Summary 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.
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 )
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, R2 = 0.045, p = 0.13). In patients with infarct size ≥15%, there was a significant negative linear association between infarct size and LVEF (slope −1.21, R2 = 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.
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 Roberto R. Giraldez, Robert P. Giugliano, Satishkumar Mohanavelu, Sabina A. Murphy, Carolyn H. McCabe, Christopher P. Cannon, Eugene Braunwald We compared outcomes in 2,986 statin-naïve acute coronary syndrome patients 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 baseline low-density lipoprotein cholesterol (LDL-C) quartiles. The benefit of atorvastatin 80 mg progressively declined as baseline LDL-C decreased. In the lowest quartile (baseline LDL-C ≤92 mg/dl), the adjusted rates of the primary (hazard ratio: 0.93, 95% confidence interval: 0.69 to 1.25) and secondary (hazard ratio: 0.98, 95% confidence interval: 0.71 to 1.35) composite end points were similar between treatments. Adjusted interaction tests between treatment and highest versus lowest baseline LDL-C quartile were significant for both end points (p = 0.03 and p = 0.007, respectively). Analyzing LDL-C as a continuous variable, atorvastatin 80 mg was associated with improved outcomes for baseline LDL-C >66 mg/dl.
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 ≥100 mg/dl) and by National Cholesterol Education Program targets (<70, 70 to <100, and ≥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 ≥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.
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 ≤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.
Thrombus Precursor Protein and Clinical Outcomes in Patients With Acute Coronary Syndromes Jessica L. Mega, David A. Morrow, James A. de Lemos, Satishkumar Mohanavelu, Christopher P. Cannon, Marc S. ...Sabatine Thrombus precursor protein is used to measure the penultimate product in the formation of fibrin, and in this study of patients post-acute coronary syndrome, increased levels of the marker were associated with an increased risk of death or ischemic complications (hazard ratio 1.45, p < 0.001). This analysis suggests that a marker of active coagulation, such as thrombus precursor protein, could add independent and incremental prognostic information in patients presenting across the spectrum of acute coronary syndrome.
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 )
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 ≤0.4 were included (n = 118). Clinical, angiographic, and electrocardiographic characteristics at the time of STEMI were evaluated to predict LVEF at ≥90 days. Multivariate analysis identified post–percutaneous coronary intervention LVEF ≤0.3 (odds ratio 5.4, 95% confidence interval 2.1 to 14.1, p = 0.001), presentation with Killip class >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 ≤0.3 at ≥90 days. The presence of all 3 factors, present in 14 patients (12%), had a positive predictive value of 100% that LVEF would be ≤0.3 at ≥90 days. In conclusion, in patients with STEMIs referred for catheterization, a post–percutaneous coronary intervention LVEF ≤0.3, presentation with Killip class >I, and pathologic Q waves after revascularization each predicted that the LVEF measured at ≥90 days would remain ≤0.3. The presence of all 3 features had a positive predictive value of 100%. These findings may identify a high-risk group of patients who might benefit from early aggressive therapy such as an implantable cardioverter-defibrillator.
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 V1 to V4 ) 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.
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