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Redefining β-blocker response in heart failure patients with sinus rhythm and atrial fibrillation: a machine learning cluster analysis.
Karwath, A, Bunting, KV, Gill, SK, Tica, O, Pendleton, S, Aziz, F, Barsky, AD, Chernbumroong, S, Duan, J, Mobley, AR, et al
Lancet (London, England). 2021;(10309):1427-1435
Abstract
BACKGROUND Mortality remains unacceptably high in patients with heart failure and reduced left ventricular ejection fraction (LVEF) despite advances in therapeutics. We hypothesised that a novel artificial intelligence approach could better assess multiple and higher-dimension interactions of comorbidities, and define clusters of β-blocker efficacy in patients with sinus rhythm and atrial fibrillation. METHODS Neural network-based variational autoencoders and hierarchical clustering were applied to pooled individual patient data from nine double-blind, randomised, placebo-controlled trials of β blockers. All-cause mortality during median 1·3 years of follow-up was assessed by intention to treat, stratified by electrocardiographic heart rhythm. The number of clusters and dimensions was determined objectively, with results validated using a leave-one-trial-out approach. This study was prospectively registered with ClinicalTrials.gov (NCT00832442) and the PROSPERO database of systematic reviews (CRD42014010012). FINDINGS 15 659 patients with heart failure and LVEF of less than 50% were included, with median age 65 years (IQR 56-72) and LVEF 27% (IQR 21-33). 3708 (24%) patients were women. In sinus rhythm (n=12 822), most clusters demonstrated a consistent overall mortality benefit from β blockers, with odds ratios (ORs) ranging from 0·54 to 0·74. One cluster in sinus rhythm of older patients with less severe symptoms showed no significant efficacy (OR 0·86, 95% CI 0·67-1·10; p=0·22). In atrial fibrillation (n=2837), four of five clusters were consistent with the overall neutral effect of β blockers versus placebo (OR 0·92, 0·77-1·10; p=0·37). One cluster of younger atrial fibrillation patients at lower mortality risk but similar LVEF to average had a statistically significant reduction in mortality with β blockers (OR 0·57, 0·35-0·93; p=0·023). The robustness and consistency of clustering was confirmed for all models (p<0·0001 vs random), and cluster membership was externally validated across the nine independent trials. INTERPRETATION An artificial intelligence-based clustering approach was able to distinguish prognostic response from β blockers in patients with heart failure and reduced LVEF. This included patients in sinus rhythm with suboptimal efficacy, as well as a cluster of patients with atrial fibrillation where β blockers did reduce mortality. FUNDING Medical Research Council, UK, and EU/EFPIA Innovative Medicines Initiative BigData@Heart.
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Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis.
Stritzke, A, Kabra, N, Kaur, S, Robertson, HL, Lodha, A
Journal of perinatology : official journal of the California Perinatal Association. 2019;(12):1584-1594
Abstract
OBJECTIVE To systematically assess the efficacy of oral beta blockage treatment in primary (before established) and secondary (in threshold stages) prevention of severe retinopathy of prematurity (ROP) in premature infants born ≤32 weeks gestational age. STUDY DESIGN Following the PRISMA guidelines, published literature was systematically assessed up to April 27, 2018. Trials and observational studies, in which beta blockage was used to prevent severe ROP (defined as stage ≥3, or requiring treatment) were included. Meta-analyses including random effects models were conducted to determine the overall effect of oral beta blockage on prevention of ROP. RESULTS Six studies (five clinical trials and one observational study) including 461 infants met inclusion criteria using propranolol. The pooled relative risk (RR) of severe ROP in the primary and secondary prophylaxis groups were 0.65 (95% CI 0.43-0.98, NNT = 7) and 0.48 (95% CI 0.35-0.65, NNT = 6) in RCTs, respectively. The RR of severe ROP in one observational study was 0.21 (95% CI 0.08-0.55) with a NNT of 3. There were low heterogeneity and publication bias. Side effects occurred in 8.4% of participants on propranolol. CONCLUSIONS Systematic assessment of studies showed that prophylactic oral propranolol appeared to be effective in preventing severe ROP in premature infants ≤32 weeks gestational age. Additional well powered, multinational, randomized control trials reporting on long-term outcomes are needed.
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Preoperative Use of Oral Beta-Adrenergic Blocking Agents and the Incidence of New-Onset Atrial Fibrillation After Cardiac Surgery. A Systematic Review and Meta-Analysis.
Thein, PM, White, K, Banker, K, Lunny, C, Mirzaee, S, Nasis, A
Heart, lung & circulation. 2018;(3):310-321
Abstract
BACKGROUND Current epidemiological data suggests that postoperative atrial fibrillation or atrial flutter (POAF) causes significant morbidity and mortality after cardiac surgery. The literature for prophylactic management of POAF is limited, resulting in the lack of clear guidelines on management recommendations. AIM: To examine the efficacy of prophylactic rate control agents in reducing the incidence of new-onset POAF in patients undergoing elective cardiac surgery. METHODS Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Medline were systematically searched for blinded randomised controlled studies (RCT) evaluating adults with no history of atrial fibrillation randomised to a pharmacological agent (either beta blocker, calcium channel blocker or digoxin), compared to placebo. Utilising Cochrane guidance, three reviewers screened, extracted and the quality of the evidence was assessed. We used a random effects meta-analysis to compare a rate-control agent with placebo. RESULTS Five RCTs (688 subjects, mean age 61±8.9, 69% male) were included. Beta blocker administration prior to elective cardiac surgery significantly reduced the incidence of POAF (OR 0.43, 95%Cl [0.30-0.61], I2=0%) without significant impact on ischaemic stroke (OR 0.49, 95%Cl [0.10-2.44], I2=0%), non-fatal myocardial infarction (OR 0.76, 95%Cl [0.08-7.44], I2=0%), overall mortality (OR 0.83, 95%Cl [0.19-3.66], I2=0%), or length of stay (mean -0.96days 95%Cl [-1.49 to -0.42], I2=0%). An increased rate of bradycardic episodes was observed (OR 3.53, 95%Cl [1.22-10.23], I2=0%). CONCLUSIONS This review suggests that selective administration of prophylactic oral beta blockers prior to elective cardiac surgery is safe and may reduce the incidence of POAF.
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Preoperative Antihypertensive Medication in Relation to Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: A Meta-Analysis.
Zhou, AG, Wang, XX, Pan, DB, Chen, AJ, Zhang, XF, Deng, HW
BioMed research international. 2017;:1203538
Abstract
Background. We undertake a systematic review and meta-analysis to evaluate the effect of preoperative hypertension and preoperative antihypertensive medication to postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Methods. We searched PubMed, Embase, and Cochrane Library (from inception to March 2016) for eligible studies. The outcomes were the effects of preoperative hypertension, preoperative calcium antagonists regimen, preoperative ACE inhibitors regimen, and preoperative beta blocking agents regimen with POAF. We calculated pooled risk ratios (OR) and 95% CIs using random- or fixed-effects models. Results. Twenty-five trials involving 130087 patients were listed. Meta-analysis showed that the number of preoperative hypertension patients in POAF group was significantly higher (P < 0.05), while we found that there are no significant differences between two groups in Asia patients by subgroup analysis, which is in contrast to other outcomes. Compared with the Non-POAF group, the number of patients who used calcium antagonists and ACE inhibitors preoperatively in POAF group was significantly higher (P < 0.05). And we found that there were no significant differences between two groups of preoperative beta blocking agents used (P = 0.08). Conclusions. Preoperative hypertension and preoperative antihypertensive medication in patients undergoing cardiac operations seem to be associated with higher risk of POAF.
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Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis.
Ham, AC, van Dijk, SC, Swart, KMA, Enneman, AW, van der Zwaluw, NL, Brouwer-Brolsma, EM, van Schoor, NM, Zillikens, MC, Lips, P, de Groot, LCPGM, et al
British journal of clinical pharmacology. 2017;(10):2292-2302
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Abstract
AIMS: To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. METHODS Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. RESULTS In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. CONCLUSION Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration.
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The effects of rhythm control strategies versus rate control strategies for atrial fibrillation and atrial flutter: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis.
Sethi, NJ, Safi, S, Nielsen, EE, Feinberg, J, Gluud, C, Jakobsen, JC
Systematic reviews. 2017;(1):47
Abstract
BACKGROUND Atrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world. Atrial flutter, another arrhythmia, occurs less often with an incidence of approximately 200,000 new patients per year in the USA. Patients with atrial fibrillation and atrial flutter have an increased risk of death and morbidities. The management of atrial fibrillation and atrial flutter is often based on interventions aiming at either a rhythm control strategy or a rate control strategy. The evidence on the comparable effects of these strategies is unclear. This protocol for a systematic review aims at identifying the best overall treatment strategy for atrial fibrillation and atrial flutter. METHODS This protocol for a systematic review was performed following the recommendations of the Cochrane Collaboration and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the effects of any rhythm control strategy versus any rate control strategy. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed and classified as either high risk of bias or low risk of bias, and our conclusions will be based on trials with low risk of bias. The analyses of the extracted data will be performed using Review Manager 5 and Trial Sequential Analysis. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table and use GRADE assessment to assess the quality of the evidence. DISCUSSION The results of this systematic review have the potential to benefit thousands of patients worldwide as well as healthcare systems and healthcare economy. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42016051433.
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Effects of blood pressure-lowering treatment. 6. Prevention of heart failure and new-onset heart failure--meta-analyses of randomized trials.
Thomopoulos, C, Parati, G, Zanchetti, A
Journal of hypertension. 2016;(3):373-84; discussion 384
Abstract
BACKGROUND AND OBJECTIVES Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization. METHODS Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions. RESULTS First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]. CONCLUSION BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists.
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Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials.
Thomopoulos, C, Parati, G, Zanchetti, A
Journal of hypertension. 2016;(10):1921-32
Abstract
BACKGROUND Choice of antihypertensive drugs is also based on the expected burden of adverse events associated with each class of agents, and we have recently identified treatment discontinuation for adverse events as a measure of treatment tolerability frequently reported in randomized controlled trials (RCTs). OBJECTIVES To investigate whether all classes of blood pressure (BP) lowering drugs increase discontinuations for adverse events when compared with placebo and whether risk of discontinuation is similar for all classes when compared in head-to-head RCTs. METHODS RCTs of BP-lowering treatment were subdivided in groups according to class of drug compared with placebo or with other classes. Risk ratios and 95% confidence intervals of major cardiovascular events and of treatment discontinuations for adverse events were calculated (random-effects model). RESULTS Thirty-eight placebo-controlled RCTs (147 788 patients) and 37 head-to-head RCTs (242 481 patients) provided comparative information on discontinuations for adverse events. All classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo: risk ratio diuretics 2.23 (1.32-3.76), beta-blockers 2.88 (1.58-5.28), calcium antagonists 2.03 (1.17-3.56), angiotensin-converting enzyme inhibitors 2.78 (1.37-5.47), central agents 1.74 (1.24-2.45), with the single exception of angiotensin receptor blockers, which did not significantly increase adverse events over placebo [risk ratio 1.13 (0.78-1.62)]. Similarly, in head-to-head comparison RCTs with other classes, angiotensin receptor blockers were the only class associated with a significantly lower risk of adverse events [risk ratio 0.71 (0.58-0.87)] when head-to-head compared with other classes. Regression analysis also shows that incidence of discontinuations for adverse events is proportional to the number of antihypertensive and other cardiovascular drugs, which accounts for the high incidence of this outcome often found in groups randomized to placebo. CONCLUSION Reduction of cardiovascular events by all classes of BP-lowering drugs is accompanied by increased treatment discontinuations for adverse events, except when angiotensin receptor blockers are used. Treatment discontinuations are also related to treatment often accompanying antihypertensive agents.
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Long-Term Anti-Hypertensive Therapy and Stroke Prevention: A Meta-Analysis.
Mukete, BN, Cassidy, M, Ferdinand, KC, Le Jemtel, TH
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2015;(4):243-57
Abstract
BACKGROUND Stroke causes approximately 6.7 million deaths worldwide per year and is the second leading cause of death. Pharmacotherapy for hypertension, an independent risk factor for stroke, significantly reduces the incidence of stroke. Although prior meta-analyses demonstrate various antihypertensive classes are superior to placebo in reducing stroke risk, which class is most effective is unclear. METHODS We conducted a systematic MEDLINE search including only randomized controlled trials (RCT) of antihypertensive medications published between 1999 and 2014 in adults with stroke as a primary or secondary outcome. Five classes compared against all others were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-adrenoceptor antagonists (β-blockers), calcium channel blockers (CCBs), and thiazide or thiazide-like diuretics (T-TLDs). Among 17 RCTs with 31 comparative arms, risk ratio was used to assess effect size, and a fixed- and random-effect model was used to calculate summary effect size, utilizing comprehensive meta-analysis statistical software version 2.0. RESULTS The 251,853 subjects (46 ± 11.4 % female; mean age 67.2 ± 6.8 years), were grouped as follows: ACEI 52,887; ARB 7278; ACEI/ARB 60,165; β-blocker 24,099; CCB 98,950; and T-TLD 68,639. The mean follow-up was 42.9 ± 15 months. A random-effect model was used to assess for summary effect size in ACEI, ACEI/ARB, ARB, and T-TLD groups. The summary risk ratio for stroke occurrence in the different antihypertensive drug classes were as follows: ACEIs 1.01 (95 % confidence interval [CI] 0.81-1.27; p = 0.92); ACEIs/ARBs 0.94 (95 % CI 0.78-1.13; p = 0.51); T-TLDs 0.90 (95 % CI 0.75-1.08; p = 0.25); ARBs 0.83 (95 % CI 0.59-1.18; p = 0.30); β-blockers 1.42 (95 % CI 1.26-1.61; p < 0.01); and CCBs 0.83 (95 % CI 0.79-0.89; p < 0.01). CONCLUSION Among the antihypertensive classes, CCBs were most effective in reducing the long-term incidence of stroke, whereas β-blockers were associated with significantly increased risk.
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Influence of beta-blockers on endothelial function: A meta-analysis of randomized controlled trials.
Peller, M, Ozierański, K, Balsam, P, Grabowski, M, Filipiak, KJ, Opolski, G
Cardiology journal. 2015;(6):708-16
Abstract
BACKGROUND Endothelial dysfunction (ED) frequently precedes cardiovascular diseases (CVD) and is a well-established risk factor of major adverse cardiac events. Beta-blockers are the fundamental drugs used in CVD treatment. METHODS A systematic literature search for randomized controlled trials investigating influence of beta-blockers on endothelial function assessed by flow-mediated dilation (FMD) was performed in the PubMed and Cochrane Databases. RESULTS Sixteen full-text studies involving a total of 1,273 patients were included in the final analysis. The mean age of participating patients ranged from 44.9 to 63.2 years, the follow-up duration from 1 to 12 months. The comparison of FMD change between the beta-blockers and placebo groups showed a statistically significant effect of beta-blockers on endothelial function (mean difference [MD] 0.83; 95% confidence interval [CI] 0.11-1.55; p = 0.02). Third generation beta-blockers improved FMD in a statistically significant manner compared with second generation beta-blockers (MD 1.65; 95% CI 0.17-3.11; p = 0.03). Beta-blockers gave an FMD change similar to that obtained with angiotensin receptor blockers (ARB), calcium channel blockers (CCB) or hydrochlorothiazide. The FMD value in the beta-blocker group was significantly lower compared with the group treated with angiotensin converting enzyme inhibitors (ACEI) (MD -0.79; 95% CI -1.37-(-0.21); p = 0.008) and higher than in the ivabradine group (1.6 ± 3.61 vs -0.3 ± 1.66; p = 0.02). CONCLUSIONS Beta-blockers improve the endothelial function compared with placebo. More-over, third generation beta-blockers improve FMD values significantly better than the second generation ones. Beta-blockers had similar effect on endothelial function as did ARB, CCB or diuretics. However, the beneficial effect of beta-blockers was lower when confronted with ACEI.