Stroke embodies one of the leading causes of death and disability worldwide. We aimed to provide a comprehensive insight into the effectiveness and safety of antiplatelet agents and anticoagulants in the secondary prevention of ischemic stroke or transient ischemic attack. A systematic search for randomized controlled trials, comparing antiplatelet or anticoagulant therapy versus aspirin or placebo among patients with ischemic stroke or transient ischemic attack, was performed in order to summarize data regarding the different regimens. Keyword-based searches in the MEDLINE, EMBASE, and Cochrane Library databases were conducted until the 1st of January 2021. Our search explored 46 randomized controlled trials involving ten antiplatelet agents, six combinations with aspirin, and four anticoagulant therapies. The review of the literature reflects that antiplatelet therapy improves outcome in patients with ischemic stroke or transient ischemic attack. Monotherapy proved to be an effective and safe choice, especially in patients with a high risk of bleeding. Intensified antiplatelet regimens further improve stroke recurrence; however, bleeding rate increases while mortality remains unaffected. Supplementing the clinical judgment of stroke treatment, assessment of bleeding risk is warranted to identify patients with the highest benefit of treatment intensification.

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. Methods: 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. Results: 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, 0.71–0.89]). Treatment with ticagrelor monotherapy did not significantly affect ischemic stroke (risk ratio, 0.88 [95% CI, 0.77–1.00]; 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, 0.91–1.07]). Conclusions: 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.

BackgroundDespite 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.MethodsSystematic 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.ResultsFifteen 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.ConclusionOur 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].

Objective As stroke represents one of the leading causes of mortality and disability worldwide, we aimed to determine the preventive effect of different antiplatelet therapies after an ischemic stroke or transient ischemic attack. Methods Network meta-analysis evaluating antiplatelet regimes after an ischemic stroke or transient ischemic attack. Searches were conducted in MEDLINE, EMBASE, and Cochrane Library databases until Nov. 23, 2021, for randomized controlled trials. Direct comparisons within trials were combined with indirect evidence from other trials by using a frequentist model. An additive network meta-analysis model was used to evaluate the influence of individual components. The primary efficacy endpoint was a recurrent stroke, the main safety outcomes were the risk of major bleeding and mortality at the longest available follow-up. Results 58 randomized controlled trials (175,730 patients) were analyzed. The analysis involved 20 antithrombotic strategies including different antiplatelet agents, combinations with aspirin, and anticoagulant therapies. Cilostazol proved to be the most efficacious in reducing stroke recurrence and the risk of bleeding (RR = 0.66, 95%CI = 0.55–0.80 and RR = 0.39, 95%CI = 0.08–2.01) compared to aspirin, respectively. Intensification with combinations of aspirin with ticagrelor or clopidogrel resulted in a lower risk of stroke recurrence (RR = 0.79, 95%CI = 0.67–0.93 and RR = 0.79, 95%CI = 0.72–0.87) but carried a higher bleeding risk (RR = 3.01, 95%CI = 1.65–5.49 and RR = 1.78 95%CI = 1.49–2.13). Conclusion The prognosis of patients with an ischemic stroke or transient ischemic attack is improved with antiplatelets. Cilostazol showed the best risk-benefit characteristics without trade-off with the risk of major bleeding. Improved stroke recurrence with intensified antiplatelet regimens is counterbalanced with higher bleeding risk, and consequently, mortality remains unaffected. Treatment decisions in stroke survivals should integrate the assessment of bleeding risk for better identification of patients with the highest benefit of treatment intensification. Systematic review registration Prospero registration number: CRD42020197143, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=197143.

IntroductionDual 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.MethodsElectronic 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.ResultsTen 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.ConclusionOur 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 registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021258502, identifier CRD42021258502.

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This comprehensive literature review assessed the effectiveness of precision medicine approaches in individualizing P2Y12 de-escalation strategies, such as platelet function testing guidance, genetic testing guidance, and uniform de-escalation, for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Analyzing six trials with a total of 13,729 patients, the cumulative analyses demonstrated a significant reduction in major adverse cardiac events (MACE), net adverse clinical events (NACE), and major and minor bleeding events with P2Y12 de-escalation. Specifically, the analysis found a 24% reduction of MACE and a 22% reduction of adverse event risk (relative risk (RR) 0.76, 95% confidence interval (CI): 0.71–0.82, and RR: 0.78, 95% CI 0.67–0.92, respectively). Reductions in bleeding events were highest with uniform unguided de-escalation, followed by guided de-escalations, while ischemic event rates were similarly lower across all three strategies. Although the review highlights the potential of individualized P2Y12 de-escalation strategies to offer a safer alternative to the long-term potent P2Y12 inhibitor-based dual antiplatelet therapy, it also indicates that laboratory-guided precision medicine approaches may not yet offer the expected benefits, necessitating further research to optimize individualized strategies and evaluate the potential of precision medicine approaches in this context.

BackgroundGliflozins 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.ObjectivesWe aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes.MethodsSystematic 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.ResultsTwenty-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.ConclusionOur 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].