Peak oxygen consumption and outcome in heart failure patients chronically treated with β-blockers

Journal of Cardiac Failure Vol. 10 No. 1 2004

Peak Oxygen Consumption and Outcome in Heart Failure Patients Chronically Treated with b-Blockers SIMON F. SHAKAR, MD,1 BRIAN D. LOWES, MD,2 JOANN LINDENFELD, MD, FACC,2 RONALD ZOLTY, MD,2 MARC SIMON, MD,2 ALASTAIR D. ROBERTSON, PhD,2 MICHAEL R. BRISTOW, MD, PhD, FACC,2 AND EUGENE E. WOLFEL, MD, FACC2 Denver, Colorado

ABSTRACT Background: Peak oxygen consumption (VO2) is an important criterion for listing patients for cardiac transplantation. β-Blockers improve survival without affecting peak VO2. We questioned the value of peak VO2 in predicting outcome in patients treated with β-blockers. Methods and Results: We reviewed the records of 127 patients who had peak VO2 measured at baseline and were subsequently treated with β-blockers for at least 3 months. We divided the patients into 2 groups with peak oxygen consumption ⬎14 (VO2 hi) and ⱕ14 ml·kg·min (VO2 lo). VO2 hi had 109 patients and VO2 lo had 18 patients. The combined end-point of death or cardiac transplantation was compared between groups. Mean peak VO2 and left ventricular ejection fraction were lower in VO2 lo versus VO2 hi: 12.4 ⫾ 1.4 ml·kg·min versus 19.1 ⫾ 3.9 ml·kg·min and 17 ⫾ 8% versus 21 ⫾ 9%, respectively. At 30 months, the percentage of patients who did not reach the combined end-point was 94% in VO2 lo versus 79% in VO2 hi (P ⫽ .47). In multivariate analysis, only changes in heart rate and LVEF from baseline to follow-up were predictive of survival. Conclusions: Current peak VO2 cutoff does not predict survival without transplantation of patients who tolerate chronic treatment with β-blockers. Key Words: Oxygen uptake, prognosis, exercise, heart transplantation.

As the number of patients waiting for cardiac transplantation continues to rise, more stringent selection criteria are needed to identify patients with poor intermediate-term prognosis who would benefit most from this therapy. This issue becomes even more important as the number of transplantation procedures performed plateaus or even declines.1 One of the most reliable criteria currently used to assess the prognosis of patients with chronic heart failure is the measurement of peak oxygen uptake (VO2). A peak VO2 less than 14 ml·kg·min (VO2 lo) is associated with high mortality at 1 year and is widely used as a criterion to list patients for trans-

plantation.2–4 The use of β-blockers has increased markedly in the last few years with the publication of several trials showing the survival benefit of these drugs in the majority of patients with heart failure.5–7 Therapy with β-blockers is associated with no or minimal improvement in peak VO2.8–11 If β-blocker–treated patients have improved survival but no change in peak VO2, one might question the utility of this parameter in timing the referral for cardiac transplantation in these patients. Therefore, we performed a retrospective analysis to determine if patients with a baseline peak VO2 ⱕ 14 ml·kg·min continue to have a poor prognosis after β-blocker therapy is successfully instituted.

From the 1Denver Veterans Administration Medical Center and the Department of Medicine, the University of Colorado Health Sciences Center, Denver, Colorado. Manuscript received May 2, 2003; revised manuscript received July 14, 2003; revised manuscript accepted July 21, 2003. Reprint requests: Simon F. Shakar, MD, University of Colorado Health Sciences Center, Division of Cardiology, Box B-120, 4200 E Ninth Avenue, Denver, CO 80262. 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/S1071-9164(03)00593-1

Methods

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Study Population The study population included all patients referred to the heart failure clinic at the University of Colorado Hospital who had a baseline measurement of peak VO2 and were subsequently treated with β-blockers for at least 3 months. Patients were excluded if they were still enrolled in a blinded trial using β-blockers. A total of 127 patients satisfied these criteria and were included in the

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study. They were seen between May 1992 and November 1999. The latter date was the time of last follow-up for all patients. The great majority of these patients were referred for transplant evaluation. During that period 665 patients were followed in the clinic. The local institutional review board approved the study. The mean duration of follow-up was 2.6 years (range 0.2 to 7.6 years). The β-blockers used (% of patients) included: carvedilol (60%), metoprolol (23%), bucindolol (16%), and sotalol (1%). The patients were divided into 2 groups based on their baseline peak VO2: VO2 hi (peak VO2 ⬎ 14 ml·kg·min) and VO2 lo (peak VO2 ⱕ 14 ml·kg·min). Procedures Cardiopulmonary exercise testing was performed using a commercially available treadmill in most patients (Quinton Medtrack ST55, Bothell, WA) and a metabolic cart (MedGraphics CardiO2CPX/D system, St Paul, MN). A modification of the Naughton protocol was used in 72% of the patients. A Bruce or modified Bruce protocol was used in 25%, and 4 patients had a cycle ergometer exercise. Online analysis of expired gases was performed every 20 seconds. The test was stopped when the patient was exhausted. We attempted to reach a respiratory exchange ratio (RER) value of at least 1 in all patients. The average of the VO2 levels obtained during the last 60 seconds of the test was used as a measure of peak VO2. Age- and sex-adjusted predicted peak VO2 was determined using the equations derived by Hossack et al.12 Ejection fraction at baseline was measured by radionuclide angiography in 89% of the patients and by echocardiography or left ventricular angiography in 8%. It was not measured in the remaining 3% until after the start of the β-blocker. Statistics

patients were taking an angiotensin-converting enzyme inhibitor (92%) and/or an angiotensin receptor blocker (10%), digoxin (94%), and a diuretic (95%). Only 26% were on spironolactone. The average maximum doses of β-blocker (mg/day ⫾ SD) were: carvedilol 62 ⫾ 27, metoprolol 117 ⫾ 54, and bucindolol 155 ⫾ 51 mg/day. Median time, from the performance of the exercise tolerance test to start of β-blocker therapy, was 35 days. Mean peak VO2 for all patients was 18.1 ⫾ 4.3 mL·kg·min. At the end of exercise, an RER ⱖ 1 was achieved in 80.8% of all patients. Table 1 describes the characteristics of the 2 patient groups. VO2 hi had 109 patients and VO2 lo had 18. VO2 hi had significantly fewer females than VO2 lo (P ⫽ .001). As expected, the LVEF and peak VO2 were significantly higher in VO2 hi. Baseline heart rate was higher in VO2 lo. There was a trend toward higher NYHA class in VO2 lo that was not statistically significant. No significant difference in age, etiology of the CMP, baseline medications (including the use of various β-blockers), or blood pressure was noted. Also, there was no statistical difference between the 2 groups in the duration of time between the exercise tolerance test and the start of the β-blocker, nor was there a difference in the mean duration of follow-up, which was 2.6 years. The quality of exercise performed in the 2 groups was similar, with an RER ⱖ 1 achieved in 82% of patients in VO2 hi

Table 1. Baseline Characteristics of the 2 Groups

The primary aim was to assess the utility of baseline peak VO2 in predicting outcome in the population studied. The outcome evaluated was a composite of all-cause mortality and cardiac transplantation (including status 1 and 2 patients). If lost to followup, patients were censored at the time of last contact. SAS statistical software version 6.12 (SAS Institute, Cary, NC) was used for all analyses. All tests used a 2-sided significance level of .05. Data are expressed as mean ⫾ standard deviation (SD). Unpaired comparisons were made by Fisher’s exact test or chi-square test for categorical variables and by Wilcoxon rank-sum test for continuous variables. Paired comparisons were made using the Wilcoxon signed-rank test. The Kaplan-Meier method was used to estimate survival curves, with differences assessed by the log rank test. Multivariate analysis used the Cox proportional hazards model.

Results Clinical Characteristics

The average age of the population was 53 ⫾ 12 years (range 17 to 80). There were 93 males (73%) and 34 females (27%). Mean left ventricular ejection fraction (LVEF) was 21 ⫾ 9%. Most patients were in New York Heart Association (NYHA) class II (30%) or III (69%). The etiology of the cardiomyopathy (CMP) was: idiopathic in 46% of patients, ischemic in 37%, hypertensive in 8%, valvular in 3%, and alcoholic in 3%. Two patients had anthracycline-induced CMP and 1 had peripartum CMP. Most

Age (y) Sex (% male)* LVEF (%)†* NYHA (%) Class II Class III Etiology (%): IDC Ischemic Other Medications (%): ACE inhibitor ARB Digoxin Diuretic Spironolactone Peak VO2* (cc/kg/min) RER ⱖ 1 (% of patients)†

SBP/DBP mmHg Resting HR (bpm)*

VO2 hi (peak VO2 ⬎ 14) (n ⫽ 109)

VO2 lo (peak VO2 ⱕ 14) (n ⫽ 18)

53 ⫾ 12 79 21 ⫾ 9

53 ⫾ 11 39 17 ⫾ 8

33 65

11 89

48 36 16

39 44 17

94 9 94 95 27 19.1 ⫾ 3.9

83 17 94 89 22 12.4 ⫾ 1.4

82 ⫾ 15

93 ⫾ 17

82 113/73

72 112/74

VO2, peak oxygen consumption; RER, respiratory exchange ratio; ACE, angiotensin-converting enzyme; ARB, angiotensin II type I receptor blocker; bpm, beats per minute; HR, heart rate; IDC, idiopathic dilated cardiomypathy; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SBP/DBP, systolic/diastolic blood pressure. *P value ⬍.05 comparing VO2 hi to VO2 lo. Data are presented as mean ⫾ SD. † The LVEF data were available only for 123 patients and the RER data for 120 patients.

Prognostic Value of Peak VO2 and β-Blockers

versus 72% in VO2 lo (P ⫽ .33). An RER ⱖ 0.99 was achieved in 86% versus 78% of patients, respectively (P ⫽ .47). Primary End Point

For the whole population, there were 14 deaths and 11 cardiac transplants. During the study, 22 patients (20%) reached the composite end point in VO2 hi, and 3 patients (17%) in VO2 lo; this difference was not statistically significant. The percentage of patients who did not reach the end point at 1 year was 94% for VO2 hi versus 94% for VO2 lo (P ⫽ NS). At 30 months these percentages were 79% and 94%, respectively (P ⫽ .47). The analysis of the data excluding the patients taking bucindolol gave similar results. Figure 1 shows the Kaplan-Meier outcome-free survival curves for the 2 groups. We performed bivariate analyses to assess the predictive power of baseline LVEF, age, NYHA class, etiology, type of β-blocker used, and sex on the occurrence of the composite end point. Only sex was predictive. Therefore, we analyzed the prognostic value of peak VO2 only in the male cohort of 93 patients and found it not to be predictive (P ⫽ .15). We also performed multivariate analysis in a model that included peak VO2, sex, change in heart rate, and change in LVEF from baseline to follow-up. The last 2 parameters were included based on known therapeutic effects of βblockers. The increase in LVEF is mirrored by an improvement in survival.13,14 The reduction in heart rate has also been correlated with improved survival.14,15 In this model, neither sex nor peak VO2 was predictive of outcome. To adjust further for the sex difference in the 2 groups,12,16 we used the percent of predicted peak VO2, instead of peak VO2, in the previously mentioned model. We found similar results.

Fig. 1. Outcome-free survival curves in VO2 lo (group with peak VO2 ⱕ 14 ml·kg·min) and VO2 hi (group with peak VO2 ⬎ 14 ml·kg·min).

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New Prognostic Parameters

We evaluated the utility of a lower cutoff for peak VO2. We found a peak VO2 of 12 ml·kg·min did not discriminate between those who reached the end point and those who did not. The number of patients was too low in VO2 lo to assess a still lower cutoff value for peak VO2. As noted previously, we included percent predicted peak VO2, sex, change in LVEF, and change in heart rate from baseline to follow-up in a multivariate analysis model. We found that only change in heart rate and LVEF were predictive of outcome (P ⫽ .02 and .04, respectively). Discussion New Findings

Our report shows that a cutoff value of 14 ml·kg·min, on a baseline peak VO2, is not adequate to assess the shortterm prognosis of patients who subsequently tolerate chronic treatment with β-blockers. We found that the survival of patients with a peak VO2 more than or less than 14 ml·kg·min is the same at 30 months of follow-up. We found that the change in heart rate and LVEF on β-blockers correlated better with outcome than peak VO2. Prospective testing of this finding in a larger population needs to be done. Comparison with Published Studies

Initially, cardiopulmonary exercise testing was used to assess the severity of heart failure and the response to therapeutic manipulations.17 This was followed by evaluating its role in predicting the prognosis of patients with chronic heart failure,2,18–20 especially for the purpose of timing referral for cardiac transplantation. In that respect, Szlachcic et al18 found a 1-year mortality of 77% in a small cohort with peak VO2 ⬍ 10 ml·kg·min. Likoff et al19 studied 201 patients. They found a mortality of 36% at 1 year in patients who had a peak VO2 ⬍ 13 ml·kg·min with an S3 and ischemic CMP versus 10% in patients who had none of the 3 risk factors. In V-HeFT-I and II,20 peak VO2 of 14.5 ml·kg·min separated the patients into high and low risk groups. Mancini et al2 studied 122 ambulatory patients screened for transplantation. They used a peak VO2 ⬎ 14 ml·kg·min prospectively to delay referral for transplantation. The survival of these patients was 94% at 1 year and 84% at 2 years, similar to that of patients after cardiac transplantation. The patients referred for transplantation (peak VO2 ⱕ 14) had a survival of 70% at 1 year. To improve the prognostic power of peak VO2, some researchers have used the percent of predicted peak VO2,21–23 lean body weight adjusted peak VO2,24 or hemodynamic data during exercise.25,26 However, it appears that for routine use, peak VO2 is a simple and still very reliable tool to assess the prognosis in heart failure patients not treated with β-blockers.27 Data for patients on β-blockers appeared only recently.28–32 Most of these data suggest that peak VO2 is not as predictive of prognosis in these patients, at least not at the cut-off value used currently (14 ml·kg·min). Gitt et al28 found that

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in 96 patients on β-blockers, the use of peak VO2 ⬍ 14 alone or in combination with ventilatory efficacy could not identify patients at high mortality risk after a follow-up of 6 months. The same parameters were predictive in 131 patients not treated with β-blockers. Pohwani et al29 compared 2 groups of patients evaluated for cardiac transplantation who had a peak VO2 ⱕ 14 ml·kg·min: 48 patients treated and 55 patients not treated with β-blockers. They found that patients treated with β-blockers had lower 1- and 3-year risk of dying, requiring transplantation, or placement of an assist device. The 1-year event-free survival was 92% versus 69%, respectively, in patients treated and not treated with β-blockers. This advantage persisted even when the comparison was between the 14 patients on β-blockers with a peak VO2 ⬍ 12 ml·kg·min and the 55 patients not taking βblockers. The study by Peterson et al30 included 369 patients. Peak VO2 cutoff value of 14 ml·kg·min was predictive of event-free (death or transplantation) survival. However, the 1-year event rate was only 13.3% for patients treated with β-blockers who had a peak VO2 ⱕ 14, similar to the 12.3% event rate for patients with a peak VO2 ⬎ 14 not treated with β-blockers. Zugck et al31 found in a cohort of 408 patients that therapy with β-blockers markedly influenced the prognostic value of peak VO2 (as well as other parameters such as LVEF and proBNP level). The 1-year event-free (no death or hospitalization for heart failure) survival mirrored the findings of Peterson et al. β-blockers treated patients had relatively low event rates. Even for those patients with a peak VO2 ⬍ 10, the annual mortality rate was only 17%. Finally, Butler et al32 reported a 1-year survival rate of 78% in patients with peak VO2 ⱕ 10 ml·kg·min (only 38.5% of the patients were on β-blockers). In the these studies, the event rates compare favorably with those after cardiac transplantation.1 Our study complements the data presented previously and looks at the problem from a different perspective. It shows that β-blockers mitigate the poor prognostic effect imparted by a low baseline peak VO2. Compared with the other studies in which patients referred for exercise were divided based on treatment with β-blockers, our patients were divided based on the baseline peak VO2 and were then treated with a minimum of 3 months of β-blockers. Thus, we avoid a potential bias of some of the previous studies (ie, comparing patients who tolerated β-blockers because they are less ill at baseline with those not on β-blockers). In heart failure increased cardiac adrenergic drive leads to decreased β-adrenergic receptor signal transduction, which contributes to decreased maximum exercise capacity.33 Increased adrenergic drive also leads to myocardial dysfunction via adverse biologic effects on the myocyte.33,34 β-Blockers improve survival by reversing the biologic effects on the myocardium, leading to reverse remodeling on the molecular, cellular and chamber levels.34,35 They also decrease sudden death.36 On the other hand, peak VO2 is generally unchanged in heart failure patients treated with βblockers, because signal transduction is not improved because of blockade of β-receptors by the antagonist.37

These somewhat contradictory effects are noted in previous studies in which β-blockers decreased peak exercise heart rate and increased stroke volume.9,10 The cardiac output, at rest or during exercise, is either unchanged or increases slightly.9,10 Peak VO2 is proportional to maximum cardiac output and thus will remain unchanged. Because there is no improvement in peak VO2, β-blockers negate the prognostic value of this parameter in patients who have exhibited a favorable LVEF response. Study Weaknesses

The study suffers from the limitations common to all retrospective studies. Although the great majority of deaths and transplants were captured, the status of patients lost to follow-up cannot be ascertained in all cases. The small number of patients did not allow us to find a cutoff value for peak VO2 that might predict outcome. It appears possible to find such a value using a larger cohort. The predominance of females in VO2 lo complicates the interpretation of the data. Female patients are known to live longer than males after being diagnosed with heart failure. The median survival of female patients in the Framingham database was 3.2 years versus 1.7 years for males. However, the difference in 1-year survival is smaller at 64% for females and 57% for males.38 To correct for this imbalance, we tested the hypothesis in the male cohort only and found peak VO2 of 14 ml·kg·min not to be predictive of outcome. We showed that sex was not predictive of outcome when entered into a multivariate analysis model. Also, the VO2 lo group was likely sicker because it had lower baseline LVEF with higher heart rate; and, although not statistically significant, NYHA class III, ischemic etiology, and bucindolol use (27% versus 14%) were all more common in VO2 lo. Our cohort is younger and has more patients with idiopathic dilated cardiomyopathy than the heart failure population at large; however, this bias is present in most similar articles and is likely the result of referral patterns in which younger patients with fewer comorbidities are referred for transplantation. We used peak VO2 performed before patients received βblockers to assess prognosis. Currently, most patients will be taking β-blockers when referred for evaluation. We know, however, that β-blockers do not change peak VO2 significantly in prospective studies.11 The previously mentioned studies showed similar results for patients already on βblockers when peak VO2 was measured. Clinical Implications

There is accumulating evidence that β-blockers mitigate the effects of low peak VO2 on prognosis. A peak VO2 cutoff of 14 ml·kg·min might not be associated with a poor enough prognosis to warrant listing for cardiac transplantation. The findings of this article suggest using a lower cut-off or a different parameter to help make this decision. Incorporating therapeutic response changes that occur with β-blockers such as effects on LVEF and heart rate into a scoring system might be useful.

Prognostic Value of Peak VO2 and β-Blockers

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36. Hjalmarson A. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the post-infarction period. Am J Cardiol 1997;80:35J–9J. 37. Linseman JV, Lowes BD, Minobe WA, Lindenfeld JA, Shakar S, Wolfel EE, et al. Marked impairment of exercise tolerance in heart

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