BACKGROUND:Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear.METHODS:We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).RESULTS:The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen.CONCLUSIONS:Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

OBJECTIVES We aimed to determine whether intensive statin therapy reduces hospitalization for heart failure (HF) in high-risk patients.BACKGROUND While the relationship between intensive statin therapy and ischemic events is well established, its relationship to the risk of HF after an acute coronary syndrome (ACS) is not well defined.METHODS The Pravastatin or Atorvastatin Evaluation and Infection Trial-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TlMI 22) study randomized 4,162 patients, stabilized after ACS, to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 days after randomization was determined during a mean follow-up of 24 months. B-type natriuretic peptide (BNP) levels were measured at baseline (median seven days after randomization).RESULTS Treatment with atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (1.6% vs. 3.1%, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.35 to 0.85, p = 0.008) independently of a recurrent myocardial infarction or prior history of HF. The risk of HF increased steadily with increasing quartiles of BNP (HR 2.6, 95% CI 1.2 to 5.5, p = 0.016 for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (> 80 pg/ml), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR 0.32, 95% CI 0.13 to 0.8, p = 0.014). A meta-analysis of four trials that included 27,546 patients demonstrates a 27% reduction in the odds of hospitalization for HF with intensive statin therapy.CONCLUSIONS Intensive statin therapy reduces the risk of hospitalization for HF after ACS with the most gain inpatients with elevated levels of BNP.

Background ST deviation and troponin are indicators of risk in unstable angina/non-ST-elevation myocardial infarction with related but distinct pathophysiology. We hypothesized that a combination of the two would offer complementary information regarding the benefit of an invasive strategy.Methods and Results Electrocardiogram and troponin data were gathered in 1846 patients in TACTICS-TIMI 18. Adjusting for baseline characteristics, the independent odds ratio (OR) (95% CI) for death or myocardial infarction by 6 months was 1.29 (0.78-2.13) for 0.05 to 0.09 mV ST deviation, 1.83 (1.22-2.75) for >= 0.10 mV ST deviation, 1.69 (0.96-2.97) for troponin T 0.01 to 0.10 ng/mL, and 2.32 (1.52-3.53) for troponin T>0.10 ng/mL. There was a significant interaction between the magnitude of ST deviation and treatment strategy (P-interaction=.04). After adjusting for troponin and other baseline characteristics, an early invasive strategy was associated with a 27% greater reduction in the odds of death or myocardial infarction in those with 0.05 to 0.09 mV of ST deviation (ORinteraction 0.73, 95% CI 0.27-2.02) and a 64% greater reduction in those with >= 0.10 mV (ORinteraction 0.36, 95% CI 0.16-0.84) compared with in those without ST deviation.Conclusions The magnitude of ST deviation and degree of troponin elevation are graded independent predictors of outcome in unstable angina/non-ST-elevation myocardial infarction. ST deviation complements troponin elevation in selecting patients for early invasive management.

Background-Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is associated with the risk of cardiovascular (CV) events in population-based studies. The prognostic value of Lp-PLA(2) in patients with acute coronary syndromes (ACS) has not been established.Methods and Results-Plasma levels of Lp-PLA(2) activity were measured at baseline (n=3648) and 30 days (n=3265) in patients randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d after ACS in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. The primary end point was death, myocardial infarction, unstable angina, revascularization, or stroke (mean follow-up 24 months). At baseline after ACS, the risk of recurrent CV events was similar across all quintiles of Lp-PLA(2) activity (P-trend=0.88). Overall, mean levels of Lp-PLA(2) were lower at 30 days of follow-up than at baseline (35.7 versus 40.9 nmol.min(-1).mL(-1), P<0.001). In particular, treatment with atorvastatin 80 mg/d was associated with a 20% reduction in Lp-PLA(2) activity (P<0.001), whereas Lp-PLA(2) rose 3.6% with pravastatin 40 mg/d (P<0.001). Patients with 30-day Lp-PLA(2) activity in the highest quintile were at significantly increased risk of recurrent CV events compared with those in the lowest quintile (26.4% versus 17.6%, P-trend=0.002). After adjustment for cardiac risk factors, treatments, achieved low-density lipoprotein (LDL), and C-reactive protein, Lp-PLA(2) activity in the highest quintile remained independently associated with a higher risk of recurrent CV events (adjusted hazard ratio 1.33, 95% confidence interval [CI] 1.01 to 1.74).Conclusions-Lp-PLA(2) is not useful for risk stratification when measured early after ACS. At 30 days, Lp-PLA(2) activity is significantly lowered with high-dose statin therapy and is associated with an increased risk of CV events independent of C-reactive protein and LDL cholesterol levels.

BACKGROUNDUnfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose.METHODSWe randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days.RESULTSThe primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001).CONCLUSIONSIn patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit. (ClinicalTrials.gov number, NCT00077792.).

Hyperglycemia in the context of acute coronary syndrome (ACS) is a common observation, and existing data suggest that high glucose levels are associated with increased in-hospital mortality. We assessed the relation between random glucose and long-term mortality in 9,020 patients with ACS who were enrolled in the OPUS-TIMI 16 trial. A significant relation between glucose level and 10-month mortality was observed (2.7% in quartile 1 vs 7.0% in quartile 4, p <0.0001). After multivariable adjustment for co-morbidity, which included history of diabetes, this relation remained significant (quartile 4 vs 1, hazard ratio 1.70, 95% confidence interval 1.16 to 2.50, p = 0.006). These observations were similar in the TACTICS-TIMI 18 trial. In addition, we observed that B-type natriuretic peptide and troponin I levels increased across glucose quartiles in the OPUS-TIMI 16 trial (p values for trend = 0.002 and 0.0001, respectively) and the TACTICS-TIMI 18 trial (p values for trend = 0.006 and 0.0001, respectively). High blood glucose during ACS is an independent predictor of long-term mortality and is significantly correlated with prognostic biomarkers. Glucose levels during ACS may be an important addition to the risk stratification of patients with ACS and a potentially important target for therapy.

Background—In the setting of an acute coronary syndrome (ACS), anemia has the potential to worsen myocardial ischemia; however, data relating anemia to clinical outcomes in ACS remain limited. Methods and Results—We examined the association between baseline hemoglobin values and major adverse cardiovascular events through 30 days in 39 922 patients enrolled in clinical trials of ACS. After adjustment for differences in baseline characteristics and index hospitalization treatments, a reverse J-shaped relationship between baseline hemoglobin values and major adverse cardiovascular events was observed. In patients with ST-elevation myocardial infarction, when those with hemoglobin values between 14 and 15 g/dL were used as the reference, cardiovascular mortality increased as hemoglobin levels fell below 14 g/dL, with an adjusted OR of 1.21 (95% CI 1.12 to 1.30, P<0.001) for each 1-g/dL decrement in hemoglobin. At the other end of the range of hemoglobin, patients with hemoglobin values >17 g/dL also had excess mortality (OR 1.79, 95% CI 1.18 to 2.71, P=0.007). In patients with non–ST-elevation ACS, with those with hemoglobin 15 to 16 g/dL used as the reference, the likelihood of cardiovascular death, myocardial infarction, or recurrent ischemia increased as the hemoglobin fell below 11 g/dL, with an adjusted OR of 1.45 (95% CI 1.33 to 1.58, P<0.001) for each 1 g/dL decrement in hemoglobin. Patients with hemoglobin values >16 g/dL also had an increased rate of death or ischemic events (OR 1.31, 95% CI 1.03 to 1.66, P=0.027). Conclusions—Anemia is a powerful and independent predictor of major adverse cardiovascular events in patients across the spectrum of ACS.

BACKGROUND:Chlamydia pneumoniae has been found within atherosclerotic plaques, and elevated titers of antibody to this organism have been linked to a higher risk of coronary events. Pilot studies have suggested that antibiotic treatment may reduce the risk of cardiovascular events.METHODS:We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and evaluated the efficacy of long-term treatment with gatifloxacin, a bactericidal antibiotic known to be effective against C. pneumoniae, in a double-blind, randomized, placebo-controlled trial. Subjects received 400 mg of gatifloxacin daily during an initial 2-week course of therapy that began 2 weeks after randomization, followed by a 10-day course every month for the duration of the trial (mean duration, 2 years), or placebo. The primary end point was a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke.RESULTS:A Kaplan-Meier analysis revealed that the rates of primary-end-point events at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.08; P=0.41). No benefit was seen in any of the prespecified secondary end points or in any of the prespecified subgroups, including patients with elevated titers to C. pneumoniae or C-reactive protein.CONCLUSIONS:Despite long-term treatment with a bactericidal antibiotic effective against C. pneumoniae, no reduction in the rate of cardiovascular events was observed.