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

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.

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.

Advanced therapy medicinal products (ATMPs) hold promise as treatments for previously untreatable and high-burden diseases. Expectations are high and active company pipelines are observed, yet only 10 market authorizations were approved in Europe. Our aim was to identify challenges experienced in European ATMP clinical development by companies. A survey-based cohort study was conducted among commercial ATMP developers. Respondents shared challenges experienced during various development phases, as well as developer and product characteristics. Descriptions of challenges were grouped in domains (clinical, financial, human resource management, regulatory, scientific, technical, other) and further categorized using thematic content analysis. A descriptive analysis was performed. We invited 271 commercial ATMP developers, of which 68 responded providing 243 challenges. Of products in development, 72% were in early clinical development and 40% were gene therapies. Most developers were small- or medium-sized enterprises (65%). The most often mentioned challenges were related to country-specific requirements (16%), manufacturing (15%), and clinical trial design (8%). The European ATMP field is still in its early stages, and developers experience challenges on many levels. Challenges are multifactorial and a mix of ATMP-specific and generic development aspects, such as new and orphan indications, novel technologies, and inexperience, adding complexity to development efforts.

Many low- and middle-income countries (LMIC) are moving towards enforcing prescription-only access to antibiotics. This systematic literature review aims to assess the interventions used to enforce existing legislation prohibiting over-the-counter (OTC) sales of antibiotics in LMICs, their impact and examine the methods chosen for impact measurement including their strengths and weaknesses.

High prices of pharmaceutical products are an increasing challenge in high- and low-income countries. Governments in many countries have implemented pricing policies to ensure affordability of medicines to patients and healthcare systems. The World Health Organization published in 2015 the Guideline on Country Pharmaceutical Pricing Policies, which was based on a series of evidence reviews in the preceding years.As part of the ongoing update of this guideline, we present a protocol for 10 systematic literature reviews on pharmaceutical pricing policies to be covered by the updated guideline.

The summary of product characteristics (SmPCs) is an important information source that includes the adverse drug reactions (ADRs) associated with the drug. Drugs with the same mechanism of action are expected to have a similar ADR profile and thus a substantial overlap of the described ADRs in the SmPC. The objective of this study is to assess this overlap. We extracted all ADRs (excluding hypersensitivity and administration site reactions) that were described in the first and all subsequent versions of the SmPCs of all approved TNF-α inhibitors in the European Union. The Medical Dictionary for Regulatory Activities was used to characterize the ADRs. At the end of follow-up, 293 unique ADRs (at high level term level) were described in the SmPCs of the 5 TNF-α inhibitors. There was substantial variation in the number of ADRs described in the SmPC among the TNF-α inhibitors. Of the 293 ADRs, 133 (45%) were described in the SmPC of one TNF-α inhibitor and 39 (13%) in the SmPCs of all 5 TNF-α inhibitors. Serious ADRs and ADRs classified as important risks were described approximately four times more often in a second SmPC than ADRs not classified as such. In conclusion, the ADRs described in the SmPCs of the TNF-α inhibitors differ considerably in number and type. In order to adequately inform prescribers and patients, acquired knowledge of the safety profile of drugs with the same mechanism of action should increasingly be taken into account in the assessment of all drugs within the class.

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

This study assessed whether five Health Technology Assessment (HTA) bodies in Europe were more negative about drugs with a Conditional Marketing Authorization (CMA) that are approved without controlled studies compared to CMA drugs that are approved based on controlled studies. The HTA recommendations were categorized into positive, restricted, and negative. A total of 92 HTA recommendations were available for 27 drugs. Thirty of 62 (48%) and 17 of 30 (57%) of the recommendations were negative for drugs with and without controlled studies, respectively. Overall, only 12 (13%) recommendations were positive. In all jurisdictions, recommendations between drugs with and drugs without controlled data were comparable, which suggests that the presence of controlled data is not decisive in HTA evaluations. The small proportion of unrestricted positive recommendations highlights difficulties with recommending the drugs in this cohort, which may be caused by scientific uncertainty or other factors. Earlier collaboration between stakeholders is advised in order to improve patient access.

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.

To evaluate the association between regulatory drug safety advisories and changes in drug utilisation.

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.

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.

Over the past 15 years, three new classes of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter-2 (SGLT-2) inhibitors have been approved to treat type 2 diabetes based on effects on glycemic control. Although large randomized controlled trials have played an important role in characterizing the efficacy and safety of these agents on a population level, questions remain about how best to individualize therapy and target the "right" medicine to the "right" patient. In contrast, few medicines have been approved to treat diabetic kidney disease and initiatives have been launched on both sides of the Atlantic to facilitate the development of effective personalized medicines for the treatment of diabetic kidney disease. Increasingly, "omics," imaging and other biomarkers will be used to match patients with therapies to which they are likely to respond best. This review addresses regulatory considerations related to precision medicine, draws lessons learned from other therapeutic areas and discusses efforts undertaken by the European (EMA) and United States (FDA) to facilitate the development of such therapies. Moving forward, an integrated approach that makes use of predictive preclinical models, innovative trial designs, observational "real-world" data and novel statistical methodologies will likely be needed to complement inherently smaller RCTs conducted in more selected populations. Patient involvement will also be critical. Regulatory agencies are ready to engage in such approaches.

Midregional proadrenomedullin (MR-proADM) has demonstrated prognostic potential after myocardial infarction (MI). Yet, the prognostic value of MR-proADM at admission has not been examined in patients with ST-segment-elevation MI (STEMI).