[Multidistrict atherosclerotic disease: epidemiological and clinical framework]. / Malattia aterosclerotica polidistrettuale: inquadramento epidemiologico e clinico.

Atherosclerosis is a systemic disease that can involve different arterial districts. Traditionally, the focus of cardiologists has been on the diagnosis and treatment of atherosclerotic coronary artery disease (CAD). However, atherosclerosis localization in other districts is increasingly common and is associated with an increased risk of CAD and, more generally, of adverse cardiovascular events. Although the term peripheral arterial disease (PAD) commonly refers to the localization of atherosclerotic disease in the arterial districts of the lower limbs, in this document, in accordance with the European Society of Cardiology guidelines, the term PAD will be used for all the locations of atherosclerotic disease excluding coronary and aortic ones. The aim of this review is to report updated data on PAD epidemiology, with particular attention to the prevalence and its prognostic impact on patients with CAD. Furthermore, the key points for an appropriate diagnostic framework and a correct pharmacological therapeutic approach are summarized, while surgical/interventional treatment goes beyond the scope of this review.

Impact of pre-admission physical activity on benefits of physiology-guided complete revascularization in older patients with myocardial infarction: insights from the FIRE trial.

AIMS: The present analysis from the Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial aims to explore the significance of pre-admission physical activity and assess whether the benefits of physiology-guided complete revascularization apply consistently to sedentary and active older patients. METHODS AND RESULTS: Patients aged 75 years or more with myocardial infarction (MI) and multivessel disease were randomized to receive physiology-guided complete revascularization or culprit-only strategy. The primary outcome was a composite of death, MI, stroke, or any revascularization within a year. Secondary endpoints included the composite of cardiovascular death or MI, as well as single components of the primary endpoint. Pre-admission physical activity was categorized into three groups: (i) absent (sedentary), (ii) light, and (iii) vigorous. Among 1445 patients, 692 (48%) were sedentary, whereas 560 (39%) and 193 (13%) performed light and vigorous physical activity, respectively. Patients engaging in light or vigorous pre-admission physical activity exhibited a reduced risk of the primary outcome compared with sedentary individuals [light hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.55-0.91 and vigorous HR 0.14, 95% CI 0.07-0.91, respectively]. These trends were also observed for death, cardiovascular death, or MI. When comparing physiology-guided complete revascularization vs. culprit-only strategy, no significant interaction was observed for primary and secondary endpoints when stratified by sedentary or active status. CONCLUSION: In older patients with MI, pre-admission physical activity emerges as a robust and independent prognostic determinant. Physiology-guided complete revascularization stands out an effective strategy in reducing ischaemic adverse events, irrespective of pre-admission physical activity status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03772743.

The Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial has shown that physiology-guided complete revascularization reduces ischaemic adverse events in older patients with myocardial infarction (MI) and multivessel disease. Older patients who engage in light or vigorous physical activity before hospitalization for MI have a reduced risk of the primary composite outcome of death, MI, stroke, or ischaemia-driven revascularization. These benefits extend to all secondary cardiovascular outcomes as well. In the present subanalysis of the FIRE trial, we find that the positive prognosis associated with physiology-guided complete revascularization holds true even for patients with a sedentary lifestyle. This means that this type of revascularization can effectively reduce ischaemic adverse events in older patients with MI and multivessel disease, regardless of their physical activity levels.

Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction.

BACKGROUND: The benefit of complete revascularization in older patients (≥75 years of age) with myocardial infarction and multivessel disease remains unclear. METHODS: In this multicenter, randomized trial, we assigned older patients with myocardial infarction and multivessel disease who were undergoing percutaneous coronary intervention (PCI) of the culprit lesion to receive either physiology-guided complete revascularization of nonculprit lesions or to receive no further revascularization. Functionally significant nonculprit lesions were identified either by pressure wire or angiography. The primary outcome was a composite of death, myocardial infarction, stroke, or any revascularization at 1 year. The key secondary outcome was a composite of cardiovascular death or myocardial infarction. Safety was assessed as a composite of contrast-associated acute kidney injury, stroke, or bleeding. RESULTS: A total of 1445 patients underwent randomization (720 to receive complete revascularization and 725 to receive culprit-only revascularization). The median age of the patients was 80 years (interquartile range, 77 to 84); 528 patients (36.5%) were women, and 509 (35.2%) were admitted for ST-segment elevation myocardial infarction. A primary-outcome event occurred in 113 patients (15.7%) in the complete-revascularization group and in 152 patients (21.0%) in the culprit-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.57 to 0.93; P = 0.01). Cardiovascular death or myocardial infarction occurred in 64 patients (8.9%) in the complete-revascularization group and in 98 patients (13.5%) in the culprit-only group (hazard ratio, 0.64; 95% CI, 0.47 to 0.88). The safety outcome did not appear to differ between the groups (22.5% vs. 20.4%; P = 0.37). CONCLUSIONS: Among patients who were 75 years of age or older with myocardial infarction and multivessel disease, those who underwent physiology-guided complete revascularization had a lower risk of a composite of death, myocardial infarction, stroke, or ischemia-driven revascularization at 1 year than those who received culprit-lesion-only PCI. (Funded by Consorzio Futuro in Ricerca and others; FIRE ClinicalTrials.gov number, NCT03772743.).

[Twenty years of epidemiology of acute coronary syndromes in Italy: how cardiovascular epidemiology can guide secondary prevention strategies]. / Vent'anni di epidemiologia delle sindromi coronariche acute in Italia: come l'epidemiologia cardiovascolare può orientare la clinica e le strategie di prevenzione secondaria.

Over the last 20 years the epidemiology of acute coronary syndromes (ACS) has significantly changed, affecting both the acute and post-acute phases. In particular, although the progressive reduction in in-hospital mortality, the trend in post-hospital mortality was found to be stable or increasing. This trend was at least in part attributed to the improved short-term prognosis due to coronary interventions in the acute phase, which ultimately have increased the population of survivors at high risk of relapse. Thus, while hospital management of ACS has shown great progress in terms of diagnostic and therapeutic efficacy, post-hospital care has not had a parallel development. This is certainly partly attributable to the inadequacy of post-discharge cardiologic facilities, so far not planned according to the level of risk of individual patients. Hence, it is crucial that patients at high risk of relapse are identified and initiated into more intensive secondary prevention strategies. On the basis of epidemiological data, the cornerstones of post-ACS prognostic stratification are represented on the one hand by the identification of heart failure (HF) at index hospitalization, on the other hand by the assessment of residual ischemic risk. In patients presenting with HF at index hospitalization, the fatal rehospitalization rate increases by 0.90% per year from 2001 to 2011, with a mortality between discharge and the first year which in 2011 was equal to 10%. The risk of fatal readmission at 1 year is therefore strongly conditioned by the presence of HF which, together with age, is the major predictor of new events. The effect of high residual ischemic risk on subsequent mortality shows increasing trend up to the second year of follow-up, moderately increasing over the years until reaching a plateau around the fifth year. These observations confirm the need for long-term secondary prevention programs and implementation of a continuous surveillance in selected patients.

Safety, efficacy and impact on frailty of mini-invasive radial balloon aortic valvuloplasty.

OBJECTIVE: The study was designed to: (1) confirm safety and feasibility of mini-invasive radial balloon aortic valvuloplasty (BAV); (2) assess its impact in terms of quality of life and frailty; and (3) evaluate whether changes in frailty after BAV are associated with death in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: 330 patients undergoing BAV in 16 Italian centres were prospectively included. The primary endpoint was the occurrence of major and minor Valve Academic Research Consortium (VARC)-2 bleeding. Secondary endpoints were scales of quality of life, frailty, evaluated at baseline and 30 days, and their relationship with the occurrence of all-cause death. RESULTS: BAV was performed by radial access in 314 (95%) patients. No VARC-2 major and six (1.8%) VARC-2 minor bleedings occurred in the study population. Quality of life, as well as frailty status, significantly improved 30 days after BAV. At 1 year, patients undergoing TAVI with baseline essential frailty toolset (EFT) <3 or achieving an EFT <3 after BAV had a comparable occurrence of all-cause death (15% vs 19%, p=0.58). On the contrary, patients with EFT ≥3 at 30 days despite BAV showed the worst prognosis (all-cause death: 40% vs 15% and 19%, p=0.006 and p=0.05, respectively). CONCLUSIONS: Mini-invasive radial BAV is safe, feasible and associated with a low rate of vascular complications. Patients improving EFT 30 days after BAV showed a favourable outcome after TAVI. TRIAL REGISTRATION NUMBER: NCT03087552.

[Periprocedural management of anticoagulation therapy and in-hospital outcomes in patients with warfarin indication undergoing percutaneous coronary intervention. Data from the WAR-STENT registry]. / Gestione periprocedurale della terapia anticoagulante ed esiti intraospedalieri nei pazienti con indicazione a warfarin sottoposti ad angioplastica coronarica. Informazioni dal registro WAR-STENT.

BACKGROUND: In patients with an indication for oral anticoagulation (OAC) with warfarin, the management of OAC peri-procedure of percutaneous coronary intervention (PCI) is still not fully defined. To investigate clinical practice and outcomes associated with continuation vs interruption of OAC, with or without bridging with low-molecular-weight heparin (LMWH), we examined the database of the observational, prospective, multicenter Italian WAR-STENT registry. METHODS: The WAR-STENT registry was conducted in 2008-2010 in 37 Italian centers and included 411 consecutive patients in 157 of whom the peri-procedural international normalized ratio (INR) value was available. In relation to the continuation vs interruption of OAC, patients were divided into group 1 (n = 106) and group 2 (n = 51) respectively, and compared. RESULTS: The basal characteristics of the two groups were similar. The most frequent indication for OAC was atrial fibrillation and for PCI acute coronary syndromes, respectively. The pre-procedural mean value of INR was significantly different in group 1 vs group 2 (2.3 ± 0.4 vs 1.5 ± 0.2; p <0.001), while the use of antithrombotic drugs did not differ, except for LMWH which, albeit limited to only 14% of cases, was used significantly more frequently in group 2 (14% vs 2%; p=0.006). The radial approach was used significantly more often in group 1 vs group 2 (72% vs 45%; p=0.002). The in-hospital incidence of major bleeding complications was similar in groups 1 and 2 (4% vs 8%; p=0.27), as well as the occurrence of major adverse cardio-cerebrovascular events, including cardiovascular death, non-fatal myocardial infarction, re-revascularization of the treated vessel, stent thrombosis, stroke and venous thromboembolism (6% vs 6%; p=0.95). There was a tendency towards a higher incidence of minor access-site bleeding complications in group 1 patients treated by the femoral route. CONCLUSIONS: In unselected patients with an indication for OAC with warfarin and undergoing PCI, the continuation vs interruption of OAC (essentially without LMWH bridging) strategies appears similar in terms of efficacy and safety. In consideration of the superior convenience, peri-procedural continuation of OAC should therefore generally be preferred, with the possible exception of patients in whom the femoral approach is required for the procedure.

Comparison of quantitative flow ratio, Pd/Pa and diastolic hyperemia-free ratio versus fractional flow reserve in non-culprit lesion of patients with non ST-segment elevation myocardial infarction.

OBJECTIVES: To investigate the correlation between quantitative flow ratio (QFR), Pd/Pa, diastolic hyperemia-free ratio (DFR) and fractional flow reserve (FFR, gold standard) in non-culprit lesion (NCL) of patients with non ST-segment elevation myocardial infarction (NSTEMI). BACKGROUND: The non-hyperemic pressure ratio (NHPR) and the angiography-based indexes have been developed to overcome the limitation of the use of the FFR. METHODS: Between January and December 2019, 184 NCL from 116 NSTEMI patients underwent physiologic assessment and were included in the study. NCLs were investigated with QFR, Pd/Pa, DFR, and FFR. Mean values of QFR, Pd/Pa, DFR and FFR were 0.85 ± 0.10, 0.92 ± 0.07, 0.93 ± 0.05 and 0.84 ± 0.07, respectively. RESULTS: DFR and FFR showed a good correlation (r = 0.76). Bland and Altman plot showed a mean difference of 0.080. DFR Diagnostic accuracy was 88%. The area under the ROC curve (AUC) for DFR was 0.946 (95%CI 0.90-0.97, p = .0001). Similar findings were reported for Pd/Pa (r = 0.73; mean difference 0.095, diagnostic accuracy 84%, AUC 0.909 [95%CI 0.85-0.94, p = .0001]) and QFR (r = 0.68; mean difference 0.01; diagnostic accuracy 88%, AUC 0.964 [95% CI 0.91-0.98, p = .0001]). FFR, QFR, Pd/Pa and DFR identified 31%, 32%, 30% and 32% potentially flow-limiting lesions, respectively. CONCLUSIONS: In NSTEMI patients, QFR, Pd/Pa and DFR showed equivalence as compared to gold standard FFR in the discrimination of non-culprit lesions requiring revascularization.

Impact of the COVID-19 pandemic on coronary invasive procedures at two Italian high-volume referral centers.

AIMS: The purpose of this study was to verify the impact on the number and characteristics of coronary invasive procedures for acute coronary syndrome (ACS) of two hub centers with cardiac catheterization facilities, during the first month of lockdown following the COVID-19 pandemic. MATERIALS AND METHODS: Procedural data of ACS patients admitted between 10 March and 10 April 2020 were compared with those of the same period of 2019. RESULTS: We observed a 23.4% reduction in ACS admissions during 2020, with a decrease for both ST-elevation myocardial infarction (STEMI) (-5.6%) and non-ST-elevation myocardial infarction (-34.5%), albeit not statistically significant (P = 0.2). During the first 15 days of the examined periods, the reduction in ACS admissions reached 52.5% (-25% for STEMI and -70.3% for non-ST-elevation myocardial infarction, P = 0.04). Among STEMI patients, the rate of those with a time delay from symptoms onset longer than 180 min was significantly higher during the lockdown period (P = 0.01). Radiograph exposure (P = 0.01) was higher in STEMI patients treated in 2020 with a slightly higher amount of contrast medium (P = 0.1) and number of stents implanted (P = 0.1), whereas the number of treated vessels was reduced (P = 0.03). Percutaneous coronary intervention procedural success and in-hospital mortality were not different between the two groups and in STEMI patients (P NS for all). CONCLUSION: During the early phase, the COVID-19 outbreak was associated with a lower rate of admissions for ACS, with a substantial impact on the time delay presentation of STEMI patients, but apparently without affecting the in-hospital outcomes.

Physiology-guided revascularization versus optimal medical therapy of nonculprit lesions in elderly patients with myocardial infarction: Rationale and design of the FIRE trial.

BACKGROUND: Myocardial infarction (MI) in elderly patients is associated with unfavorable prognosis, and it is becoming an increasingly prevalent condition. The prognosis of elderly patients is equally impaired in ST-segment elevation (STE) or non-STE (NSTE), and it is markedly worsened by the common presence of multivessel disease (MVD). Given the limited evidence available for elderly patients, it has not yet been established whether, as for younger patients, a complete revascularization strategy in MI patients with MVD should be advocated. We present the design of a dedicated study that will address this research gap. METHODS AND DESIGN: The FIRE trial is a prospective, randomized, international, multicenter, open-label study with blinded adjudicated evaluation of outcomes. Patients aged 75 years and older, with MI (either STE or NSTE), MVD at coronary artery angiography, and a clear culprit lesion will be randomized to culprit-only treatment or to physiology-guided complete revascularization. The primary end point will be the patient-oriented composite end point of all-cause death, any MI, any stroke, and any revascularization at 1 year. The key secondary end point will be the composite of cardiovascular death and MI. Quality of life and physical performance will be evaluated as well. All components of the primary and key secondary outcome will be tested also at 3 and 5 years. The sample size for the study is 1,400 patients. IMPLICATIONS: The FIRE trial will provide evidence on whether a specific revascularization strategy should be applied to elderly patients presenting MI and MVD to improve their clinical outcomes.

[Impact of the COVID-19 pandemic on admissions for acute coronary syndrome: review of the literature and single-center experience]. / Impatto della pandemia COVID-19 sui ricoveri per sindrome coronarica acuta: revisione della letteratura ed esperienza monocentrica.

During the early phase of the lockdown following the COVID-19 pandemic, an alarm on the impact on cardiology admissions for cardiac causes, particularly in the field of acute coronary syndromes (ACS), has emerged. In order to evaluate this trend, we analyzed the literature data published since the beginning of the COVID-19 pandemic to date, in addition to our intensive cardiac care unit (ICCU) experience. This analysis showed (i) a reduction of the overall ICCU admissions up to 50%; (ii) a 40-50% reduction of ACS admissions, greater for non-ST-elevation myocardial infarction (NSTEMI) than for ST-elevation myocardial infarction (STEMI); (iii) a reduction greater than 50% of coronary angiography and percutaneous coronary angioplasty; (iv) a higher time delay of STEMI; and (v) a higher number of ICCU admissions for non-primarily cardiac problems. In conclusion, the lockdown imposed due to the spread of COVID-19 infection has led to a change in the number and type of cardiology admissions. It seems therefore necessary that patients, especially for time-dependent diseases such as ACS, continue to refer to hospital care; that contemporary standard of care for acute cardiac disease should be guaranteed, and that intensivist cardiologists acquire specific skills for the treatment of patients with clinical conditions normally treated by other specialists.

Comparison of Verapamil versus Heparin as Adjunctive Treatment for Transradial Coronary Procedures: The VERMUT Study.

OBJECTIVE: We sought to demonstrate that the combination of a local vasodilator (verapamil), modern materials, patent hemostasis, and intravenous anticoagulant only in the case of percutaneous coronary intervention, as compared to default heparin administration after sheath insertion, may optimize a combined endpoint, including radial artery oc-clusion (RAO), radial artery spasm (RAS), and access site complication. METHODS: This is a prospective, single-center, double-blind randomized trial. Overall, 418 patients undergoing a transradial approach (TRA) for coronary procedures were randomized 1: 1 to receive intraradial verapamil (5 mg) or heparin (5,000 IU) after a 6-Fr sheath insertion. The primary outcome was the 24-h occurrence of RAO (ultrasound confirmation), access site complication, and RAS requiring the bailout administration of vasodilators. RESULTS: The combined primary outcome occurred in 127 (30%) patients. It was significantly lower in patients randomized to verapamil as compared to others (26 vs. 35%, p = 0.03). This was mainly due to a significant reduction in RAS (3 vs. 10%, p = 0.006). The 24-h and 30-day occurrence of RAO did not differ between the study groups. CONCLUSION: Local administration of verapamil versus heparin reduces RAS, without increasing RAO, which appears to be strictly related to radial artery diameter and hemostasis time.

Bioresorbable vascular scaffold overlap evaluation with optical coherence tomography after implantation with or without enhanced stent visualization system (WOLFIE study): a two-centre prospective comparison.

To assess if enhanced stent visualization (ESV)-guided implantation of overlapping bioresorbable vascular scaffold (BVS) is superior to angiography alone-guided implantation in the reduction of overlap length. WOLFIE is a two-centre prospective open study enrolling 30 patients treated with implantation of at least two overlapping BVS. In the first centre (London), BVS implantation was guided by conventional angiography, while in the second centre (Ferrara), an ESV system was systematically employed. The primary endpoint of the study was overlap length. Secondary endpoints were: stacked struts number, area, thickness, and amount of clusters. In the ESV-guided group, overlap length was significantly lower compared to angiography-guided group [0.9 (0.6-1.8) vs. 2.2 (1.3-3.2) mm, p = 0.02]. Similarly, all secondary endpoints were significantly reduced. ESV-guided implantation of overlapping BVS is safe and effective in minimizing both overlap length and number of stacked struts.

Thrombin generation assay: a new tool to predict and optimize clinical outcome in cardiovascular patients?

Antithrombotic therapy (including antiplatelet and anticoagulant drugs) is the cornerstone of the current medical treatment of patients with acute coronary syndromes (ACS). This therapy and particularly the new antiplatelet and anticoagulant drugs have significantly reduced the ischemic risk, but have increased bleeding complications. Recently, several studies have emphasized the negative prognostic impact on long-term mortality of these bleeding adverse events. Thus, new assays to estimate the bleeding risk and the efficacy of these antithrombotic drugs are clearly in demand. Regarding the anticoagulant drugs, new promising data have emerged about the thrombin generation assay (TGA). TGA measures the ability of plasma to generate thrombin. TGA may be used to check coagulation function, to value risk of thrombosis and to compare the efficacy of different anticoagulants employed in clinical management of patients with ACS. The TGA result is a curve which describes the variation of thrombin's amount during the activation of the coagulation cascade. All available anticoagulant drugs influence the principal parameters generated by TGA and so it is possible to evaluate the effects of the medical treatment. In this review we provide a brief description of the assay and we summarize the principals of previous studies by analyzing the relationship between anticoagulant drugs and TGA. Moreover, a brief summary of its ability to predict ischemic and bleeding risks has been provided.

Latest clinical data on testing for high on-treatment platelet reactivity.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and in those who are undergoing percutaneous coronary intervention (PCI). Clopidogrel, a second-generation thienopyridine antiplatelet agent, is currently used to prevent vascular complications in atherothrombotic patients, to prevent stent thrombosis in patients undergoing PCI, and in the long-term prevention of cardiovascular and cerebrovascular events. Unfortunately, despite treatment with clopidogrel, some patients continue to have cardiovascular events. This may be due in part to a suboptimal response to the drug, with minimal inhibition of platelet aggregation and/or high on-treatment platelet reactivity. Point-of-care testing of clopidogrel response, together with a reliable diagnostic cutoff, can identify patients with high on-treatment platelet reactivity and optimize their clinical management. This article reviews the impact of poor clopidogrel responsiveness on clinical outcomes, the major clinical studies using VerifyNow P2Y12 Assay® (Accumetrics, San Diego, CA) to assess on-clopidogrel platelet reactivity, and efforts to determine a reliable cutoff.

Genetic determinants of on-clopidogrel high platelet reactivity.

Clopidogrel has been used (alone or in association with aspirin) to prevent vascular complications in atherothrombotic patients, to prevent stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) and as a long-term prevention of cardiovascular and cerebrovascular events. Unfortunately, it is important to note that there are a number of patients who, during clopidogrel therapy, show and maintain a high platelet reactivity (PR), similar to that observed before the start of antiplatelet therapy. Clopidogrel pro-drug is absorbed in the intestine and this process is influenced by P-glycoprotein-1 (P-GP). Its conversion into 2-oxo clopidogrel is regulated by cytochromes (CYP) called CYP2C19, CYP2B6 and CYP1A2. Whereas, the final transformation into the active metabolite is regulated by CYP called CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5 and, as recently emerged, by the glycoprotein paraoxonase-1 (PON1). The genes encoding these enzymes are characterized by several polymorphisms. Some of these are able to modify the activity of proteins, reducing the concentration of active metabolite and the values of on-clopidogrel PR. Only one gene polymorphism (CYP2C19*17) increases the clopidogrel metabolization and so the clopidogrel-induced platelet inhibition. Several studies have clearly associated these gene polymorphisms to both ischemic and bleeding complications in patients receiving dual antiplatelet therapy. The aim of this review is to describe the principal gene polymorphisms influencing on-clopidogrel PR and their relationship with long-term clinical outcome.

Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy.

OBJECTIVES: The purpose of this study was to investigate the long-term outcome after elective percutaneous coronary intervention in low-risk patients screened for aspirin and/or clopidogrel responsiveness in the 3T/2R (Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel) trial. BACKGROUND: The impact of aspirin and/or clopidogrel poor response on long-term outcome is debated. METHODS: Aspirin and clopidogrel response was measured with the VerifyNow system aspirin and P2Y12 assays. After percutaneous coronary intervention (PCI), death, stroke, and myocardial infarction were assessed up to 1 year. RESULTS: Overall, 1,277 patients were screened, and 826 (65%) were treated with PCI. In all, 124 patients were found to be aspirin poor responders, and there were 179 clopidogrel poor responders (totally, 278 poor responders). The 1-year end point was significantly higher in poor responders as compared to full responders (15.8% vs. 8.6%, p=0.002), which is principally due to more myocardial infarction occurrence. At multivariable analysis, clopidogrel poor response emerged as an independent predictor (hazard ratio: 1.15, 95% confidence interval: 1.03 to 1.28). Receiver-operator characteristic analysis identifies≤23 of percentage of platelet inhibition and ≥208 of P2Y12 reactivity units as optimal cut offs to predict 1-year end point. Excluding periprocedural events, also peri-PCI myocardial infarction, which is strongly related to aspirin/clopidogrel poor response, was an independent predictor (hazard ratio: 1.25, 95% confidence interval: 1.14 to 1.37). Glycoprotein IIb/IIIa inhibitor administration reduces this risk in poor responders (21.2% vs. 34.7%, p=0.02), but not in full responders (6.3% vs. 6.5%, p=0.8). CONCLUSIONS: Poor response to clopidogrel is an independent predictor of periprocedural myocardial infarction and worse 1-year outcome in low-risk patients undergoing PCI, whereas poor response to aspirin failed to predict a worse outcome. Contrary to what was observed in poor responders, glycoprotein IIb/IIa inhibitor therapy failed to provide a benefit in aspirin and/or clopidogrel full responders.

Poor response to clopidogrel: current and future options for its management.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions (PCI). Clopidogrel, a thienopyridine antiplatelet agent, has been used to prevent vascular complication in atherothrombotic patients, to prevent stent thrombosis in patients undergoing PCI, and in long term prevention of cardiovascular and cerebrovascular events. More than 40 million patients in the world receive clopidogrel but unfortunately about 20% of these are either non or poor responders. Several methods have been used to assess clopidogrel-induced antiplatelet effects. However, none of these tests have been fully standardized or fully agreed upon to measure clopidogrel responsiveness. Nevertheless, many studies using different techniques, platelet agonists and definitions, showed that patients with a poor response to clopidogrel have an increased risk of death, reinfarction and stent thrombosis. The mechanisms leading to poor responsiveness are not fully clarified and are likely multifactorial: genetic factors, accelerated platelet turnover, up-regulation of the P2Y(12) pathways, high baseline platelet reactivity, poor compliance, under-dosing and drug-drug interactions. The management of these patients is very difficult, but some evidence showed that a strategy of higher maintenance dose or switch to different thienopyridine (e.g. ticlopidine or prasugrel) or use of glycoprotein IIb/IIIa inhibitors during PCI may be helpful to overcome poor responsiveness and improve the long-term clinical outcome. This paper reviews the impact of clopidogrel poor responsiveness on clinical outcomes, the mechanisms leading to poor effect and the different assays to assess it. Finally, current and future options for its management is discussed.

[Current options to manage clopidogrel poor responsiveness]. / Scarsa risposta al clopidogrel: attuali opzioni di trattamento e scenari futuri.

Antiplatelet therapy (aspirin + clopidogrel) is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions (PCI). More than 40 million patients worldwide receive clopidogrel, but about 20% of them are nonresponders or poor responders. Many studies using different techniques, platelet agonists and definitions have shown that patients who are poor responders to clopidogrel have an increased risk of death, reinfarction and stent thrombosis. The mechanisms leading to poor responsiveness are not fully elucidated and are likely multifactorial: genetic factors, accelerated platelet turnover, up-regulation of the P2Y12 pathways, high baseline platelet reactivity, poor compliance, underdosing and drug-drug interactions. The management of these patients is very difficult, but evidence does exist showing that a strategy of higher maintenance dose or switch to different thienopyridines (e.g. ticlopidine or prasugrel) or use of glycoprotein IIb/IIIa inhibitors during PCI may be helpful to overcome poor responsiveness and improve the long-term clinical outcome. This review describes the impact of poor responsiveness to clopidogrel on clinical outcomes, the mechanisms leading to poor effect, and the different assays to assess it. Finally, current and future options for its management are discussed.

Boosting platelet inhibition in poor responder to aspirin and clopidogrel undergoing percutaneous coronary intervention: role of tirofiban.

Nowadays, aspirin (acetylsalicylic acid) and clopidogrel form the cornerstone in prevention of cardiovascular events and their clinical effectiveness has been well established. The thienopyridine clopidogrel is a prodrug that, after hepatic metabolization, strongly inhibits adenosine diphosphate-induced platelet aggregation. Aspirin is a non-steroidal anti-inflammatory drug that exerts its anti-platelet action through the irreversible acetylation of platelet cyclooxygenase (COX)-1, blocking thromboxane A2 production. However, despite dual-antiplatelet therapy, some patients still develop recurrent cardiovascular ischemic events. Many studies have clearly showed that a marked variability exists in the responsiveness to aspirin and clopidogrel, being the poor responder patients at higher risk of short (peri-procedural) and long-term ischemic complications. In particular, these patients showed a major recurrence of myocardial infarction and, after stent implantation, of stent thrombosis. The mechanisms of aspirin and clopidogrel poor response are numerous and not fully elucidated, and are likely multifactorial (eg, genetic polymorphisms, elevated baseline platelet reactivity, drug interaction). How to improve the short- and long-term outcome of these patients is currently unknown. Recently published and ongoing clinical trials are evaluating different strategies for the acute and chronic treatments (eg, reload of clopidogrel, double clopidogrel maintenance dose, switching to prasugrel). In this paper, we reviewed all available evidence on aspirin and clopidogrel resistance and focused our attention on tirofiban, a glycoprotein IIb/IIIa inhibitor that may be used to obtain a better platelet inhibition in poor responder patients during the acute phase and in particular during percutaneous coronary intervention.