Michael P. Hudson

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

BACKGROUND Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

Thrombolysis and counterpulsation to improve survival in myocardial infarction complicated by hypotension and suspected cardiogenic shock or heart failure: results of the TACTICS Trial.

Background: Sustained hypotension, cardiogenic shock, and heart failure all imply a poor prognosis in acute myocardial infarction (MI). We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation (IABP) to standard treatment for MI, in an international trial among hospitals without primary angioplasty capabilities.Methods: We randomized 57 patients with MI complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure to receive either fibrinolytic therapy and IABP or fibrinolysis alone. The primary end point was all-cause mortality at 6 months.Results: In all, IABP was inserted in 27 of 30 assigned patients a median 30 minutes after fibrinolysis began and continued for a median 34 hours. Of the 27 patients assigned to fibrinolysis alone, 9 deteriorated such that IABP was required. The IABP group was at slightly higher risk at baseline, but the incidence of the primary end point did not differ significantly between groups (34% for combined treatment versus 43% for fibrinolysis alone; adjusted P = 0.23). Patients with Killip class III or IV showed a trend toward greater benefit from IABP (6-month mortality 39% for combined therapy versus 80% for fibrinolysis alone; P = 0.05).Conclusions: While early IABP use was not associated with a definitive survival benefit when added to fibrinolysis for patients with MI and hemodynamic compromise in this small trial, its use suggested a possible benefit for patients with the most severe heart failure or hypotension.Abbreviated Abstract. We assessed the benefit of adding 48 hours of intra-aortic balloon counterpulsation to fibrinolytic therapy among 57 patients with acute myocardial infarction complicated by sustained hypotension, possible cardiogenic shock, or possible heart failure. The primary end point, mortality at 6 months, did not differ between groups (34% for combined treatment versus 43% for fibrinolysis alone [n = 27]; adjusted P = 0.23), although patients with Killip class III or IV did show a trend toward greater benefit from IABP (39% for combined therapy versus 80% for fibrinolysis; P = 0.05).

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

BACKGROUND The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. TRIAL DESIGN TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. CONCLUSION TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

Baseline Q-Wave Surpasses Time From Symptom Onset as a Prognostic Marker in ST-Segment Elevation Myocardial Infarction Patients Treated With Primary Percutaneous Coronary Intervention

OBJECTIVES We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI). BACKGROUND Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes. METHODS We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed. RESULTS Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized < or =3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF. CONCLUSIONS Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637).

Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease

Hypothesis/Introduction The risks and benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with end-stage renal disease (ESRD) after cardiac events are unknown. We sought to determine the independent effect of ACE inhibitors (ACE-I) on long-term mortality in ESRD patients after cardiac events. Materials and methods We analysed a prospective coronary care unit registry and identified 527 ESRD patients, 368 with complete data on medications prescribed, over eight years at a single, tertiary centre. Results The overall mean age was 64.4 13.8 years with 54.9% men, and 59.2% African-American. A total of 143/386 (37.0%) were prescribed ACE-I during the hospital stay for cardiac reasons, including congestive heart failure (CHF) 52.8% and acute coronary syndromes (ACS) 47.2%. There were no significant differences in the rates of hypotension or arrhythmias in those who were treated with ACE-I versus those who were not. Survival analysis over three years, adjusted for known confounders, demonstrated a 37% reduction in all-cause mortality in those who received ACE-I, (p=0.0145). Conclusions In the setting of coronary care unit admission for CHF and ACS, ESRD patients selected for ACE-I, did not have increased rates of adverse haemodynamic or arrhythmic complications. The use of ACE-I conferred an independent mortality reduction over long-term follow-up.

Transcutaneous ultrasound-facilitated coronary thrombolysis during acute myocardial infarction

In preclinical experiments, the combination of transcutaneous, low-frequency ultrasound and thrombolytic therapy has shown improved patency rates over thrombolytics alone. A total of 25 patients with myocardial infarction were treated with a thrombolytic agent and adjunctive transcutaneous ultrasound. No unanticipated major adverse events were observed.

The prognostic significance of serial myoglobin, troponin I, and creatine kinase-MB measurements in patients evaluated in the emergency department for acute coronary syndrome.

STUDY OBJECTIVE We sought to determine the value of serial measurements of myoglobin, cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB) to predict 30-day adverse events in patients evaluated in the emergency department (ED) for possible acute coronary syndrome. METHODS Serum myoglobin, cTnI, and CK-MB levels were measured at presentation, 90 minutes, 3 hours, and 9 hours in patients evaluated in the ED for possible acute coronary syndrome. In 764 consecutive patients, the ability of each individual marker and combination of markers to predict a 30-day adverse event (death or myocardial infarction) over time was calculated. RESULTS There were 109 (14%) patients with an adverse event at 30 days (84 myocardial infarctions and 43 deaths). The sensitivities of initial measurements of myoglobin, cTnI, and CK-MB for identifying adverse events were 60%, 47%, and 52%, respectively. The combined sensitivity of myoglobin and cTnI measurements during a 9-hour period was 94%; specificity was 50%. Measurement of CK-MB did not improve sensitivity. CONCLUSION The measurement of both myoglobin and cTnI during a 9-hour period was the most predictive of subsequent adverse events in patients evaluated in the ED for possible acute coronary syndrome.

Clinical and safety impact of an inpatient Pharmacist‐Directed anticoagulation service

BACKGROUND Warfarin is implicated in approximately 30% of reported anticoagulant-related errors. In order to improve anticoagulation management and safety, our institution implemented an inpatient Pharmacist-Directed Anticoagulation Service (PDAS). OBJECTIVE To evaluate the impact of this service on both transition of care and safety of patients receiving warfarin anticoagulation. DESIGN Cluster randomized trial. SETTING Large, urban teaching hospital and level 1 trauma center. PATIENTS All patients receiving warfarin on two medical and two cardiology units. INTERVENTION A PDAS provided dosing, monitoring, and coordination of transition from the inpatient-to-outpatient setting. MEASUREMENTS Endpoints were assessed during hospitalization and 30 days after discharge. Transition of care was considered effective if compliance with all of the transition of care metrics occurred. The transition of care metrics included: appropriate enrollment in the anticoagulation clinic, documented inpatient-to-outpatient provider contact, documented inpatient provider-to-anticoagulation clinic communication and patient follow-up with the anticoagulation clinic within five days of discharge. Safety was measured by the composite endpoint of thromboembolism, major bleeding, or international normalized ratio (INR) ≥5. RESULTS This study included 500 patients. Transition of care metric compliance occurred in 73% more patients in the PDAS group (P < 0.001). There was also a 32% reduction in the composite safety endpoint in the PDAS group (P = 0.103). This finding was driven by a reduction in rate of INR ≥5 (P = 0.076). CONCLUSIONS Implementation of a PDAS provides a net improvement in quality of care for the patient taking warfarin in the inpatient setting.

Mortality implications of primary percutaneous coronary intervention treatment delays: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction trial.

Background— Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI. Methods and Results— We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P<0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively, P<0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (&khgr;2 6.0, P<0.014), and symptom onset-to-hospital arrival (&khgr;2 9.8, P<0.007) remained independent determinants. Conclusions— Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00091637.