Sodium-Glucose Cotransporter-2 Inhibitors and Primary Prevention of Atherosclerotic Cardiovascular Disease: A Meta-Analysis of Randomized Trials and Systematic Review.

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce atherosclerotic cardiovascular disease (ASCVD) events in patients with prior ASCVD and type 2 diabetes; however, this benefit is uncertain in patients without established ASCVD. Methods and Results Large-scale cardiovascular outcome randomized controlled trials or their prespecified subgroup analyses were selected, evaluating SGLT2 inhibitors versus placebo for primary prevention of ASCVD (inception, March 2023). The primary outcome was atherosclerotic major adverse cardiovascular events (MACEs), which was a composite of cardiovascular mortality, myocardial infarction, and stroke. The secondary outcomes were individual components of MACEs and all-cause mortality. The outcomes were reported as random-effect relative risk (RR) with a 95% CI. This analysis, comprising 23 987 patients enrolled in 5 randomized controlled trials with a mean follow-up duration of ≈135 weeks, found no significant reduction in atherosclerotic MACEs with SGLT2 inhibitors in comparison to placebo (RR, 0.85 [95% CI, 0.71-1.01]; P=0.07; I2=44). There were no significant differences in cardiovascular mortality (RR, 0.93 [95% CI, 0.77-1.14]; P=0.50; I2=0), myocardial infarction (RR, 0.88 [95% CI, 0.69-1.11]; P=0.28; I2=23), and stroke (RR, 0.84 [95% CI, 0.62-1.16]; P=0.29; I2=46). SGLT2 inhibitors significantly improved all-cause mortality (RR, 0.85 [95% CI, 0.72-1.0]; P=0.04; I2=23). On subgroup analyses, the use of SGLT2 inhibitors led to significant reductions in MACEs (RR, 0.74 [95% CI, 0.61-0.89]; P=0.001), myocardial infarction (RR, 0.67 [95% CI, 0.47-0.97]; P=0.03), and stroke (RR, 0.61 [95% CI, 0.41-0.91]; P=0.01) primarily in patients with chronic kidney disease along with type 2 diabetes, whereas these benefits were not observed in patients with type 2 diabetes without chronic kidney disease. Conclusions SGLT2 inhibitors significantly reduced atherosclerotic MACEs in subjects having both chronic kidney disease and type 2 diabetes without established ASCVD.

Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis.

BACKGROUND: The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy. METHODS: In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL). RESULTS: In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81-1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75-1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20-0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94-0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51-0.87) (P-interaction = .006). CONCLUSION: PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.

Effects of high-density lipoprotein targeting treatments on cardiovascular outcomes: A systematic review and meta-analysis.

BACKGROUND: The effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain. DESIGN: We conducted a meta-analysis to investigate the effects of high-density lipoprotein cholesterol modifiers (niacin, fibrates and cholesteryl ester transfer protein inhibitors) on cardiovascular outcomes. METHODS: Thirty-one randomized controlled trials (154,601 patients) with a follow-up of 6 months or more and a sample size of 100 or more patients were selected using MEDLINE, EMBASE and CENTRAL database (inception January 2018). RESULTS: High-density lipoprotein cholesterol modifiers had no statistically significant effect on cardiovascular mortality in terms of relative risk (RR) (RR 0.94, 95% confidence interval (CI) 0.89-1.00, P = 0.05, I2 = 13%) or absolute risk (risk difference -0.0001, 95% CI -0.0014, 0.0011, P = 0.84, I2 = 28%). High-density lipoprotein cholesterol modifiers reduced the RR of myocardial infarction (RR 0.87, 95% CI 0.82-0.93, P < 0.001, I2 = 37%). This significant effect was derived by the use of fibrates (RR 0.80, 95% CI 0.73-0.87, P < 0.001, I2 = 22%) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol. High-density lipoprotein cholesterol modifiers had no effect on stroke (RR 1.00, 95% CI 0.93-1.09, P = 0.94, I2 = 25%) or all-cause mortality (RR 1.02, 95% CI 0.97-1.08, P = 0.48, I2 = 49%). Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints. In studies with background statin therapy, high-density lipoprotein cholesterol modifiers had no statistically significant impact on cardiovascular mortality, myocardial infarction, stroke or all-cause mortality ( P > 0.05). CONCLUSION: The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality, stroke or all-cause mortality. The beneficial effect on myocardial infarction was lost when drugs were used with statin therapy.

Association of Lowering Low-Density Lipoprotein Cholesterol With Contemporary Lipid-Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Background The relationship between lowering LDL (low-density lipoprotein) cholesterol with contemporary lipid-lowering therapies and incident diabetes mellitus ( DM ) remains uncertain. Methods and Results Thirty-three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline , Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid-lowering therapy. More intensive lipid-lowering therapy was defined as the more potent pharmacological strategy ( PCSK 9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta-analyses were conducted using a random-effects model. No significant association was noted between 1-mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid-lowering therapy (risk ratio: 0.95; 95% CI , 0.87-1.04; P=0.30; R2=14%) or for statins or PCSK 9 inhibitors. More intensive lipid-lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI , 1.03-1.11; P<0.001; I2=0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI , 1.05-1.15; P<0.001; I2=0%), whereas PCSK 9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI , 0.93-1.07; P=0.96; I2=0%; P=0.02 for interaction). Conclusions Among intensive lipid-lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM . The risk of incident DM was higher with statins, whereas PCSK 9 inhibitors had no association with risk of incident DM .

Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack.

Background and Purpose- The role of aspirin plus clopidogrel (A+C) therapy compared with aspirin monotherapy in patients presenting with acute ischemic stroke (IS) or transient ischemic attack remains uncertain. We conducted this study to determine the optimal period of efficacy and safety of A+C compared with aspirin monotherapy. Methods- Ten randomized controlled trials (15 434 patients) were selected using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) (inception June 2018) comparing A+C with aspirin monotherapy in patients with transient ischemic attack or IS. The primary efficacy outcome was recurrent IS, and the primary safety outcome was major bleeding. The secondary outcomes were major adverse cardiovascular events (composite of stroke, myocardial infarction, and cardiovascular mortality) and all-cause mortality. We stratified analysis based on the short- (≤1 month), intermediate- (≤3 month), and long-term (>3 month) A+C therapy. Effects were estimated as relative risk (RR) with 95% CI. Results- A+C significantly reduced the risk of recurrent IS at short-term (RR, 0.53; 95% CI, 0.37-0.78) and intermediate-term (RR, 0.72; 95% CI, 0.58-0.90) durations. Similarly, major adverse cardiovascular event was significantly reduced by short-term (RR, 0.68; 95% CI, 0.60-0.78) and intermediate-term (RR, 0.76; 95% CI, 0.61-0.94) A+C therapy. However, long-term A+C did not yield beneficial effect in terms of recurrent IS (RR, 0.81; 95% CI, 0.63-1.04) and major adverse cardiovascular events (RR, 0.87; 95% CI, 0.71-1.07). Intermediate-term (RR, 2.58; 95% CI, 1.19-5.60) and long-term (RR, 1.87; 95% CI, 1.36-2.56) A+C regimens significantly increased the risk of major bleeding as opposed to short-term A+C (RR, 1.82; 95% CI, 0.91-3.62). Excessive all-cause mortality was limited to long-term A+C (RR, 1.45; 95% CI, 1.10-1.93). Conclusions- Short-term A+C is more effective and equally safe in comparison to aspirin alone in patients with acute IS or transient ischemic attack.

Meta-Analysis of Efficacy and Safety of Proton Pump Inhibitors with Dual Antiplatelet Therapy for Coronary Artery Disease.

BACKGROUND: There is inconsistency in the literature regarding the clinical effects of proton pump inhibitors (PPI) when added to dual antiplatelet therapy (DAPT) in subjects with coronary artery disease (CAD). We performed meta-analysis stratified by study design to explore these differences. METHODS AND RESULTS: 39 studies [4 randomized controlled trials (RCTs) and 35 observational studies) were selected using MEDLINE, EMBASE and CENTRAL (Inception-January 2018). In 221,204 patients (PPI = 77,731 patients, no PPI =143,473 patients), RCTs restricted analysis showed that PPI did not increase the risk of all-cause mortality (Risk Ratio (RR): 1.35, 95% Confidence Interval (CI), 0.56-3.23, P = 0.50, I2 = 0), cardiovascular mortality (RR: 0.94, 95% CI, 0.25-3.54, P = 0.92, I2 = 56), myocardial infarction (MI) (RR: 0.97, 95% CI, 0.62-1.51, P = 0.88, I2 = 0) or stroke (RR: 1.11, 95% CI, 0.25-5.04, P = 0.89, I2 = 26). However, PPI significantly reduced the risk of gastrointestinal (GI) bleeding (RR: 0.32, 95% CI, 0.20-0.52, P < 0.001, I2 = 0). Conversely, analysis of observational studies showed that PPI significantly increased the risk of all-cause mortality (RR: 1.25, 95% CI, 1.11-1.41, P < 0.001, I2 = 82), cardiovascular mortality (RR: 1.25, 95% CI, 1.03-1.52, P = 0.02, I2 = 71), MI (RR: 1.30, 95% CI, 1.16-1.47, P < 0.001, I2 = 82) and stroke (RR: 1.60, 95% CI, 1.43-1.78, P < 0.001, I2 = 0), without reducing GI bleeding (RR: 0.74, 95% CI, 0.45-1.22, P = 0.24, I2 = 79). CONCLUSION: Meta-analysis of RCTs endorsed the use of PPI with DAPT for reducing GI bleeding without worsening cardiovascular outcomes. These findings oppose the negative observational data regarding effects of PPI with DAPT.

A Bayesian network meta-analysis of preventive strategies for contrast-induced nephropathy after cardiac catheterization.

BACKGROUND: The optimal preventive strategy for contrast induced acute kidney injury (CIAKI) in patients undergoing cardiac catheterization remains uncertain. OBJECTIVE: We conducted Bayesian network meta-analysis (NMA) to compare different preventive strategies for CIAKI in these cohorts. METHODS: Forty-nine randomized controlled trials were extracted using MEDLINE, EMBASE and CENTRAL data bases (inception-1st December 2017). We calculated median of the odds ratio (OR) with the corresponding 95% credible interval (CrI). The ranking probability of each treatment was based on SUCRA (surface under the cumulative ranking curve). RESULTS: In NMA of 28,063 patients [normal saline (NS: 9716 patients), sodium bicarbonate (NaHCO3: 4484 patients), statin (2542 patients), N-acetylcysteine (NAC: 3006 patients), NAC + NaHCO3 (774 patients), NS + NAC (3807 patients), NS + NaHCO3 (135 patients) and placebo (3599 patients)], statins reduced the relative risk of CIAKI compared with NS (OR: 0.50; 95% CrI, 0.25-0.99), and placebo (OR: 0.44; 95% CrI, 0.24-0.83). Subgroup analyses showed that in patients receiving low osmolar contrast, statins reduced the relative risk of CIAKI by 58% versus NS, and 51% versus placebo. There were no significant differences across all the treatments in terms of risk of hemodialysis or all-cause mortality. Statins had the highest probability for reducing the risk of CIAKI (SUCRA, 0.86), risk of hemodialysis (SUCRA, 0.88) and all-cause mortality (SUCRA, 0.81). CONCLUSION: Statins were the superior preventive strategy for reducing the risk of CIAKI compared with NS alone and placebo.

Meta-analysis of safety and efficacy of oral anticoagulants in patients requiring catheter ablation for atrial fibrillation.

BACKGROUND: The ideal oral anticoagulant agent during catheter ablation (CA) for atrial fibrillation (AF) remained unclear. HYPOTHESIS: Novel oral anticoagulants (NOACs) are safer and effective compared to uninterrupted vitamin K antagonists (U-VKA) among patients requiring CA for AF. METHODS: Four randomized controlled trials (RCTs) and 9 observational studies (OS) were selected using PubMed/Medline, EMBASE and the CENTRAL data bases (Inception-December-2017). Estimates were reported as random effects risk ratio (RR) with 95% confidence interval (CI). The primary safety outcome was major bleeding and main efficacy endpoint was thromboembolism. RESULTS: In RCTs restricted analysis, NOACs significantly reduced the relative risk of major bleeding by 72% compared to U-VKA (RR, 0.28, 95% CI, 0.14-0.58, P < 0.001). This significant effect was not achieved in OS based analysis (RR, 0.86, 95% CI, 0.42-1.78, P = 0.68). In terms of thromboembolism, both anticoagulation strategies were equally effective in analysis of RCTs (RR, 0.28, 95% CI, 0.05-1.70, P = 0.17) or OS (RR, 1.43, 95% CI, 0.46-4.39, P = 0.54). In sensitivity analysis, there was no difference among uninterrupted NOACs (U-NOACs) and U-VKA in terms of major bleeding [(RCTs: RR, 0.33, 95% CI, 0.10-1.06, P = 0.06); (OS: RR, 0.70, 95% CI, 0.28-1.78, P = 0.46)] or thromboembolism [(RCTs: RR, 0.25, 95% CI, 0.03-2.29, P = 0.22); (OS: RR, 0.68, 95% CI, 0.08-5.53, P = 0.72)]. CONCLUSION: NOACs, either interrupted or un-interrupted, are safer and equally effective drugs compared to U-VKA in AF patients requiring CA.

Revascularization strategies in cardiogenic shock complicating acute myocardial infarction: A systematic review and meta-analysis.

BACKGROUND: The optimal revascularization strategy in patients with multi-vessel disease (MVD) presenting with acute myocardial infarction (AMI) and cardiogenic shock (CS) remains unclear. OBJECTIVE: To investigate the comparative differences between culprit-only revascularization (COR) versus instant multi-vessel revascularization (IMVR) in AMI and CS. METHODS: 13 studies were selected using MEDLINE, EMBASE and the CENTRAL (Inception - 31 November2017). Outcomes were assessed at short-term (in-hospital or ≤30 days duration) and long-term duration (≥6 months). Estimates were reported as random effects relative risk (RR) with 95% confidence interval (CI). RESULTS: In analysis of 7311 patients, COR significantly reduced the relative risk of short-term all-cause mortality (RR: 0.87; 95% CI, 0.77-0.97; p = 0.01, I2 = 50%) and renal failure (RR: 0.75; 95% CI, 0.61-0.94; p = 0.01, I2 = 7%) compared with IMVR. There were no significant differences between both the strategies in terms of reinfarction (RR: 1.25; 95% CI, 0.59-2.63; p = 0.56, I2 = 0%), major bleeding (RR: 0.88; 95% CI, 0.75-1.04; p = 0.14, I2 = 0%) and stroke (RR: 0.77; 95% CI, 0.50-1.17; p = 0.22, I2 = 0%) at short term duration. Similarly, no significant differences were observed between both groups regarding all-cause mortality (RR; 1.01; 95% CI, 0.85-1.20; p = 0.93, I2 = 61%) and reinfarction (RR: 0.71; 95% CI, 0.34-1.47; p = 0.35, I2 = 26%) at long term duration. CONCLUSION: In MVD patients presenting with AMI and CS, IMVR was comparable to COR in terms of all-cause mortality at long term follow up duration. These results are predominantly derived from observational data and more randomized controlled trials are required to validate this impression.

Implantable cardioverter defibrillator in nonischemic cardiomyopathy: A systematic review and meta-analysis.

The evidence to support implantable cardioverter defibrillator (ICD) in subjects with nonischemic cardiomyopathy (NICM) for primary prevention of sudden cardiac death (SCD) is not robust. This meta-analysis intends to assess the impact of routine ICD implantation for primary prevention of mortality due to SCD in NICM based on all the published randomized clinical trials (RCTs). Six RCTs were selected using PubMed/Medline, EMBASE, and CENTRAL from inception to December 2016. Outcomes were calculated as random-effects relative risk (RR) and risk difference (RD) with 95% confidence interval (CI). Patients were randomized to ICD arm and control arm (usual care, medical treatment, and anti-arrhythmic drugs). ICD significantly reduced all-cause mortality in NICM patients (RR, 0.74, 95% CI, 0.56-0.97, P = .03, I2 = 40). Mortality benefit was achieved due to a significant reduction in sudden cardiac death (SCD) (RR, 0.47, 95% CI, 0.30-0.73, P < .001, I2 = 0). There were no statistical differences between two groups with regard to risk of noncardiac mortality, non-SCD, cardiac arrest, cardiac transplant, sustained ventricular tachycardia (VT), and VT requiring medical treatment. Our results support efficacy of ICDs at reducing all-cause mortality due to a reduction in SCD.

The Clinical Benefits and Mortality Reduction Associated With Catheter Ablation in Subjects With Atrial Fibrillation: A Systematic Review and Meta-Analysis.

OBJECTIVES: This study sought to compare the efficacy and safety of catheter ablation (CA) with those of medical therapy (MT) for the treatment of atrial fibrillation (AF). BACKGROUND: The preferred therapeutic strategy for subjects with AF remains unclear. METHODS: A total of 17 randomized controlled trials were selected using Medline, EMBASE, and CENTRAL (September 1998 to 2 February 2018). The analysis was stratified at the trial level according to the following: 1) patients with AF and heart failure (HF); and 2) patients with AF without HF. RESULTS: A total of 2,272 patients with AF (775 patients with HF and 1,497 patients without HF) participated in this analysis. In patients with HF, CA was associated with significant relative risk reduction in all-cause mortality (risk ratio [RR]: 0.52; 95% confidence interval [CI]: 0.36 to 0.76; p < 0.001; I2 = 0), recurrent atrial arrhythmia (RR: 0.44; 95% CI: 0.31 to 0.61; p <0.001; I2 = 56), and cardiac hospitalization (RR: 0.63; 95% CI: 0.46 to 0.87; p = 0.01; I2 = 43) compared with MT. Conversely, in patients without HF, CA had no beneficial effect on the risk of all-cause mortality compared with MT (RR: 0.88, 95% CI: 0.29 to 2.61; p = 0.81; I2 = 0). However, CA reduced the risk of recurrent atrial arrhythmia (RR: 0.40; 95% CI: 0.31 to 0.52; p < 0.001; I2 = 73) and cardiac hospitalization (RR: 0.32; 95% CI: 0.23 to 0.45; p < 0.001; I2 = 0) in patients without HF. CONCLUSIONS: This meta-analysis suggests that although CA reduced the risk of cardiac hospitalization and recurrent atrial arrhythmia both in subjects with HF and in subjects without HF, the reduction in all-cause mortality was limited to subjects with HF only.

A Bayesian network meta-analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes.

Background The comparative effects of statins, ezetimibe with or without statins and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors remain unassessed. Design Bayesian network meta-analysis was conducted to compare treatment groups. Methods Thirty-nine randomized controlled trials were selected using MEDLINE, EMBASE, and CENTRAL (inception - September 2017). Results In network meta-analysis of 189,116 patients, PCSK9 inhibitors were ranked as the best treatment for prevention of major adverse cardiovascular events (Surface Under Cumulative Ranking Curve (SUCRA), 85%), myocardial infarction (SUCRA, 84%) and stroke (SUCRA, 80%). PCSK9 inhibitors reduced the risk of major adverse cardiovascular events compared with ezetimibe + statin (odds ratio (OR): 0.72; 95% credible interval (CrI), 0.55-0.95; Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria: moderate), statin (OR: 0.78; 95% CrI: 0.62-0.97; GRADE: moderate) and placebo (OR: 0.63; 95% CrI: 0.49-0.79; GRADE: high). The PCSK9 inhibitors were consistently superior to groups for major adverse cardiovascular event reduction in secondary prevention trials (SUCRA, 95%). Statins had the highest probability of having lowest rates of all-cause mortality (SUCRA, 82%) and cardiovascular mortality (SUCRA, 84%). Compared with placebo, statins reduced the risk of all-cause mortality (OR: 0.88; 95% CrI: 0.83-0.94; GRADE: moderate) and cardiovascular mortality (OR: 0.84; 95% CrI: 0.77-0.90; GRADE: high). For cardiovascular mortality, PCSK9 inhibitors were ranked as the second best treatment (SUCRA, 78%) followed by ezetimibe + statin (SUCRA, 50%). Conclusion PCSK9 inhibitors were ranked as the most effective treatment for reducing major adverse cardiovascular events, myocardial infarction and stroke, without having major safety concerns. Statins were ranked as the most effective therapy for reducing mortality.

A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea.

Aims: To assess whether continuous positive airway pressure (CPAP) therapy reduces major adverse cardiovascular events (MACE) in patients with moderate-to-severe obstructive sleep apnoea (OSA). Methods and results: A total of 235 articles were recovered using MEDLINE, EMBASE and Cochrane library (inception-December 2016) and references contained in the identified articles. Seven randomized controlled trials (RCTs) were selected for final analysis. Analysis of 4268 patients demonstrated non-significant 26% relative risk reduction in MACE with CPAP [risk ratio (RR) 0.74; 95% confidence interval (CI) 0.47-1.17; P = 0.19, I2 = 48%]. A series of sensitivity analyses suggested that increased CPAP usage time yielded significant risk reduction in MACE. and stroke. Subgroup analysis revealed that CPAP adherence time ≥4 hours (h)/night reduced the risk of MACE by 57% (RR 0.43; 95% CI 0.23-0.80; P = 0.01, I2 = 0%). CPAP therapy showed no beneficial effect on myocardial infarction (MI), all-cause mortality, atrial fibrillation/flutter (AF), or heart failure (HF) (P > 0.05). CPAP had positive effect on mood and reduced the daytime sleepiness [Epworth Sleepiness Scale (ESS): mean difference (MD) -2.50, 95% CI - 3.62, -1.39; P < 0.001, I2 = 81%]. Conclusion: CPAP therapy might reduce MACE and stroke among subjects with CPAP time exceeding 4 h/night. Additional randomized trials mandating adequate CPAP time adherence are required to confirm this impression.