Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: The ESCAPE Trial - PDF

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Online article and related content current as of August 3, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: The ESCAPE Trial The ESCAPE Investigators
Online article and related content current as of August 3, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness: The ESCAPE Trial The ESCAPE Investigators and ESCAPE Study Coordinators* JAMA. 2005;294(13): (doi: /jama ) Correction Citations Topic collections Related Articles published in the same issue Related Letters Contact me if this article is corrected. This article has been cited 71 times. Contact me when this article is cited. Revascularization; Cardiovascular System; Quality of Care; Quality of Care, Other; Surgery; Surgical Interventions; Cardiovascular/ Cardiothoracic Surgery; Congestive Heart Failure/ Cardiomyopathy; Cardiovascular Intervention Contact me when new articles are published in these topic areas. Impact of the Pulmonary Artery Catheter in Critically Ill Patients: Meta-analysis of Randomized Clinical Trials Monica R. Shah et al. JAMA. 2005;294(13):1664. Searching for Evidence to Support Pulmonary Artery Catheter Use in Critically Ill Patients Jesse B. Hall. JAMA. 2005;294(13):1693. Pulmonary Artery Catheter Effectiveness in Congestive Heart Failure Christine Won et al. JAMA. 2006;295(10):1121. In Reply: Lynne W. Stevenson et al. JAMA. 2006;295(10):1121. Subscribe Alerts Permissions Reprints/E-prints ORIGINAL CONTRIBUTION Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness TheESCAPETrial The ESCAPE Investigators and ESCAPE Study Coordinators* ADVANCES IN MEDICAL THERAPY have improved outcomes for many ambulatory patients with heart failure and low ejection fraction (EF). 1-4 However, each year an estimated to patients are hospitalized for heart failure with low EF, 5 and the 1-year survival rate after hospitalization may be as low as 50%, even with recommended medical therapies. 6,7 In nonrandomized studies, patients undergoing therapy with vasodilators and diuretics to reduce filling pressures to near normal levels have had acute and sustained improvements in hemodynamics, mitral regurgitation, and exercise tolerance Without a randomized study of hemodynamic monitoring with the pulmonary artery catheter (PAC), however, it could not be determined whether PACs improved outcomes in addition to other components of intensive heart failure management. There is considerable controversy over use of the PAC in critical illness. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) trial demonstrated higher mortality for patients thought to require PAC during hospitalization, although without excess risk for patients with heart failure. 16 Reports from acute myocardial infarc- See also pp 1664 and Context Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. Objective To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. Design, Setting, and Participants The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone.the target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. Main Outcome Measures The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. Results Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 meq/l; urea nitrogen, 35 mg/dl (12.40 mmol/l); and creatinine, 1.5 mg/dl (132.6 µmol/l). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, ]; P=.99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, ]; P=.35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, ]; P=.67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P=.04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, ]; P=.97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. Conclusions Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients. JAMA. 2005;294: *Authors are listed at the end of this article. Corresponding Author: Lynne W. Stevenson, MD, Brigham and Women s Hospital, Cardiovascular Division, Department of Medicine, 75 Francis St, PBB-1, Boston, MA American Medical Association. All rights reserved. (Reprinted) JAMA, October 5, 2005 Vol 294, No tion populations further raised concerns that PACs increased mortality, and a moratorium on PAC use was proposed. 17 Recommendations from a working group of representatives from the National Heart, Lung, and Blood Institute (NHLBI), the Food and Drug Administration, and academic experts in cardiology, pulmonology, surgery, nursing, and critical care led to a trial designed to test the PAC in patients with chronic heart failure. 18 The complexity of this population and the challenge of hemodynamic measurement made experience in hemodynamic studies desirable. However, refinement of clinical assessment based on prior hemodynamic investigation could diminish the impact of PAC information. Recognizing this conflict, 18 the decision was made to test the PAC with experienced heart failure investigators. For the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), the primary hypothesis was that for patients with severe heart failure, therapy guided by PAC monitoring and clinical assessment would lead to more days alive and fewer days hospitalized during 6 months compared with therapy guided by clinical assessment alone. METHODS Trial Organization ESCAPE was an NHLBI-sponsored randomized trial conducted at 26 experienced heart failure centers in the United States and Canada. The Brigham and Women s Hospital served as the clinical coordinating center, and Duke Clinical Research Institute was the data coordinating center and performed all statistical analyses. The NHLBI appointed an independent data and safety monitoring board. Participating institutional review boards approved the protocol, and written informed consent was obtained from all patients. Patients Inclusion criteria were designed to select patients with severe symptomatic heart failure despite recommended therapies. 18 The target patient was sufficiently ill with advanced heart failure to make use of the PAC reasonable, but also sufficiently stable to make crossover to PAC for urgent management unlikely. Severity prior to admission could be met by the following criteria: (1) hospitalization for heart failure within the past year; (2) urgent visit to the emergency department; or (3) treatment during the preceding month with more than 160 mg of furosemide daily (or equivalent). Randomization required at least 3 months of symptoms despite angiotensin-converting enzyme (ACE) inhibitors and diuretics, left ventricular (LV) EF 30% or less, systolic blood pressure 125 mm Hg or less, and at least 1 sign and 1 symptom of congestion. Exclusion criteria to minimize confounding comorbidities or urgent crossover included creatinine level greater than 3.5 mg/dl (309.4 µmol/ L), or prior use of dobutamine or dopamine more than 3 µg/kg/min, or any prior use of milrinone during the current hospitalization. Right heart catheterization to assess pulmonary hypertension during transplant evaluation was permitted in patients receiving therapy guided by clinical assessment alone if performed at the end of hospitalization. A concurrent PAC registry was established to characterize hospitalized patients receiving PACs considered to be required during heart failure management. Study Design and Analyses Patients were randomly assigned 1:1 to therapy guided by clinical assessment only (clinical assessment group) or therapy guided by clinical assessment and the PAC (PAC group). Randomization was stratified by site using random block sizes of 2 or 4 through a central telephone center. The treatment goal in the clinical assessment group was resolution of clinical signs and symptoms of congestion, particularly jugular venous pressure elevation, edema, and orthopnea. Treatment goals in the PAC group were the same, with the addition of pulmonary capillary wedge pressure (PCWP) of 15 mm Hg and right atrial pressure of 8 mm Hg. Therapy was adjusted in both groups to avoid progressive renal dysfunction or symptomatic systemic hypotension. The protocol did not specify drug selection or dosing. Investigators were encouraged to follow national guidelines for treatment of heart failure and to primarily use intravenous diuretics and vasodilators. The use of inotropic agents for routine management was consistently and explicitly discouraged. No specific instructions were given regarding nesiritide, which became available during the course of the trial. The Pulmonary Artery Catheter Education Project, a computer-based program created by the NHLBI, the Food and Drug Administration, and the American College of Physicians, was used at study initiation to train investigators and coordinators (http: //www.pacep.org/asahq). Catheters were selected according to individual institutional practice. In the PAC group, hemodynamics were measured twice at baseline and at least twice daily thereafter, with pressure measurement from paper readings. A specific case report form listed anticipated PAC complications. Patients were seen at 7 to 14 days, and 1, 2, 3, and 6 months after discharge. Data were collected on clinical status, medications, exercise, and quality of life measurements. Race and ethnicity were assessed by the study coordinator from patients and chart information to determine degree of diverse representation in the study population. The primary end point, days alive out of the hospital during 6 months following randomization, was analyzed using the Cox proportional hazards model. Component end points included time to events. End points were calculated with patients receiving transplant or assist devices coded as dead, then recalculated coded as alive. Because patients and physicians were not blinded to treatment, physiologic secondary end points, focusing on mitral regurgitation (the subject of pending analysis), natriuretic peptides, and peak oxygen consumption, were se JAMA, October 5, 2005 Vol 294, No. 13 (Reprinted) 2005 American Medical Association. All rights reserved. lected as measurable without knowledge of group assignment. Other functional end points were 6-minute walk distance, 19 the Minnesota Living with Heart Failure questionnaire, 20 and the time trade-off tool, 21 which quantifies how many months of life out of 24 months patients would trade to feel better, through a series of binary questions asked by a trained coordinator, as has been described for moderate-severe heart failure. All baseline functional measures were made before randomization. A new end point of time trade-off adjusted survival was prospectively defined for exploratory analysis as the integrated product of the days alive and the proportion of months preferred in current health at each time point. The original design included 500 randomized patients, based on the assumption that the control group would have an expected 40 days dead or hospitalized with an SD of 30. The treated group was assumed to have an expected number of days of 32 (0.8 40). This resulted in an estimated power of 84%, assuming normality of days hospitalized (assuming a 2-sided test at an level of.05). Interim unblinded analyses for efficacy occurred after 19%, 46%, 59%, and 67% of the patients had been enrolled. Approximate O Brien-Fleming boundaries were used based on the groupsequential methods of Lan et al. 22 No provision was made for stopping early for futility. None of the tests were close to the stopping boundaries. The secondary end points, including exercise, natriuretic peptides, and quality of life, were analyzed with the t test using SAS version 8.2 (SAS Institute Inc, Cary, NC) with an level of.05. All analyses were based on intention to treat. RESULTS Baseline Characteristics From January 18, 2000, to November 17, 2003, 433 patients were enrolled (FIGURE 1). The data and safety monitoring board recommended that the NHLBI stop the trial before enrolling 500 patients due to concerns of early adverse events and the unlikelihood of achieving a significant difference in the primary end point. The 2 randomized groups had similar baseline characteristics (TABLE 1), with 391 (90%) taking ACE inhibitors or angiotensin-receptor blockers, 268 (62%) taking -blockers, and 31 (7%) with implantable defibrillators. During the same time, patients receiving the PAC without randomization (PAC registry) had higher LVEF, but more compromise of blood pressure, serum sodium and creatinine levels, and inotropic therapy (35% vs 15%). Treatment After Randomization Intravenous diuretics were used in all patients. Vasodilator therapy was used in 80 (37%) patients in the PAC group and 42 patients (19%) in the clinical assessment group (total nesiritide, 66 [15%]; nitroprusside, 50 [12%]; nitroglycerin, 16 [4%]). Inotropic therapy was used in 94 (44%) patients in the PAC group and 86 patients (39%) in the clinical assessment group. Discharge prescriptions included ACE inhibitors/ angiotensin-receptor blockers for 196 (91%) patients in the PAC group and 195 patients (89%) in the clinical assessment group, and -blockers for 140 (65%) patients in the PAC group and 128 patients (59%) in the clinical assessment group. PACs were placed for adjustment of therapy in 198 (92%) patients in the PAC group and 21 patients (10%) in the clinical assessment group during hospitalization. PACs in patients in the treatment group were in place for a median of 1.9 days, during which all hemodynamic parameters improved (TABLE 2). Substantial impact of therapy on clinical goals by the time of discharge was similar in both groups (TABLE 3). Although average weight loss was 3.2 kg for patients in the clinical assessment group vs 4.0 kg for patients in the PAC group, serum creatinine level worsened less often in the PAC group. Primary End Point Use of the PAC did not affect the primary end point of days alive out of Figure 1. CONSORT Diagram 215 Assigned to PAC Guided Therapy + Clinical Assessment 17 Did Not Receive PAC 4 Withdrew Permission 2 Lost to Follow-up of Vital Status 3 Lost to Follow-up of Primary End Point 209 Included in Survival Analysis 206 Included in Analysis of Primary End Point 433 Patients Randomized 218 Assigned to Clinical Assessment Only 21 Received PAC Later 2 Withdrew Permission 4 Lost to Follow-up of Vital Status 5 Lost to Follow-up of Primary End Point 212 Included in Survival Analysis 207 Included in Analysis of Primary End Point CONSORT diagram depicting the progress of the 433 patients randomly assigned over the course of the trial and their contribution to the assessment of survival and the primary end point. Seventeen patients randomized to the pulmonary artery catheter (PAC) plus clinical assessment group did not receive a PAC due to logistic limitations of placement and subsequent monitoring. Patients randomized to the clinical assessment only group could receive an elective PAC as part of transplant evaluation, but all analyses were done based on original intention to treat. the hospital (FIGURE 2). The overall neutrality of the intervention was consistent across demographic subgroups (FIGURE 3). There were no significant differences in time to death or hospitalization, deaths, or days hospitalized (TABLE 4). Both groups had a median of 2.0 hospitalizations per patient. Coding the 36 patients who underwent cardiac transplantation or LV assist device placement as either dead or alive did not change the results. There were no clinical subgroups in which benefit or harm was shown. There was a trend for better PAC outcomes in the centers with higher volume enrollment. There was no evidence of benefit or harm from the PAC in relation to intravenous vasoactive therapy (TABLE 5). Safety of the PAC Adverse events specifically attributed to PACs occurred in 9 patients in the PAC group and 1 patient in the clinical assessment group later receiving a PAC 2005 American Medical Association. All rights reserved. (Reprinted) JAMA, October 5, 2005 Vol 294, No Table 1. Baseline Characteristics of Randomized Patients and Patients Receiving Pulmonary Artery Catheterization (PAC) Without Randomization in ESCAPE Trial Clinical Assessment (n = 218) P Value, Clinical Assessment vs PAC* P Value, Randomized vs Registry Characteristic PAC (n = 215) PAC Registry (n = 439) Age, mean (SD), y 56 (14) 56 (14) (14).001 Male, % Race, No. (%) White 124 (58) 134 (62) 348 (81).42 Minority 91 (42) 84 (39) 80 (19).001 Etiology, No. (%) Ischemic 110 (51) 105 (49) 240 (55).60 Nonischemic 105 (49) 113 (51) 199 (45).16 Heart rate, mean (SD), beats/min 83 (15) 82 (16) (18).67 Ejection fraction, mean (SD), % 19 (7) 20 (6) (14).001 Systolic blood pressure, mean (SD), mm Hg 106 (17) 106 (15) (21).008 Sodium, mean (SD), meq/l 137 (4.4) (n = 213) 137 (4.4) (n = 216) (5.3).001 Urea nitrogen, mean (SD), mg/dl 34 (21) 36 (24) (30).004 Creatinine, mean (SD), mg/dl 1.5 (0.6) 1.5 (0.6) (1.5).001 (n = 215) (n = 216) Baseline BNP, mean (SD), pg/mmol 974 (1216) 1018 (1400).96 NA NA Peak VO 2, mean (SD) 10.2 (3.9) (n = 61) 6-min walk, mean (SD), ft 390 (400) (n = 193) 9.9 (2.9) (n = 650) 437 (431) (n = 198).90 NA NA.37 NA NA Baseline MLHF score, mean (SD) 74 (17) 73 (18).60 NA NA Abbreviations: BNP, brain natriuretic peptide; ESCAPE, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness; MLHF, Minnesota Living with Heart Failure; NA, not applicable; VO2, peak oxygen consumption. SI conversion factors: To convert urea nitrogen to mmol/l, multiply by 0.357; creatinine to µmol/l, multiply by *P value for comparison between PAC and clinical assessment groups. P value for comparison between ESCAPE trial and PAC registry. Table 2. Impact of Therapy Guided by Pulmonary Artery Catheterization During the Course of Hospitalization* Hemodynamic Measurement Baseline Final Right atrial pressure, mm Hg 14 (10) 10 (7) Pulmonary capillary wedge pressure, mm Hg 25 (9) 17 (7) Cardiac index, L/min/m (0.6) 2.4 (0.7) Cardiac output, L/min 3.8 (1.2) 4.8 (2.1) Systemic vascular resistance, dynes sec/cm (800) 1100 (500) *Data are expressed as mean (SD). P.001 for all variables. The final hemodynamics are th
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