Individualized or Uniform De-Escalation Strategies for Antiplatelet Therapy in Acute Coronary Syndrome: A Review of Clinical Trials with Platelet Function Testing and Genetic Testing-Based Protocols.

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.

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.

Use of drug-eluting stents in elderly patients with acute myocardial infarction: An analysis of the Hungarian Myocardial Infarction Registry.

BACKGROUND: Bare-metal stents (BMS) are frequently implanted in elderly patients instead of drug-eluting stents (DES). We aimed to compare the prognosis of patients treated for myocardial infarction with the two types of stents over the age of 75. METHODS: Data of patients registered in the Hungarian Myocardial Infarction Registry, a mandatory nationwide programme for hospitals treating patients with myocardial infarction were processed. From patients included between January 2014 and December 2017 we created two groups according to DES and BMS implantation. The outcome measures included all-cause mortality, the composite of cardiac events (MACE), repeated revascularisation and transfusion. Propensity score matching was used to balance the groups and Cox proportional hazards' models to estimate the risk during the 1st year after the index event. RESULTS: From 7383 patients (age: 81.08 ± 4.38 years) 3266 (44.2%) patients received DES. The PS-matched cohort included 5780 cases with balanced characteristics. In the DES group, the mortality (HR 0.66 [0.60-0.72]), MACE (HR 0.66 [0.60-0.72]) and the rate of transfusion (HR 0.84 [0.73-0.97]) were significantly lower. The PS-matched cohort showed a similar trend but with a lower rate of benefits with a 21% reduction of mortality and 23% of MACE. Difference in transfusion did not reach the level of significance. In multivariate models, stent type prevailed as an independent predictor of mortality and but not of transfusion. CONCLUSIONS: Based on our analysis of a real-life, high-risk population, implantation of DES seems to be an advantageous strategy for elderly patients.

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.

Prognosis Impact and Prediction of Trans-Radial Access Failure in Patients With STEMI, A Nationwide Observational Study.

Trans-radial access (TRA) is the primary arterial approach for percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). However, occasionally, a crossover to trans-femoral access is necessary because of unsuccessful TRA. The impact of failed TRA on the prognosis in STEMI patients and the utility of predictive models for TRA failure remains uncertain. Data from the Hungarian Myocardial Infarction Registry (January 2014 to December 2020) were analyzed. Primary endpoints were 1-year mortality and major adverse cardiovascular events. Propensity score matching was employed to create a balanced cohort for comparing successful and failed TRA. The impact of unsuccessful TRA on prognosis was evaluated using Cox regression analysis. Machine learning techniques were applied to predict TRA failure. The performance and the clinical applicability of the novel and previous prediction models were comprehensively evaluated. Of 76,625 registered patients, 34,293 (69.8 ± 13.4 years, male/female: 21,893/12,400) underwent TRA (33,573) or failed TRA (720) PCI for STEMI. After propensity score matching, in the unsuccessful TRA group, the risk of mortality (34.3% vs 22.5%, hazard ratio 1.6, 95% confidence interval 1.3 to 2.0, p <0.001) and major adverse cardiovascular events (37.4% vs 26.8%, hazard ratio 1.5, 95% confidence interval 1.3 to 1.8, p <0.001) were significantly higher. Door-to-balloon time did not differ significantly (p = 0.835). In predictive analysis, Regularized Discriminant Analysis emerged as the most promising model, surpassing previous prediction models (area under the curve: 0.66, sensitivity: 0.32, specificity: 0.86). Nevertheless, Global Registry of Acute Coronary Events (GRACE) 2.0 score demonstrated a remarkable performance (area under the curve: 0.65, sensitivity: 0.51, specificity: 0.73). This study underscores the pivotal role of successful TRA in enhancing outcomes in STEMI cases, advocating for its prioritization. The inability to conclude interventions through this approach is linked to a poorer prognosis, even in risk-adjusted analyses. Our findings indicate that prediction models utilizing clinical parameters do not outperform the established GRACE 2.0 algorithm, questioning their utility. In conclusion, the results emphasize the significance of TRA success and the continued relevance of the GRACE score in clinical decision-making to optimize patient outcomes.

Comparing Endovascular Approaches in Lower Extremity Artery Disease: Insights from a Network Meta-Analysis.

BACKGROUND: Endovascular therapy offers an alternative for treating femoropopliteal (FP) and infrapopliteal (IP) lesions related to occlusive lower extremity artery disease. Despite numerous trials, the effectiveness of restenosis prevention using local drug delivery devices remains a topic of debate. OBJECTIVES: An updated systematic review and network meta-analysis was conducted. Our overall aim was to summarize the most recent clinical evidence regarding endovascular approaches for FP and IP atherosclerotic lesions. METHODS: We conducted a search for randomized trials in the MEDLINE database, and extracted data related to clinical endpoints. Our primary focus was on the rate of major adverse events (MAEs), including mortality, amputation, and target lesion revascularization (TLR). A multiple treatment network meta-analysis supplemented with component network analyses was performed to examine the impact of combined treatment. RESULTS: Our search yielded 33 randomized controlled trials encompassing 5766 patients. This included 19 studies focused on femoropopliteal and 14 on IP lesions, accounting for 3565 and 2201 patients, respectively. Drug-coated balloons (DCBs) and drug-eluting stents (DESs) displayed a reduced MAE risk in comparison to plain old balloon angioplasty (POBA)-RR for DCB: 0.64 (95% CI: 0.52-0.77) and for DES: 0.71 (95% CI: 0.51-0.99). The bare-metal stent (BMS) group manifested the most substantial MAE risk, being 59% higher relative to the DCB cohort (BMS vs. DCB RR: 1.59; 95% CI: 1.03-2.47). For FP lesions, DES was the standout performer, curtailing MAE risk by 55% relative to POBA. Within IP lesions, DES mitigated the MAE risk by 25% versus POBA. DCB did not exhibit any notable MAE reduction when pitted against POBA. CONCLUSION: In FP arteries, both DESs and DCBs yielded significantly diminished MAEs, thus outpacing other techniques. Regarding IP arteries, only DESs resulted in significantly fewer MAEs. In alignment with contemporary research, our findings revealed no signs of elevated mortality in patients undergoing treatment with drug-eluting apparatuses.

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.

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].

Antithrombotic therapy for secondary prevention in patients with stroke or transient ischemic attack: A multiple treatment network meta-analysis of randomized controlled trials.

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.

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].

Antithrombotic Therapy for Secondary Prevention in Patients with Non-Cardioembolic Stroke or Transient Ischemic Attack: A Systematic Review.

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.

Clinical outcomes in patients treated for coronary in-stent restenosis with drug-eluting balloons: Impact of high platelet reactivity.

BACKGROUND: The impact of high platelet reactivity (HPR) on clinical outcomes after elective percutaneous coronary interventions (PCI) with drug-eluting balloons (DEB) due to in-stent restenosis (ISR) is unknown. OBJECTIVE: We sought to evaluate the prognostic importance of HPR together with conventional risk factors in patients treated with DEB. METHODS: Patients treated with DEB due to ISR were enrolled in a single-centre, prospective registry between October 2009 and March 2015. Only patients with recent myocardial infarction (MI) received prasugrel, others were treated with clopidogrel. HPR was defined as an ADP-test >46U with the Multiplate assay and no adjustments were done based on results. The primary endpoint of the study was a composite of cardiovascular mortality, MI, any revascularization or stroke during one-year follow-up. RESULTS: 194 stable angina patients were recruited of whom 90% were treated with clopidogrel. Clinical characteristics and procedural data were available for all patients; while platelet function testing was performed in 152 subjects of whom 32 (21%) had HPR. Patients with HPR had a higher risk for the primary endpoint (HR: 2.45; CI: 1.01-5.92; p = 0.03). The difference was primarily driven by a higher risk for revascularization and MI. According to the multivariate analysis, HPR remained a significant, independent predictor of the primary endpoint (HR: 2.88; CI: 1.02-8.14; p = 0.04), while total DEB length and statin treatment were other independent correlates of the primary outcome. CONCLUSION: HPR was found to be an independent predictor of repeat revascularization and MI among elective patients with ISR undergoing PCI with DEB.