderate/severe). Patients co-treated with antidepressant drugs, lithium, and other antipsychotic drugs were excluded. Outcome was 6-month all-cause mortality, estimated with multivariable Cox regression. Patients were divided into seven serum potassium levels using restricted cubic splines (reference: 4.2-4.4 mmol/L) and stratified according to the included antipsychotic drugs. Of 6729 patients (median age: 74.0 years; women: 65.3%), 10.8% had hypokalemia and 4.9% had hyperkalemia. Hyperkalemia (>5.0 mmol/L, HR 2.82 [95% CI 2.25-3.54]), hypokalemia (<3.5 mmol/L, HR 1.59 [95% CI 1.29-1.95]), and high normal potassium levels (4.5-4.7 mmol/L, HR 1.44 [95% CI 1.19-1.75]; 4.8-5.0 mmol/L, HR 1.60 [95% CI 1.26-2.04]) were associated with an increased risk of 6-month all-cause mortality. This risk was independent of antipsychotic drugs (interaction: P = 0.06). Our findings imply that excess mortality in patients co-treated with antipsychotic and diuretic drugs is related to serum potassium levels and independent of antipsychotic drugs.

The risk of peripheral artery disease (PAD) in patients with diabetes mellitus (DM) and coronary artery disease (CAD) is an important and inadequately addressed issue. Our aim is to examine the impact of DM on risk of PAD in patients with different degrees of CAD characterized by coronary angiography (CAG).

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: -24.6 PRU [-44.7, -4.6], p = 0.016; A208G GG: -24.6 PRU [-44.3, -4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

To evaluate the association between common biomarkers, death and intensive care unit (ICU) admission in patients with COVID-19.

Background Guideline-based cardioprotective medical therapy is intended to reduce the burden of adverse cardiovascular and limb outcomes in patients with peripheral artery disease (PAD). However, contemporary data describing trends in use of medication remains limited. The present study, therefore, aims to investigate changes in use of cardioprotective medication in PAD. Methods and Results By using Danish national healthcare registries, we identified all patients with first-time diagnosis of PAD (1997-2016) and classified them into two groups: (1) PAD+ that includes all patients with PAD with a history of cardiovascular disease, ie, myocardial infarction, atrial fibrillation, and stroke (n=162 627); and (2) PAD (n=87 935) that comprise patients without a history of cardiovascular disease. We determined the use of medication in the first 12 months after the incident diagnosis of PAD and estimated age standardized 1-year mortality rates. Our results showed increase in use of cardioprotective medication throughout the study period in both groups. However, PAD+ had a higher use of medication (acetylsalicylic acid, 3.5%-48.4%; Clopidogrel, 0%-17.6%; vitamin K antagonists, 0.9%-7.8%; new oral anticoagulants, 0.0%-10.1%; Statins, 1.9%-58.1%; angiotensin-converting enzyme inhibitors, 1.2%-20.6%), compared with PAD (acetylsalicylic acid, 2.9%-54.4%; Clopidogrel, 0%-11.9%; vitamin K antagonists, 0.9%-2.4%; new oral anticoagulants, 0.0%-3.4%; Statins, 1.5%-56.9%; angiotensin-converting enzyme, 0.9%-17.2%), respectively. Furthermore, 1-year mortality rates in PAD declined with increased use of medications during study. Conclusions In this nationwide study, use of cardioprotective medication increased considerably with time, but compared to patients with other atherosclerotic diseases, there remains an underuse of guideline-based medical therapy in patients with PAD.

Background Citizen responder programs are implemented worldwide to dispatch volunteer citizens to participate in out-of-hospital cardiac arrest resuscitation. However, the risk of injuries in relation to activation is largely unknown. We aimed to assess the risk of physical injury for dispatched citizen responders. Methods and Results Since September 2017, citizen responders have been activated through a smartphone application when located close to a suspected cardiac arrest in the Capital Region of Denmark. A survey was sent to all activated citizen responders, including a specific question about risk of acquiring an injury during activation. We included all surveys from September 1, 2017, to May 15, 2020. From May 15, 2019, to May 15, 2020, we followed up on all survey nonresponders by phone call, e-mail, or text messages to examine if nonresponders were at higher risk of severe or fatal injuries. In 1665 suspected out-of-hospital cardiac arrests, 9574 citizen responders were dispatched and 76.6% (7334) answered the question regarding physical injury. No injury was reported by 99.3% (7281) of the responders. Being at risk of physical injury was reported by 0.3% (24), whereas 0.4% (26) reported an injury (25 minor injuries and 1 severe injury [ankle fracture]). When following up on nonresponders (2472), we reached 99.1% (2449). No one reported acquired injuries, and only 1 reported being at risk of injury. Conclusions We found low risk of physical injury reported by volunteer citizen responders dispatched to out-of-hospital cardiac arrest. Risk of injury should be considered and monitored as a safety measure in citizen responder programs.

Background Little is known about how COVID-19 influenced engagement of citizen responders dispatched to out-of-hospital cardiac arrest (OHCA) by a smartphone application. The objective was to describe and analyze the Danish Citizen Responder Program and bystander interventions (both citizen responders and nondispatched bystanders) during the first COVID-19 lockdown in 2020. Methods and Results All OHCAs from January 1, 2020, to June 30, 2020, with citizen responder activation in 2 regions of Denmark were included. We compared citizen responder engagement for OHCA in the nonlockdown period (January 1, 2020, to March 10, 2020, and April 21, 2020, to June 30, 2020) with the lockdown period (March 11, 2020, to April 20, 2020). Data are displayed in the order lockdown versus nonlockdown period. Bystander cardiopulmonary resuscitation rates did not differ in the 2 periods (99% versus 92%; P=0.07). Bystander defibrillation (9% versus 14%; P=0.4) or return-of-spontaneous circulation (23% versus 23%; P=1.0) also did not differ. A similar amount of citizen responders accepted alarms during the lockdown (6 per alarm; interquartile range, 6) compared with the nonlockdown period (5 per alarm; interquartile range, 5) (P=0.05). More citizen responders reported performing chest-compression-only cardiopulmonary resuscitation during lockdown compared with nonlockdown (79% versus 59%; P=0.0029), whereas fewer performed standardized cardiopulmonary resuscitation, including ventilations (19% versus 38%; P=0.0061). Finally, during lockdown, more citizen responders reported being not psychologically affected by attending an OHCA compared with nonlockdown period (68% versus 56%; P<0.0001). Likewise, fewer reported being mildly affected during lockdown (26%) compared with nonlockdown (35%) (P=0.003). Conclusions The COVID-19 lockdown in Denmark was not associated with decreased bystander-initiated resuscitation in OHCAs attended by citizen responders.

Decentralised clinical trial activities-such as participant recruitment via social media, data collection through wearables and direct-to-participant investigational medicinal product (IMP) supply-have the potential to change the way clinical trials (CTs) are conducted and with that to reduce the participation burden and improve generalisability. In this study, we investigated the decentralised and on-site conduct of trial activities as reported in CT protocols with a trial start date in 2019 or 2020.

In Denmark, multiple national initiatives have been associated with improved bystander defibrillation and survival following out-of-hospital cardiac arrest (OHCA) in public places. However, OHCAs in residential neighbourhoods continue to have poor outcomes. The Cardiac Arrest in Residential Areas with MoBile volunteer responder Activation trial aims to improve bystander defibrillation and survival following OHCA in residential neighbourhoods with a high risk of OHCA. The intervention consists of: (1) strategically deployed automated external defibrillators accessible at all hours, (2) cardiopulmonary resuscitation (CPR) training of residents and (3) recruitment of residents for a volunteer responder programme.

Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit.

ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²⁺ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO₂.

Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension.

Renal function is an important predictor of mortality in patients with myocardial infarction (MI), but changes in the impact over time have not been well described.We examined the importance of renal function by estimated GFR (eGFR) and se-creatinine as an independent long-term prognostic factor.

To assess the association of hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of type 2 diabetic patients at increased cardiovascular risk.

Non-inferiority (NI) trials in drug research are used to demonstrate that a new treatment is not less effective than an active comparator. Since phase IV trials typically aim at informing a clinical decision, the value of a phase IV non-inferiority trial hinges also on its clinical relevance. In such trials, clinical relevance would refer to the added benefit claims of a specific drug, apart from efficacy, relative to its comparator drug in the trial.

Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms.