considerazioni conclusive: la sintesi per una proposta razionale SCA-NSTE considerazioni conclusive: la sintesi per una proposta razionale Dott. Marco Tubaro Unità Coronarica – Dipartimento Cardiovascolare Ospedale San Filippo Neri – Roma MT

SCA-NSTE in Lombardia, Friuli Venezia Giulia ed Emilia Romagna proporzione SCA-NSTE/STEMI STEMI We determined the effects of early statin treatment in acute myocardial infarction (AMI) on in-hospital morbidity and mortality. Experimental models of ischemia and reperfusion have shown that statins have early cardioprotective effects. However, the effect of statin use within the first 24 hours of admission on early morbidity and mortality in AMI has not been well studied. Data were collected on 300,823 patients who had AMI in the National Registry of Myocardial Infarction 4. In-hospital events were compared between patients who continued statin therapy received before the index AMI hospitalization (n 17,118) or newly started statin therapy within the first 24 hours of hospitalization (n 21,978) and patients who did not receive early statin treatment (n 126,128) or whose statin therapy was discontinued (n 9,411). New or continued treatment with a statin in the first 24 hours was associated with a decreased risk of mortality compared with no statin use (4.0% and 5.3% compared with 15.4% no statin). Discontinuation of statin treatment was associated with a slightly increased risk of mortality (16.5%). Early statin use was also associated with a lower incidence of cardiogenic shock, arrhythmias, cardiac arrest, rupture, but not recurrent myocardial infarction. Propensity analysis yielded mortality odds ratios of 0.46 for continued therapy, 0.42 for newly started therapy, and 1.25 for discontinued therapy for matched pairs versus no statin therapy (all p values <0.0001). In conclusion, the use of statin therapy within the first 24 hours of hospitalization for AMI is associated with a significantly lower rate of early complications and in-hospital mortality mortalità SCA-NSTE MT FIC SCA-NSTE, GIC 2009

reparto di ricovero e mortalità MT FIC SCA-NSTE, GIC 2009

linee guida ESC: stratificazione del rischio nelle SCA NSTE elevated troponin levels dynamic ST-T changes (symptomatic or silent) diabetes renal dysfunction (GFR < 60 mL/min/1.73 m2) EF < 40% early post-infarction angina prior MI PCI within 6 months prior CABG GRACE score: intermediate - high mt

GRACE risk score mt

routine vs selective invasive strategies in NSTEACS - a metanalysis of 7 trials - OR (95% CI) outcome in hospital total death 1.60 (1.14 - 2.25) 0.92 (0.77 - 1.09) death / MI 1.36 (1.12 - 1.66) 0.82 (0.72 - 0.93) Tn + ve 0.69 (0.55 – 0.86) Tn –ve 0.89 (0.67 - 1.18) TIMI III B, MATE, VANQWISH, TACTICS, VINO, RITA, FRISC II Data Synthesis A total of 7 trials (N=9212 patients) were eligible. Overall, death or MI was reduced from 663 (14.4%) of 4604 patients in the selective invasive group to 561 (12.2%) of 4608 patients in the routine invasive group (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.72-0.93; P=.001). There was a nonsignificant trend toward fewer deaths (6.0% vs 5.5%; OR, 0.92; 95% CI, 0.77-1.09; P=.33) and a significant reduction in MI alone (9.4% vs 7.3%; OR, 0.75; 95% CI, 0.65-0.88; P.001). Higher-risk patients with elevated cardiac biomarker levels at baseline benefited more from routine intervention, with no significant benefit observed in lower-risk patients with negative baseline marker levels. During the initial hospitalization, a routine invasive strategy was associated with a significantly higher early mortality (1.1% vs 1.8% for selective vs routine, respectively; OR, 1.60; 95% CI, 1.14-2.25; P=.007) and the composite of death or MI (3.8% vs 5.2%; OR, 1.36; 95% CI, 1.12-1.66; P=.002). But after discharge, the routine invasive strategy was associated with fewer subsequent deaths (4.9% vs 3.8%; OR, 0.76; 95% CI, 0.62-0.94; P=.01) and the composite of death or MI (11.0% vs 7.4%; OR, 0.64; 95% CI, 0.56-0.75; P.001). At the end of follow-up, there was a 33% reduction in severe angina (14.0% vs 11.2%; OR, 0.77; 95% CI, 0.68-0.87; P.001) and a 34% reduction in rehospitalization (41.3% vs 32.5%; OR, 0.66; 95% CI, 0.60-0.72; P.001) with a routine invasive strategy. MT Mehta SR JAMA 2005

ICTUS: intended invasive strategy vs actual revascularization Note 1: Standard risk adjustment techniques, such as logistic regression or propensity scores, that are commonly used in analysing observation data can only account for measured confounders and thereby inevitably suffers from residual confounding. There are other alternative approaches, like instrumental variable analysis, that are designed to control for hidden bias as well. An instrumental variable is an observable factor that is associated with a specific treatment pattern but is otherwise unrelated to patient characteristics and does not directly affect the outcome of interest. Note 2: actual revascularization during hospital admission was associated with lower mortality and fewer MIs, even after the use of appropriate risk adjustment techniques. This apparent discrepancy is primarily driven by the poor prognosis in patients who underwent angiography but were not revascularized because of co-morbidities and anticipated high procedure-related risks. Therefore, we conclude that the observation that revascularization is associated with improved prognosis cannot be used as evidence to support that an early invasive treatment strategy leads to a better outcome compared with a selective invasive treatment strategy. Aims In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality.We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial. Methods and results The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year followup and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37–0.96] and 0.46 (95% CI 0.31–0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70–1.74) for death and 1.27 (95% CI 0.88–1.85) for death or spontaneous MI. Conclusion The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies MT Hirsch A. Eur Heart J 2008

MASCARA: early invasive strategy in NSTEACS high risk low-intermediate risk - EIS pts have a lower GRACE risk score (128.2 vs 138.5) - CORO availability is the strongest predictor of EIS (OR 13.7; 7.1-25) - the benefit of EIS was not apparent after statistical adjustement, in the whole population (OR 0.8; CI 0.55-1.1) or in high-risk patients (OR 0.7; CI 0.461.1) Background The patterns of use and the benefit of an early invasive strategy (EIS) in patients with non–ST-segment elevation acute coronary syndrome in a real-life population are not well established. Methods All consecutive patients hospitalized because of non–ST-segment elevation acute coronary syndrome between November 2004 and June 2005 in 32 randomly selected hospitals were prospectively included. Patients were stratified by their baseline risk profile using the Global Registry of Acute Coronary Events (GRACE) risk score in 2 groups. Inhospital mortality and 1- and 6-month mortality or rehospitalization for acute coronary syndromes were analyzed. To ensure optimal adjustment propensity score, conventional logistic regression and Cox regression were used. Results Of 2,856 patients analyzed, 1,616 (56%) had low/intermediate risk (GRACE ≤140) and 1,240 had high risk (GRACE N140). Patients who underwent EIS had lower risk than those who did not (GRACE score 128.2 ± 41 vs 138.5 ± 43, P b .001). Coronary angiography facility emerged as the strongest predictor of EIS (odds ratio [OR] 13.7 [95% CI 7.1-25]).Patients who underwent EIS had lower rate of the 6-month outcome in both the whole population (9% [95% CI 6.6-11.9] vs 14% [95% CI 12.5-15.6], P = .003) and in high-risk patients (16.5% [95% CI 11-23] vs 23.6% [95% CI 20.8-26.5], P = .04). However, this benefit of EIS was not apparent after statistical adjustment in the whole population (OR 0.8, CI 0.55-1.1, P = .17) or in high-risk patients (OR 0.7, CI 0.46-1.1, P = .16). Conclusions In a real-life population, EIS was mainly performed in patients of low/intermediate risk. An obvious benefit of this strategy could not be found MT Ferreira-Gonzales I. Am Heart J 2008;156:946.

TIMACS: early vs delayed invasive intervention in ACS Background Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain. Methods We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography ≤24 hours after randomization) or delayed intervention (coronary angiography ≥36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, or refractory ischemia at 6 months. Results Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6% of patients in the early-intervention group, as compared with 11.3% in the delayed intervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P = 0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group (12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P = 0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P = 0.01 for heterogeneity). Conclusions Early intervention did not differ greatly from delayed intervention in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, myocardial infarction, or refractory ischemia and was superior to delayed intervention in high-risk patients. MT Mehta SR. NEJM 2009;360:2165.

strategies in high risk NSTEACS - PRESTO ACS Registry - Tubaro M, ESC Congress 2008 MT

TACTICS: elderly patients NNT 250 21 9 Background: Although increasing age is an important risk factor for adverse outcome among patients with acute coronary syndromes, elderly patients are more often managed conservatively. Objective: To examine outcome according to age and management strategy for patients with unstable angina and non–ST segment elevation myocardial infarction (MI). Design: Randomized, controlled trial conducted from December 1997 to June 2000. Setting: 169 community and tertiary care hospitals in 9 countries. Patients: 2220 patients hospitalized with unstable angina and non–ST-segment elevation MI who were randomly assigned to an early invasive or conservative management strategy. Interventions: Medical therapy and coronary angiography at 4 to 48 hours versus medical therapy and predischarge exercise testing. Measurements: Rates of 30-day and 6-month mortality, nonfatal MI, rehospitalization, stroke, and hemorrhagic complications. Results: Among patients 65 years of age and older, the early invasive strategy compared with the conservative strategy yielded an absolute reduction of 4.8 percentage points (8.8% vs. 13.6%; P 0.018) and a relative reduction of 39% in death or MI at 6 months. Outcomes of the 2 strategies were similar, however, among patients younger than 65 years of age (6.1% vs. 6.5%; P > 0.2). Among patients older than 75 years of age, the early invasive strategy conferred an absolute reduction of 10.8 percentage points (10.8% vs. 21.6%; P 0.016) and a relative reduction of 56% in death or MI at 6 months. The additional cost per death or MI prevented with the early invasive strategy was lower for elderly patients, but major bleeding rates were higher with this strategy in patients older than 75 years of age (16.6% vs. 6.5%; P 0.009). Limitations: Because this study involved patients in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction (TACTICS–TIMI) 18 trial, its generalizability to elderly patients with excluded comorbid conditions is unknown. Conclusion: Despite an increased risk for major bleeding in patients older than 75 years of age, a routine early invasive strategy can significantly improve ischemic outcomes in elderly patients with unstable angina and non–ST-segment elevation MI. Bach RG. Ann Intern Med 2004;141:186 MT

considerazioni per il trattamento degli anziani con SCA NSTE MT Alexander KP, Circulation 2007

gender and therapeutic strategies in NSTEACS - a metanalysis of 8 studies - EI vs EC OR (95% CI( D/MI/reH for ACS ------------------------ ------------------------------------------ women 0.81 (0.65-1.01) women biom +ve 0.67 (0.50-0.83) women biom –ve 0.94 (0.61-1.44) men 0.73 (0-55-0.98) men biom +ve 0.56 (0.45-0.67) men biom –ve 0.72 (0.51-1.01) Context Although an invasive strategy is frequently used in patients with non–STsegment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. Study Selection Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. Data Synthesis Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction=.26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction=.36) and was associated with a nonsignificant35%higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction=.08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction=.09). Conclusions In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women. MT O'Donoghue M. JAMA 2008;300:71.

SWEDEHEART: funzione renale e mortalità Background—It is unknown whether patients with non–ST-elevation myocardial infarction derive a similar benefit from an early invasive therapy at different levels of renal function. Methods and Results—A total of 23 262 consecutive non–ST-elevation myocardial infarction patients 80 years old were included in a nationwide coronary care unit register between 2003 and 2006. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula. Patients were divided into medically or invasively treated groups if revascularized within 14 days of admission. A propensity score for the likelihood of invasive therapy was calculated. A Cox regression model with adjustment for propensity score and discharge medication was used to assess the association between early revascularization and 1-year mortality across renal function stages. There was a gradient, with significantly fewer patients treated invasively with declining renal function: eGFR 90 mL · min1 · 1.73 m2, 62%; eGFR 60 to 89 mL · min1 · 1.73 m2, 55%; eGFR 30 to 59 mL · min1 · 1.73 m2, 36%; eGFR 15 to 29 mL · min1 · 1.73 m2, 14%; and eGFR15 mL · min1 · 1.73 m2/dialysis, 15% (P0.001). After adjustment, the overall 1-year mortality was 36% lower (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P0.001) with an invasive strategy. The magnitude of survival difference was similar in normal-to-moderate renal function groups. The lower mortality observed with invasive therapy declined with lower renal function, with no difference in mortality in patients with kidney failure (eGFR 15 mL · min1 · 1.73 m2) or in those receiving dialysis (hazard ratio 1.61, 95% confidence interval 0.84 to 3.09, P0.15). Conclusions—Early invasive therapy is associated with greater 1-year survival in patients with non–ST-elevation myocardial infarction and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis. (Circulation. 2009;120:851-858.) MT Szummer K. Circulation 2009;120:851

SWEDEHEART: funzione renale e procedure di rivascolarizzazione Background—It is unknown whether patients with non–ST-elevation myocardial infarction derive a similar benefit from an early invasive therapy at different levels of renal function. Methods and Results—A total of 23 262 consecutive non–ST-elevation myocardial infarction patients 80 years old were included in a nationwide coronary care unit register between 2003 and 2006. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula. Patients were divided into medically or invasively treated groups if revascularized within 14 days of admission. A propensity score for the likelihood of invasive therapy was calculated. A Cox regression model with adjustment for propensity score and discharge medication was used to assess the association between early revascularization and 1-year mortality across renal function stages. There was a gradient, with significantly fewer patients treated invasively with declining renal function: eGFR 90 mL · min1 · 1.73 m2, 62%; eGFR 60 to 89 mL · min1 · 1.73 m2, 55%; eGFR 30 to 59 mL · min1 · 1.73 m2, 36%; eGFR 15 to 29 mL · min1 · 1.73 m2, 14%; and eGFR15 mL · min1 · 1.73 m2/dialysis, 15% (P0.001). After adjustment, the overall 1-year mortality was 36% lower (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P0.001) with an invasive strategy. The magnitude of survival difference was similar in normal-to-moderate renal function groups. The lower mortality observed with invasive therapy declined with lower renal function, with no difference in mortality in patients with kidney failure (eGFR 15 mL · min1 · 1.73 m2) or in those receiving dialysis (hazard ratio 1.61, 95% confidence interval 0.84 to 3.09, P0.15). Conclusions—Early invasive therapy is associated with greater 1-year survival in patients with non–ST-elevation myocardial infarction and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis. (Circulation. 2009;120:851-858.) MT Szummer K. Circulation 2009;120:851

variabili di rischio e strategia invasiva BLITZ 2 FIC – SCA NTE utilizzo della rete età > 75 anni Killip > 1 diabete troponina PAS < 100 mmHg CORO immediata - angina refrattaria o ricorrente - instabilità emodinamica - instabilità elettrica (TVS, FV) CORO < 24 ore - GRACE > 140 - > 3 variabili di rischio > 3 variabili 17% eventi a 30 gg MT FIC SCA-NSTE, GIC 2009

GRACE: use of interventions according to risk Objective: To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less aggressive revascularisation strategies. Methods: GRACE (Global Registry of Acute Coronary Events) is a multinational, observational cohort study. This study involved 24 189 patients enrolled at 73 hospitals with on-site angiographic facilities. Results: Overall, 32.5% of patients with a non-ST elevation acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI)) and 7.2% underwent coronary artery bypass grafting (CABG; 4.0% in STEMI). The cumulative rate of in-hospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2% in low-risk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic = 0.83). PCI procedures were more likely to be performed in low- (40% non-STEMI, 60% STEMI) than medium- (35%, 54%) or highrisk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2233.7%, n = 7210 observations), medium (35.7251.4%, n = 7913 observations) or high rates (52.6277.0%, n = 8942 observations) of intervention. Conclusions: A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient’s risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation procedures, in contrast to current international practice. MT Fox KAA. Heart 2007;93:177.

CRUSADE: early (< 48 h) transfer pattern in NSTEACS low risk moderate risk high risk Background Practice guidelines for non–ST-segment elevation acute coronary syndromes (NSTE ACS) recommend early invasive management (cardiac catheterization and revascularization within 48 hours of hospital presentation) for highrisk patients, but interhospital transfer is necessary to provide rapid access to revascularization procedures for patients who present to community hospitals without revascularization capabilities. Methods We analyzed patterns and factors associated with interhospital transfer among 19,238 patients with NSTE ACS (positive cardiac markers and/or ischemic ST-segment changes) from 124 community hospitals without revascularization capabilities in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines quality improvement initiative from January 2001 through June 2004. Results Less than half of the patients (46.3%) admitted to community hospitals were transferred to tertiary hospitals, and fewer (20%) were transferred early (within 48 hours of presentation). Early transfer rates increased by 16% over 10 quarters in patients with a predicted low or moderate risk of inhospital mortality, compared with 5% in high-risk patients. By the last quarter of the analysis, 41.4% of low-risk patients were transferred early versus 12.5% of high-risk patients. Factors significantly associated with early transfer included younger age, lack of prior heart failure, cardiology inpatient care, and ischemic ST-segment electrocardiographic changes. Among patients who were not transferred, 29% had no further risk stratification performed with stress testing, ejection fraction measurement, or diagnostic cardiac catheterization (at hospitals with catheterization laboratories). Conclusions Most patients with NSTE ACS presenting to community hospitals without revascularization capabilities are not rapidly transferred to tertiary hospitals, and lower-risk patients appear to be preferentially transferred early. Further investigation is needed to determine if improved risk-based triage at community hospitals can optimize transfer decision making for high-risk patients with NSTE ACS. MT Roe MT. Am Heart J 2008;156:185

hs cTnI nella diagnosi precoce dell'IMA Background Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. Methods In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. Results For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P = 0.003). Conclusions The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset. Keller T. NEJM 09 MT

cTnT nell'insufficienza cardiaca cronica stabile Val-HeFT cTnT nell'insufficienza cardiaca cronica stabile 100 80 60 40 20 92.0 elevated cTnT (% pts) 10.4 Background—Circulating cardiac troponin T, a marker of cardiomyocyte injury, predicts adverse outcome in patients with heart failure (HF) but is detectable in only a small fraction of those with chronic stable HF. We assessed the prognostic value of circulating cardiac troponin T in patients with stable chronic HF with a traditional (cTnT) and a new precommercial highly sensitive assay (hsTnT). Methods and Results—Plasma troponin T was measured in 4053 patients with chronic HF enrolled in the Valsartan Heart Failure Trial (Val-HeFT). Troponin T was detectable in 10.4% of the population with the cTnT assay (detection limit 0.01 ng/mL) compared with 92.0% with the new hsTnT assay (0.001 ng/mL). Patients with cTnT elevation or with hsTnT above the median (0.012 ng/mL) had more severe HF and worse outcome. In Cox proportional hazards models adjusting for clinical risk factors, cTnT was associated with death (780 events; hazard ratio2.08; 95% confidence interval, 1.72 to 2.52; P0.0001) and first hospitalization for HF (655 events; hazard ratio1.55; 95% confidence interval, 1.25 to 1.93; P0.0001). HsTnT was associated with the risk of death in unadjusted analysis for deciles of concentrations and in multivariable models (hazard ratio1.05; 95% confidence interval, 1.04 to 1.07 for increments of 0.01 ng/mL; P0.0001). Addition of hsTnT to well-calibrated models adjusted for clinical risk factors, with or without brain natriuretic peptide, significantly improved prognostic discrimination (C-index, P0.0001 for both outcomes). Conclusions—In this large population of patients with HF, detectable cTnT predicts adverse outcomes in chronic HF. By the highly sensitive assay, troponin T retains a prognostic value at previously undetectable concentrations cTNT hs cTnT DL < 0.01 DL < 0.001 ng/mL ng/mL MT Latini R Circulation 2007

clopidogrel nelle SCA CURE PCI-CURE Background Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. Methods We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months. Results The first primary outcome — a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke — occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome — the first primary outcome or refractory ischemia — occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86, P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes. Conclusions The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel. (N Engl J Med 2001;345: 494-502.) Background Despite the use of aspirin, there is still a risk of ischaemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI. Methods 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly assigned double-blind treatment with clopidogrel (n=1313) or placebo (n=1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (>80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularisation within 30 days of PCI. The main analysis was by intention to treat. Findings There were no drop-outs. 59 (4·5%) patients in the clopidogrel group had the primary endpoint, compared with 86 (6·4%) in the placebo group (relative risk 0·70 [95% CI 0·50–0·97], p=0·03). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=0·03), and of cardiovascular death or myocardial infarction (p=0·047). Overall (including events before and after PCI) there was a 31% reduction cardiovascular death or myocardial infarction (p=0·002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0·001). At follow-up, there was no significant difference in major bleeding between the groups (p=0·64). Interpretation In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo. Lancet 2001; 358: 527–33 N Engl J Med 2001 Mehta SR. Lancet 2001 MT

CREDO: clopidogrel loading dose timing CONTEXT: Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. OBJECTIVES: To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy. DESIGN, SETTING, AND PARTICIPANTS: The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001. INTERVENTIONS: Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. MAIN OUTCOME MEASURES: One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. RESULTS: At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P =.23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P =.051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P =.07). CONCLUSIONS: Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events. MT Steinhubl SR. JACC 2006

variability in platelet responsiveness to clopidogrel OBJECTIVES We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population. BACKGROUND Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of “non-responders” and a majority of “responders.” Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications. METHODS We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n 94) and patients after coronary stenting (n 405), with heart failure (n 25), and after stroke (n 20). RESULTS The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 20.8% when aggregation was induced by 5 mol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel. CONCLUSIONS Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events. MT Serebruany, JACC 2005

Cyt P 450 polymorphism & response to clopidogrel Background Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. Results In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON–TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P = 0.02). Conclusions Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers. MT Mega JL, NEJM '09

attività piastrinica residua con clopidogrel e outcome nelle SCA con stent Background—The clinical impact of platelet aggregation assessed by point-of-care assays is unknown. We sought to evaluate whether high residual platelet reactivity (RPR) to ADP during clopidogrel therapy, measured by a point-of-care assay, predicts adverse clinical events in acute coronary syndrome patients undergoing percutaneous coronary intervention. Methods and Results—We used the VerifyNow P2Y12 assay (Accumetrics Inc, San Diego, Calif) to determine RPR to ADP in 683 patients with acute coronary syndrome undergoing dual-antiplatelet therapy who underwent percutaneous coronary intervention with bare-metal or drug-eluting stent implantation. All patients received a single 600-mg clopidogrel loading dose followed by 75 mg of clopidogrel daily and 100 to 325 mg of aspirin daily. The end points of the study at follow-up of 12 months were cardiovascular death, nonfatal myocardial infarction (MI), and target-vessel revascularization. At a 12-month follow-up, we found 51 ischemic events (24 cardiovascular deaths [3.5%], 27 nonfatal MIs [3.9%]) and 40 target-vessel revascularizations (5.8%). By receiver operating characteristic curve (ROC) analysis, the optimal cutoff value in predicting 12-month cardiovascular death and nonfatal MI was P2Y12 reaction unit values 240. RPR, defined in the presence of P2Y12 reaction unit values above this cutoff, was found to be a significant and independent predictor of cardiovascular death and nonfatal MI in a model that adjusted for cardiovascular risk factors, renal failure, reduced left ventricular ejection fraction, multivessel disease, total stent length, bifurcation lesions, number of lesions treated, type of stent, and use of glycoprotein IIb/IIIa inhibitors (cardiovascular death: hazard ratio 2.55, 95% CI 1.08 to 6.07, P0.034; nonfatal MI: hazard ratio 3.36, 95% CI 1.49 to 7.58, P0.004). No significant association was found between high RPR and the risk of target-vessel revascularization. Conclusions—RPR to ADP with clopidogrel therapy, measured by the point-of-care assay VerifyNow P2Y12, is able to detect acute coronary syndrome patients at risk of 12-month cardiovascular death and nonfatal MI. The optimal cutoff value was identified as being 240 P2Y12 reaction units. (Circulation. 2009;119:237-242.) Marcucci R. Circulation 2009 MT

resistenza ai farmaci antipiastrinici (attività piastrinica residua) Oral antiplatelet drugs are a cornerstone of modern pharmacotherapy in cardiovascular atherothrombotic diseases. The efficacy of acetylsalicylic acid (ASA, aspirin) and clopidogrel in decreasing the risk of adverse events in coronary heart disease patients has been ell established in the past 20 years. Despite chronic oral antiplatelet therapy, a number of atherothombotic events continue to occur. In recent years, a number of reports in the literature have shown possible relationships between residual platelet activity, as measured with a variety of laboratory tests, and clinical outcome, raising the possibility that ‘resistance’ to oral antiplatelet drugs may underlie many such clinical adverse events. The present position paper, conveyed within a group of clinical cardiologists with expertise in thrombosis appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, has been further elaborated and endorsed by the Working Group on Thrombosis of the European Society of Cardiology. It aims at summarizing the main findings in this complex area, issuing opinions in cases of high controversy, and fostering future research in this area to obtain reliable laboratory and clinical data for the resolution of the many problems still open. MT Kuliczkowski W. EHJ 2009

PRINCIPLE TIMI 44: prasugrel vs high dose clopidogrel Background—The increasing use of higher-than-approved doses of clopidogrel in clinical practice is based in part on the desire for greater levels of inhibition of platelet aggregation (IPA). Prasugrel is a new thienopyridine that is more potent than standard-dose clopidogrel in healthy subjects and patients with stable coronary artery disease. The relative antiplatelet effects of prasugrel versus high-dose clopidogrel in percutaneous coronary intervention patients are unknown. Methods and Results—Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) was a randomized, double-blind, 2-phase crossover study of prasugrel compared with high-dose clopidogrel in patients undergoing cardiac catheterization for planned percutaneous coronary intervention. The primary end point of the loading-dose phase (prasugrel 60 mg versus clopidogrel 600 mg) was IPA with 20 mol/L ADP at 6 hours. Patients with percutaneous coronary intervention entered the maintenance-dose phase, a 28-day crossover comparison of prasugrel 10 mg/d versus clopidogrel 150 mg/d with a primary end point of IPA after 14 days of either drug. In this study, 201 subjects were randomized. IPA at 6 hours was significantly higher in subjects receiving prasugrel (meanSD, 74.813.0%) compared with clopidogrel (31.821.1%; P0.0001). During the maintenance-dose phase, IPA with 20 mol/L ADP was higher in subjects receiving prasugrel (61.317.8%) compared with clopidogrel (46.121.3%; P0.0001). Results were consistent across all key secondary end points; significant differences emerged by 30 minutes and persisted across all time points. Conclusions—Among patients undergoing cardiac catheterization with planned percutaneous coronary intervention, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy with prasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d clopidogrel. (Circulation. 2007;116:2923-2932.) Wiviott SD, Circulation 2007 MT

TRITON TIMI 38: risultati di efficacia e sicurezza Background Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. Methods To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Conclusions In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. MT Wiviott SD. N Engl J Med 2007;357:2001

TRITON TIMI 38: emorragie Background Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. Methods To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Conclusions In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. MT Wiviott SD. N Engl J Med 2007;357:2001

TRITON-TIMI 38 Efficacy and Safety: Post-hoc Analysis for Age, Body Weight, and Prior Stroke/TIA History Prasugrel n/N (%) Clopidogrel HR (95% CI) P value P Interaction At least one of: Age > 75 y, Body Weight < 60 kg, or history of prior stroke/TIA CV Death/ Nonfatal MI/ Nonfatal Stroke 198/1320 (16.1) 199/1347 (16.0) 1.02 (0.84-1.24) 0.83 Non-CABG related TIMI Major Bleeding 52/1305 (4.3) 38/1328 (3.3) 1.42 (0.93-2.15) 0.10 Death from any cause, nonfatal MI, nonfatal stroke, nonfatal TIMI Major bleed (non-CABG) 249/1320 (20.2) 239/1347 (19.0) 1.07 (0.90-1.28) 0.43 Ideal Population 433/5421 (8.3) 569/5383 (11.0) 0.74 (0.66-0.84) <0.001 0.008 91/5390 (2.0) 73/5337 (1.5) 1.24 (0.91-1.69) 0.17 0.64 522/5421 (10.2) 641/5383 (12.5) 0.80 (0.71-0.89) 0.006 Adapted from Wiviott et al. NEJM 2007;357:2001-2015

PLATO: ticagrelor vs clopidogrel in ACS primary end-point major bleedings Background Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. Methods In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. Results At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. Conclusions In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non– procedure-related bleeding. MT Wallentin L, NEJM 2009

PLATO: non-CABG and CABG-related major bleeding fatal bleeds T (n° p.) C (n° p.) p no ICH 9 21 0.03 ICH 11 1 0.02 9 Ticagrelor Clopidogrel NS 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 4 3.8 p=0.025 2.8 3 2.2 Background Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. Methods In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. Results At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs. 5.1%, P = 0.001) but not stroke alone (1.5% vs. 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. Conclusions In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non– procedure-related bleeding. 2 1 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding MT Wallentin L, NEJM 2009

Troponin level and benefit with abciximab abciximab vs placebo death/MI/UTVR 20 troponin +ve: RR=0.71 [0.54-0.95] 15 % 10 troponin -ve: RR=0.99 [0.56-1.76] 5 5 10 15 20 25 30 days after randomization Kastrati A et al. JAMA 2006;295:1531-38 MT

tirofiban nelle sindromi coronariche acute e nella PCI - metanalisi - morte / IMA 0.69 (0.55-0.89) tirofiban upstream vs. P 0.56 (0.37-0.84) tirofiban HD bolus downstream vs. P 0.87 (0.56-1.35) tirofiban HD bolus vs. abciximab Aims To perform a thorough and updated systematic review of randomized clinical trials comparing tirofiban vs. placebo or vs. abciximab. Methods and results We searched for randomized trials comparing tirofiban vs. placebo or any active control. Odds ratios (OR) were computed from individual studies and pooled with random-effect methods. Thirty-one studies were identified involving 20 006 patients (12 874 comparing tirofiban vs. heparin plus placebo or bivalirudin alone, and 7132 vs. abciximab). When compared with placebo, tirofiban was associated at 30 days with a significant reduction in mortality [OR 1/4 0.68 (0.54–0.86); P 1/4 0.001] and death or myocardial infarction (MI) [OR 1/4 0.69 (0.58–0.81); P , 0.001]. The treatment benefit persisted at follow-up but came at an increased risk of minor bleedings [OR 1/4 1.42 (1.13, 1.79), P 1/4 0.002] or thrombocytopenia. When compared with abciximab, mortality at 30 days did not differ [OR 1/4 0.90 (0.53, 1.54); P 1/4 0.70], but in the overall group tirofiban trended to increase the composite of death or MI [OR 1/4 1.18 (0.96, 1.45); P 1/4 0.11]. No such trend persisted at medium-term follow-up or when appraising studies testing tirofiban at 25 mg/kg bolus regimen. Conclusion Tirofiban administration reduces mortality, the composite of death or MI and increases minor bleedings when compared with placebo. An early ischaemic hazard disfavouring tirofiban was noted when compared with abciximab in studies based on 10 but not 25 mg/kg tirofiban bolus regimen 0.4 0.6 0.8 1.0 1.2 1.4 vantaggio tirofiban vantaggio controllo MT Valgimigli M, Eur Heart J 2009

OASIS 5: early bleeding and long-term risk MT

Context It is unclear if blood transfusion in anemic patients with acute coronary syndromes is associated with improved survival. Objective To determine the association between blood transfusion and mortality among patients with acute coronary syndromes who develop bleeding, anemia, or both during their hospital course. Design, Setting, and Patients Weanalyzed 24112 enrollees in 3 large international trials of patients with acute coronary syndromes (theGUSTOIIb,PURSUIT,andPARAGON B trials). Patients were grouped according to whether they received a blood transfusion during the hospitalization. The association between transfusion and outcome was assessed using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate and the propensity to receive blood, and a landmark analysis. Main Outcome Measure Thirty-day mortality. Results Of the patients included, 2401 (10.0%) underwent at least 1 blood transfusion during their hospitalization. Patients who underwent transfusion were older and had more comorbid illness at presentation and also had a significantly higher unadjusted rate of 30-day death (8.00% vs 3.08%; P.001), myocardial infarction (MI) (25.16% vs 8.16%; P.001), and death/MI (29.24% vs 10.02%; P.001) compared with patients who did not undergo transfusion. Using Cox proportional hazards modeling that incorporated transfusion as a time-dependent covariate, transfusion was associated with an increased hazard for 30-day death (adjusted hazard ratio [HR], 3.94; 95% confidence interval [CI], 3.26-4.75) and 30-day death/MI (HR, 2.92; 95% CI, 2.55-3.35). In the landmark analysis that included procedures and bleeding events, transfusion was associated with a trend toward increased mortality. The predicted probability of 30-day death was higher with transfusion at nadir hematocrit values above 25%. Conclusions Blood transfusion in the setting of acute coronary syndromes is associated with higher mortality, and this relationship persists after adjustment for other predictive factors and timing of events. Given the limitations of post hoc analysis of clinical trials data, a randomized trial of transfusion strategies is warranted to resolve the disparity in results between our study and other observational studies. We suggest caution regarding the routine use of blood transfusion to maintain arbitrary hematocrit levels in stable patients with ischemic heart disease. Rao SV. JAMA 2004;292:1555 MT

Background—Treatments for non–ST-segment elevation myocardial infarction (NSTEMI) reduce ischemic events but increase bleeding. Baseline prediction of bleeding risk can complement ischemic risk prediction for optimization of NSTEMI care; however, existing models are not well suited for this purpose. Methods and Results—We developed (n71 277) and validated (n17 857) a model that identifies 8 independent baseline predictors of in-hospital major bleeding among community-treated NSTEMI patients enrolled in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) Quality Improvement Initiative. Model performance was tested by c statistics in the derivation and validation cohorts and according to postadmission treatment (ie, invasive and antithrombotic therapy). The CRUSADE bleeding score (range 1 to 100 points) was created by assignment of weighted integers that corresponded to the coefficient of each variable. The rate of major bleeding increased by bleeding risk score quintiles: 3.1% for those at very low risk (score 20); 5.5% for those at low risk (score 21–30); 8.6% for those at moderate risk (score 31–40); 11.9% for those at high risk (score 41–50); and 19.5% for those at very high risk (score 50; Ptrend 0.001). The c statistics for the major bleeding model (derivation0.72 and validation0.71) and risk score (derivation0.71 and validation0.70) were similar. The c statistics for the model among treatment subgroups were as follows: 2 antithrombotics0.72; 2 antithrombotics0.73; invasive approach0.73; conservative approach0.68. Conclusions—The CRUSADE bleeding score quantifies risk for in-hospital major bleeding across all postadmission treatments, which enhances baseline risk assessment for NSTEMI care. Subherwal S, Circulation 2009

OASIS 5 – emorragie maggiori a 9 giorni Enoxaparin 0.04 HR 0.52 95% CI 0.44-0.61 P<<0.00001 0.03 Cumulative Hazard 0.02 Background The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding. Methods We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months. Results The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combinedoutcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P = 0.13) and at the end of the study (1222 vs. 1308, P = 0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P = 0.02) and at 180 days (574 vs. 638, P = 0.05). Conclusions Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.) Fondaparinux 0.01 0.0 1 2 3 4 5 6 7 8 9 Days N Engl J Med 2006; 354, 1464-76 MT

OASIS 5 – outcome (efficacia) a 6 mesi Enox Fonda Death/MI/RI 13.1% 12.1% Death/MI 11.2% 10.3% Death 6.3% 5.6% MI 6.0% Strokes 1.6% 1.3% Death/MI/Stroke 12.3% 11.1% P=0.055 P=0.036 P=0.037 P=0.33 P=0.029 Background The combined use of anticoagulants, antiplatelet agents, and invasive coronary procedures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding. Methods We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months. Results The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combinedoutcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P = 0.13) and at the end of the study (1222 vs. 1308, P = 0.06). The rate of major bleeding at nine days was markedly lower with fondaparinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a significantly reduced number of deaths at 30 days (295 vs. 352, P = 0.02) and at 180 days (574 vs. 638, P = 0.05). Conclusions Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mortality and morbidity. (ClinicalTrials.gov number, NCT00139815.) P=0.005 0.8 1 1.2 MT

ACUITY: età, rischio emorragico e bivalirudin Antiplatelet agents play an important role in the treatment of non–ST-segment elevation acute coronary syndromes (NSTE ACS), particularly for those at high risk, such as older adults (aged >75 years) where treatment may yield the greatest benefits. Paradoxically, older adults are also at higher risk from bleeding complications. Most randomized trials have enrolled few older persons, so data are sparse with which to guide clinical practice. In this review, we highlight the relevant trial evidence for antiplatelet therapy (aspirin, P2Y12 inhibitors, and small molecule glycoprotein IIb/ IIIa inhibitors) in NSTE ACS in relation to age, taking into consideration the risks and benefits, dose, concomitant therapy, and duration of use. Given greater potential benefits from primary and secondary prevention strategies in cardiovascular care, it is important to apply guideline recommendations in older adults. However, given their complexity, it is important to further consider the application of existing and new therapies and strategies of care in “real-world” settings. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104[suppl]:16C–21C) MT Lopez RD, AJC 2009

PRESTO ACS: vascular substudy Transradial access (TRA) decreased bleeding after coronary interventions compared with femoral access (FA). However, no large study focused on arterial access–related outcomes in patients with acute coronary syndromes, although procedure-related bleeding significantl impaired prognosis. The aim was to evaluate access site–related outcomes of patients who underwent an invasive coronary procedure in the PRESTO-ACS Study. The cumulative primary study end point was death or reinfarction during hospitalization and at 1-year follow-up. Secondary end points were in-hospital bleeding and a net clinical outcome (combination of the primary end point and bleeding). Of 1,170 patients studied, 863 underwent a percutaneous coronary procedure using FA, and 307, using TRA. Compared with FA, TRA was associated with higher glycoprotein IIb/IIIa inhibitor use (52% vs 34%; p <0.0001). The in-hospital primary end point was similar between TRA (2.6%) and FA (2.9%; p 0.79). However, TRA was associated with a significant decrease in bleeding (0.7% vs 2.4%; p 0.05) and a nonsignificant decrease in net clinical outcome (3.3% vs 4.6%; p 0.30). At 1-year follow-up, the TRA group had a statistically significant decrease in death or reinfarction (4.9% vs 8.3%; p 0.05), bleeding (0.7% vs 2.7%; p 0.03), and net clinical outcome (5.5% vs 9.9%; p 0.02). In conclusion, in patients with non–STelevation acute coronary syndromes, use of TRA was associated with lower bleeding complications and identified patients with better long-term outcomes. (Am J Cardiol 2009;103:796–800) Sciahbasi A. Am J Cardiol 2009 MT

ESC ACC/AHA confronto delle linee guida "NSTEACS" di ESC e di ACC/AHA urgent invasive bivalirudin I B UFH I C enoxaparin IIa B enoxaparin I A fondaparinux* I B bivalirudin I B early invasive fondaparinux * I A enoxaparin IIa B conservative fondaparinux I A UFH I A fondaparinux I B fonda > UFH/enox I B ( bleeding risk) * plus UFH in case of PCI MT

terapia antitrombinica nel post-infarto 728 pazienti, 50-75 aa, QWMI 6-18 mesi eparina calcica 12.500 UI x 2/die follow-up 708+265 gg re-IMA morte morte CV 10 20 30 40 50 60 70 riduzione % - 33 % 728 patients aged 50-75 years who had had Q-wave myocardial infarction 6-18 months previously were enrolled in a randomised, multicentre trial of low-dose heparin in prevention of reinfarction. The control group (365 patients) received their study centres' usual therapy; the heparin group (363 patients) also received subcutaneous calcium heparin (12 500 IU daily). Mean (SD) follow-up was 708 (265) days in the heparin group and 687 (251) in the control group. The reinfarction rate was 63% lower in the heparin than in the control group (4/303, 1·32% υ 13/365, 3·56%). The difference in cumulative reinfarction rate between the groups was significant by both drug-efficacy (χ2=3·99, p<0·05) and intention-to-treat analysis (χ2=3·84, p=0·05). Heparin treatment reduced the cumulative general mortality rates by 48% on drug-efficacy analysis (χ2=3·88, p<0·05) and by 34% on intention-to-treat analysis (χ2=2·05, not significant). Cardiovascular mortality was also reduced (33%) but not significantly. However, fatal events attributable to thromboembolism (fatal reinfarction, stroke, pulmonary embolism) were significantly less frequent in the heparin than in the control group (1 υ 7, p<0·05). 60 patients (16·5%) discontinued heparin treatment, but only 23 patients (6·3%) stopped because of side-effects. Low-dose heparin appears to be effective, safe, well tolerated, and free from haemorrhagic risk for the prevention of myocardial reinfarction. - 48 % - 63 % MT Neri Serneri, Lancet 1987

formazione di trombina dopo SCA Background The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization. Methods and Results We prospectively measured the plasma concentrations of prothrombin fragment 1+2 (F1+2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n=80) or acute myocardial infarction (n=32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n=57; myocardial infarction, n=23). We quantitated the plasma levels of F1+2 and FPA in control patients with stable angina (n=37) or healthy individuals (n=32) who were matched for age and sex. The median plasma concentrations of F1+2 and EPA are significantly higher in patients presenting with unstable angina (F1+2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1+2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1+2, 0.74 nmol/L; FPA, 1.3 nmol/L; P<.0001) or healthy individuals (F1+2, 0.71 nmol/L; FPA, 0.80 nmol/L; P<.0001). At 6 months, the median plasma levels of F112 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P=NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P=NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P=.0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P=.0028). Conclusions During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin. (Circulation. 1994;90:61-68.) MT Merlini PA, Circulation 1994

ATLAS TIMI 46: rivaroxaban nelle SCA Background Rivaroxaban is an oral direct factor Xa inhibitor that has been eff ective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. Methods In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5–20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. Findings Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25–3.91] for 5 mg, 335 [2.31–4.87] for 10 mg, 3.60 [2,32–5.58] for 15 mg, and 5.06 [3.45–7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60–1.05], p=0.10). Rivaroxaban reduced the main secondary effi cacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI .50–0ÅE96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). Interpretation The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. MT Mega JL. Lancet 2009

Conclusioni i pazienti con NSTE SCA sono sempre più numerosi e la loro prognosi non è migliorata con gli anni la strategia precocemente invasiva è da riservare prevalentemente ai pazienti ad alto rischio (utilizzando la rete dello STEMI, quando necessario) ai pazienti anziani devono essere riservate cure ugualmente intensive, anche se attente al loro rischio globale nei pazienti ad alto rischio ischemico: prasugrel (e ticagrelor) nei pazienti ad alto rischio emorragico: clopidogrel, fondaparinux, bivalirudin l'approccio radiale è sempre preferibile la terapia anticoagulante a lungo termine potrebbe costituire un progresso ulteriore mt