Prinzip der mendelschen Randomisierung und Anwendung in der kardiovaskulären Medizin

Zusammenfassung: Hintergrund: Die Methode der mendelschen Randomisierung wird zunehmend zur Auswertung genetischer und epidemiologischer Daten genutzt. Korrekt angewendet, können wichtige Erkenntnisse für die klinische Forschung, Entwicklung neuer Pharmaka und die Patientenversorgung gewonnen werden. Ziel der Arbeit: Die vorliegende Übersichtsarbeit soll das Prinzip, Anwendungsmöglichkeiten und Limitationen der mendelschen Randomisierung anhand von Beispielen aus der kardiovaskulären Medizin aufzeigen. Material und Methode: Es erfolgte eine selektive Literaturrecherche in PudMed. Weiterhin flossen Erfahrungen der Autoren in der Anwendung der mendelschen Randomisierung ein. Ergebnisse: Mithilfe der mendelschen Randomisierung können Menschen anhand von genetischen Markern randomisiert werden. Geeignete genetische Marker sind direkt mit einer lebenslangen Exposition assoziiert. Bei Nachweis einer Assoziation zwischen dem genetischen Marker und einer Erkrankung kann man von einer kausalen Beziehung zwischen der Exposition und der Erkrankung ausgehen. Somit können aus epidemiologischen Daten Schlussfolgerungen zur Kausalität einer Assoziation und deren quantitativer Ausprägung gezogen werden. Weiterhin können mithilfe der mendelschen Randomisierung die Ergebnisse klinischer Studien antizipiert werden, was Rückschlüsse über bekannte Wirkstoffe erlaubt und der Entwicklung neuer pharmakologischer Prinzipien dient. Die Limitationen der mendelschen Randomisierung müssen bei der Interpretation der gewonnenen Erkenntnisse beachtet werden. Schlussfolgerung: Um Studien, welche auf dem Prinzip der mendelschen Randomisierung beruhen, kritisch interpretieren zu können, ist ein grundlegendes Verständnis der Möglichkeiten und Grenzen der Methode notwendig

Is the SMART risk prediction model ready for real-world implementation? A validation study in a routine care setting of approximately 380 000 individuals

AIMS: Reliably quantifying event rates in secondary prevention could aid clinical decision-making, including quantifying potential risk reductions of novel, and sometimes expensive, add-on therapies. We aimed to assess whether the SMART risk prediction model performs well in a real-world setting. METHODS AND RESULTS: We conducted a historical open cohort study using UK primary care data from the Clinical Practice Research Datalink (2000-2017) diagnosed with coronary, cerebrovascular, peripheral, and/or aortic atherosclerotic cardiovascular disease (ASCVD). Analyses were undertaken separately for cohorts with established (≥6 months) vs. newly diagnosed ASCVD. The outcome was first post-cohort entry occurrence of myocardial infarction, stroke, or cardiovascular death. Among the cohort with established ASCVD [n = 244 578, 62.1% male, median age 67.3 years, interquartile range (IQR) 59.2-74.0], the calibration and discrimination achieved by the SMART model was not dissimilar to performance at internal validation [Harrell's c-statistic = 0.639, 95% confidence interval (CI) 0.636-0.642, compared with 0.675, 0.642-0.708]. Decision curve analysis indicated that the model outperformed treat all and treat none strategies in the clinically relevant 20-60% predicted risk range. Consistent findings were observed in sensitivity analyses, including complete case analysis (n = 182 482; c = 0.624, 95% CI 0.620-0.627). Among the cohort with newly diagnosed ASCVD (n = 136 445; 61.0% male; median age 66.0 years, IQR 57.7-73.2), model performance was weaker with more exaggerated risk under-prediction and a c-statistic of 0.559, 95% CI 0.556-0.562. CONCLUSIONS: The performance of the SMART model in this validation cohort demonstrates its potential utility in routine healthcare settings in guiding both population and individual-level decision-making for secondary prevention patients

Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk

Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.Dr Oliver-Williams is supported by Homerton College, University of Cambridge. Dr Butterworth is supported by the European Research Council. Dr Danesh is supported by the Medical Research Council, British Heart Foundation, and the National Institute for Health Research. Dr Davey Smith works within the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_12013/1) and the University of Bristol

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus:Pooled Analyses from Five Placebo-Controlled Phase 3 Studies

Introduction: Diabetes mellitus (DM) carries an elevated risk for cardiovascular disease. Here, we assessed alirocumab efficacy and safety in people with/without DM from five placebo-controlled phase 3 studies. Methods: Data from up to 78 weeks were analyzed in individuals on maximally tolerated background statin. In three studies, alirocumab 75 mg every 2 weeks (Q2W) was increased to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dL; two studies used alirocumab 150 mg Q2W throughout. The primary endpoint was percentage change in LDL-C from baseline to week 24. Results: In the alirocumab 150 mg pool (n = 2416), baseline LDL-C levels were 117.4 mg/dL (DM) and 130.6 mg/dL (without DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C reductions from baseline were observed in persons with DM (− 59.9%; placebo, − 1.4%) and without DM (− 60.6%; placebo, + 1.5%); 77.7% (DM) and 76.8% (without DM) of subjects achieved LDL-C < 70 mg/dL. In the alirocumab 75/150 mg group, 26% (DM) and 36% (without DM) of subjects received dose increase. In this group, week 24 LDL-C levels changed from baseline by − 43.8% (DM; placebo, + 0.3%) and − 49.7% (without DM; placebo, + 5.1%); LDL-C < 70 mg/dL was achieved by 68.3% and 65.8% of individuals, respectively. At week 24, alirocumab was also associated with improved levels of other lipids. Adverse event rates were generally comparable in all groups (79.8–82.0%). Conclusions: Regardless of DM status, alirocumab significantly reduced LDL-C levels; safety was generally similar. Funding Sanofi and Regeneron Pharmaceuticals, Inc. Plain Language Summary Plain language summary available for this article. Electronic supplementary material The online version of this article (10.1007/s13300-018-0439-8) contains supplementary material, which is available to authorized users

No evidence for cardiac dysfunction in Kif6 mutant mice.

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function

Differential Effects of Aerobic Exercise, Resistance Training and Combined Exercise Modalities on Cholesterol and the Lipid Profile:Review, Synthesis and Recommendations

There is a direct relationship between chronically elevated cholesterol levels (dyslipidaemia) and coronary heart disease. A reduction in total cholesterol is considered the gold standard in preventative cardiovascular medicine. Exercise has been shown to have positive impacts on the pathogenesis, symptomatology and physical fitness of individuals with dyslipidaemia, and to reduce cholesterol levels. The optimal mode, frequency, intensity and duration of exercise for improvement of cholesterol levels are, however, yet to be identified. This review assesses the evidence from 13 published investigations and two review articles that have addressed the effects of aerobic exercise, resistance training and combined aerobic and resistance training on cholesterol levels and the lipid profile. The data included in this review confirm the beneficial effects of regular activity on cholesterol levels and describe the impacts of differing volumes and intensities of exercise upon different types of cholesterol. Evidence-based exercise recommendations are presented, aimed at facilitating the prescription and delivery of interventions in order to optimize cholesterol levels

Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins