Alistair S. Hall

Cardiovascular disease is the leading cause of mortality worldwide, affecting a wide range of patients at different stages across the cardiovascular continuum. Hypertension is one of the earliest risk factors in this continuum and can be controlled in most patients with currently available antihypertensive agents. However, goals are often not met because treatments are not optimized in terms of tailoring therapy to individual patients based on their hypertension subclass and cardiovascular risk profile and initiating early use of adapted-dose, single-pill combinations. In this context, beta-blockers in combination with angiotensin-converting enzyme (ACE) inhibitors are of special interest as a result of their complementary actions on the sympathetic nervous system and renin–angiotensin–aldosterone system, two interlinked pathways that influence cardiovascular risk and disease outcomes. In addition to their antihypertensive actions, beta-blockers are used to manage arrhythmias and treat angina pectoris and heart failure, while ACE inhibitors provide cardioprotection in patients with acute coronary syndromes and treat congestive heart failure. A broad range of patients may therefore receive the combination in routine clinical practice. This paper examines the supporting evidence for beta-blockers and ACE inhibitors in each of the above indications and considers the rationale for combining these agents into a single pill, using data from bisoprolol and perindopril randomized controlled trials as supporting evidence. Combining these established antihypertensive agents into a single pill continues to provide effective blood pressure lowering and improved cardiovascular outcomes while allowing a greater proportion of patients to rapidly achieve treatment targets.

Aims ACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population. Methods In 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0–29.6 years). Results By 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%. Conclusion For patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.

Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not—a phenomenon described as the ‘ARB-MI paradox’. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP. A comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists (two-tailed p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger’s statistic. This systematic review will provide a detailed synthesis of evidence regarding the relationship between BP reduction and clinical outcomes with ACEi and ARBs. Greater understanding of the dependency of the effect of each class on BP reduction will advance insight into the nature of the ARB-MI paradox and guide the future usage of these agents. PROSPERO CRD42017072988

The cause of adverse weekend clinical outcomes remains unknown. In 2013, the “NHS Services, Seven Days a Week” project was initiated to improve access to services across the seven-day week. Three years on, we sought to analyse the impact of such changes across the English NHS. Aggregated trust-level data on crude mortality rates, Summary Hospital-Level Mortality Indicator (SHMI), mean length of stay (LOS), A&E admission and four-hour breach rates were obtained from national Hospital Episode Statistics and A&E datasets across the English NHS, excluding mental and community health trusts. Trust annual reports were analysed to determine the presence of any seven-day service reorganisation in 2013–2014. Funnel plots were generated to compare institutional performance and a difference in differences analysis was performed to determine the impact of seven-day changes on clinical outcomes between 2013 and 2014, 2014–2015 and 2015–2016. Data was summarised as mean (SD). Of 159 NHS trusts, 79 (49.7%) instituted seven-day changes in 2013–2014. Crude mortality rates, A&E admission rates and mean LOS remained relatively stable between 2013 and 2016, whilst A&E four-hour breach rates nearly doubled from 5.3 to 9.7%. From 2013 to 2014 to 2014–2015 and 2015–2016, there were no significant differences in the change in crude mortality (2014–2015 p = 0.8, 2015–2016 p = 0.9), SHMI (2014–2015 p = 0.5, 2015–2016 p = 0.5), mean LOS (2014–2015 p = 0.5, 2015–2016 p = 0.4), A&E admission (2014–2015 p = 0.6, 2015–2016 p = 1.0) or four-hour breach rates (2014–2015 p = 0.06, 2015–2016 p = 0.6) between trusts that had implemented seven-day changes compared to those which had not. Adverse weekend clinical outcomes may not be ameliorated by large scale reorganisations aimed at improving access to health services across the week. Such changes may negatively impact care quality without additional financial investment, as demonstrated by worsening of some outcomes. Detailed prospective research is required to determine whether such reallocation of finite resources is clinically effective.

Rationale : Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective:: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results:: We sequenced the exons of the CETP gene in 58 469 participants from 12 case–control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case–control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18–27; P −4 ), lower low-density lipoprotein cholesterol (−12.2 mg/dL; 95% confidence interval, −23 to −0.98; P =0.033), and lower triglycerides (−6.3%; 95% confidence interval, −12 to −0.22; P =0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54–0.90; P =5.1×10 ⁻³ ). Conclusions:: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Background: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. Methods: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of –3 (Bonferroni correction for 50 tests). Results: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers ( P =1.3×10 ^–16 ) in comparison with 5% in ever-smokers ( P =2.5×10 ^–4 ), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10 ^–5 ). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. Conclusions: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Opposing Viewpoint, see p 2085 Individual trials of angiotensin II receptor blockers (ARBs) and systematic meta-analyses have repeatedly demonstrated the ARB class to significantly reduce systemic blood pressure, stroke, and the subsequent development of heart failure and diabetes mellitus.1 However, no individual trial or meta-analysis has observed an impact of ARB treatment on the incidence of myocardial infarction (MI), cardiovascular mortality, or all-cause mortality (Table). All-cause mortality is the most comprehensive summary indicator of cardiovascular benefit of treatment2 and, consequently, it is surprising that ARBs have no impact given the other clinical benefits we have just acknowledged. View this table: Table. Risk of Myocardial Infarction, Cardiovascular Mortality, and All-Cause Mortality in Parallel Meta-Analyses of Placebo-Controlled Trials of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers A systematic review/meta-analysis conducted by Bangalore et al3 demonstrated that in 20 trials of ARB versus placebo (n=66 282) and 21 trials of ARB versus active comparator (n=39 738), ARB in no individual trial improved all-cause mortality. Furthermore, when the trials were analyzed in combination, the impact of ARB on mortality was precisely zero compared with placebo (odds ratio, 1.01; 95% confidence limit, 0.96–1.06) and virtually zero compared with an active comparator (odds ratio, 0.99; 95% confidence limit, 0.95–1.03). Placebo-controlled trials are the most rigorous method of assessing treatment efficacy (as well as harm), and, consequently, it is concerning that other meta-analyses of ARBs versus …

The enzymatic activity of lipoprotein lipase (LPL) serves as the rate-determining step in the postprandial clearance of circulating triglyceride-rich lipoproteins.¹ Homozygous LPL deficiency, known as familial chylomicronemia syndrome, is associated with marked elevations in chylomicrons, severe hypertriglyceridemia, and recurrent pancreatitis.² However, an increased risk of coronary artery disease (CAD) in this condition has not been observed, potentially because the large circulating chylomicrons are unable to penetrate the arterial wall.^3,4 By contrast, in heterozygous LPL deficiency, the attenuated capacity for lipolysis leads to a buildup of circulating chylomicron remnants and intermediate-density lipoproteins that are rich in both triglycerides and cholesterol. A study of 9 such individuals suggested an increased risk of CAD,⁵ but this association has not been confirmed.