Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51.

OBJECTIVES: The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. BACKGROUND: Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. METHODS: The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. RESULTS: Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). CONCLUSIONS: Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study.

BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin. METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730. FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening. INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. FUNDING: Amgen.

Circadian variation in patient characteristics and outcomes in ST-segment elevation myocardial infarction.

A morning peak in ST-segment elevation myocardial infarction (STEMI) has been described. The authors explored the relationship between variation of symptom onset, patient characteristics, and outcomes in two worldwide fibrinolytic trials. A total of 35 492 patients with STEMI were grouped into 8-h intervals by time of symptom onset: early (06:00 to 13:59 h), late-day (14:00 to 21:59 h), overnight (22:00 to 05:59 h). The authors correlated timing with patient characteristics and outcomes (adjusted for thrombolysis in myocardial infarction [TIMI] risk score) first in InTIME II-TIMI 17 trial (N = 15 031), and confirmed in the ExTRACT-TIMI 25 trial (N = 20 461). Timing was similar in the derivation (early 49%, late-day 30%, and overnight 21%; p < .001) and validation set (48%, 31%, and 21%, respectively; p < .001). Some patient characteristics consistently varied with time of symptom onset. Patients in the early cohort were older with poorer renal function. The late-day group had more smokers with higher initial heart rate and systolic blood pressure. Those with overnight symptom onset had higher rates of obesity, prior myocardial infarction, and treatment delays. Prior use of aspirin and beta-blockers was also highest in the overnight group. Relative to the early cohort, adjusted mortality was higher with late-day onset (derivation odds ratio [OR]: 1.19, p = .04; validation OR: 1.18, p = .01), but there was no excess in mortality overnight compared with early (derivation OR: .97, p = .72; validation OR: 1.01, p = .90). Composite endpoints followed similar patterns. This study indicates that circadian patterns in onset of STEMI continue to exist with patient characteristics differing by time of day. Despite a potential physiologic resistance to morning thrombolysis, outcomes were best in the early cohort, intermediate overnight, and worst with late-day symptom onset. Efforts to reduce smoking and improve control of blood pressure could reduce the number of patients with late-day onset of STEMI who experience the worst outcomes.

Association between angiographic complications and clinical outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention: an EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) angiographic substudy.

OBJECTIVES: The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized. METHODS: The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients. RESULTS: Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant. CONCLUSIONS: Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion. (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-segment Elevation Acute Coronary Syndrome [EARLY ACS]; NCT00089895).

Angiographic and clinical outcomes among patients with acute coronary syndromes presenting with isolated anterior ST-segment depression: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) substudy.

OBJECTIVES: This study sought to determine angiographic and clinical outcomes among patients with acute coronary syndrome (ACS) presenting with isolated anterior ST-segment depression on 12-lead electrocardiogram (ECG). BACKGROUND: In patients with ACS, anterior ST-segment depression on 12-lead ECG may represent plaque rupture with: 1) acute thrombotic occlusion with elevation of cardiac biomarkers (+Tn); 2) a patent artery with +Tn; or 3) a patent artery with -Tn. METHODS: The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) enrolled 13,608 ACS patients. Those with isolated anterior (leads V(1) to V(4)) ST-segment depression were analyzed. Angiograms and ECGs were interpreted by local investigators. RESULTS: There were 1,198 (8.8%) patients with isolated anterior ST-segment depression. Of those, 314 (26.2%) had an occluded culprit artery (TIMI flow grade 0/1) and +Tn, 641 (53.5%) had a patent culprit artery (TIMI flow grade 2/3) and +Tn, and 243 (20.3%) had TIMI flow grade 2/3 and -Tn. Among patients with an occluded artery, the culprit artery was most often the left circumflex artery (48.4%). The 30-day incidence of the composite of death and MI was significantly higher among patients with an occluded artery (8.6%) than among those with a patent culprit artery and either +Tn (6.3%) or -Tn (2.9%) (3-way p = 0.006). Among patients with an occluded artery, the median time from ECG to percutaneous coronary intervention was 29.4 h (interquartile range 26.1 to 44.1 h). CONCLUSIONS: Among ACS patients presenting with isolated anterior ST-segment depression, over one-quarter had an occluded culprit artery and elevated cardiac biomarkers. These patients had significantly worse clinical outcomes, and few underwent urgent angiography.

Relation between infarct size in ST-segment elevation myocardial infarction treated successfully by percutaneous coronary intervention and left ventricular ejection fraction three months after the infarct.

The goal of this analysis was to determine the relation between myocardial infarct size and left ventricular (LV) ejection fraction (EF) in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI) using cardiovascular magnetic resonance imaging (CMR). After STEMI, LVEF and infarct size correlate with prognosis, but the relation between infarct size and LVEF is incompletely known. Consecutive subjects presenting to a single center with STEMI treated with pPCI were enrolled, and cine functional and late gadolinium enhancement CMR was performed 3 months after presentation. From cine images, LVEF was calculated using volumetric summation of disks method. Infarct size was measured as percent LV myocardial volume with late gadolinium enhancement. In the 78 patients enrolled (mean age 54.5 years, range 42 to 82), median LVEF was 56% (interquartile range 49 to 62) and median infarct size was 11% (interquartile range 5 to 18). Of the 53 patients with infarct size <15%, all had LVEF >40%, and there was no significant relation between infarct size and LVEF (slope -0.43, R(2) = 0.045, p = 0.13). In patients with infarct size > or =15%, there was a significant negative linear association between infarct size and LVEF (slope -1.21, R(2) = 0.66, p <0.001), such that for every 5% increase in infarct size, there was a 6.1% decrease in LVEF. In conclusion, there is a negative linear relation between infarct size and LVEF for moderate to large infarcts. For small infarcts there is no significant relation between infarct size and LVEF. Up to 15% of LV myocardial volume may be infarcted before there is any appreciable decrease in LVEF.

Relations between bleeding and outcomes in patients with ST-elevation myocardial infarction in the ExTRACT-TIMI 25 trial.

AIMS: To evaluate the association of bleeding with mortality in ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We studied 20 323 patients with STEMI receiving fibrinolytic therapy and an antithrombin in ExTRACT-TIMI 25. Relationships between in-hospital bleeding, patient characteristics, treatments, and in-hospital cardiovascular complications with mortality were evaluated using Cox models. Likelihood ratios estimated each variable's model contribution. High 30-day mortality after major bleeding (n = 309, 37.6% mortality) was driven by the poor prognosis of intracranial haemorrhage (ICH; n = 143, 65.4% mortality, model contribution 7.8%). The adjusted hazard ratios (HRs) for 30-day death for any major bleeding and for ICH were 2.9 [2.4-3.6] and 10.3 [8.2-12.8], respectively. Neither non-ICH major nor minor bleeding was associated with 30-day death after adjustment. Cardiogenic shock (HR 13.5, 61% contribution) and age (HR 1.6/decade, 17% contribution) were most strongly correlated with 30-day death. Among 30-day survivors, age (HR 1.6/decade, contribution 43%) and heart rate (HR 1.2 per 10 b.p.m., contribution 18%) were most strongly associated with mortality between Days 31 and 365. CONCLUSION: Cardiogenic shock, age, and ICH were important independent correlates of 30-day and 1-year mortality in STEMI patients receiving fibrinolytic therapy. In-hospital non-ICH major and minor bleeding were not independently associated with increased mortality at 30 days or 1 year.

Acute decline in renal function, inflammation, and cardiovascular risk after an acute coronary syndrome.

BACKGROUND AND OBJECTIVES: Chronic kidney disease is associated with a higher risk of cardiovascular outcomes. The prognostic significance of worsening renal function has also been shown in various cohorts of cardiac disease; however, the predictors of worsening renal function and the contribution of inflammation remains to be established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Worsening renal function was defined as a 25% or more decrease in estimated GFR (eGFR) over a 1-mo period in patients after a non-ST or ST elevation acute coronary syndromes participating in the Aggrastat-to-Zocor Trial; this occurred in 5% of the 3795 participants. RESULTS: A baseline C-reactive protein (CRP) in the fourth quartile was a significant predictor of developing worsening renal function (odds ratio, 2.48; 95% confidence interval, 1.49, 4.14). After adjusting for baseline CRP and eGFR, worsening renal function remained a strong multivariate predictor for the combined cardiovascular composite of CV death, recurrent myocardial infarction (MI), heart failure or stroke (hazard ratio, 1.6; 95% confidence interval, 1.1, 2.3). CONCLUSIONS: Patients with an early decline in renal function after an acute coronary syndrome are at a significant increased risk for recurrent cardiovascular events. CRP is an independent predictor for subsequent decline in renal function and reinforces the idea that inflammation may be related to the pathophysiology of progressive renal disease.

Streptokinase and enoxaparin as an alternative to fibrin-specific lytic-based regimens: an ExTRACT-TIMI 25 analysis.

BACKGROUND: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction 25) trial. OBJECTIVE: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin. METHODS: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician's discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic. RESULTS: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [OR(adj)] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 2.74; 95% CI 1.81; 4.14; p < 0.001) but intracranial haemorrhage (ICH) was similar (OR(adj) 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (OR(adj) 0.88; 95% CI 0.73, 1.06; p = 0.17; and OR(adj) 0.77; 95% CI 0.63, 0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (OR(adj) 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes. CONCLUSIONS: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.

Safety and efficacy of achieving very low low-density lipoprotein cholesterol levels with rosuvastatin 40 mg daily (from the ASTEROID Study).

Clinical trial evidence supports the use of intensive statin therapy for patients with coronary artery disease. High doses of potent statins have shown the greatest clinical benefit, but concerns persist regarding the efficacy and safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. We grouped patients treated with 40 mg of rosuvastatin daily by the LDL cholesterol achieved according to previous work (<40, 40 to <60, 60 to <80, 80 to <100, and > or =100 mg/dl) and by National Cholesterol Education Program targets (<70, 70 to <100, and > or =100 mg/dl) in A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID). The rates of key safety end points, including death, hemorrhagic stroke, and liver and muscle enzyme elevations, and key efficacy end points (atheroma burden) were compared using chi-square testing or Fisher's exact testing. The analysis included 471 patients who had had their LDL cholesterol measured at 3 months, of whom 340 (72.2%) had LDL cholesterol of <70 mg/dl, exhibiting excellent achievement of even the most stringent guideline-based goals. Of these 471 subjects, 192 (40.8%) had LDL cholesterol > or =40 mg/dl but <60 mg/dl, and 57 (12.1%) had LDL cholesterol <40 mg/dl. Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol. Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol. In conclusion, although the power to detect such changes was limited, these data showed no clear relation between the LDL cholesterol achieved by intensive statin therapy with rosuvastatin and adverse effects. Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved.

Predicting irreversible left ventricular dysfunction after acute myocardial infarction.

Patients with reduced left ventricular ejection fractions (LVEFs) and previous myocardial infarctions or heart failure are at increased mortality risk. Implantable cardioverter-defibrillators may mitigate this risk. The aim of this study was to identify patient characteristics at the time of presentation with ST elevation myocardial infarction (STEMI) that predict irreversible left ventricular dysfunction. From January 2003 to December 2005, patients presenting with STEMIs and an LVEFs after percutaneous coronary intervention or=90 days. Multivariate analysis identified post-percutaneous coronary intervention LVEF I (odds ratio 4.4, 95% confidence interval 1.5 to 12.6, p = 0.006), and Q waves on postrevascularization electrocardiography (odds ratio 6.3, 95% confidence interval 1.5 to 26.5, p = 0.011) to be significantly more common in the group with LVEFs or=90 days. The presence of all 3 factors, present in 14 patients (12%), had a positive predictive value of 100% that LVEF would be or=90 days. In conclusion, in patients with STEMIs referred for catheterization, a post-percutaneous coronary intervention LVEF I, and pathologic Q waves after revascularization each predicted that the LVEF measured at >or=90 days would remain

Ischemia detected on continuous electrocardiography after acute coronary syndrome: observations from the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) trial.

OBJECTIVES: The purpose of this study was to assess the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS). BACKGROUND: The small size of prior studies evaluating cECG prevented full evaluation of the risk associated with ischemia across subpopulations and compared with other methods of risk stratification. Ranolazine, a new antianginal agent, reduces ischemic symptoms in patients with chronic angina and after ACS but the anti-ischemic effect, as detected by cECG, is not known. METHODS: In all, 6,560 patients hospitalized with non-ST-segment elevation ACS were randomly assigned to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) trial. The cECG was performed for 7 days after randomization. Outcomes were followed for a median of 348 days. Clinical events that occurred during cECG recording were excluded from analysis. RESULTS: A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with >or=1 episode of ischemia on cECG (n = 1,271, 20%) were at increased risk of cardiovascular death (7.7% vs. 2.7%, p < 0.001), MI (9.4% vs. 5.0%, p < 0.001), and recurrent ischemia (17.5% vs. 12.3%, p < 0.001). The relationship with cardiovascular death was independent of baseline characteristics or elevated biomarkers (adjusted hazard ratio: 2.46, p < 0.001). Ischemia on cECG was associated with significantly worse outcomes in several subgroups. Ranolazine did not reduce the rate of ischemia detected on cECG (19.9% vs. 21.0%, hazard ratio: 0.93, p = 0.21). CONCLUSIONS: In more than 6,300 patients with ACS, ischemia detected on cECG occurred frequently and was strongly and independently associated with poor cardiovascular outcomes, including cardiovascular death. Continuous ECG monitoring to detect ischemia after ACS may help to identify patients at increased risk. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes [MERLIN]; NCT00099788).

Baseline hemoglobin concentration and creatinine clearance composite laboratory index improves risk stratification in ST-elevation myocardial infarction.

BACKGROUND: Hemoglobin (Hgb) and creatinine clearance (CrCl) are readily-available, routinely-obtained laboratory parameters that predict acute coronary syndrome outcomes. We sought to develop a laboratory index (LI) to predict early mortality in ST-elevation myocardial infarction (STEMI) and determine the additional risk stratification offered by adding the LI to the TIMI Risk Score (TRS) for STEMI. METHODS AND RESULTS: The association between Hgb and CrCl values obtained at hospitalization and 30-day mortality was evaluated in 14,373 STEMI patients undergoing fibrinolysis in Intravenous NPA for the Treatment of Infarcting Myocardium Early II-Thrombolysis In Myocardial Infarction-17 (InTIME II-TIMI 17). Logistic regression models determined the optimal combination of laboratory variables into a LI. Prognostic utility of the LI was validated in 18,427 STEMI patients from Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)-TIMI 25. In InTIME II, Hgb levels <15.0 g/dL and CrCl <100 mL/min were significantly and independently associated with increased risk of death (OR(adj) 1.22, 95% CI 1.15-1.29 for each 1 g/dL decrease in Hgb, P < .001, and OR(adj) 1.23, 95% CI 1.17-1.29 for each 10 mL/min decrease in CrCl, P < .001, respectively). In multivariable analysis, the optimal weighting of Hgb and CrCl to form an LI to predict mortality was (15-Hgb) + (100-CrCl)/8. The LI revealed a 10-fold increase in death across prespecified groups (P < .001). The LI offered additional risk stratification across all TRS groups and improved the discriminatory ability of the TRS (c-statistic from 0.755 to 0.789, P < .001). External validation in ExTRACT showed similar enhancement of the prognostic capacity of the TRS (c-statistic from 0.747 to 0.777, P < .001). CONCLUSIONS: The LI is a simple, powerful tool to predict death in STEMI, either separately or with the TRS.

Relation of death within 90 days of non-ST-elevation acute coronary syndromes to variability in electrocardiographic morphology.

Electrocardiographic measures can facilitate the identification of patients at risk of death after acute coronary syndromes. This study evaluates a new risk metric, morphologic variability (MV), which measures beat-to-beat variability in the shape of the entire heart beat signal. This metric is analogous to heart rate variability (HRV) approaches, which focus on beat-to-beat changes in the heart rate. MV was calculated using a dynamic time-warping technique in 764 patients from the DISPERSE2 (TIMI 33) trial for whom 24-hour continuous electrocardiograph was recorded within 48 hours of non-ST-elevation acute coronary syndrome. The patients were evaluated during a 90-day follow-up for the end point of death. Patients with high MV showed an increased risk of death during follow-up (hazard ratio 8.46; p <0.001). The relationship between high MV and death could be observed even after adjusting for baseline clinical characteristics and HRV measures (adjusted hazard ratio 6.91; p = 0.001). Moreover, the correlation between MV and HRV was low (R < or =0.25). These findings were consistent among several subgroups, including patients under the age of 65 and those with no history of diabetes or hyperlipidemia. In conclusion, our results suggest that increased variation in the entire heart beat morphology is associated with a considerably elevated risk of death and may provide information complementary to the analysis of heart rate.

Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive lipid-lowering therapy: a PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) analysis.

OBJECTIVES: This study sought to determine whether the benefit of intensive lipid-lowering therapy (LLT) is dependent on baseline low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Aggressive LDL-C reduction with statins improves cardiovascular outcomes in acute and chronic coronary heart disease (CHD). The importance of baseline LDL-C is unclear. METHODS: We compared 2-year composites of death, myocardial infarction (MI), unstable angina, revascularization >30 days, and stroke (primary end point), and CHD death, MI, and revascularization >30 days (secondary end point) in 2,986 statin-naïve patients with recent acute coronary syndrome (ACS) randomized to atorvastatin 80 mg versus pravastatin 40 mg in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) study stratified by quartiles of baseline LDL-C. Multivariable models assessed whether the treatment benefit was dependent on baseline LDL-C. RESULTS: A significant reduction in the hazards of the primary (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.47 to 0.85, p = 0.002) and secondary (HR: 0.57, 95% CI: 0.42 to 0.79, p = 0.001) end points occurred in patients within the highest quartile (>132 mg/dl) of baseline LDL-C treated with atorvastatin 80 mg. The benefit of intensive therapy progressively declined as baseline LDL-C decreased. The lowest quartile (LDL-C < or =92 mg/dl) experienced similar rates of the primary (HR: 0.93, 95% CI: 0.69 to 1.25, p = 0.63) and secondary (HR: 0.98, 95% CI: 0.71 to 1.35, p = 0.89) end points. Adjusted interaction tests between treatment and highest versus lowest baseline LDL-C quartile were significant for the primary and secondary end points (p = 0.03 and p = 0.007, respectively). Analyzing baseline LDL-C as a continuous variable, atorvastatin 80 mg was associated with improved outcomes provided the baseline LDL-C was >66 mg/dl. CONCLUSIONS: A progressive reduction in the benefit of intensive LLT with atorvastatin 80 mg over pravastatin 40 mg occurred in statin-naïve ACS patients as baseline LDL-C declined. (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22]; NCT00382460).

Thrombus precursor protein and clinical outcomes in patients with acute coronary syndromes.

OBJECTIVES: We sought to test the prognostic performance of thrombus precursor protein (TpP) in patients presenting with an acute coronary syndrome (ACS). BACKGROUND: Because thrombus formation is a critical step in the development of ACS, a measurement of activated coagulation could yield important information. Thrombus precursor protein is a biomarker that is used to measure soluble fibrin polymers, which are the penultimate products in fibrin formation. METHODS: We measured the levels of TpP in 284 healthy volunteers and in 2,349 patients with ACS. RESULTS: Median TpP concentrations were 3.6 mug/ml (interquartile range 2.6 to 5.5) in the volunteers and 8.9 mug/ml (interquartile range 4.9 to 15.9) in the ACS patients (p < 0.001). Patients with ACS who had elevated TpP were older, more likely to be women, and more likely to have diabetes and pre-existing CAD (p < 0.02 for each). Thrombus precursor protein levels greater than the median were associated with a significantly increased risk for the composite of death, myocardial infarction (MI), or recurrent ischemia leading to rehospitalization or urgent revascularization through 10 months (hazard ratio [HR] 1.45, p < 0.001), as well as death or MI (HR 1.42, p = 0.02). We found that TpP correlated only weakly with cardiac troponin I, B-type natriuretic peptide, and high-sensitivity C-reactive protein (|r| <0.15 for each). After adjusting for clinical characteristics, cardiac troponin I, high-sensitivity C-reactive protein, and B-type natriuretic peptide, we found that patients with TpP levels greater than the median remained at significantly increased risk for the composite outcome (adjusted HR 1.51, p = 0.001) and death or MI (adjusted HR 1.58, p = 0.02). CONCLUSIONS: In patients with ACS, increased levels of TpP are associated with an increased risk of death or ischemic complications. The incorporation of a marker of activated coagulation, such as TpP, with established cardiovascular risk factors may offer valuable complementary insight into risk assessment in ACS.

TIMI risk index and the benefit of enoxaparin in patients with ST-elevation myocardial infarction.

PURPOSE: The purpose of the study was to evaluate the cause of death, risk of nonfatal complications, and relative outcomes with an enoxaparin versus unfractionated heparin strategy in ST-elevation myocardial infarction stratified using the Thrombolysis in Myocardial Infarction (TIMI) Risk Index (TRI). METHODS: We evaluated 30-day outcomes in 19,941 patients with ST-elevation myocardial infarction treated with fibrinolysis and unfractionated heparin or enoxaparin. Patients were categorized on the basis of prespecified ranges of the TRI [heart rate x (age/10)2/systolic blood pressure]. RESULTS: There was a strongly graded increase in 30-day mortality with increasing TRI (1.2%-20.7%, P<.0001). The proportion of deaths due to mechanical causes (congestive heart failure, shock, and myocardial rupture) increased progressively with the TRI. There also was a significant positively graded association between the TRI and nonfatal heart failure or shock (0.4%-4.4%, P<.0001). In contrast, death resulting from recurrent ischemic events predominated in the lowest TRI group. The relative reduction in death/myocardial infarction with the enoxaparin strategy appeared inversely graded with the TRI. There was a 38% reduction in the lowest risk group (relative risk 0.62, 95% confidence interval 0.45-0.86) and a decrease in the relative benefit of enoxaparin with increasing risk index. CONCLUSIONS: The TRI was a strong predictor of all-cause mortality in a broad population, with a positive association with the risk of death due to mechanical complications and an inverse association with deaths due to recurrent ischemia. The enoxaparin strategy was superior to unfractionated heparin in a majority of patients with ST-elevation myocardial infarction, except for the group at the highest risk for severe mechanical complications, in whom the 2 anticoagulant strategies showed similar results.

Diabetes and mortality following acute coronary syndromes.

CONTEXT: The worldwide epidemic of diabetes mellitus is increasing the burden of cardiovascular disease, the leading cause of death among persons with diabetes. The independent effect of diabetes on mortality following acute coronary syndromes (ACS) is uncertain. OBJECTIVE: To evaluate the influence of diabetes on mortality following ACS using a large database spanning the full spectrum of ACS. DESIGN, SETTING, AND PATIENTS: A subgroup analysis of patients with diabetes enrolled in randomized clinical trials that evaluated ACS therapies. Patients with ACS in 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials from 1997 to 2006 were pooled, including 62,036 patients (46,577 with ST-segment elevation myocardial infarction [STEMI] and 15,459 with unstable angina/non-STEMI [UA/NSTEMI]), of whom 10 613 (17.1%) had diabetes. A multivariable model was constructed to adjust for baseline characteristics, aspects of ACS presentation, and treatments for the ACS event. MAIN OUTCOME MEASURES: Mortality at 30 days and 1 year following ACS among patients with diabetes vs patients without diabetes. RESULTS: Mortality at 30 days was significantly higher among patients with diabetes than without diabetes presenting with UA/NSTEMI (2.1% vs 1.1%, P < .001) and STEMI (8.5% vs 5.4%, P < .001). After adjusting for baseline characteristics and features and management of the ACS event, diabetes was independently associated with higher 30-day mortality after UA/NSTEMI (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.24-2.56) or STEMI (OR, 1.40; 95% CI, 1.24-1.57). Diabetes at presentation with ACS was associated with significantly higher mortality 1 year after UA/NSTEMI (hazard ratio [HR], 1.65; 95% CI, 1.30-2.10) or STEMI (HR, 1.22; 95% CI, 1.08-1.38). By 1 year following ACS, patients with diabetes presenting with UA/NSTEMI had a risk of death that approached patients without diabetes presenting with STEMI (7.2% vs 8.1%). CONCLUSION: Despite modern therapies for ACS, diabetes confers a significant adverse prognosis, which highlights the importance of aggressive strategies to manage this high-risk population with unstable ischemic heart disease.

Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis.

AIMS: We compared outcomes of ST-elevation myocardial infarction (STEMI) patients randomized to a strategy of either enoxaparin or unfractionated heparin (UFH) to support fibrinolysis. METHODS AND RESULTS: In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial, 20,479 patients undergoing fibrinolysis for STEMI with a fibrin-specific agent (N = 16,283) or streptokinase (SK) (N = 4139) were randomized to enoxaparin throughout their hospitalization or UFH for at least 48 h. The primary end point of death or nonfatal recurrent MI through 30 days occurred in 12.0% of patients in the UFH and 9.8% in the enoxaparin groups when treated with fibrin-specific lytics [odds ratio(adjusted) (OR(adj)) 0.78; 95% CI 0.70-0.87; P < 0.001] and 11.8 vs. 10.2%, respectively, when treated with SK (OR(adj) 0.83; 95% CI 0.66-1.04; P = 0.10; P(interaction) = 0.58). Major bleeding rates including intracranial hemorrhage within the fibrin-specific cohort were 1.2 and 2.0% in the UFH and enoxaparin groups, respectively (P < 0.001) and 2.0% in UFH and 2.4% in enoxaparin patients in the SK cohort (P = 0.16). Interaction tests between antithrombin- and lytic-type were non-significant (P = 0.20). Death, nonfatal MI, or major bleeding was significantly reduced with enoxaparin in the fibrin-specific cohort (OR(adj) 0.82; 95% CI 0.74-0.91; P < 0.001) and favoured enoxaparin in the SK cohort (OR(adj) 0.89; 95% CI 0.72-1.10; P = 0.29; P(interaction) = 0.53). CONCLUSION: The benefits of an enoxaparin strategy over UFH were observed in both SK and fibrin-specific-treated STEMI patients. Therefore, an enoxaparin strategy is preferred over UFH to support fibrinolysis for STEMI regardless of lytic agent.