Plasma potassium concentration and cardiac repolarisation markers, Tpeak-Tend and Tpeak-Tend/QT, during and after exercise in healthy participants and in end-stage renal disease.

PURPOSE: The cardiac T-wave peak-to-end interval (Tpe) is thought to reflect dispersion in ventricular repolarisation, with abnormalities in Tpe associated with increased risk of arrhythmia. Extracellular K+ modulates cardiac repolarisation, and since arterial plasma K+ concentration ([K+]) rapidly increases during and declines following exercise, we investigated the relationship between [K+] and Tpe with exercise. METHODS: Serial ECGs (Tpe, Tpe/QT ratio) and [K+] were obtained from 8 healthy, normokalaemic volunteers and 22 patients with end-stage renal disease (ESRD), at rest, during, and after exhaustive exercise. RESULTS: Post-exercise [K+] nadir was 3.1 ± 0.1, 5.0 ± 0.2 and 4.0 ± 0.1 mmol.L-1 (mean ± SEM) for healthy participants and ESRD patients before and after haemodialysis, respectively. In healthy participants, compared to pre-exercise, recovery-induced low [K+] was associated with a prolongation of Tpe (110 ± 8 vs. 87 ± 5 ms, respectively, p = 0.03) and an increase in Tpe/QT ratio (0.28 ± 0.01 vs. 0.23 ± 0.01, respectively, p = 0.01). Analyses of serial data revealed [K+] as a predictor of Tpe in healthy participants (ß = -0.54 ±0.05, p < 0.0001), in ESRD patients (ß = -0.75 ± 0.06, p < 0.0001) and for all data pooled (ß = -0.61 ± 0.04, p < 0.0001). The [K+] was also a predictor of Tpe/QT ratio in healthy participants and ESRD patients. CONCLUSIONS: Tpe and Tpe/QT ratio are predicted by [K+] during exercise. Low [K+] during recovery from exercise was associated with increased Tpe and Tpe/QT, indicating accentuated dispersion of ventricular repolarisation. The findings suggest that variations in [K+] with physical exertion may unmask electrophysiological vulnerabilities to arrhythmia.

Facing the challenge of polypharmacy when prescribing for older people with cardiovascular disease. A review by the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Population ageing has resulted in an increasing number of older people living with chronic diseases (multimorbidity) requiring five or more medications daily (polypharmacy). Ageing produces important changes in the cardiovascular system and represents the most potent single cardiovascular risk factor. Cardiovascular diseases (CVDs) constitute the greatest burden for older people, their caregivers, and healthcare systems. Cardiovascular pharmacotherapy in older people is complex because age-related changes in body composition, organ function, homeostatic mechanisms, and comorbidities modify the pharmacokinetic and pharmacodynamic properties of many commonly used cardiovascular and non-cardiovascular drugs. Additionally, polypharmacy increases the risk of adverse drug reactions and drug interactions, which in turn can lead to increased morbi-mortality and healthcare costs. Unfortunately, evidence of drug efficacy and safety in older people with multimorbidity and polypharmacy is limited because these individuals are frequently underrepresented/excluded from clinical trials. Moreover, clinical guidelines are largely written with a single-disease focus and only occasionally address the issue of coordination of care, when and how to discontinue treatments, if required, or how to prioritize recommendations for patients with multimorbidity and polypharmacy. This review analyses the main challenges confronting healthcare professionals when prescribing in older people with CVD, multimorbidity, and polypharmacy. Our goal is to provide information that can contribute to improving drug prescribing, efficacy, and safety, as well as drug adherence and clinical outcomes.

The role of pharmacogenomics in contemporary cardiovascular therapy: a position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation, and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas, such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level.

Challenges in cardiovascular pharmacogenomics implementation: a viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources, and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on pharmacogenomics implementation. Clinical workforce upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.

Update on management of hypokalaemia and goals for the lower potassium level in patients with cardiovascular disease: a review in collaboration with the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Hypokalaemia is common in patients with cardiovascular disease. In this review, we emphasize the importance of tight potassium regulation in patients with cardiovascular disease based on findings from observational studies. To enhance the understanding, we also describe the mechanisms of potassium homeostasis maintenance, the most common causes of hypokalaemia and present strategies for monitoring and management of low potassium levels. We propose elevation of potassium in asymptomatic patients with lower normal concentrations and concurrent cardiovascular disease. These proposals are intended to assist clinicians until more evidence is available.

The age of randomized clinical trials: three important aspects of randomized clinical trials in cardiovascular pharmacotherapy with examples from lipid, diabetes, and antithrombotic trials.

This review article aims to explain the important issues that data safety monitoring boards (DSMB) face when considering early termination of a trial and is specifically addressed to the needs of clinical and research cardiologists. We give an insight into the overall background and then focus on the three principal reasons for stopping trials, i.e. efficacy, futility, and harm. The statistical essentials are also addressed to familiarize clinicians with the key principles. The topic is further highlighted by numerous examples from lipid trials and antithrombotic trials. This is followed by an overview of regulatory aspects, including an insight into industry-investigator interactions. To conclude, we summarize the key elements that are the basis for a decision to stop a randomized clinical trial (RCT).

Antithrombotic therapy and major adverse limb events in patients with chronic lower extremity arterial disease: systematic review and meta-analysis from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy in Collaboration with the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases.

AIMS: The role and selection of antithrombotic therapy to improve limb outcomes in chronic lower extremity artery disease (LEAD) is still debated. We conducted a meta-analysis to examine the efficacy and safety of antithrombotic and more intense antithrombotic therapy on limb outcomes and limb salvage in patients with chronic LEAD. METHODS AND RESULTS: Study inclusion criteria were: enrolment of patients with LEAD, randomized allocation to more vs. less intense antithrombotic therapy [more vs. less intense single-antiplatelet therapy (SAPT); dual-antiplatelet therapy vs. SAPT; dual antithrombotic therapy vs. SAPT or oral anticoagulant]; enrolment of ≥200 patients; reporting of at least one of following outcomes: limb amputation or revascularization. Seven randomized studies enrolling 30 447 patients were included. Over a median follow-up of 24 months, more vs. less intense antithrombotic therapy or placebo significantly reduced the risk of limb revascularization [relative risk (RR) 0.89, 95% confidence interval (CI) 0.83-0.94] and limb amputation (RR 0.63, 95% CI 0.46-0.86), as well as stroke (RR 0.82, 95% CI 0.70-0.97). There was no statistically significant effect on the risk of myocardial infarction (RR 0.98, 95% CI 0.87-1.11), all-cause (RR 0.93, 95% CI 0.86-1.01), and cardiovascular death (RR 0.97, 95% CI 0.86-1.08). Risk of major bleeding increased (RR 1.23, 95% CI 1.04-1.44). CONCLUSION: In patients with LEAD, more intense antithrombotic therapy reduces the risk of limb amputation and revascularization as well as stroke with an increase in the risk of bleeding events.

Oral anticoagulation in patients with non-valvular atrial fibrillation and a CHA2DS2-VASc score of 1: a current opinion of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Council on Stroke.

Oral anticoagulation in patients presenting with non-valvular atrial fibrillation and a CHA2DS2-VASc score of 1 (CHA2DS2-VASc of 2 in women) remains a challenging approach in clinical practice. Therapeutic decisions need to balance the individual benefit of reducing thromboembolic risk against the potential harm due to an increase in bleeding risk in this intermediate risk patient population. Within the current opinion statement of the European Society of Cardiology working group of cardiovascular pharmacotherapy and the European Society of Cardiology council on stroke the currently available evidence on the anti-thrombotic management in patients presenting with a CHA2DS2-VASc of 1 is summarized. Easily applicable tools for a personalized refinement of the individual thromboembolic risk in patients with atrial fibrillation and a CHA2DS2-VASc score of 1 that guide clinicians through the question whether to anticoagulate or not are provided.

Potassium homoeostasis and pathophysiology of hyperkalaemia.

Determination of potassium level is one of the most frequent laboratory tests in clinical medicine. Hyperkalaemia is defined as a potassium level >5.0 mmol/L and is one of the most clinically important electrolyte abnormalities, because it may cause dangerous cardiac arrhythmia and sudden cardiac death. Here, we review methodological challenges in the determination of potassium levels, important clinical aspects of the potassium homoeostasis as well as of the pathophysiology of hyperkalaemia.

Reasons for disparity in statin adherence rates between clinical trials and real-world observations: a review.

With statins, the reported rate of adverse events differs widely between randomized clinical trials (RCTs) and observations in clinical practice, the rates being 1-2% in RCTs vs. 10-20% in the so-called real world. One possible explanation is the claim that RCTs mostly use a run-in period with a statin. This would exclude intolerant patients from remaining in the trial and therefore favour a bias towards lower rates of intolerance. We here review data from RCTs with more than 1000 participants with and without a run-in period, which were included in the Cholesterol Treatment Trialists Collaboration. Two major conclusions arise: (i) the majority of RCTs did not have a test dose of a statin in the run-in phase. (ii) A test dose in the run-in phase was not associated with a significantly improved adherence rate within that trial when compared to trials without a test dose. Taken together, the RCTs of statins reviewed here do not suggest a bias towards an artificially higher adherence rate because of a run-in period with a test dose of the statin. Other possible explanations for the apparent disparity between RCTs and real-world observations are also included in this review albeit mostly not supported by scientific data.

Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Renin angiotensin aldosterone system inhibitors/antagonists/blockers (RAASi) are a cornerstone in treatment of patients with cardiovascular diseases especially in those with heart failure (HF) due to their proven effect on surrogate and hard endpoints. Renin angiotensin aldosterone system inhibitors are also the basis in treatment of arterial hypertension, and they are furthermore indicated to reduce events and target organ damage in patients with diabetes and chronic kidney disease, where they have specific indication because of the evidence of benefit. Renin angiotensin aldosterone system inhibitor therapy, however, is associated with an increased risk of hyperkalaemia. Patients with chronic kidney disease and HF are at increased risk of hyperkalaemia and ∼50% of these patients experience two or more yearly recurrences. A substantial proportion of patients receiving RAASi therapy have their therapy down-titrated or more often discontinued even after a single episode of elevated potassium (K+) level. Since RAASi therapy reduces mortality and morbidity in patients with cardiovascular disease steps should, when hyperkalaemia develops, be considered to lower K+ level and enable patients to continue their RAASi therapy. The use of such measures are especially important in those patients with the most to gain from RAASi therapy.

Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol.

Intense exercise induces pronounced hyperkalemia, followed by transient hypokalemia in recovery. We investigated whether the ß2 agonist salbutamol attenuated the exercise hyperkalemia and exacerbated the postexercise hypokalemia, and whether hypokalemia was associated with impaired cardiac repolarization (QT hysteresis). Eleven healthy adults participated in a randomized, counterbalanced, double-blind trial receiving either 1,000 µg salbutamol (SAL) or placebo (PLAC) by inhalation. Arterial plasma potassium concentration ([K+]a) was measured at rest, during 3 min of intense rowing exercise, and during 60 min of recovery. QT hysteresis was calculated from ECG ( n = 8). [K+]a increased above baseline during exercise (rest, 3.72 ± 0.7 vs. end-exercise, 6.81 ± 1.4 mM, P < 0.001, mean ± SD) and decreased rapidly during early recovery to below baseline; restoration was incomplete at 60 min postexercise ( P < 0.05). [K+]a was less during SAL than PLAC (4.39 ± 0.13 vs. 4.73 ± 0.19 mM, pooled across all times, P = 0.001, treatment main effect). [K+]a was lower after SAL than PLAC, from 2 min preexercise until 2.5 min during exercise, and at 50 and 60 min postexercise ( P < 0.05). The postexercise decline in [K+]a was correlated with QT hysteresis ( r = 0.343, n = 112, pooled data, P = 0.001). Therefore, the decrease in [K+]a from end-exercise by ~4 mM was associated with reduced QT hysteresis by ~75 ms. Although salbutamol lowered [K+]a during exercise, no additive hypokalemic effects occurred in early recovery, suggesting there may be a protective mechanism against severe or prolonged hypokalemia after exercise when treated by salbutamol. This is important because postexercise hypokalemia impaired cardiac repolarization, which could potentially trigger arrhythmias and sudden cardiac death in susceptible individuals with preexisting hypokalemia and/or heart disease. NEW & NOTEWORTHY Intense rowing exercise induced a marked increase in arterial potassium, followed by a pronounced decline to hypokalemic levels. The ß2 agonist salbutamol lowered potassium during exercise and late recovery but not during early postexercise, suggesting a protective effect against severe hypokalemia. The decreased potassium in recovery was associated with impaired cardiac QT hysteresis, suggesting a link between postexercise potassium and the heart, with implications for increased risk of cardiac arrhythmias and, potentially, sudden cardiac death.

CardioScape mapping the cardiovascular funding landscape in Europe.

Aims: The burden of cardiovascular disease is increasing worldwide, which has to be reflected by cardiovascular (CV) research in Europe. CardioScape, a FP7 funded project initiated by the European Society of Cardiology (ESC), identified where CV research is performed, how it is funded and by whom. It could be transformed into an on-line and up-to-date resource of great relevance for researchers, funding bodies and policymakers and could be a role model for mapping CV research funding in Europe and beyond. Methods and results: Relevant funding bodies in 28 European Union (EU) countries were identified by a multistep process involving experts in each country. Projects above a funding threshold of 100 k€ during the period 2010-2012 were included using a standard questionnaire. Results were classified by experts and an adaptive text analysis software to a CV-research taxonomy, integrating existing schemes from ESC journals and congresses. An on-line query portal was set up to allow different users to interrogate the database according to their specific viewpoints. Conclusion: CV-research funding varies strongly between different nations with the EU providing 37% of total available project funding and clear geographical gradients exist. Data allow in depth comparison of funding for different research areas and led to a number of recommendations by the consortium. CardioScape can support CV research by aiding researchers, funding agencies and policy makers in their strategic decisions thus improving research quality if CardioScape strategy and technology becomes the basis of a continuously updated and expanded European wide publicly accessible database.