Karen S. Pieper

Predictors of Outcome in Patients With Acute Coronary Syndromes Without Persistent ST-Segment Elevation Results From an International Trial of 9461 Patients

BACKGROUND Appropriate treatment policies should include an accurate estimate of a patients baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation. METHODS AND RESULTS We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81). CONCLUSIONS The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.

Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).

Objective To develop a clinical risk prediction tool for estimating the cumulative six month risk of death and death or myocardial infarction to facilitate triage and management of patients with acute coronary syndrome. Design Prospective multinational observational study in which we used multivariable regression to develop a final predictive model, with prospective and external validation. Setting Ninety four hospitals in 14 countries in Europe, North and South America, Australia, and New Zealand. Population 43 810 patients (21 688 in derivation set; 22 122 in validation set) presenting with acute coronary syndrome with or without ST segment elevation enrolled in the global registry of acute coronary events (GRACE) study between April 1999 and September 2005. Main outcome measures Death and myocardial infarction. Results 1989 patients died in hospital, 1466 died between discharge and six month follow-up, and 2793 sustained a new non-fatal myocardial infarction. Nine factors independently predicted death and the combined end point of death or myocardial infarction in the period from admission to six months after discharge: age, development (or history) of heart failure, peripheral vascular disease, systolic blood pressure, Killip class, initial serum creatinine concentration, elevated initial cardiac markers, cardiac arrest on admission, and ST segment deviation. The simplified model was robust, with prospectively validated C-statistics of 0.81 for predicting death and 0.73 for death or myocardial infarction from admission to six months after discharge. The external applicability of the model was validated in the dataset from GUSTO IIb (global use of strategies to open occluded coronary arteries). Conclusions This risk prediction tool uses readily identifiable variables to provide robust prediction of the cumulative six month risk of death or myocardial infarction. It is a rapid and widely applicable method for assessing cardiovascular risk to complement clinical assessment and can guide patient triage and management across the spectrum of patients with acute coronary syndrome.

Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus

BACKGROUND & AIMS We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphisms clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Prognostic Implications of Abnormalities in Renal Function in Patients With Acute Coronary Syndromes

Background—Outcomes in patients with mild to moderate renal function (RF) abnormalities presenting with acute coronary syndromes (ACS) are not well defined. Methods and Results—A convenience sample of 4 ACS trial databases including all enrolled patients was assessed to determine 30- and 180-day outcomes. The 4 trials were Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb, GUSTO-III, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A). Patients were stratified into ST-segment elevation (STE) and non–ST-segment elevation (NSE) groups and by the presence or absence of abnormal RF (creatinine clearance <70 mL/min). In the STE group, 7670 of 18 621 patients (41%) had abnormal RF. In the NSE group, 8152 of 19 304 (42%) had abnormal RF. Patients with abnormal RF were older, more often female, and more likely to have adverse baseline characteristics. They had higher mortality and higher mortality/nonfatal myocardial infarction (MI) at both 30 and 180 days, regardless of ST-segment status. Creatinine clearance was independently associated with risk of mortality (hazard ratio 0.79 in the STE group and 0.81 in the NSE group) and with risk of mortality/MI (hazard ratio 0.93) in the NSE group at 180 days. Conclusions—Patients presenting with ACS frequently have abnormal RF. Abnormal RF is a marker of adverse baseline clinical characteristics and is independently associated with increased risk of death and death/MI.

Risk Factors, Angiographic Patterns, and Outcomes in Patients With Ventricular Septal Defect Complicating Acute Myocardial Infarction

BACKGROUND Ventricular septal defect (VSD) complicating acute myocardial infarction has been studied primarily in small, prethrombolytic-era trials. Our goal was to determine clinical predictors and angiographic and clinical outcomes of this complication in the thrombolytic era. METHODS AND RESULTS We compared enrollment characteristics, angiographic patterns, and outcomes (30-day and 1-year mortality) of patients enrolled in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial with and without a confirmed diagnosis of VSD. Univariable and multivariable analyses were used to assess relations between enrollment factors and the development of VSD. In all, 84 of the 41 021 patients (0.2%) developed VSD, a smaller percentage than reported in the prethrombolytic era. The median time from symptom onset to VSD diagnosis was 1 day. Enrollment factors most associated with this complication were advanced age, anterior infarction, female sex, and no previous smoking. The infarct artery was more often the left anterior descending and more likely to be totally occluded in patients who developed VSD. Mortality at 30 days was higher in patients with VSDs than in those without this complication (73.8% versus 6.8%, P<0.001). Patients with VSDs selected for surgical repair (n=34) had better outcomes than patients treated medically (n=35; 30-day mortality, 47% versus 94%). CONCLUSIONS Compared with historical control subjects, patients who undergo thrombolysis within 6 hours of infarction onset may have a reduced risk of later VSD. If patients develop this mechanical complication, however, it typically occurs sooner than described in the prethrombolytic era. Despite improvements in medical therapy and percutaneous and surgical techniques, mortality with this complication remains extremely high.

Contrast Nephrotoxicity: A Randomized Controlled Trial of a Nonionic and an Ionic Radiographic Contrast Agent

Experimental studies have suggested that nonionic contrast agents are less nephrotoxic than ionic contrast agents. To examine the relative nephrotoxicity of the two types of agents, we randomly assigned 443 patients to receive either iopamidol (nonionic) or diatrizoate (ionic) for cardiac catheterization. The patients were stratified into low-risk (n = 283) or high-risk (n = 160) groups, on the basis of the presence of diabetes mellitus, heart failure, or preexisting renal insufficiency (base-line serum creatinine level, greater than 133 mumol per liter). Serum and urine analyses were performed at base line and 24 and 48 hours after the infusion of contrast material. Nephrotoxicity was defined as an increase in the serum creatinine level within 48 hours of at least 44 mumol per liter. The median maximal rise in the serum creatinine level was 18 mumol per liter in both the diatrizoate group (n = 235) and the iopamidol group (n = 208) (P not significant; power to detect a difference greater than 9 mumol per liter, greater than 90 percent). Creatinine levels increased by at least 44 mumol per liter (0.5 mg per deciliter) in 10.2 percent of the patients receiving diatrizoate and 8.2 percent of the patients receiving iopamidol (P not significant). Among the high-risk patients, creatinine levels increased by at least 44 mumol per liter in 17 percent of the patients in the diatrizoate group, as compared with 15 percent of the patients in the iopamidol group (P not significant). We were unable to demonstrate a difference in the incidence of nephrotoxicity between patients receiving a non-ionic contrast agent and those receiving an ionic contrast agent.

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

BACKGROUND In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world. METHODS AND RESULTS Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. CONCLUSIONS The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: Findings from OPTIMIZE-HF

BACKGROUND Few studies have examined factors identified as contributing to heart failure (HF) hospitalization, and, to our knowledge, none has explored their relationship to length of stay and mortality. This study evaluated the association between precipitating factors identified at the time of HF hospital admission and subsequent clinical outcomes. METHODS During 2003 to 2004, 259 US hospitals in OPTIMIZE-HF submitted data on 48 612 patients, with a prespecified subgroup of at least 10% providing 60- to 90-day follow-up data. Identifiable factors contributing to HF hospitalization were captured at admission and included ischemia, arrhythmia, nonadherence to diet or medications, pneumonia/respiratory process, hypertension, and worsening renal function. Multivariate analyses were performed for length of stay, in-hospital mortality, 60- to 90-day follow-up mortality, and death/rehospitalization. RESULTS Mean patient age was 73.1 years, 52% of patients were female, and mean ejection fraction was 39.0%. Of 48 612 patients, 29 814 (61.3%) had 1 or more precipitating factors identified, with pneumonia/respiratory process (15.3%), ischemia (14.7%), and arrhythmia (13.5%) being most frequent. Pneumonia (odds ratio, 1.60), ischemia (1.20), and worsening renal function (1.48) were independently associated with higher in-hospital mortality, whereas uncontrolled hypertension (0.74) was associated with lower in-hospital mortality. Ischemia (1.52) and worsening renal function (1.46) were associated with a higher risk of follow-up mortality. Uncontrolled hypertension as a precipitating factor was associated with lower postdischarge death/rehospitalization (hazard ratio, 0.71). CONCLUSIONS Precipitating factors are frequently identified in patients hospitalized for HF and are associated with clinical outcomes independent of other predictive variables. Increased attention to these factors, many of which are avoidable, is important in optimizing the management of HF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00344513.

Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study

BACKGROUND An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist. METHODS We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912. FINDINGS 257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561). INTERPRETATION Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

Balloon aortic valvuloplasty in adults: Failure of procedure to improve long-term survival

OBJECTIVES This study sought to determine the long-term outcome of adult patients undergoing percutaneous balloon aortic valvuloplasty. BACKGROUND Percutaneous balloon aortic valvuloplasty has been offered as an alternative to aortic valve replacement for selected patients with valvular aortic stenosis. Although balloon aortic valvuloplasty produces an immediate reduction in the transvalvular aortic gradient, a high incidence of restenosis frequently leads to recurrent symptoms. Therefore, it is unclear whether balloon aortic valvuloplasty impacts on the long-term outcome of these patients. METHODS Clinical, hemodynamic and echocardiographic data were collected at baseline in 165 patients undergoing balloon aortic valvuloplasty and examined for their ability to predict long-term outcome. RESULTS The median duration follow-up was 3.9 years (range 1 to 6). Ninety-nine percent follow-up was achieved. During this 6-year period, 152 patients (93%) died or underwent aortic valve replacement, and 99 (60%) died of cardiac-related causes. The probability of event-free survival (freedom from death, aortic valve replacement or repeat balloon aortic valvuloplasty) 1, 2 and 3 years after valvuloplasty was 40%, 19% and 6%, respectively. In contrast, the probability of survival 3 years after balloon aortic valvuloplasty in a subset of 42 patients who underwent subsequent aortic valve replacement was 84%. Survival after aortic valvuloplasty was poor regardless of the presenting symptom, but patients with New York Heart Association functional class IV congestive heart failure had events earliest. Univariable predictors of decreased event-free survival were younger age, advanced congestive heart failure symptoms, lower ejection fraction, elevated left ventricular end-diastolic pressure, presence of coronary artery disease and increased left ventricular internal diastolic diameter. Stepwise multivariable logistic regression analysis found that only younger age and a lower left ventricular ejection fraction contributed independent adverse prognostic information (chi-square 14.89, p = 0.0006). CONCLUSIONS Long-term event-free and actuarial survival after balloon aortic valvuloplasty is dismal and resembles the natural history of untreated aortic stenosis. Aortic valve replacement may be performed in selected subjects with good results. However, the prognosis for the remainder of patients who are not candidates for aortic valve replacement is particularly poor.