Guidelines recommend the use of potent P2Y₁₂ inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y₁₂ inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y₁₂ inhibiting therapy in patients with ACS. We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y₁₂ inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y₁₂ inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65–0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96–1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. In patients with an ACS, compared with routine selection of potent P2Y₁₂ inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y₁₂ inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y₁₂ inhibiting therapy in patients with ACS. This study is registered in PROSPERO (CRD42021258603). A guided selection of P2Y₁₂ inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y₁₂-inhibiting therapy in acute coronary syndrome has not been explored. In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. A guided selection of P2Y₁₂-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y₁₂ inhibiting therapy in patients with acute coronary syndrome. Forest plots and ranking of treatments for primary outcomes. Guided selection of P2Y₁₂ inhibiting was the only strategy associated with reduced major adverse cardiovascular events without any increase of bleeding (forest plots). Ranking of treatments according to P-scores showed guided therapy to be the strategy with the best balance between safety and efficacy. P-scores range between 0 and 1: the higher the P-score value, the higher the likelihood that a therapy is more effective or safe. Guided approach showed the best P-score for MACE (0.931) and the second-best P-score for all bleeding (0.569). Clopidogrel showed the best P-score for all bleeding (0.983) but the poorest P-score for MACE (0.199). Prasugrel showed the second-best P-score for MACE (0.673) but a poor P-score for all bleeding (0.233). Ticagrelor showed a poor P-score for both MACE and all bleeding (0.198 and 0.214, respectively). CI, confidence interval; IRR, incidence rate ratio; MACE, major adverse cardiovascular events.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant cardiovascular (CV) benefits particularly in patients with diabetes mellitus (DM), but the safety and efficacy of different GLP-1 RAs across diverse populations remain insufficiently defined. Previous meta-analyses of GLP-1 RAs have been limited by restricted populations, omission of recent trials, or incomplete safety synthesis; this study integrates the latest evidence across 21 RCTs and diverse populations using advanced meta-analytic methods. Randomized controlled trials comparing GLP-1 RAs vs controls or placebo were included. Analyses were conducted in pre-specified subgroups based on the GLP-1 RA used. Pre-specified subgroups according to DM, kidney function, obesity or heart failure (HF) were also performed. Main outcomes comprised mortality (all-cause and CV), trial-defined major adverse cardiovascular events (MACE) and serious adverse events (SAEs). GRADE and trial sequential analyses were performed to evaluate certainty and conclusiveness of findings, respectively. A total of 21 trials encompassing 99,592 patients were included. Eight different GLP-1 RAs were used (lixisenatide, liraglutide, exenatide, semaglutide, efpeglenatide, dulaglutide, albiglutide, and tirzepatide), each administered at therapeutic doses and compared vs placebo or controls. Mean follow-up duration was 2.4 years. We found conclusive, high certainty, evidence that GLP-1 RAs reduced all-cause death (IRR 0.88, 95% CI 0.84-0.92, NNT=121), CV death (IRR 0.87, 95% CI 0.81-0.92, NNT=170) and MACE (IRR 0.87, 95% CI 0.83-0.91, NNT=66), compared with controls. GLP-1 RAs reduced SAE (-9%), myocardial infarction (-15%), acute kidney failure (-9%), HF (-15%), and infections (-10%), but increased gastrointestinal (GI; +63%) and gallbladder (+26%) disorders. There were no differences in stroke, pancreatitis or neoplasm between groups. Results were mostly consistent across subgroups. Analysis by GLP-1 RA type revealed potential differences in efficacy and safety profiles. GLP-1 RAs reduce mortality and MACE in high-risk populations, highlighting benefits beyond glycemic control. These come at increased GI and gallbladder risks. Variation in efficacy and tolerability supports tailoring GLP-1 RA therapy to individual patient characteristics and treatment goals.

Aims: To compare the safety and efficacy of very short (≤3 months), short (6 months), standard (12 months), and extended (>12 months) dual antiplatelet therapy (DAPT), and of subsequent monotherapies, after coronary drug-eluting stent (DES) implantation. Methods and results: Twenty-two randomized control trials (n = 110 059 patients/year) were selected and included in a Bayesian network meta-analysis. The primary efficacy endpoint (PEP) was a composite of cardiac death, myocardial infarction (MI), and stent thrombosis (ST), with each of the components of the PEP being a secondary efficacy endpoint. The primary safety endpoint was major bleeding rate. Compared to standard, we found a lower rate of MI [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.44–0.77] in extended, a lower rate of major bleeding (OR 0.61, 95% CI 0.39–0.87) in very short, and a lower rate of any bleeding (OR 0.61, 95% CI 0.38–0.90) in short DAPT. All DAPT durations were comparable regarding the secondary efficacy endpoints. Very short DAPT followed by P2Y12 inhibition was the treatment of choice to reduce both major bleeding and MI. In the ACS subgroup, extended DAPT (as compared to standard) reduced PEP and ST rates (but not MIs). Conclusion: The efficacy of short and very short is comparable with that of standard DAPT after DES implantation, whereas extended DAPT reduces MI rate. Very short DAPT is associated with lower haemorrhagic events and, followed by a P2Y12 inhibitor monotherapy, should be preferred in order to pursue a trade-off between major bleeding and ischaemic events.

Low-dose (LD) direct oral anticoagulants (DOACs) in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), have been tested to prevent ischaemic events in patients with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the overall safety and efficacy of LD DOACs vs placebo on a background of antiplatelet therapy. All randomized controlled trials (RCTs) comparing LD DOAC (defined as a dosage below the lowest approved for stroke prevention) vs placebo among patients with CVD receiving single or dual antiplatelet therapy (DAPT) in at least 50% of the population and followed for at least 6 months, were included. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used to overcome different follow-up durations across trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint major bleeding. A pre-specified subgroup analysis was performed for different DOAC-dose regimens. A total of 49 802 patients from 7 RCTs were included. Low-dose DOACs vs placebo were associated with significant reductions in MACE (IRR 0.85, 95% CI 0.78–0.91, number needed to treat, NNT, 86) and myocardial infarction (IRR 0.86, 95% CI 0.78–0.95, NNT 355) and significant increases of major (IRR 2.05, 95% CI 1.50–2.80, number needed to harm, NNH, 89) or all bleeding (IRR 1.82, 95% CI 1.49–2.22, NNH 23). Cardiovascular death (IRR 0.90, 95% CI 0.79–1.03, NNT 784), intracranial (IRR 1.18, 95% CI 0.71–1.96, NNH 1810), and fatal bleeding (IRR 1.13, 95% CI 0.76–1.69, NNH 3170) did not differ significantly between strategies. Non-significant reductions of all-cause death (IRR 0.90, 95% CI 0.80–1.01, NNT 821) and stroke (IRR 0.73, 95% CI 0.53–1.01, NNT 315) favoured LD DOACs. Meta-regression analyses showed a significant interaction between percentage of DAPT use and increased risk of major bleeding (P = 0.04), intracranial haemorrhage (P = 0.035), and stroke (P = 0.0003). Subgroup analysis of very LD DOAC, defined as ≤1/3 of the lowest approved dose for stroke prevention (i.e. rivaroxaban 2.5 mg twice daily) seemed to mitigate the risk of bleeding without any trade-off in efficacy compared to other LD DOAC regimens. In patients with CVD, LD DOAC vs placebo on a background of antiplatelet therapy, reduced ischaemic events at the expense of increased major and all bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular or total mortality and stroke was not statistically significant. A DPI with very LD DOAC (i.e. rivaroxaban 2.5 mg twice daily) appeared particularly advantageous, especially when combined with a single antiplatelet agent and used among patients at high ischaemic and low bleeding risk. This study is registered in PROSPERO (CRD42021232744).

Background: The optimal management of patients with spontaneous coronary artery dissection remains debated. Methods: Patients enrolled in the DISCO (Dissezioni Spontanee Coronariche) Registry up to December 2020 were included. The primary end point was major adverse cardiovascular events, a composite of all-cause death, nonfatal myocardial infarction, and repeat percutaneous coronary intervention (PCI). Independent predictors of PCI and medical management were investigated. Results: Among 369 patients, 129 (35%) underwent PCI, whereas 240 (65%) were medically managed. ST-segment–elevation myocardial infarction (68% versus 35%, P <0.001), resuscitated cardiac arrest (9% versus 3%, P <0.001), proximal coronary segment involvement (32% versus 7%, P <0.001), and Thrombolysis in Myocardial Infarction flow 0 to 1 (54% versus 20%, P <0.001) were more frequent in the PCI arm. In-hospital event rates were similar. Between patients treated with PCI and medical therapy, there were no differences in terms of major adverse cardiovascular events at 2 years (13.9% versus 11.7%, P =0.467), all-cause death (0.7% versus 0.4%, P =0.652), myocardial infarction (9.3% versus 8.3%, P =0.921) and repeat PCI (12.4% versus 8.7%, P =0.229). ST-segment–elevation myocardial infarction at presentation (odds ratio [OR], 3.30 [95% CI, 1.56–7.12]; P =0.002), proximal coronary segment involvement (OR, 5.43 [95% CI, 1.98–16.45]; P =0.002), Thrombolysis in Myocardial Infarction flow grade 0 to 1 and 2 (respectively, OR, 3.22 [95% CI, 1.08–9.96]; P =0.038; and OR, 3.98 [95% CI, 1.38–11.80]; P =0.009) and luminal narrowing (OR per 5% increase, 1.13 [95% CI, 1.01–1.28]; P =0.037) were predictors of PCI, whereas the 2B-angiographic subtype predicted medical management (OR, 0.25 [95% CI, 0.07–0.83]; P =0.026). Conclusions: Clinical presentation and procedural variables drive the choice of the initial therapeutic approach in spontaneous coronary artery dissection. If PCI is needed, it seems to be associated with a similar risk of short-to-mid-term adverse events compared to medical treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04415762.

Carriers of cytochrome 2C19 (CYP2C19) loss of function (LoF) alleles treated with clopidogrel have impaired drug metabolism resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios (OR) and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y₁₂ reaction unit (PRU). The secondary outcome was the rate of HPR. Standard-dose of clopidogrel (75 mg daily) was used as reference treatment. A total of 12 RCTs testing 6 alternative strategies (i.e., clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD-42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel. Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.