David S. Rendall

Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial

CONTEXT Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. OBJECTIVE To test the efficacy and safety of exercise training among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. INTERVENTIONS Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. MAIN OUTCOME MEASURES Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. RESULTS The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. CONCLUSIONS In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Factors Related to Morbidity and Mortality in Patients with Chronic Heart Failure with Systolic Dysfunction: The HF-ACTION Predictive Risk Score Model

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ⩽0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Detection of restenosis after elective percutaneous transluminal coronary angioplasty using the exercise treadmill test

To determine the value of a 6-month exercise treadmill test for detecting restenosis after elective percutaneous transluminal coronary angioplasty (PTCA), 303 consecutive patients with successful PTCA and without a recent myocardial infarction were studied. Among the 228 patients without interval cardiac events, early repeat revascularization or contraindications to treadmill testing, 209 (92%) underwent follow-up angiography, and 200 also had a follow-up treadmill test and formed the study population. Restenosis (greater than or equal to 75% luminal diameter stenosis) occurred in 50 patients (25%). Five variables were individually associated with a higher risk of restenosis: recurrent angina (p = 0.0002), exercise-induced angina (p = 0.0001), a positive treadmill test (p = 0.008), more exercise ST deviation (p = 0.04) and a lower maximum exercise heart rate (p = 0.05). However, only exercise-induced angina (p = 0.002), recurrent angina (p = 0.01) and a positive treadmill test (p = 0.04) were independent predictors of restenosis. Using these 3 variables, patient subsets could be identified with restenosis rates ranging from 11 to 83%. The exercise treadmill test added independent information to symptom status about the risk of restenosis after elective PTCA. Nevertheless, 20% of patients with restenosis had neither recurrent angina nor exercise-induced ischemia at follow-up. For more accurate detection of restenosis, the exercise treadmill test must be supplemented by a more definitive test.

Repeat Percutaneous Transluminal Coronary Angioplasty and Predictors of Recurrent Restenosis

One hundred seventeen consecutive patients undergoing repeat percutaneous transluminal coronary angioplasty (PTCA) were studied to assess procedural success and recurrent restenosis rates. Clinical, anatomic and procedural variables were examined as predictors of recurrent restenosis using stepwise logistic regression analysis. Primary success was achieved in 114 patients (97.5%). One patient (0.8%) died after acute occlusion. No other in-hospital complications were encountered. After a mean follow-up interval of 218 +/- 160 days, 72 of 114 successfully dilated patients (63%) remained angina free. There were no late deaths. Three patients (2.6%) experienced a late myocardial infarction. Follow-up arteriography was performed in 100 patients (88%), of whom 32% had recurrent restenosis (greater than 50% luminal diameter narrowing). On univariate analysis, the presence of 3 clinical variables at repeat PTCA was associated with significantly higher recurrent restenosis rates compared with their absence, that is, unstable angina (48 vs 20%, p = 0.003), diabetes (61 vs 26%, p = 0.003) and hypertension (46 vs 18%, p = 0.003). Patients with recurrent restenosis had a shorter interval between first and second PTCA compared with those who remained patent (136 +/- 116 vs 214 +/- 163 days, p = 0.018). Multivariate analysis confirmed unstable angina, diabetes and hypertension as independent predictors of recurrent restenosis. Repeat PTCA may be performed for restenosis with a high likelihood of success and low incidence of complications. The rate of recurrent restenosis is similar to that reported for initial angioplasty. Patients with unstable angina, diabetes and hypertension appear to be at higher risk for recurrent restenosis.

Relation Between Volume of Exercise and Clinical Outcomes in Patients With Heart Failure

OBJECTIVES This study determined whether greater volumes of exercise were associated with greater reductions in clinical events. BACKGROUND The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization. METHODS Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 months after randomization were included (n = 959). Median follow-up was 28.2 months. Clinical endpoints were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization. RESULTS A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. On the basis of Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p = 0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p = 0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 metabolic equivalent (MET)-h and 5 to <7 MET-h per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r = 0.10; p = 0.005). CONCLUSIONS In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3 to 7 MET-h per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients.

Factors Related to Morbidity and Mortality in Patients With Chronic Heart Failure With Systolic DysfunctionClinical Perspective

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ⩽0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Exercise treadmill testing is a poor predictor of anatomic restenosis after angioplasty for acute myocardial infarction.

This study evaluated whether an exercise treadmill test could predict restenosis in 289 patients 6 months after a successful emergency angioplasty of the infarct-related artery for acute myocardial infarction. After excluding those with interim interventions (64), medical events (36), or medical contraindications to follow-up testing (25), both a treadmill test and a cardiac catheterization were completed in 144 patients, 88% of those eligible for this assessment. Four patients with left bundle branch block or pacemaker rhythm at the time of treadmill testing were also excluded from analysis. Of six follow-up clinical and treadmill variables examined by multivariable logistic regression analysis, only exercise ST deviation was independently correlated with restenosis at follow-up (chi 2 = 5, p = 0.02). The clinical diagnosis of angina at follow-up, although marginally related to restenosis when considered by itself (p = 0.04), did not add significant information once ST deviation was known. The sensitivity of ST deviation of 0.10 mV or greater for detecting restenosis was only 24% (13 of 55 patients), and the specificity was 88% (75 of 85 patients). The sensitivity of exercise-induced ST deviation for detection of restenosis was not affected by extent or severity of wall motion abnormalities at follow-up, by the timing of thrombolytic therapy or of angioplasty, or by the presence of collateral blood flow at the time of acute angiography. A second multivariable analysis evaluating the association of the same variables with number of vessels with significant coronary disease at the 6-month catheterization found an association with both exercise ST deviation (p = 0.003) and exercise duration (p = 0.04). Angina symptoms and exercise treadmill test results in this population had limited value for predicting anatomic restenosis 6 months after emergency angioplasty for acute myocardial infarction.

Late restenosis after emergent coronary angioplasty for acute myocardial infarction: comparison with elective coronary angioplasty

The late restenosis rate after emergent percutaneous transluminal coronary angioplasty for acute myocardial infarction was assessed by performing outpatient follow-up cardiac catheterization in 79 (87%) of 91 consecutive patients who had been discharged from the hospital with a successful coronary angioplasty. The majority of patients (90%) received high dose intravenous thrombolytic therapy with streptokinase in addition to angioplasty. Similar follow-up data were obtained in 206 (90%) of 228 consecutive patients who had successful elective angioplasty during the same period. The interval from angioplasty to follow-up was 28 +/- 9 weeks for the myocardial infarction group and 30 +/- 11 weeks for the elective group. Baseline clinical variables were similar for both the myocardial infarction and elective groups except for a higher percentage of men in the infarction group (81 versus 63%, p = 0.001). The number of coronary lesions undergoing angioplasty and the incidence of intimal dissection were similar, but multivessel angioplasty was more common in the elective group (13 versus 4%, p = 0.02). The rate of in-hospital reocclusion was higher in the patients receiving angioplasty for myocardial infarction (13 versus 2%, p = 0.0001). At the time of late follow-up after hospital discharge, the patients with myocardial infarction were more often asymptomatic (79 versus 55%, p = 0.0001), and the rate of angiographic coronary restenosis was lower for the infarction group both overall (19 versus 35%, p = 0.006) and when multivessel angioplasty patients were excluded (19 versus 33%, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary angioplasty performed with gradual and prolonged inflation using a perfusion balloon catheter: Procedural success and restenosis rate

The results of routine coronary angioplasty using gradual and prolonged balloon inflation with a perfusion balloon catheter were evaluated. One hundred forty patients were treated with inflation of the balloon to 6 atm over 3 minutes, with a median inflation time of 15 minutes. The procedural success rate (residual stenosis less than or equal to 50%) was 99%. In-hospital major complications occurred in five patients (3.6%), with one patient experiencing a periprocedural infarction, three patients requiring bypass surgery for abrupt closure, and one patient dying after elective bypass surgery following previous successful angioplasty of a culprit lesion. The restenosis rate in the 117 patients with angiographic follow-up (87% of those eligible) was 42%. Thus gradual and prolonged inflation using a perfusion balloon catheter resulted in a high procedural success rate and a restenosis rate similar to that reported in large studies of patients treated with standard angioplasty. These results warrant further study using a prospective randomized trial design.

Factors Related to Morbidity and Mortality in Patients With Chronic Heart Failure With Systolic Dysfunction

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ⩽0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.