The prognostic value of functional capacity in patients with mild to moderate heart failure

Volume 114 Number 2

21. Calvin JE, Baer RW, Glantz SA. Pulmonary artery constriction produces a greater right ventricular dynamic afterload than lung microvascular injury in the open chest dog. Circ Res 1985;56:40. 22. Wagenvoort CA, Wagenvoort N. Pathology of pulmonary hypertension. New Y&k: John Wiley & Sons, Inc, 1977:232. 23. Milstein JM. Hirai C. Bennett SH. Goetzman BW. Comnarative effects’of hypoxia and group B streptococci (GBS) on pulmonary vascular impedance (abstr). Clin Res 1987; 35:203A. 24. Kahler RL, Goldblatt A, Braunwald E. The effects of acute hypoxia on the systemic venous and arterial systems and on myocardial contractile force. J Clin Invest 1962;41:1553. 25. Coleridge JCG, Kidd C. Reflex effects of stimulating baroreceptors in the pulmonary artery. J Physiol 1963;166:197. 26. Juratsch CE, Jengo JA, Laks MM. Role of the autonomic nervous system and pulmonary artery receptors in production of experimental pulmonary hypertension. Chest 1977; 71:265.

RV afterload

and LV function

in newborns

27. Lewin RJ, Cross CE, Rieben A, Salisbury PF. Stretch reflexes from the main pulmonary artery to the systemic circulation. Circ Res 1961;9:585. 28. Milstein JM, Goetzman BW. Effect of pulmonary artery distention on systemic vascular resistance in newborn lambs. Am J Cardiol 1985;56:681. 29. Friedman WF. The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 1972;15:87. 30. Eliot l%J, Lam R, A&l R, Hobel C, Fisher DA. Norepinenhrine (NE). eninenhrine (E) and donamine (DA) levels at birth in the iu;an In cord ad newborn samples (abstr). Clin Res 1978;26:198A. 31. Geis WP, Tatooles CJ, Priola DV, Friedman WF. Factors influencing neurohumoral control of the heart in the newborn dog. Am J Physiol 1975;228:1685. 32. Whitsett JA, Pollinger J, Matz S. P-adrenergic receptors and catecholamine sensitive adenylate cyclase in developing rat ventricular myocardium: Effect of thyroid status. Pediatr Res 1982:16:463.

The prognostic value of functional capacity in patients with mild to moderate heart failure Thirty patients with ischemic (n = 14) or idiopathic dilated (n = 16) cardiomyopathy were followed long-term to determine the prognostic value of measuring entry exercise capacity. At the time of referral for management of symptomatic heart failure, studies included radionuclide angiography, M-mode echocardiography, 24-hour Halter and graded exercise testing with measured oxygen peak consumption (peak VOz). Inclusion criteria were (1) NYHA class II (n = 16) or III (n = 14) despite at least 3 months of treatment with digitalis and diuretics, (2) left ventricular ejection fraction 50 mm, and (4) exercise capacity limited by dyspnea or fatigue. Patients were treated with diuretics (lOO%), digitalis (83%), and vasodllators (60%) and were followed for at least 6 months (mean 15). The l-, 2- and 3-year cumulative survival rates were 75.4%, 70.2%, and 70.2%, respectively. Univariate predictors of survival included measured peak VOI (p = 0.0026), as well as age, estimated peak V02 (based on exercise time), presence of left bundle branch block, LVEDD, and frequency of ventricular arrhythmias. Multivariate analysis revealed that measured peak VOn was the single best independent predictor of survival (p < 0.001). We conclude that assessment of functional capacity provides useful independent prognostic information in patients with mild to moderate heart failure. (AM HEART J 1987;114:377.)

Harold J. Willens, M.D., Roger D. Blevins, Pharm.D., David Wrisley, M.D., Denise Antonishen, R.N., Dorothy Reinstein, R.N., and Melvyn Rubenfire, M.D. Detroit, Mich.

Chronic heart failure afKcts approximately 2 million Americans and reported annual mortality rates From the Section of Cardiovascular Diseases, Department of Medicine, Sinai Hospital of Detroit, and Wayne State University. Received for publication Aug. 19, 1986; accepted Jan. 5, 1987. Reprint requests: Dr. Roger D. Blevins, Department of Medicine, Sinai Hospital of Detroit, 6767 West Outer Drive, Detroit, MI 48235.

range from less than 10% to more than 50% .I-6 Numerous investigators have reported the prognostic value of various invasive and noninvasive measurements, including hemodynamic parameters,4s7-g left ventricular (LV)l”-12 and right ventricular (RV) ejection fraction (EF),‘$ presence of left bundle branch block (LBBB)2p8 or arrhythmias,14s15 as well 377

378

Wiltens

et al.

Table

I. Weber classification of functional capacity

Cluss

Adapted

Measured

American

rn~~~rn~~

oxygen

&onsumpti~n

A

>20

B C

16-20 ml/min/kg

D


lo-16

from

Weber

et al. (reference

ml/min/kg ml/min/kg ml/min/kg

32).

as various histologic indices of myocardial biopsy specimens.16, l7 Although ph~macologic interventions can effectively relieve symptoms and improve hemodynamic abnormalities, few studies have demonstrated the beneficial effect of drug therapy on long-term survival.33 Assessment of functional capacity by means of graded exercise testing in patients with mild to moderately severe heart failure has gained increasing acceptance. However, symptomatic status often correlates poorly with fun~ion~ capacity.18v20 Similarly, indices of hemodynamics or LV function at rest do not correlate well with measured functional capacity in patients with chronic LV failure.21-26 ~nfortuna~ly, little is known about the prognostic significance of exercise capacity in these patients.27-28 The primary objective of this study was to assess the prognostic value of functional capacity, relative to other known prognosticators, in patients with mild to moderate heart failure. METHODS Patients. The potential study population consisted of 112 consecutive patients referred to our Heart Failure Research Clinic for ~n~ement of chronic heart failure. Baseline evaluation of these patients included a complete medical history and physical examination, M-mode echocardiographic assessment of LV end-diastolic dimension (LVEDD), determination of resting LVEF and RVEF by radionu~lide angiography, and standard 1%lead and 24hour Holter ECG assessment of atria1 and/or ventricular dysrhythmia, all performed within 1 week of referral. From this population we selected patients by the following criteria: (1) presence of New York Heart Association (NYHA) functional class II or III exertional dyspnea or fatigue, (2) symptomatic despite at least 3 months of digitalis and diuretic therapy, (2) LVEF <50%, (4) LVEDD >50 mm, and (5) assessment of functional capacity by graded exercise testing that was limited only by dyspnea or fatigue. Excluded were patients with restrictive c~diomyopathy, primary valvular heart disease, primary pulmonary disease, or myocardial infarction within 3 months. Thirty patients met these strict entry criteria and were the subjects of this study. Graded exercm taetlng. Exercise testing was performed within 1 month of all other baseline measurement. Exercise tests were performed with the Naughton proto-

August tea7 Heart Journal

II. Univariate discriminants of survival in patients with mild to moderate heart failure .P Survivors Nonsurvivors value

Table

Number of patients Weber class Peak VO, (METS) Age (yr) Peak VOz (ml/min/kg) LBBB LVEDD (mm) Couplets124 hr VPCdhr >lO VPCsfhr Weight (kg) NYHA class VT LVEF RVEF Sex (% male) Etiology (ischemic)

22 2.1 tt 0.8 5.7 rt 1.7 51 I 11 17.9 k 5.4 8% 59 zk 9 i 59 zt 42% 82 rt 2.4 rt: 13% 27 + 34 zt 73% 42%

12 24 142 22 0.5

10% 11%

3.3 3.5 65 11.6

8 It 0.7 + 1.3 -c 10 AZ 4.1

50 % 70 -t 14 198 + 453 170 rfr 213 15% 71 r?: 14 2.6 zt 0.5 38% 25 $: 12% 33It5% 63% 38%

0.00~ 0.0010 0.0013 0.0026 0.0089 0.0159 0.0221 0.0506 0.1023 0.1017 0.1150 0.1168 0.3138 0.3831 0.5902 0.8414

LBBB = left bundle branch block, LVEDD = left ventricuiar end-diastolic dimension; LVEF = left ventricular ejection fraction; Peak VO, (METS) = peak oxygen consumption estimated from exercise time; Peak VO, (ml/min/kg) = peek oxygen consumption calculated from gas exchange dats; RVEF = right ventricular ejection fraction; VPC = ventricular premature complex; VT = ventricular tachycardia; NYHA = New York Heart Aaeociation.

1~01.~Three-channel ECGs (leads VI, Vg, and aV,) were monitored continuously during exercise by means of the Marquette computer-assisted system. Twelve-lead tracings were obtained at rest, at the end of each 3-minute stage, and at maximal exercise. Respiratory data were obtained throughout each test with the Ergo-Pne~otest III/Dataspir EDV-8 system (Erich-Jaeger, Rockford, Ill.), as previously described.31 Oxygen consumption, carbon dioxide production, and respiratory exchange ratios were measured at 15-second intervals and were recorded through an on-line computer assembly. Prior to each exercise test, the pneumo~chome~r was calibrated with a 1 L syringe and the gas analyzers were calibrated with room air and certified O$CO, concentration (Ohmeda, Madison, Wise.). Oxygen consumption was expressed in ml/min~ or metabolic equivalents (METS), where 1 MET = 3.5 ml/min/kg. Peak oxygen consumption (peak VO,) was defined as the oxygen consumption attained at the end of the test, which was limited by dyspnea or fatigue in all cases. Measured peak VOz was calculated from gas exchange data while estimated peak VO, was derived from exercise time.% In addition, the Weber classification of functional capacity was determined (Table 1)32,with the assumption that peak VO, approximated maximal oxygen consumption (VO, max). Long-term folkaw-up. All patients in this series were followed for at least 6 months. Treatment consisted of diuretics in all patients, digitalis in 25 patients (63 % ), and

Volumel14 Number2

vasodilators (nitrates and/or captopril) in 18 patients (60% ). Thirteen patients (43% ) had frequent and complex ventricular arrhythmias requiring the continued use of procainamide in eight patients, quinidine in three, mexiletine in one, and amiodarone in one. No patient had significant atria1 arrhythmias. The length of follow-up was determined from the day of baseline graded exercise testing. The vital status of all patients was known at the end of the study. Statistical analysis. Patients were grouped by survival &&us, and univariate analysis was performed to determine which of 16 baseline clinical variables were significantly different between groups. Univariate analysis consisted of the Student’s unpaired t test for parametric data and chi square evaluation or Fisher’s exact method for proportional data. The Weber classes A through D were assigned numerical values 1 through 4. To determine which variables were significant independent predictors of survival status, multivariate step-wise logistic regression analysis was perfored using the Biomedical Data Package (BMDP) statistical package. The regression model incorporated those variables that were borderline significant by univariate methods (p < 0.10). The three measures of functional capacity (i.e., measured peak VOz, estimated peak VOz, and Weber class) were expected to be interrelated. Therefore, one regression model included only measured peak VO, to assess the relative value of measured functional capacity, and a second model included only estimated peak VO, to assess the relative value of estimated functional capacity. Chi square improvement was used to determine the reIative importance of each variable in each model and statistical significance was inferred at p < 0.05. Correlations between measures of functional capacity and ventricular function were established by linear regression and the l-, 2-, and 3-year cumulative survival rate for all patients was determined by standard actuarial analysis. RESULTS

Among 30 patients with NYHA class II or III heart failure, eight (26.7%) died over an average follow-up period of 15 months (range Cl to 35 months). The l-, 2-, and $-year cumulative survival rates were 75.4%, 70.2 % , and 70.2%, respectively. Four of the eight nonsurvivors died during the first month of follow-up and six of the deaths were sudden. The univariate determinants of survival, in order of significance, are presented in Table II. Demographic factors. There were no s~tistic~y significant differences between survivors and nonsurvivors with respect to the proportion of males (73% vs 63 % , p = 0.5902). However, survivors were significantly younger (51 vs 65 years, p = 0.0013). Thirteen patients (43 % ) had ischemic and 17 (57 % ) had idiopathic dilated cardiomyopathy, and the distribution of an ischemic etiology was not different between survivors and nonsurvivors.

Functional

Table

111.Significant multivariate

capacity

in CHF

379

discriminants of surviv-

al in patients with mild to moderate heart failure Variable

X2

p value

First model: Measured peak VO, Age Presence of LBBB Second model:

11.80 8.61 1.76


13.93 4.74 4.55


Estimated peak VO, Presence Age

of LBBB

First model = regression model includes only measured peak VO, (using gas exchange data) among exercise parameters; Second model = regression model includes only estimated peak VO, fusing exercise time) among exercise parameters; x2 = model improvement by ehi square evaluation. Abbreviations as in Table II.

Ventricular function. The left ventricular enddiastolic diameter was greater (59 vs 70 mm, p = 0.0159) and left bundle branch block more common (8% vs 50%, p = 0.0089) among the patients who died. Neither LVEF (27 % vs 25%) p = 0.3138) nor RVEF (34% vs 33%, p = 0.3831) were significantly different between groups. Similarly, the average NYHA class of these patients was not different (2.4 vs 2.6, p = 0.1150). Arrhythmias. None of the patients in this series had clinically sign~~t atrial ~h~rni~. However, both ventricular arrhythmias and LBBB were common. Nine survivors (42%) and six nonsurvivors (75%) had frequent ventricular premature complexes (VPCs) (i.e., greater than lo/hour), although this difference was not statistically significant. Number of VPCs/bour (59 vs 170, p = 0.0506) and coupled VPCs/24 hours (9 vs 198, p = 0.0221) were significantly higher among those who died. Three survivors (13 %) and three nonsurvivors (38% ) had ventricular tachycardia on baseline Holter recordings, although the difference did not achieve statistical significance (p = 0.1168). Functional capacity. Exercise capacity was effortlimited in all patients. The average respiratory exchange ratio at peak oxygen consumption was 1.00 * 0.12 (mean + s.d.), indicating that near physiologic maximum exercise had been achieved, and this value was not signific~tly different between survivors and nonsurvivors. Among the most significant univariate discriminants of survival were measures of functional capacity. Peak oxygen consumption was higher among survivors, whether measured (17.9 vs 11.6 mllminlkg, p = 0.0026) or estimated (5.7 vs 3.5 METS, p = 0.0010). The measured peak VO, for individual patients (grouped by survival) is illustrated in Fig. 1. Similarly, survivors

380

Willens et al.

American

August 1987 Heart Journal

20I .

26-

. :

20MEASURED PEAK Vo, (ml/min/ka)

+

,I)-

lo-

l

:. . I. .

ESTIMATED PEAK Vo, (met4

m - . . :

Synwl$ra .

MEASURED PEAK Vo2 (met4

NotQSur~lvorr

Fig.

1. Measured peak oxygen consumption (PEAK VOJ obtained at the time of referral for management of symptomatic mild to moderate heart failure (NYHA class II or III). Data grouped by survival status after a minimum follow-up of 6 months (mean 15 months). The mean VO, max between survivors (17.9 ml/min/kg) and nonsurvivors (11.6 ml/min/kg) was significantly different

Fig.

(p = 0.0026).

DISCUSSION

were in a lower average functional class compared to nonsurvivors (Weber class 2.1 vs 3.3, p = 0.0006). Independent predictors of survival. Multivariate analysis revealed that functional capacity was the single most powerful independent predictor of survival. The model designed to assess measured functional capacity found measured peak VO, to be the most important factor (x2 = 11.80, p < O.OOl), followed by age (x2 = 8.61, p = 0.003) and the presence of LBBB (x2 = 7.76, p = 0.005) (Table III). The model designed to evaluate estimated functional capacity based on exercise time found that estimated peak VO, was most important (x2 = 13.93, p < O.OOl), again followed by the presence of LBBB age (x2 = 4.55, (x2 = 4.74, p = 0.029) and p = 0.033). Correlations of functional capacity and ventricular function. There was a reasonably good correlation

between estimated and measured functional capacity. Fig. 2 illustrates that the correlation between estimated peak V02 and measured peak V02, both expressed in metabolic equivalents (METS), was r = 0.71 (p = 0.001). However, measured peak V02 did not correlate well with either LVEF (F = 0.10, p = NS) or RVEF (r = 0.03, p = NS). There was also a poor correlation between Weber and NYHA classifications (r = 0.32, p = NW.

2. The correlation by linear regression between estimated peak VO, (based on exercise duration) and measured peak VO, (based on gas exchange analysis). Data expressed in metabolic equivalents (1 MET = 3.5 ml/ min/kg) .

Numerous investigators have reported the prognostic value of various measures of heart failure. Among these are hemodynamic abnormalities? 7-v LVEF and/or RVEF,1°-13 presence of LBBB2e8 or of arrhythmias,14v l5 and histologic abnormalities myocardial biopsy specimens.*6*‘7 Although treatment is frequently aimed at alleviating symptoms and correcting these abnormalities, few studies have assessed whether drug therapy improves long-term survival rates.33 Recently, measures of functional capacity by exercise testing have gained importance in the overall assessment of patients with heart failure. Despite the use of these measurements to assess functional impairment and evaluate response to chronic therapy, little is known about the prognostic significance of exercise capacity in patients with chronic LV failure. Previous studies. Investigations on the prognostic value of exercise testing in heart failure have been controversial. In a preliminary report, Franciosa et aI.27 studied 73 symptomatic heart failure patients with a l-year mortality rate of 25%. The measured VO, max was not different between survivors (13.1 ml/min/kg) and nonsurvivors (12.0 ml/kg/min), and this was true among the subgroups with either ischemic or primary cardiomyopathy. They concluded that measured functional capacity does not appear to relate to long-term survival in symptomat-

Volume 114 Number 2

ic patients. However, Szlachcic et a1.28reported that measured exercise capacity provided useful prognostic information. Among 27 symptomatic heart failure patients with a l-year mortality rate of 40%) they reported 77% mortality in the subgroup with VO, max lO ml/min/kg (p < 0.001). The discrepancy between these studies may have been due to differences in patient population, methods of measuring maximal oxygen consumption, and methods of analyzing the data. Furthermore, neither study addressed the value of functional capacity relative to other known prognosticators in this group. Present study. In our study of 30 patients with mild to moderate heart failure, univariate analysis revealed numerous determinants of survival that were consistent with previous reports. These included age, presence of left bundle branch block, left ventricular size, and ventricular arrhythmic frequency. In addition, however, various measures of exercise tolerance appeared to discriminate between survivors and nonsurvivors. In order to establish the relative significance of these predictors, multivartiate step-wise regression analysis was performed. Both measured and estimated peak VO, were the best independent predictors of survival in their respective models. Furthermore, there was a good correlation between these measures of functional capacity. This indicates that assessment of functional capacity, with or without gas exchange analysis, provides useful prognostic data in this group. The poor correlation between symptomatic status and exercise tolerance has been well documented.1s-20 In this series, there was a rather poor correlation (r = 0.32, p = NS) between NYHA class (based on symptoms) and Weber class (based on measured VO, max). The discordance between functional capacity and LV function assessed by EF has also been reported.21-26 Consistent with these studies, we found a poor correlation between LVEF and measured peak VO, (r = 0.10, p = NS). It appears to be controversial whether RV function is more closely correlated with exercise capacity. Baker et a1.2g reported a reasonably good correlation (r = 0.70, p < 0.001) between RVEF and VO, max in patients with a mean LVEF of 26% and an RVEF of 41% . Szlachcic et a1.28 reported an insignificant correlation between RVEF and peak V02 (r = 0.55, p = NS) in patients with a mean LVEF of 22% and an RVEF of 24%. Similarly, we found a poor correlation between RVEF and VO, max (r = 0.03, p = NS) in patients with an average LVEF of 27%

Functional

capacity

in CHF

381

and an RVEF of 34%. Differences between these studies may be due in part to differences in the degree of biventricular failure and the relative contribution of RV failure to exercise tolerance in these patients. Resting measures of LV function correlate poorly with mortality, possibly because they do not measure an important factor of cardiac function, namely the reserve capacity of the myocardium. Functional capacity measured by exercise duration is an easily and safely obtained parameter that accurately assesses the functional reserve capacity of the ventricle. Unfortunately, the poor correlation between measured functional capacity and symptomatic status by the NYHA classification indicates that the patient’s history alone does not provide an accurate assessment of myocardial reserve. Treadmill testing, therefore, may provide useful information in the clinical evaluation of patients with mild to moderate heart failure. Limitiations. This study was designed to assess the prognostic value of functional capacity specifically in patients with mild to moderate heart failure whose natural history may be affected by intervention. Although strict entry criteria provided a relatively homogeneous group, it also limited the number of subjects enrolled. Despite the small sample size, multivariate analysis was possible and permitted rank order assessment of several potentially useful prognosticators. There was also some degree of overlap between survivors and nonsurvivors with respect to measured peak V02, suggesting that other factors, such as norepinephrine, beta-receptor density and function, or angiotensin maybe involved. Finally, six of the eight survivors in this series had sudden death, presumably arrhythmic, and functional capacity would seem to be less predictive in this subgroup. However, measured oxygen consumption was a more useful prognosticator then several common indices of arrhythmia, despite the encountered proportion of sudden death. Conclusions. This study supports the assessment of functional capacity, with or without gas exchange analysis, in patients with mild to moderately symptomatic (NYHA class II to III) heart failure. Although larger studies are needed to confirm our findings, the data indicate that assessment of functional capacity provides useful prognostic information on the survival of these patients and may be the best indicator available. Exercise testing should be included in future studies designed to assess the impact of drug therapy, diet and/or exercise on the natural history of this disease.

382

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August 1997 Heart Journal

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