Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials.

Background: Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results. Objectives: We aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes. Methods: Systematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke. Results: Twenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin. Conclusion: Our meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition. Systematic review registration: [www.ClinicalTrials.gov], identifier [CRD42022358078].

Combination of antiplatelet and anticoagulant therapy, component network meta-analysis of randomized controlled trials.

Background: Despite numerous randomized clinical trials (RCT), data regarding the efficacy of antiplatelet and anticoagulant combinations are still conflicting. We aimed to analyze treatment options tested in various fields of cardiovascular prevention, regarding their efficacy and bleeding risk. Methods: Systematic searches of electronic databases were conducted until June 2022. A component network meta-analysis was performed in R. Risk estimates across trials were pooled using random-effects model selecting risk ratio (RR) with 95% confidence intervals (95% CIs) as summary statistics. The primary endpoint of interest was the rate of major cardiac adverse events (MACE). Major bleeding events were assessed as main safety endpoint. Secondary outcomes included cardiovascular- and overall mortality, myocardial infarction (MI), stent thrombosis, and stroke. Results: Fifteen studies randomizing 73,536 patients were identified. The MACE risk reflected heterogeneity among the anticoagulants with dabigatran and apixaban significantly reducing the risk of MACE (RR 0.56; 95% CI 0.39-0.80 and RR 0.75; 95% CI 0.58-0.98, respectively). Vitamin K antagonist (VKA), rivaroxaban, or edoxaban did not reduced of MACE while it was associated with a significant increase of bleeding risk (RR 1.66; 3.66, and 5.47, respectively). The direct anticoagulant (DOAC) dose reduction resulted in tendencies of fewer bleeding but higher MACE risk, while combination with aspirin was followed with increased risk for bleeding, however, remained non-significant in these cases. Conclusion: Our meta-analysis supports that the ischemic-bleeding balance is different among direct-acting oral anticoagulants (DOACs) while this is not significantly affected by the dose reduction approaches. Long-term aspirin treatment as part of the anticoagulant and dual antiplatelet regimen provides no ischemic benefit but may increase bleeding risk. Systematic review registration: [https://www.crd.york.ac.uk/prospero/], identifier [259703].

Abatement of potent P2Y12 antagonist-based dual antiplatelet therapy after coronary intervention: A network meta-analysis of randomized controlled trials.

Introduction: Dual antiplatelet therapy (DAPT) including prasugrel or ticagrelor is recommended in patients with acute coronary syndromes (ACS) treated with coronary intervention (PCI). Acknowledging the importance of bleeding, multiple trials tested abatement schemes including uniform or guided de-escalation from the potent P2Y12 inhibitor (P2Y12-De) or P2Y12 inhibitor monotherapy (P2Y12-Mo) with heterogeneous results. We aimed to perform a systematic review and network meta-analysis of the impact of DAPT abatement strategies in patients with PCI. Methods: Electronic databases were searched for relevant randomized clinical studies evaluating clinical outcomes of patients after PCI. The rate of adverse events was evaluated using a frequentist network metanalysis. The random-effects model was used to combine risk estimates across trials and risk ratio (RR) with 95% confidence intervals (95% CIs) served as summary statistics. The primary endpoints of interest were the rate of major cardiac adverse events (MACE, defined as the composite of cardiovascular mortality, myocardial infarction and stroke) and bleeding. Results: Ten studies were identified randomizing 42511 patients. 6359 switched to the P2Y12-De and 13062 switched to the P2Y12-Mo. The risk of MACE, reflected a 24% reduction in the P2Y12-De and a 14% in the P2Y12-Mo in comparison with the DAPT strategy using potent P2Y12 inhibitors (RR: 0.76 [0.62, 0.94], and RR: 0.86 [0.75, 0.99], p < 0.05 both). A 35% risk reduction of major bleeding was seen with monotherapy (RR: 0.65 [0.46, 0.91],) contrasting the de-escalation trials where this effect was not significant (RR: 0.84 [0.57, 1.22]). All bleeding and minor bleeding events were reduced with both strategies. Indirect P2Y12-Mo versus P2Y12-De comparisons exhibited them as similar alternatives without significant differences. Conclusion: Our analysis suggests that both P2Y12-De and P2Y12-Mo reduce ischemic events and bleeding among PCI-treated ACS patients. Ischemic benefit was more expressed with P2Y12-De, however, reduction of major bleeding was only significant with P2Y12-Mo strategy. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021258502, identifier CRD42021258502.

Network Meta-Analysis of Ticagrelor for Stroke Prevention in Patients at High Risk for Cardiovascular or Cerebrovascular Events.

Background and Purpose: Preventive antiplatelet therapy is recommended for patients with cardiac or cerebrovascular atherosclerosis. Ticagrelor has an improved safety and efficacy profile in patients with acute coronary syndrome; however, data regarding stroke prevention remain controversial. We conducted a network meta-analysis to compare ticagrelor with other receptor antagonists (P2Y12) inhibitors and aspirin in monotherapy or combination in the treatment of patients with high risk for cardiovascular or cerebrovascular disease, defined as coronary artery disease, acute coronary syndrome, stroke or transient ischemic attack, or peripheral artery disease.Systematic searches of MEDLINE, EMBASE, and the Cochrane Library were conducted until August 1, 2020. Search terms included ticagrelor, AZD 6140, and stroke. The risk of bias was assessed using the Cochrane Collaboration assessment tool. Random-effects model was used to combine risk estimates across trials and risk ratio with 95% CIs served as summary statistics. The influence of individual components was evaluated in an additive network meta-analysis model. The primary efficacy end point was the occurrence of stroke. The safety end points included bleeding and all-cause mortality.Twenty-six randomized clinical trials comprising 124 495 patients were analyzed. When compared with controls, ticagrelor plus aspirin significantly reduced the risk of ischemic stroke by 20% (risk ratio, 0.80 [95% CI, 0.71­0.89]). Treatment with ticagrelor monotherapy did not significantly affect ischemic stroke (risk ratio, 0.88 [95% CI, 0.77­1.00]; P=0.05). Compared with aspirin alone, major bleeding was in similar ranges with antiplatelet monotherapies while the relative risk was twice higher with combined antiplatelet therapies. There was no considerable difference in the risk of mortality with ticagrelor plus aspirin (risk ratio, 0.99 [95% CI, 0.91­1.07]).Ticagrelor on top of aspirin may provide more favorable outcomes on secondary stroke prevention in patients with vascular risk factors; however, this benefit may come with the price of increased bleeding risk including intracranial bleeding.

Oral anticoagulation and outcomes in patients with acute myocardial infarction: Insights from the Hungarian Myocardial Infarction Registry.

INTRODUCTION: Anticoagulation reduces the risk of stroke and embolization and is recommended in most patients with atrial fibrillation. Patients after coronary intervention and acute coronary syndromes require antiplatelet treatment. Although oral anticoagulation (OAC) therapy may interfere with the outcome of patients after coronary intervention, its exact impact remains unclear. Importantly, risk-benefit relations may be considerably different after myocardial infarction. MATERIAL AND METHODS: Data of patients registered from the Hungarian Myocardial Infarction Registry, a mandatory nationwide program for hospitals treating patients with myocardial infarction, were processed. Patients registered between 01.2014. and 12.2017 were included. All-cause mortality, the composite of cardiac events (MACE), and transfusion were compared between patients receiving OAC treatment and a propensity score (PS) matched control group. Subgroup analyses of different anticoagulation and antiplatelet strategies were performed with propensity weighted Cox proportional hazards' models to estimate risk during the first year after the index event. RESULTS: From 30 681 patients 1875 cases received OAC treatment and had apparently worse prognosis. After PS-matching, however, we found no difference regarding mortality (hazard ratio [HR]: 0.91 95% CI 0.77-1.09, P = .303), MACE (HR: 0.92 95% CI 0.78-1.09, P = .335) or transfusion (HR: 1.21, 95% CI 0.97-1.49, P = .086). In PS-adjusted analyses for the OAC group, patients who received aspirin were associated with lower mortality (HR: 0.77, 95% CI: 0.60-0.997, P = .048) and MACE (HR:0.73, 95% CI 0.58-0.92, P = .008) compared to those without aspirin. CONCLUSIONS: In patients with acute myocardial infarction, the prognosis of OAC-treated patients was comparable to the PS matched control; however, the omission of aspirin therapy was associated with unfavorable outcomes.