AIMS:Cangrelor is approved for oral P2Y12 inhibitor naïve patients undergoing percutaneous coronary intervention (PCI). Pharmacodynamic (PD) investigations in different clinical settings, using various assays, have shown contrasting data in terms of entity of platelet inhibition and rates of high residual platelet reactivity (HRPR). We assessed the PD effects in patients with or without ST elevation myocardial infarction (STEMI) receiving cangrelor during PCI. METHODS AND RESULTS:The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is an investigator-initiated, prospective study assessing PD at four time points with three assays. From March 2021 to June 2024, 126 patients naïve from oral P2Y12 inhibitors underwent PCI with cangrelor [32 with STEMI and 94 without (NSTE-ACS = 30, CCS = 64)]. All STEMI patients switched from cangrelor to ticagrelor, while most patients without STEMI switched to clopidogrel. Inhibition of platelet aggregation (IPA%) during cangrelor infusion was lower in patients with STEMI compared with those without STEMI (LTA 20-μM-ADP 51.5 ± 16.2% vs. 59.7 ± 16.2%; P = 0.017). Conversely, after switching from cangrelor to an oral P2Y12 inhibitor, IPA was greater in patients with STEMI compared with those without STEMI. Rates of HRPR were consistent with lower platelet inhibition in STEMI during cangrelor and greater after its discontinuation compared with patients without STEMI. Within STEMI patients, cangrelor-induced IPA was lower compared with ticagrelor-induced IPA (P = 0.036). CONCLUSION:Cangrelor-induced platelet inhibition was lower in patients with STEMI compared with those without STEMI and was lower than that induced by ticagrelor among STEMI patients. The switch from cangrelor to an oral P2Y12 inhibitor exposed patients without STEMI to greater HRPR compared with those with STEMI.

No data are available on the pharmacodynamic and pharmacokinetic profile of a low dose of ticagrelor as alternative to its standard dose during the early phase after acute coronary syndrome (ACS) according to diabetic status. We reported a post-hoc analysis of a randomized, crossover trial (NCT04739384) comparing ticagrelor 60 vs. 90 mg in elderly patients with ACS according to the presence or absence of diabetes. The primary endpoint was the pre-dose P2Y12 reaction units (PRU) using the VerifyNow-P2Y12 (Accumetrics, San Diego, CA, USA) at 14 days after treatment with ticagrelor 60 or 90 mg twice daily. Out of 50 patients, 24 (48 What is the key research question? What is new? How might this study influence clinical practice?

BACKGROUND:Complex percutaneous coronary intervention (PCI) is increasingly performed among patients undergoing myocardial revascularisation. AIMS:We conducted a systematic review and meta-analysis to evaluate the association between complex PCI and the risk of ischaemic and bleeding outcomes. METHODS:Hazard ratios (HRs) were pooled using a random-effects model within a Bayesian framework. The primary analysis was restricted to studies providing adjusted risk estimates, whereas the secondary analysis included unadjusted risk estimates. The primary outcomes were myocardial infarction and major bleeding. The secondary outcomes were all-cause death, stent thrombosis, cardiovascular death, target lesion or vessel revascularisation, and stroke. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework for prognostic studies was used to determine the level of certainty in the association between complex PCI and the risk of events. RESULTS:We included 290,039 patients, of whom 94,633 (33%) underwent complex PCI. Compared with non-complex PCI, patients undergoing complex PCI had a higher risk of myocardial infarction (adjusted HR 1.71, 95% credible interval [CrI]: 1.49-1.96), major bleeding (adjusted HR 1.24, 95% CrI: 1.14-1.35), all-cause death (adjusted HR 1.21, 95% CrI: 1.12-1.32), cardiovascular death (adjusted HR 1.29, 95% CrI: 1.15-1.46), stent thrombosis (adjusted HR 1.76, 95% CrI: 1.49-2.14), target lesion or vessel revascularisation (adjusted HR 1.99, 95% CrI: 1.58-2.50), and stroke (adjusted HR 1.21, 95% CrI: 1.03-1.42). The posterior probability of a higher risk associated with complex versus non-complex PCI was >99% for all study outcomes. Except for stroke (which was low certainty), the certainty of evidence was moderate to high for all other outcomes. Secondary analysis, including unadjusted risk estimates, provided consistent results. CONCLUSIONS:Patients undergoing complex PCI have an increased risk of both ischaemic and bleeding events compared with patients undergoing non-complex PCI (PROSPERO: CRD420250656254).

BACKGROUND AND AIMS:Angina with non-obstructive coronary arteries (ANOCA) is a prevalent myocardial ischaemic syndrome, and women are disproportionately affected. Mechanisms of ischaemia are challenging to diagnose and treatment is empirical. METHODS:Consecutive patients with angina (or equivalent symptoms), no angiographically severe stenosis and fractional flow reserve > 0.80 undergoing coronary functional testing were prospectively enrolled in nine centres in Europe and North America. Haemodynamic endotypes were assessed measuring coronary flow reserve and resistance using an intracoronary pressure- and temperature-sensitive sensor and bolus thermodilution. Measurements were obtained during resting conditions and following adenosine and acetylcholine. Chest pain and electrocardiographic ischaemic changes were recorded. The participant characteristics of each haemodynamic endotype were investigated using regression analysis. A three-step Delphi consensus method was applied to identify endotype-specific therapies. RESULTS:Overall, 1001 participants (mean age 62 ± 11years, 56% female) were enrolled and eight distinct endotypes were defined by adenosine testing (n = 3) and acetylcholine testing (n = 5), respectively: high resting coronary blood flow (n = 195, 19%); high resistance (n = 125, 13%); compensated high resistance (n = 112, 11%); epicardial coronary spasm (n = 162, 17%); microvascular spasm (n = 75, 8%); endothelial dysfunction (n = 96, 10%); ischaemia w/o haemodynamic changes (n = 68, 7%); and enhanced cardiac nociception (n = 79, 8%). More than one endotype occurred in 119 (12%) individuals and normal responses occurred in 234 (23%) individuals. Each endotype was associated with distinct clinical correlates. The Delphi consensus (100% 'agree' or 'strongly agree') identified endotype-specific medical therapy with a Likert scale score ≥ 6 for all endotypes. CONCLUSIONS:In patients with suspected ANOCA, assessment of the symptomatic, electrocardiographic, and haemodynamic responses to adenosine and acetylcholine identifies distinct endotypes and enables mechanism-guided stratified medicine.

INTRODUCTION:Residual coronary microvascular dysfunction (CMD) is common after STEMI despite successful primary PCI and may contribute to ongoing ischemia and impaired recovery. INaMICRON will test the hypothesis that early late INa current inhibition with ranolazine, added to guideline-directed medical therapy, favorably modulates microvascular function during the early post-infarction phase. METHODS AND RESULTS:INaMICRON is a prospective, multicenter, randomized (1:1), open-label phase IIb trial enrolling adults with STEMI treated with successful primary PCI and at least one significant non-culprit lesion suitable for staged PCI. Participants will be randomized to standard therapy plus ranolazine (500 mg bid for 7 days, then 750 mg bid up to 42 ± 7 days) or standard therapy alone. Coronary microvascular function will be assessed using IMR and/or angioIMR in the culprit vessel after primary PCI (baseline) and during staged PCI (follow-up); non-culprit vessel physiology will also be assessed during the staged procedure. Complementary evaluations include peripheral endothelial function testing (EndoPAT), a single CMR at 42 ± 7 days, and paired blood sampling for translational multi-omics analyses. The planned sample size is 100 patients (50 per group), and analyses will compare between-group differences in physiology and related measures and explore predefined correlations. The study is designed to estimate the magnitude of microvascular modulation in the experimental group. CONCLUSIONS:This trial will provide feasibility data and an estimate of the magnitude of microvascular modulation achievable with early ranolazine after STEMI, informing the design of larger outcome-oriented studies and future precision approaches to post-MI care.

BACKGROUND:Angina or ischemia with nonobstructive coronary arteries (ANOCA/INOCA) and heart failure with preserved ejection fraction (HFpEF) are increasingly recognized conditions that may present with similar clinical presentation. Their underlying mechanisms and interplay remain incompletely understood. This case highlights how ANOCA/INOCA and HFpEF can coexist and be simultaneously diagnosed through a single invasive assessment. CASE SUMMARY:A 63-year-old man presented with recurrent exertional angina and dyspnea despite optimal medical therapy. Noninvasive testing and prior angiography had shown nonobstructive coronary disease. A comprehensive invasive evaluation including coronary angiography, physiology testing (adenosine and acetylcholine), and right heart catheterization was performed in a single procedure, revealing both coronary microvascular dysfunction and HFpEF. Target therapy led to symptomatic improvement. DISCUSSION:This case illustrates the clinical overlap and potential coexistence of HFpEF and ANOCA/INOCA, emphasizing the value of integrated invasive testing to achieve accurate diagnosis and tailored treatment. TAKE-HOME MESSAGE:A comprehensive invasive evaluation can uncover concomitant HFpEF and ANOCA/INOCA, improving diagnostic accuracy and patient outcomes.

BACKGROUND:Few data are available on polymer-free drug-eluting stents in patients undergoing percutaneous coronary intervention (PCI). AIMS:We aimed to determine the efficacy and safety of a polymer-free amphilimus-eluting stent (AES), using a reservoir-based technology for drug delivery, compared with a biodegradable-polymer everolimus-eluting stent (EES). METHODS:This was a randomised, investigator-initiated, assessor-blind, non-inferiority trial conducted at 14 hospitals in Italy (ClinicalTrials.gov: NCT04135989). All-comer patients undergoing PCI were randomly assigned to either polymer-free AES or biodegradable-polymer EES. The primary endpoint was a device-oriented composite endpoint, including cardiovascular death, target vessel myocardial infarction, or target lesion revascularisation at 1-year follow-up. RESULTS:Between January 2020 and June 2022, a total of 2,107 patients with 3,042 coronary lesions were randomised to polymer-free AES (1,051 patients) or biodegradable-polymer EES (1,056 patients). At 1-year follow-up, the primary endpoint occurred in 86 (8.2%) patients randomised to polymer-free AES and 76 (7.2%) patients randomised to biodegradable-polymer EES (risk difference 1%, upper limit of the 1-sided 95% confidence interval [CI] of 2.9%; p for non-inferiority=0.041). There were no significant differences in the incidence of the components of the primary endpoint between groups. However, definite or probable stent thrombosis occurred more frequently in patients randomised to polymer-free stents (1.0% vs 0.3%; hazard ratio 3.72, 95% CI: 1.04-13.33; p=0.044) due to an increased risk of early stent thrombosis within 30 day Conclusions: In all-comer patients undergoing PCI, polymer-free AES were non-inferior to biodegradable-polymer EES at 1-year follow-up in terms of a device-oriented composite endpoint despite being associated with an increased risk of early stent thrombosis.

BACKGROUND:Dual antiplatelet therapy (DAPT) is recommended for patients undergoing percutaneous coronary intervention (PCI), although its optimal duration remains uncertain. OBJECTIVES:The authors performed a randomized trial comparing a personalized duration of DAPT, based on a risk score, for 3, 6, or 24 months with a standard duration of DAPT for 12 months after PCI. METHODS:We randomly assigned 2,107 patients undergoing PCI to receive either a personalized or a standard DAPT. The primary endpoint was a net adverse clinical event (NACE) at 24 months, defined as the composite of all-cause death, myocardial infarction, stroke, urgent target vessel revascularization, or type 2, 3, or 5 bleeding according to the Bleeding Academic Research Consortium criteria. RESULTS:At 24 months, NACE occurred in 196 of 1,055 patients (18.6%) in the personalized DAPT group and in 232 of 1,052 patients (22.2%) in the standard DAPT group (difference, 3.54 percentage points; 95% CI: -6.99 to -0.99; P = 0.040). This difference was mainly related to decreased rates of myocardial infarction (difference, -2.29 percentage points; 95% CI: -4.43 to -0.14) and urgent target vessel revascularization (difference, -1.30 percentage points; 95% CI: -2.55 to -0.05). Bleeding occurred at similar rates between the 2 groups (difference, -0.41 percentage points; 95% CI: -2.92 to 2.10). CONCLUSIONS:In patients undergoing PCI, a personalized DAPT duration from 3 to 24 months based on a clinical risk score led to a lowered risk of NACE than standard care consisting of 12 months of DAPT. (Personalized Vs. Standard Duration of Dual Antiplatelet Therapy and New-generation Polymer-Free vs- Biodegradable-Polymer DES [PARTHENOPE]; NCT04135989).

BACKGROUND:Cangrelor is approved for oral P2Y12 inhibitor-naïve patients undergoing percutaneous coronary intervention (PCI). Pharmacodynamic (PD) investigations in various clinical settings, with various assays, have shown contrasting data in terms of the extent of platelet inhibition and rates of high residual platelet reactivity (HRPR). AIMS:We aimed to assess the PD effects of cangrelor in all patients receiving it during PCI. METHODS:PharmacOdynaMic Effects of Cangrelor in PatiEnts wIth Acute or chronIc Coronary Syndrome Undergoing Percutaneous Coronary Intervention (POMPEII Registry; ClinicalTrials.gov: NCT04790032) is an investigator-initiated, prospective study assessing PD effects at 4 timepoints with 3 assays. Clinical outcomes at 30 days were also assessed. RESULTS:From March 2021 to June 2024, 150 patients undergoing PCI and receiving cangrelor were enrolled (64 patients underwent elective PCI; 30 had non-ST-elevation acute coronary syndrome; and 56 had ST-segment elevation myocardial infarction [STEMI], of whom 24 were pretreated with ticagrelor). Most patients switched from cangrelor to either clopidogrel or ticagrelor. Inhibition of platelet aggregation was moderate during cangrelor infusion (light transmittance aggregometry with adenosine diphosphate 20 μM: 57.6±16.5%), with rates of 3.2% for HRPR and 1.3% for bailout tirofiban. Rates of HRPR were relevant at 3 h (37.9%) and 4-6 h (15.3%), and HRPR occurred significantly more frequently in patients switching to clopidogrel compared with ticagrelor. Rates of ischaemic and bleeding events were low. CONCLUSIONS:Cangrelor provided effective platelet inhibition in most patients with ACS or CCS undergoing PCI, including those with STEMI who were pretreated with ticagrelor. Switching from cangrelor to an oral P2Y12 inhibitor, mainly clopidogrel, exposed a large number of patients to a variable period of on-treatment HRPR.

Coronary artery disease (CAD) has traditionally been diagnosed and managed based on anatomical assessments of the epicardial coronary arteries. However, a growing body of evidence highlights the limitations of coronary angiography in evaluating the ischemic burden of atherosclerotic plaques. The coronary microcirculation is increasingly recognized for its pivotal role in myocardial ischemia. Coronary microvascular dysfunction (CMD) contributes significantly to both acute and chronic coronary syndromes, even in the absence of obstructive epicardial disease. Despite its clinical significance, CMD remains underdiagnosed due to the lack of routine assessment in contemporary cardiac catheterization practices. Emerging invasive and noninvasive techniques now enable comprehensive evaluation of coronary microvascular dysfunction (CMD) by assessing microvascular resistance, coronary flow reserve, and tissue-level perfusion. Advances in thermodilution-based indices, intracoronary Doppler, and functional coronary angiography continue to provide quantitative insights into microvascular physiology, whereas noninvasive modalities-including cardiac magnetic resonance (MRI), positron-emitted tomography (PET), transthoracic Doppler echocardiography, and computed tomography-based perfusion imaging-offer powerful tools for diagnosing CMD without the need for catheter-based assessment. Integrating these complementary approaches into clinical practice enhances risk stratification and supports personalized management strategies, particularly in patients with ischemia and nonobstructive coronary arteries (INOCA). This review explores in-depth the diagnostic tools and the quantitative metrics used or the invasive assessment of CMD, emphasizing their clinical utility and impact on patient management.

No sex-based data are available on the pharmacodynamic and pharmacokinetic profile of ticagrelor 60 mg twice daily as alternative to its standard dose during the early phase after acute coronary syndrome (ACS). This post-hoc study is a sex-based secondary analysis of the PLINY THE ELDER randomized, crossover trial (NCT04739384), which compared ticagrelor 60 vs. 90 mg in elderly patients with ACS undergoing percutaneous coronary intervention (PCI). The primary endpoint was the pre-dose P2Y 12 reaction units (PRU) using the VerifyNow-P2Y 12 (Accumetrics, San Diego, CA, USA) at 14 days after treatment with ticagrelor 60 or 90 mg twice daily. A total of 50 elderly patients with ACS was included in the study. Of these patients, 28 (56%) were males and 22 (44%) females. The two doses of ticagrelor had a comparable PRU in both males (pre-dose: LSM difference 60 vs. 90 -7.00, 95%CI -25.3 to 11.3, p = 0.44; post-dose: LSM difference 60 vs. 90 3.90, 95%CI -10.6 to 18.5, p = 0.59) and females (pre-dose: LSM difference 60 vs. 90 -0.89, 95%CI -20.3 to 18.5, p = 0.93; post-dose: LSM difference 60 vs. 90 -1.10, 95%CI -16.6 to 14.3, p = 0.88), with no evidence of sex-based interaction (pre-dose: p for interaction = 0.88; post-dose: p for interaction = 0.65). Consistently, transmittance aggregometry and multiple electrode aggregometry showed a similar pharmacodynamic profile between the two doses of ticagrelor in both male and female patients. Plasma levels of ticagrelor were significantly lower using the reduced dose of ticagrelor as compared with the standard dose in both males (pre-dose: LSM difference 60 vs. 90 -212, 95%CI -391 to -33.0, p < 0.002; post-dose: LSM difference 60 vs. 90 -308, 95%CI -510 to -105, p = 0.004) and females (pre-dose: LSM difference 60 vs. 90 -131, 95%CI -332 to 69.1, p = 0.19; post-dose: LSM difference 60 vs. 90 -670, 95%CI -898 to -442, p < 0.001). Ticagrelor 60 mg and ticagrelor 90 twice daily yielded the same magnitude of platelet inhibition among elderly patients with ACS irrespective of sex. Graphical abstract

BackgroundIschemia with non-obstructive coronary artery (INOCA) disease is being progressively acknowledged as one of the pathophysiological mechanisms of chronic coronary syndrome (CCS) in an increasingly wide range of clinical pictures. Although the research has already begun to move towards a defined diagnostic pathway and a specific medical therapy for this disease, at present it remains a clinical challenge, especially if not thoroughly investigated.Methods and resultsThe INOCA IT Multicenter Registry RF-2019-12369486 is a prospective, multicentric, non-randomized, single-arm, open label clinical study which aims to evaluate the efficacy of a stratified diagnostic and therapeutic approach on adverse events prevention and symptom relief in Italian patients with INOCA disease. The study population includes patients with a clinical presentation of CCS for angina and/or positive stress test for myocardial ischemia and evidence of non-obstructive coronary artery disease (CAD) at coronary angiography. In these patients a complete invasive coronary physiology assessment is performed with the guidewire-based measurement of coronary flow reserve (CFR) and index of microvascular resistance (IMR), followed by acetylcholine (ACh) spasm provocation test. On the basis of the results of coronary function testing, patients are stratified into different INOCA endotypes (coronary microvascular disease, vasospastic angina, microvascular spasm, non-cardiac chest pain) and given a tailored medical therapy in accordance with the latest scientific evidence. At one year follow-up the impact of such a target therapy on angina class and quality of life, as well as on cardiovascular adverse events (hospitalization and coronary revascularization) is evaluated.ConclusionsThe INOCA-IT Multicenter Registry will inform clinicians on sex-specific prevalence of INOCA in Italy and will show the impact of a stratified diagnostic and therapeutic approach on symptoms burden and prognosis of INOCA patients.

Heart failure (HF) has a global prevalence of 1–2%, and the incidence around the world is growing. The prevalence increases with age, from around 1% for those aged <55 years to >10% for those aged 70 years or over. Based on studies in hospitalized patients, about 50% of patients have heart failure with reduced ejection fraction (HFrEF), and 50% have heart failure with preserved ejection fraction (HFpEF). HF is associated with high morbidity and mortality, and HF-related hospitalizations are common, costly, and impact both quality of life and prognosis. More than 5–10% of patients deteriorate into advanced HF (AdHF) with worse outcomes, up to cardiogenic shock (CS) condition. Right heart catheterization (RHC) is essential to assess hemodynamics in the diagnosis and care of patients with HF. The aim of this article is to review the evidence on RHC in various clinical scenarios of patients with HF.