Elevated lipoprotein(a) increases risk of subsequent major adverse cardiovascular events (MACE) and coronary revascularisation in incident ASCVD patients: a cohort study from the UK biobank

Background and aims: Elevated lipoprotein(a) [Lp(a)] is a genetic driver for atherosclerotic cardiovascular disease (ASCVD). We aimed to provide novel insights on the associated risk of elevated versus normal Lp(a) levels on major adverse cardiovascular events (MACE) in an incident ASCVD cohort. Methods: This was an observational cohort study of incident ASCVD patients. MACE counts and incidence rates (IRs) per 100-person-years were reported for patients with normal (<65 nmol/L) and elevated (>150 nmol/L) Lp(a) within the first year after incident ASCVD diagnosis and overall follow-up. Cox proportional hazard models quantified the risk of MACE associated with a 100 nmol/L increase in Lp(a). Results: The study cohort included 32,537 incident ASCVD patients; 5204 with elevated and 22,257 with normal Lp(a). Of those with elevated Lp(a), 41.2% had a subsequent MACE, versus 35.61% with normal Lp(a). Within the first year of follow-up, the IRs of composite MACE and coronary revascularisation were significantly higher (p < 0.001) in patients with elevated versus normal Lp(a) (IR difference 6.79 and 4.66). This trend was also observed in the overall follow-up (median 4.7 years). Using time to first subsequent MACE, a 100 nmol/L increase in Lp(a) was associated with an 8.0% increased risk of composite MACE, and 18.6% increased risk of coronary revascularisation during the overall follow-up period. Conclusions: The association of elevated Lp(a) with increased risk of subsequent MACE and coronary revascularisation, highlights a population who may benefit from earlier and more targeted intervention for cardiovascular risk including Lp(a), particularly within the first year after ASCVD diagnosis. Proactive Lp(a) testing as part of routine clinical practice can help to identify and better manage these higher-risk individuals

Does the Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

BACKGROUND: Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D) polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease. METHODS: Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives) responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality. RESULTS: Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes. CONCLUSION: Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers

Real-world comparative effectiveness of ARNI versus ACEi/ARB in HF with reduced or mildly reduced ejection fraction

Aims Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) with a class-1 guideline recommendation. We assessed the real-world effectiveness of ARNI versus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) on all-cause and cardiovascular (CV)-related mortality and hospitalizations in heart failure (HF) with reduced or mildly reduced ejection fraction (EF). Methods Patient-level clinical, laboratory, drug dispensation, hospitalization, and mortality data were derived from the Swedish Heart Failure Registry (SwedeHF) and interlinked databases (1 April 2016-31 December 2020). Eligible ARNI:ACEi/ARB patients (n = 7275:24,604) had a left ventricular EF &amp;lt; 50%. Mortality and hospitalizations with ARNI (&amp;lt;= 3 months pre-/post-1 April 2016 index [SwedeHF]; n = 1506) versus ACEi/ARB (&amp;lt;= 3 months post-index; n = 17,108) were assessed using propensity score matching (1:1 ratio) with clinical variables, and sensitivity analysis (1:2/1:3 with, and 1:2 without clinical variables). Results ARNI induced a 23% reduction in all-cause mortality versus ACEi/ARB (1:1 hazard ratio [HR; 95% confidence interval (CI)]: 0.77 [0.63-0.95], p = 0.013), and a non-significant 23% relative risk reduction in CV-related mortality (0.77 [0.54-1.09], p = 0.13), but no difference in all-cause or CV-related hospitalization (1.02 [0.91-1.13]; p = 0.76; 1.01 [0.91-1.15]; p = 0.84, respectively). Sensitivity analyses confirmed all-cause mortality was reduced for ARNI versus ACEi/ARB (HR 0.90 [95% CI 0.82-0.99], p = 0.026), but not CV-related mortality (HR 1.04 [95% CI 0.89-1.22], p = 0.63). Conclusions In this nationwide real-world study including a population of patients with HF with reduced or mildly reduced EF, ARNI as part of guideline-led Swedish clinical practice was associated with a statistically significant relative risk reduction in all-cause mortality compared with ACEi/ARB.Funding Agencies|University of Gothenburg - Novartis Sweden AB</p

Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease

BACKGROUND: Pulmonary rehabilitation has become a cornerstone in the management of patients with stable Chronic Obstructive Pulmonary Disease (COPD). Systematic reviews have shown large and important clinical effects of pulmonary rehabilitation in these patients. In unstable COPD patients who have suffered from an exacerbation recently, however, the effects of pulmonary rehabilitation are less established. OBJECTIVES: To assess the effects of pulmonary rehabilitation after COPD exacerbations on future hospital admissions (primary outcome) and other patient-important outcomes (mortality, health-related quality of life and exercise capacity). SEARCH STRATEGY: Trials were identified from searches of CENTRAL, MEDLINE, EMBASE, PEDRO and the Cochrane Central Register of Controlled Trials. Searches were current as of July 2008. SELECTION CRITERIA: Randomized controlled trials comparing pulmonary rehabilitation of any duration after exacerbation of COPD with conventional care. Pulmonary rehabilitation programmes needed to include at least physical exercise. Control groups received conventional community care without rehabilitation. DATA COLLECTION AND ANALYSIS: We calculated pooled odds ratios and weighted mean differences (WMD) using fixed-effects models. We requested missing data from the authors of the primary studies. MAIN RESULTS: We identified six trials including 219 patients. Pulmonary rehabilitation significantly reduced hospital admissions (pooled odds ratio 0.13 [95% CI 0.04 to 0.35], number needed to treat (NNT) 3 [95% CI 2 to 4], over 34 weeks) and mortality (pooled odds ratio 0.29 [95% CI 0.10 to 0.84], NNT 6 [95% CI 5 to 30] over 107 weeks). Effects of pulmonary rehabilitation on health-related quality of life were well above the minimal important difference (weighted mean differences for dyspnea, fatigue, emotional function and mastery domains of the Chronic Respiratory Questionnaire between 1.15 (95% CI: 0.94, 1.36) and 1.88 (95% CI:1.67, 2.09) and between -9.9 (95% CI:-18.05, -1.73) and -17.1 (95% CI: -23.55, -10.68) for total, impact and activity limitation domains of the St. Georges Respiratory Questionnaire). In all trials, pulmonary rehabilitation improved exercise capacity (60-215 meters in six-minute or shuttle walk tests). No adverse events were reported (two studies). AUTHORS' CONCLUSIONS: Evidence from small studies of moderate methodological quality suggests that pulmonary rehabilitation is a highly effective and safe intervention to reduce hospital admissions and mortality and to improve health-related quality of life in COPD patients after suffering an exacerbation

Clinical characteristics and mortality of patients with heart failure in Southern Sweden from 2013 to 2019 : a population-based cohort study

OBJECTIVES: To describe clinical characteristics and prognosis related to heart failure (HF) phenotypes in a community-based population by applying a novel algorithm to obtain ejection fractions (EF) from electronic medical records. DESIGN: Retrospective population-based cohort study. SETTING: Data were collected for all patients with HF in Southwest Sweden. The region consists of three acute care hospitals, 40 inpatient wards, 2 emergency departments, 30 outpatient specialty clinics and 48 primary healthcare. PARTICIPANTS: 8902 patients had an HF diagnosis based on the International Classification of Diseases, Tenth Revision during the study period. Patients <18 years as well as patients declining to participate were excluded resulting in a study population of 8775 patients. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was distribution of HF phenotypes by echocardiography. The secondary outcome measures were 1 year all-cause mortality and HR for all-cause mortality using Cox regression models. RESULTS: Out of 8775 patients with HF, 5023 (57%) had a conclusive echocardiography distributed into HF with reduced EF (35%), HF with mildly reduced EF (27%) and HF with preserved EF (38%). A total of 43% of the cohort did not have a conclusive echocardiography, and therefore no defined phenotype (HF-NDP). One-year all-cause mortality was 42% within the HF-NDP group and 30% among those with a conclusive EF. The HR of all-cause mortality in the HF-NDP group was 1.27 (95% CI 1.17 to 1.37) when compared with the confirmed EF group. There was no significant difference in survival within the HF phenotypes. CONCLUSIONS: This population-based study showed a distribution of HF phenotypes that varies from those in selected HF registries, with fewer patients with HF with reduced EF and more patients with HF with preserved EF. Furthermore, 1-year all-cause mortality was significantly higher among patients with HF who had not undergone a conclusive echocardiography at diagnosis, highlighting the importance of correct diagnostic procedure to improve treatment strategies and outcomes

Cost-effectiveness of pharmacogenetic testing to predict treatment response to angiotensin-converting enzyme inhibitor

OBJECTIVE: This study aimed to assess the potential cost-effectiveness of testing patients with nephropathies for the I/D polymorphism before starting angiotensin-converting enzyme (ACE) inhibitor therapy, using a 3-year time horizon and a healthcare perspective. METHODS: We used a combination of a decision analysis and Markov modeling technique to evaluate the potential economic value of this pharmacogenetic test by preventing unfavorable treatment in patients with nephropathies. The estimation of the predictive value of the I/D polymorphism is based on a systematic review showing that DD carriers tend to respond well to ACE inhibitors, while II carriers seem not to benefit adequately from this treatment. Data on the ACE inhibitor effectiveness in nephropathy were derived from the REIN (Ramipril Efficacy in Nephropathy) trial. We calculated the number of patients with end-stage renal disease (ESRD) prevented and the differences in the incremental costs and incremental effect expressed as life-years free of ESRD. A probabilistic sensitivity analysis was conducted to determine the robustness of the results. RESULTS: Compared with unselective treatment, testing patients for their ACE genotype could save 12 patients per 1000 from developing ESRD during the 3 years covered by the model. As the mean net cost savings was euro 356,000 per 1000 patient-years, and 9 life-years free of ESRD were gained, selective treatment seems to be dominant. CONCLUSION: The study suggests that genetic testing of the I/D polymorphism in patients with nephropathy before initiating ACE therapy will most likely be cost-effective, even if the risk for II carriers to develop ESRD when treated with ACE inhibitors is only 1.4% higher than for DD carriers. Further studies, however, are required to corroborate the difference in treatment response between ACE genotypes, before genetic testing can be justified in clinical practice