Monotherapy with P2Y12-inhibitors after dual antiplatelet therapy: Filling gaps in evidence.

BACKGROUND: Whether P2Y12 inhibitor monotherapy (P2Y12-I) is superior to aspirin following DAPT discontinuation post-PCI remains to be established. METHODS: We updated our prior network meta-analysis where P2Y12-I and aspirin had been compared with DAPT or directly with each other. The focus is specifically on the available direct evidence, now consisting of the three head-to-head comparisons of P2Y12-I and aspirin in event-free PCI patients after DAPT. We include a Trial Sequential Analysis of the direct evidence based on meta-analytical literature. RESULTS: The main finding reveals a 39% significantly lower risk of myocardial infarction with P2Y12-I (RR 0.61, 95% CI 0.47-0.78, p = 0.0001, I2 = 0%) with no difference in bleeding. Trial Sequential Analysis demonstrates clinically meaningful evidence for a reduction in the incidence of myocardial infarction with P2Y12-I that is also supported by statistical significance. CONCLUSIONS: Accruing data highlight that P2Y12-I following DAPT discontinuation after PCI is associated with lower risk for MI and a similar risk for bleeding as compared with ASA. In light of potential limitations to the widespread adoption of life-long P2Y12-I treatment, clinicians should consider identifying selected patients who are expected to derive the highest benefit.

Cangrelor in contemporary patients with ST-segment elevation myocardial infarction pretreated with Ticagrelor: Pharmacodynamic data from the POMPEII study.

Background: There are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor. Methods: The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator's discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test. Results: We analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4-6 h (corresponding to 1 h and 2-4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays. Conclusions: PD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

Long-term impact of intravascular ultrasound-guidance for percutaneous coronary intervention on unprotected left main. The IMPACTUS-LM, an observational, multicentric study.

INTRODUCTION: The potential benefit on long term outcomes of Percutaneous Coronary Intervention (PCI) on Unprotected Left Main (ULM) driven by IntraVascular UltraSound (IVUS) remains to be defined. METHODS: IMPACTUS LM-PCI is an observational, multicenter study that enrolled consecutive patients with ULM disease undergoing coronary angioplasty in 13 European high-volume centers from January 2002 to December 2015. Major Adverse Cardiovascular Events (MACEs) a composite of cardiovascular (CV) death, target vessel revascularization (TVR) and myocardial infarction (MI) were the primary endpoints, while its single components along with all cause death the secondary ones. RESULTS: 627 patients with ULM disease were enrolled, 213 patients (34%) underwent IVUS-guided PCI while 414 (66%) angioguided PCI. Patients in the two cohorts had similar prevalence of risk factors except for active smoking and clinical presentation. During a median follow-up of 7.5 years, 47 (22%) patients in the IVUS group and 211 (51%) in the angio-guided group underwent the primary endpoint (HR 0.42; 95% CI [0.31-0.58] p < 0.001). After multivariate adjustment, IVUS was significantly associated with a reduced incidence of the primary endpoint (adj HR 0.39; 95% CI [0.23-0.64], p < 0.001), mainly driven by a reduction of TVR (ad HR 0.30, 95% CI [0.15-0.62], p = 0.001) and of all-cause death (adj HR 0.47, 95% CI [0.28-0.82], p = 0.008). IVUS use, age, diabetes, side branch stenosis, DES and creatinine at admission were independent predictors of MACE. CONCLUSIONS: In patients undergoing ULM PCI, the use of IVUS was associated with a reduced risk at long-term follow-up of MACE, all-cause death and subsequent revascularization.

Aspirin-free antiplatelet strategies after percutaneous coronary interventions.

Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the standard antithrombotic treatment after percutaneous coronary interventions (PCI). Several trials have challenged guideline-recommended DAPT after PCI by testing the relative clinical effect of an aspirin-free antiplatelet approach-consisting of P2Y12 inhibitor monotherapy after a short course (mostly 1-3 months) of DAPT-among patients undergoing PCI without a concomitant indication for oral anticoagulation (OAC). Overall, these studies have shown P2Y12 inhibitor monotherapy after short DAPT to be associated with a significant reduction in the risk of bleeding without an increase in thrombotic or ischaemic events compared with continued DAPT. Moreover, the effects of the P2Y12 inhibitor monotherapy without prior DAPT or following a very short course of DAPT after PCI are being investigated in emerging studies, of which one has recently reported unfavourable efficacy results associated with the aspirin-free approach compared with conventional DAPT. Finally, P2Y12 inhibitor alone has been compared with aspirin alone as chronic therapy after DAPT discontinuation, thus challenging the historical role of aspirin as a standard of care for secondary prevention following PCI. A thorough understanding of study designs, populations, treatments, results, and limitations of trials testing P2Y12 inhibitor monotherapy vs. DAPT or vs. aspirin is required to consider adopting this treatment in clinical practice. This review addresses the use of aspirin-free antiplatelet strategies among patients undergoing PCI without a concomitant indication for OAC, providing an overview of clinical evidence, guideline indications, practical implications, ongoing issues, and future perspectives.

Use of cangrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Study design and interim analysis of the ARCANGELO study.

BACKGROUND: The itAlian pRospective Study on CANGrELOr (ARCANGELO) was aimed to assess the safety of using cangrelor during percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) in the daily practice. HYPOTHESIS: The safety of cangrelor after the transition to oral P2Y12 inhibitors was evaluated as the incidence of bleeding outcomes in the 30 days following PCI according to postauthorization safety study guidelines. METHODS: Adults with ACS who were treated with cangrelor in one of the 28 centers involved in the study. Patients who consented to participate were followed in the 30 days following their PCI. Bleedings (Bleeding Academic Research Consortium [BARC] classification), major adverse cardiac events (MACEs), and adverse events were recorded. The interim results at two-thirds of the enrollment period are presented. RESULTS: A total of 17 bleedings were observed in the 320 patients who completed the study at this stage. All bleedings were classified as BARC Type 1-2, except for one case of Type 3a (vessel puncture site hematoma). Four patients experienced MACEs (2 acute myocardial infarctions, 1 sudden cardiac death, 1 noncardiovascular death due to respiratory distress, and multiorgan failure). None of the bleedings was rated as related to cangrelor. CONCLUSIONS: The interim results of the ARCANGELO study provide a preliminary confirmation that the use of cangrelor on patients with ACS undergoing PCI is not associated with severe bleedings.

Sex Differences in Outcomes After Percutaneous Coronary Intervention or Coronary Artery Bypass Graft for Left Main Disease: From the DELTA Registries.

Background Controversy exists over whether sex has significant interaction with revascularization strategy for unprotected left main coronary artery disease. Higher mortality has been reported among women treated with percutaneous coronary intervention compared with coronary artery bypass grafting. Methods and Results The DELTA (Drug-Eluting Stents for Left Main Coronary Artery Disease) and DELTA-2 registries are international, multicentric registries evaluating the outcomes of subjects undergoing coronary revascularization for unprotected left main coronary artery disease. The primary outcome was a composite of death, myocardial infarction, or cerebrovascular accidents. The population consisted of 6253 patients, including 1689 (27%) women. Women were older and more likely to have diabetes and chronic kidney disease than men (P<0.05). At a median follow-up of 29 months (interquartile range 12-49), a significant interaction between sex and revascularization strategy was observed for the primary end point (pint=0.012) and all-cause death (pint=0.037). Among women, compared with percutaneous coronary intervention, coronary artery bypass grafting was associated with lower risk of the primary end point (event rate 9.5% versus 15.3%; adjusted hazard ratio [AHR], 0.53; 95% CI, 0.35-0.79, P<0.001) and all-cause death (event rate 5.6% versus 11.7% AHR, 0.50; 95% CI, 0.30-0.82) and no significant differences were observed in men. Conclusions In women undergoing coronary revascularization for unprotected left main coronary artery disease, coronary artery bypass grafting was associated with lower risk of death, myocardial infarction, or cerebrovascular accidents whereas no significant differences between coronary artery bypass grafting and percutaneous coronary intervention were observed in men. Further dedicated studies are needed to determine the optimal revascularization strategy in women with unprotected left main coronary artery disease.

Tackling the gap in platelet inhibition with oral antiplatelet agents in high-risk patients undergoing percutaneous coronary intervention.

Introduction: Oral P2Y12 inhibitors represent the mainstay therapy for the prevention of thrombotic complications in patients presenting with an acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI). However, the onset of antiplatelet action of the oral P2Y12 inhibitors is affected by their need to be absorbed in the gastrointestinal (GI) tract before becoming systemically available.Areas covered: Following oral intake of P2Y12 inhibitors, the timeframe required for GI absorption leads to a window of inadequate antiplatelet protection during which patients are at increased thrombotic risk. The onset of action of the oral P2Y12 inhibitors is even further delayed in high-risk patients, underscoring the need to define strategies to bridge the gap in platelet inhibitory effects following their intake.Expert opinion: Multiple mechanisms may impair GI absorption leading to a delay in the onset of action of oral P2Y12 inhibitors. Several strategies have been tested to overcome the gap in platelet inhibition in high-risk patients undergoing PCI. These include administration of crushed or chewed tablets to improve the dissolution rate and use of opioid receptor antagonists or metoclopramide to counteract impairment of gastric motility induced by opioids. However, intravenous antiplatelet therapies represent the most effective strategy to bridge such gap in platelet inhibition.

Antithrombotic Management of Elderly Patients With Coronary Artery Disease.

Antithrombotic therapy represents the mainstay of treatment in patients with coronary artery disease (CAD), including elderly patients who are at increased risk for ischemic recurrences. However, the elderly population is also more vulnerable to bleeding complications. Numerous mechanisms, including abnormalities in the vasculature, thrombogenicity, comorbidities, and altered drug response, contribute to both increased thrombotic and bleeding risk. Age-related organ changes and drug-drug interactions secondary to polypharmacy lead to distinct pharmacokinetic and pharmacodynamic profiles of antithrombotic drugs. Overall these factors contribute to the risk-benefit profiles of antithrombotic therapies in elderly subjects and underscore the need for treatment regimens that can reduce bleeding while preserving efficacy. Given that the prevalence of CAD, as well as concomitant diseases with thromboembolic potential, such as atrial fibrillation, increases with age and that the elderly population is in continuous growth, understanding the safety and efficacy of different antithrombotic regimens is pivotal for patient-centered care. In the present overview the authors appraise the available data on the use of antithrombotic therapy in older patients with CAD to assist with the management of this high-risk population and define knowledge gaps that can set the basis for future research.

Pharmacodynamics During Transition Between Platelet P2Y12 Inhibiting Therapies.

Several platelet P2Y12 inhibiting agents, both oral and intravenous, are available for clinical use. The oral P2Y12 inhibitors comprise clopidogrel, prasugrel, and ticagrelor. Cangrelor is the only intravenous P2Y12 inhibitor. Numerous pharmacodynamic studies have been performed to assess the impact of P2Y12 inhibitor switching on platelet reactivity profiles and to define the optimal strategy if switching is needed, with the goal of minimizing the risk of having inadequate platelet inhibition due to potential drug-drug interactions occurring during the drug overlap phase. This article provides an overview of pharmacodynamic studies assessing switching between P2Y12 inhibitors and recommendations on switching modalities based on these findings.

Switching between P2Y12 inhibitors: Rationale, methods, and expected consequences.

The pharmacological and clinical differences of the three recommended oral P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) enable physicians to switch from one agent to another that it is considered more appropriate in the specific clinical setting. Moreover, the recent availability of cangrelor, the only intravenous P2Y12 inhibitor with a rapid onset and offset of its antiplatelet action, makes it necessary to switch from this agent to an oral P2Y12 inhibitor for a continued platelet inhibition after percutaneous coronary intervention. Several pharmacodynamic studies have provided information on how to change drug, in terms of timing and dosage, without running the risk of a temporary impairment of platelet inhibition. In addition, several studies have assessed the impact of the switching between P2Y12 inhibitors on clinical outcomes. Overall, these evidences have prompted the development of an extensive expert consensus document, have set the basis for recent practice guidelines recommendations, and have stimulated several systematic overviews. The present article provides a brief and schematic summary on the topic of switching between P2Y12 inhibitors, focusing on three main practical issues: why and how to switch therapies and what are the clinical consequences of such strategy.

[ANMCO/GISE/SICCH Inter-Society Consensus Document: Antithrombotic therapy after surgery or structural interventional procedures for valvular heart diseases: how to treat postoperative complications]. / Documento di consenso intersocietario ANMCO/GISE/SICCH: Terapia antitrombotica nei pazienti sottoposti a chirurgia e/o interventistica cardiaca valvolare: come trattare le complicanze.

Continuous improvement of technologies, devices and drugs needs a renewal and update of current recommendations and guidelines on antithrombotic strategies, especially in those fields where literature lacks of established scientific evidences. Accordingly, the aim of this consensus statement is to provide support for antithrombotic therapy based on current guidelines and the most recent scientific evidences.After an overview on the currently available devices, the appropriate therapy according to type of procedure and implanted device is discussed. The occurrence of postoperative thromboembolic and/or hemorrhagic complications is analyzed, along with the appropriate diagnostic tools and therapeutic approach. A section is dedicated to counseling to pregnancy in women with heart valve prosthesis. Finally, the role of novel oral anticoagulants is discussed, and indications are provided for the management of patients undergoing surgery or interventional procedures on oral anticoagulation therapy.

Impact of coronary artery disease and percutaneous coronary intervention in women undergoing transcatheter aortic valve replacement: From the WIN-TAVI registry.

OBJECTIVES: To evaluate the impact of coronary artery disease (CAD) with or without recent (≤ 30 days) percutaneous coronary intervention (PCI) in women undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Although women display a specific risk-profile for both PCI and TAVR, the impact of CAD and PCI in the setting of TAVR in women is unclear. METHODS: The multinational Women's International Transcatheter Aortic Valve implantation registry enrolled consecutive female patients undergoing contemporary TAVR in 19 centers between 2013 and 2015. Patients with available coronary angiography or CT scan in the pre-operative assessment of TAVR were categorized as without CAD, with CAD but no recent PCI and CAD and recent PCI (≤30 days). All events were adjudicated according to the VARC-2 criteria. RESULTS: A total of 787 patients were included in this analysis, among whom 459 (58.3%) had no CAD, 247 (31.4%) had CAD without recent PCI and 81 (10.3%) underwent recent PCI (≤ 30 days before TAVR). After multivariable adjustment, both groups of CAD patients, without and with recent PCI, presented with higher risk of death, myocardial infarction or stroke, compared with patients without CAD (adj HR 1.56, 95%CI 1.03-2.39, P = 0.038 and adj HR 1.96, 95% CI 1.1-3.5, P = .021, respectively). Patients with recent PCI had increased risk of all-cause death (adj HR 1.89, 95% CI 1.0-3.5, P = 0.04) and stroke (adj HR 3.7, 95% CI 1.0-13.5, P = 0.046) compared with patients without CAD. CONCLUSION: The presence of CAD in women undergoing TAVR, with or without recent PCI, was associated with long-term poorer outcomes.

[Coronary artery disease: when to withhold a decision and call in the Heart Team? Almost never]. / Cardiopatia ischemica cronica: quando fermarsi e discutere in Heart Team? Quasi mai.

The expansion of the options for the treatment of patients with stable multivessel coronary artery disease (CAD), including medical therapy or myocardial revascularization by a surgical or a percutaneous strategy, has raised the need to set the decision-making process to select the optimal therapy on a multidisciplinary approach. Indeed, this latter would potentially lead to identify the most appropriate strategy for a given patient in the most transparent, shared and comprehensive way as possible. The multidisciplinary approach has been widely encouraged in the cardiovascular field, where it has been defined as "Heart Team" (HT), a collegial system essentially including a cardiac surgeon, a clinical cardiologist and an interventionalist. However, due to the unavailability of on-site surgery in many centers, along with the increasing use of sophisticated materials and advanced technologies, the growing confidence of interventionalists with more meticulous and complex techniques, in addition to sharper guideline indications, the HT approach may currently lead to an anachronistic and unjustified slowdown of the decision-making process, sometimes until impasse, with subsequent increase in social and health costs. Therefore, the present article will examine the possibilities to judiciously restrict the actual HT use for choosing the treatment of patients with stable multivessel CAD at higher complexity.

Incidence of Long-Term Structural Valve Dysfunction and Bioprosthetic Valve Failure After Transcatheter Aortic Valve Replacement.

Background Long-term data on durability of currently available transcatheter heart valves are sparse. We sought to assess the incidence of long-term (8-year) structural valve dysfunction and bioprosthetic valve failure in a cohort of patients with transcatheter aortic valve replacement ( TAVR ) who reached at least 5-year follow-up. Methods and Results Consecutive patients with at least 5-year follow-up available undergoing TAVR from June 4, 2007 to March 30, 2012 were included. Structural valve dysfunction and bioprosthetic valve failure were defined according to newly standardized European Association of Percutaneous Cardiovascular Interventions/ European Society of Cardiology/European Association for Cardio-Thoracic Surgery criteria and reported as cumulative incidence function to account for the competing risk of death. A total of 288 consecutive patients with a mean age of 80.7±5.3 years and with a mean Society of Thoracic Surgery mortality score of 8.1±5.1% were analyzed. Survival rate at 8 years was 29.8%. Mean pressure gradients decreased from 53.3±15.9 mm Hg (pre- TAVR ) to 10.5±4.5 mm Hg (in-hospital post- TAVR ) ( P<0.001). There was a small, not significant, increase in the transaortic gradient throughout follow-up. Bioprosthetic valve failure was observed in a total of 11 patients (8-year cumulative incidence function: 4.51%; 95% confidence interval , 1.95%-8.76%). Severe and moderate structural valve dysfunctions were reported in 7 patients (8-year cumulative incidence function: 2.39%; 95% confidence interval, 0.77%-5.71%) and 13 patients (8-year cumulative incidence function: 5.87%; 95% confidence interval , 3.06%-9.96%), respectively. Aortic valve reintervention (redo TAVR ) was successfully performed in 2 patients (0.7%) presenting with symptomatic severe restenosis and intraprosthetic regurgitation subsequent to endocarditis. Conclusions In an aged population of patients with symptomatic severe aortic stenosis treated with first-generation bioprostheses, TAVR was associated with a survival rate of 30% but low rates of bioprosthetic valve failure and structural valve dysfunction at 8 years.

Pharmacokinetics of new oral anticoagulants: implications for use in routine care.

INTRODUCTION: Since 2008, new oral anticoagulants (NOACs) have been approved for the prevention of venous thromboembolism (VTE) in patients receiving hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE). Premarketing randomized clinical trials (RCTs) of NOACs demonstrated their non-inferiority in terms of efficacy vs. warfarin (traditional oral anticoagulant - TOA), with lower risk of serious adverse drug reactions, especially cerebral hemorrhages. In clinical practice, pharmacokinetic aspects of NOACs have to be carefully taken into account to optimize the benefit-risk profile of these drugs. Areas covered: An overview of major issues related to pharmacokinetics of NOACs, such as drug-drug interactions, over- and underdosage in special populations (e.g. elderly, underweight, and chronic kidney disease patients), and impact on adherence and persistence to NOACs therapy and ultimately clinical outcomes in real-world setting, is provided. Expert opinion: NOACs have been proven to be a better option than traditional anticoagulants due to better tolerability and ease of use. However, given specific pharmacokinetic characteristics, NOAC therapy has to be carefully tailored and monitored in relation to patient characteristics with the final goal of maximizing benefits and minimizing risks.

Appraisal of key trials in aortic and mitral fields.

Aortic stenosis and mitral regurgitation are increasingly treated by percutaneous interventions including transcatheter aortic valve implantation (TAVI) and several mitral valve repair techniques, changing the landscape of valvular therapies in which surgery was predominant. Several randomised studies on TAVI have led to the use of this procedure in patients at intermediate or higher operative risk and have set strong foundations for future trials aiming to expand indications or to overcome several residual issues with TAVI. On the other hand, randomised evidence for percutaneous mitral valve repair (PMVR) techniques is still limited, supporting restricted indications to patients with high surgical risk when medical therapy fails. However, in the mitral field, several ongoing trials comparing PMVR with medical therapy or surgery will help to define optimal mitral regurgitation management in this era of evolving catheter-based treatment options. The present review will summarise randomised trials comparing TAVI or PMVR with medical therapy or surgery across the risk spectrum which have set the basis for guideline recommendations and for clinical use of transcatheter interventions. Characteristics, results, implications, unresolved issues and cost-effectiveness analysis of those trials, grouped according to the surgical risk of enrolled patients, will be appraised.

[The new frontiers of patent foramen ovale]. / Le nuove frontiere del forame ovale pervio.

Several evidences support the hypothesis that patent foramen ovale (PFO), especially when associated with specific anatomical features, relates to an increased incidence of paradoxical embolism including ischemic stroke. According to current guidelines, clinicians may offer percutaneous closure of PFO in rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified (American Academy of Neurology 2016) or deep venous thrombosis at high risk of recurrence (American Heart Association/American Stroke Association 2014).Recently, a device that allows percutaneous suturing of PFO with polypropylene stitches has been introduced. Preliminary data suggest that this new strategy is effective and safe because it could reduce the adverse events of the conventional approach. Moreover, it avoids to preclude any future percutaneous transeptal procedure. Larger and randomized controlled studies are warranted to validate the results obtained.