Evaluation of the Incremental Prognostic Utility of Increasingly Complex Testing in Chronic Heart Failure

Details of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study have been previously published.^5,6 Briefly, HF-ACTION (clinicaltrials.gov: NCT00047437) was a randomized clinical trial evaluating the effect of exercise training versus usual care on long-term morbidity and mortality in 2331 well-treated patients with chronic HF because of left ventricular systolic dysfunction (New York Heart Association classes II–IV; LVEF, <35%). Patients were randomized to either usual HF care or a structured, group-based, supervised exercise program. All patients, regardless of treatment group, received detailed self-management educational materials that included information on medications, fluid management, symptom exacerbation, sodium intake, and amount of activity recommended by the American Heart Association guidelines.⁷

Demographics, socioeconomic status, past medical history, current medications, a physical examination, and the most recent laboratory tests were obtained at the baseline clinic visit before randomization. Participants reported race and ethnicity at the time of study enrollment using categories defined by the National Institutes of Health. All patients underwent baseline assessments, which included (1) cardiopulmonary exercise testing; (2) a 6-minute walk distance (6MWD); (3) transthoracic echocardiography; (4) quality of life measures, ascertained using several validated psychometric instruments measuring health-related quality of life, pain, depression, and social support, including the Kansas City Cardiomyopathy Questionnaire (KCCQ)⁸; and (5) levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in a subset of patients who agreed to participate in the biomarker substudy.^9,10

The primary end point was a composite of all-cause mortality and all-cause hospitalization over a median follow-up of 2.6 years. We examined the following secondary clinical end points: all-cause mortality and Cardiovascular Death and HF Hospitalization. An independent clinical event committee that was blinded to treatment assignment adjudicated all deaths and first hospitalizations. Local institutional review boards approved HF-ACTION, and all enrolled patients provided written informed consent.

Among patients used in this analysis, categorical data were summarized as percentages and differences in patients with and without NT-proBNP data were compared using χ² tests and Wilcoxon signed-rank tests. A series of Cox proportional hazards regression models with a priori variable selection were fit for each clinical end point in the full patient population and the subgroup with NT-proBNP. The models were as follows (with incremental addition of variables [Figure 1]): (1) baseline clinical assessment: age, sex, race, education level, marital status, employment status, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, New York Heart Association class, diabetes mellitus, chronic obstructive pulmonary disease, smoking status, peripheral vascular disease, atrial fibrillation, hyperlipidemia, stroke, depression, any HF hospitalization in the past 6 months, cause of HF, and Canadian Cardiovascular Society angina class; (2) health-related quality of life: KCCQ; (3) laboratory assessments: sodium, creatinine, and blood urea nitrogen±NT-proBNP; (4) echocardiographic assessments: LVEF and mitral regurgitation; (5) walk distance: 6MWD; and (6) exercise parameters: peak oxygen consumption (VO₂) and exercise duration.

We also performed a sensitivity analysis, by considering the 6MWD before laboratory information because this assessment is theoretically cheaper and easier to perform in the outpatient setting. We estimated the incremental cost of each additional assessment using the 2012 American Medical Association Current Procedural Terminology manual.¹¹ To account for deviations from the linearity assumption in proportional hazards regression, linear splines were used for age (>60), 6MWD (<450), peak VO₂ (<20), and creatinine (between 1.0 and 2.3). Hazard ratios are interpreted as the average hazard over the follow-up period to address potential deviations from proportional hazards. The time-point for comparison for all analyses was 30 months, with censoring of events occurring after 30 months. Each of the models was compared with the baseline clinical model that included only variables collected at the clinic visit using a 2-category net reclassification index (NRI) split at the end point incidence rate; 95% confidence intervals for the NRI were created by estimating bootstrap SEs from 50 bootstrap samples. Patients lost to follow-up before 30 months were considered nonevents for NRI calculations. We compared full and reduced models using likelihood ratio tests. The same methodology was repeated in the biomarker subset with the addition of log-transformed NT-proBNP to the list of laboratory assessments. These steps were taken for the 3 end points: all-cause death or hospitalization, all-cause death, and cardiovascular death or HF hospitalization. Finally, we also examined individual association or variables with outcomes using the χ² statistic. We considered P<0.05 to be statistically significant. All analyses were performed using SAS version 9.2 (SAS Institute, Inc, Cary, NC).

Complete clinical data were available on 1631 of 2331 HF-ACTION participants; of these, 1023 had baseline levels of NT-proBNP. Excluded patients were generally similar to those included in the analysis. The Table displays the characteristics of the patient population, as well as those with and without baseline NT-proBNP levels. Median age of the study cohort was 59 years (25th and 75th percentile: 51 and 68); 574 (35%) patients were black and 1167 (72%) were men. The majority of patients were New York Heart Association class II (n=1036; 64%) or class III (n=580; 36%) at baseline. Median LVEF was 25%, β-blockers were used in 1545 (95%) patients, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were used in 1538 (94%). At baseline, 675 (41%) patients had an implantable cardioverter defibrillator and 300 (18%) had a cardiac resynchronization therapy device. The median 6MWD was 368 m, and the median peak VO₂ level was 14.3 mL/kg per minute. Figure 1 depicts the overall characteristics of the study population, followed by the variables analyzed during increments of clinical assessments. Sets of evaluations were organized according to usual temporality during the initial assessment of a patient with HF, beginning with a clinical assessment, then proceeding with laboratory testing, echocardiography, and exercise testing. Comparison between patients with and without available NT-proBNP levels is shown in Table I in the Data Supplement. There were 1031 deaths or hospitalizations in the overall cohort (646 in NT-proBNP subset), 223 deaths (134 in NT-proBNP subset), and 470 cardiovascular death/HF hospitalizations (304 in NT-proBNP subset).

We performed a sensitivity analysis, by considering the 6MWD before laboratory information, as this assessment is theoretically cheaper and easier to perform in the outpatient setting (Tables VI–VII in the Data Supplement). For the composite of all-cause mortality and hospitalization, the NRI improved from 0.017 for baseline clinical information, KCCQ, and 6MWD to 0.065 with laboratory data, and 0.109 for the overall set of variables. When this analysis was performed in the patients with available NT-proBNP levels, the increase in NRI was more dramatic (0.016→0.130), with modest increases for the full model (0.162). The C-index increased from 0.64 for the baseline clinical model+KCCQ+6MWD to 0.67 with laboratory information (including NT-proBNP) and did not increase further with inclusion of other variables. For the outcome of all-cause mortality, the increase in NRI was similarly higher in the cohort with available NT-proBNP levels (clinical information+KCCQ+6MWD=0.014; +laboratories=0.085; full=0.094) than in those without (clinical information+KCCQ+6MWD=0.007; +laboratories=0.056; full=0.079). For the outcome of cardiovascular death and HF hospitalization, similar trends were noted, with large increases in C-statistics and NRI after inclusion of laboratory data with NT-proBNP.

Figure 4 depicts the additional costs of each set of assessments, based on Medicare and Medicaid reimbursement data, with the clinical assessment and quality of life survey as the referent. All assessments together were close to $500; the largest increases in cost were related to echocardiography and exercise testing. The addition of NT-proBNP increased the cost of each assessment by ≈$50. Of note, costs would be expected to vary considerably based on geographic region and insurance status, and true costs may be higher in clinical practice.

Our study has several limitations that need careful consideration. First, our findings only pertain to the incremental prognostic value of clinical testing—there are numerous other reasons why testing may be performed on patients with HF to guide therapeutic decision making (eg, timing of surgery). Second, exercise testing in HF-ACTION was not performed for ischemia evaluation, which is the most frequent reason why it is performed in the clinical setting. Third, patients qualifying for the HF-ACTION study required an LVEF of <35% at the outset; therefore, the patient population was already known to have systolic HF before the study echocardiogram. Fourth, all testing were done for research purposes rather than for clinical care. Although this is a limitation of the majority of clinical trials, we cannot draw firm conclusions about how this information might have different clinical implications outside of a study setting where there is often incomplete data available. Our study population also consisted of only ambulatory patients with impaired ejection fraction (LVEF, <35%), so our results may not be generalizable to the general population of patients with HF. Fifth, since we only considered prognosis with regard to prespecified outcomes used in the original study, observed associations may vary when considering additional clinical end points. Sixth, there was far greater improvement in net reclassification indices among patients without events than in those with events, indicating that additional data may improve discrimination more in this group of patients. Finally, these findings should be considered hypothesis generating and require replication and validation in additional cohorts of patients with chronic HF.

In conclusion, we examined the incremental prognostic value of sequential clinical assessments in a large cohort of well-treated patients with chronic systolic HF. Clinical data and readily available laboratory tests may provide similar prognostic information to more complex models that include assessments of echocardiographic and exercise variables. In the absence of clear linkage between precise estimation of risk and specific therapies, the marginal benefit of increasingly complex prognostic evaluations should be weighed against potential risk to the patient and escalation in costs of care.