Ivabradine added to usual care in patients with heart failure: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVES: To assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure. DESIGN: A systematic review with meta-analysis and trial sequential analysis. ELIGIBILITY CRITERIA: Randomised clinical trials comparing ivabradine and usual care with usual care (with or without) placebo in participants with heart failure. INFORMATION SOURCES: Medline, Embase, CENTRAL, LILACS, CNKI, VIP and other databases and trial registries up until 31 May 2021. DATA EXTRACTION: Primary outcomes were all-cause mortality, serious adverse events and quality of life. Secondary outcomes were cardiovascular mortality, myocardial infarction and non-serious adverse events. We performed meta-analysis of all outcomes. We used trial sequential analysis to control risks of random errors, the Cochrane risk of bias tool to assess the risks of systematic errors and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence. RESULTS: We included 109 randomised clinical trials with 26 567 participants. Two trials were at low risk of bias, although both trials were sponsored by the company that developed ivabradine. All other trials were at high risk of bias. Meta-analyses and trial sequential analyses showed that we could reject that ivabradine versus control reduced all-cause mortality (risk ratio (RR)=0.94; 95% CI 0.88 to 1.01; p=0.09; high certainty of evidence). Meta-analysis and trial sequential analysis showed that ivabradine seemed to reduce the risk of serious adverse events (RR=0.90; 95% CI 0.87 to 0.94; p<0.00001; number needed to treat (NNT)=26.2; low certainty of evidence). This was primarily due to a decrease in the risk of 'cardiac failure' (RR=0.83; 95% CI 0.71 to 0.97; p=0.02; NNT=43.9), 'hospitalisations' (RR=0.89; 95% CI 0.85 to 0.94; p<0.0001; NNT=36.4) and 'ventricular tachycardia' (RR=0.59; 95% CI 0.43 to 0.82; p=0.001; NNT=212.8). However, the trials did not describe how these outcomes were defined and assessed during follow-up. Meta-analyses showed that ivabradine increased the risk of atrial fibrillation (RR=1.19; 95% CI 1.04 to 1.35; p=0.008; number needed to harm (NNH)=116.3) and bradycardia (RR=3.95; 95% CI 1.88 to 8.29; p=0.0003; NNH=303). Ivabradine seemed to increase quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference (MD)=2.92; 95% CI 1.34 to 4.50; p=0.0003; low certainty of evidence), but the effect size was small and possibly without relevance to patients, and on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) (MD=-5.28; 95% CI -6.60 to -3.96; p<0.00001; very low certainty of evidence), but the effects were uncertain. Meta-analysis showed no evidence of a difference between ivabradine and control when assessing cardiovascular mortality and myocardial infarction. Ivabradine seemed to increase the risk of non-serious adverse events. CONCLUSION AND RELEVANCE: High certainty evidence shows that ivabradine does not seem to affect the risks of all-cause mortality and cardiovascular mortality. The effects on quality of life were small and possibly without relevance to patients on the KCCQ and were very uncertain for the MLWHFQ. The effects on serious adverse events, myocardial infarction and hospitalisation are uncertain. Ivabradine seems to increase the risk of atrial fibrillation, bradycardia and non-serious adverse events.PROSPERO registration number: CRD42018112082.

Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis.

OBJECTIVE: To determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease. METHODS: We conducted a systematic review. We included randomised clinical trials comparing ivabradine versus placebo or no intervention for patients with angina pectoris due to coronary artery disease published prior to June 2020. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Cochrane methodology, Trial Sequential Analysis, Grading of Recommendations Assessment, Development, and Evaluation, and our eight-step procedure. Primary outcomes were all-cause mortality, serious adverse events and quality of life. RESULTS: We included 47 randomised clinical trials enrolling 35 797 participants. All trials and outcomes were at high risk of bias. Ivabradine compared with control did not have effects when assessing all-cause mortality (risk ratio [RR] 1.04; 95% CI 0.96 to 1.13), quality of life (standardised mean differences -0.05; 95% CI -0.11 to 0.01), cardiovascular mortality (RR 1.07; 95% CI 0.97 to 1.18) and myocardial infarction (RR 1.03; 95% CI 0.91 to 1.16). Ivabradine seemed to increase the risk of serious adverse events after removal of outliers (RR 1.07; 95% CI 1.03 to 1.11) as well as the following adverse events classified as serious: bradycardia, prolonged QT interval, photopsia, atrial fibrillation and hypertension. Ivabradine also increased the risk of non-serious adverse events (RR 1.13; 95% CI 1.11 to 1.16). Ivabradine might have a statistically significant effect when assessing angina frequency (mean difference (MD) 2.06; 95% CI 0.82 to 3.30) and stability (MD 1.48; 95% CI 0.07 to 2.89), but the effect sizes seemed minimal and possibly without any relevance to patients, and we identified several methodological limitations, questioning the validity of these results. CONCLUSION: Our findings do not support that ivabradine offers significant benefits on patient important outcomes, but rather seems to increase the risk of serious adverse events such as atrial fibrillation and non-serious adverse events. Based on current evidence, guidelines need reassessment and the use of ivabradine for angina pectoris should be reconsidered. PROSPERO REGISTRATION NUMBER: CRD42018112082.

Coronary artery bypass surgery plus medical therapy versus medical therapy alone for ischaemic heart disease: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Despite increasing survival, cardiovascular disease remains the primary cause of death worldwide with an estimated 7.4 million annual deaths. The main symptom of ischaemic heart disease is chest pain (angina pectoris) most often caused by blockage of a coronary artery. The aim of coronary artery bypass surgery is revascularisation achieved by surgically grafting harvested arteries or veins distal to the coronary lesion restoring blood flow to the heart muscle. Older evidence suggested a clear survival benefit of coronary artery bypass graft surgery, but more recent trials yield less clear evidence. We want to assess the benefits and harms of coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease. METHODS: This protocol for a systematic review follows the recommendations of Cochrane and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all randomised clinical trials assessing coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease. 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 as high risk or low risk of bias, and our conclusions will primarily be based on trials at low risk of bias. The analyses of the extracted data will be performed using Review Manager 5, STATA 16 and trial sequential analysis. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table and use GRADE to assess the certainty of the evidence. DISCUSSION: Coronary artery bypass surgery is invasive and can cause death, which is why its use must be thoroughly studied to determine if it yields a large enough long-term benefit for the thousands of patients receiving it every year. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID 131924.

Selective serotonin reuptake inhibitors are still harmful and ineffective. Responses to the comments by Hieronymus et al.

In this response, we address point by point the additional issues raised by Hieronymus et al. in their second round of critique of our systematic review on selective serotonin reuptake inhibitors for major depression. We repulse that we are biased or mistaken in any major ways. We acknowledge that we missed a few small, mostly unpublished trials, and we made a few minor errors in our systematic review. However, these omissions and errors neither have any impact on our overall results nor on our conclusions. The critique by Hieronymus et al. seems to raise questions about their understanding of the systematic review process, and, on several occasions, they wrongly claimed that we made errors. Our analyses should be impartial and free from any biases or prejudices as we do not have any obligation to support the interests of sponsors or other groups.

Great boast, small roast on effects of selective serotonin reuptake inhibitors: response to a critique of our systematic review.

Our systematic review in BMC Psychiatry concluded that selective serotonin reuptake inhibitors (SSRIs) compared with placebo significantly increase the risk of serious adverse events (SAEs) in patients with major depression and the potential beneficial effects of SSRIs seem to be outweighed by the harms. Hieronymus et al. accused us of methodological inaccuracies and blatant errors. In their post-hoc analysis of our data, they reported that SSRIs only increase the risk of SAEs in elderly and seems safe for non-elderly patients. They also found our review misleading because our efficacy analyses were based on the 17-item Hamilton Depression Rating Scale; we included suboptimal SSRI doses; and we missed some 'pivotal trials'. We do not agree with Hieronymus et al. regarding several of the 'errors' they claim that we have made. However, we acknowledge that they have identified minor errors and that we missed some trials. After rectifying the errors and inclusion of the missed trials by us and Hieronymus et al., we re-analysed the data. The updated analyses are even more robust and confirm our earlier conclusions. SSRIs significantly increase the risk of an SAE both in non-elderly (p=0.045) and elderly (p=0.01) patients [overall odds ratio 1.39; 95% confidence interval (CI) 1.13 to 1.73; p=0.002; I2=0%]. Moreover, SSRIs did not change noticeably the 17-item Hamilton Depression Rating Scale, the internationally accepted scale (mean difference -2.02 points; 95% CI -2.38 to -1.66; p<0.00001). We found no differential effect of dose (p=0.20).