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European Journal of Heart Failure 2006 8(5):502-508; doi:10.1016/j.ejheart.2005.11.001
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© 2005 European Society of Cardiology

Signs and symptoms in chronic heart failure: Relevance of clinical trial results to point of care—data from Val-HeFT

Maylene Wonga,*, Lidia Staszewskyb, Elisa Carrettab, Simona Barlerab, Roberto Latinib, Yann-Tong Chiangc, Robert D. Glazerc and Jay N. Cohnd

a VA Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA Los Angeles, United States
b Istituto di Ricerche Farmacologiche Mario Negri Milan, Italy
c Novartis Pharmaceuticals Corporation East Hanover, NJ, United States
d University of Minnesota Minneapolis, MN, United States

* Corresponding author. 1661 Pine Street, #819 San Francisco, CA 94109, United States. Tel.: +1 415 447 5467. E-mail address: maylene617{at}yahoo.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 6. Conclusions
 References
 
Background: Clinical trials emphasize mortality and morbidity endpoints.

Aims: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S).

Methods: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis.

Results: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III.

Conclusion: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.

Key Words: Orthopnoea • Resting and paroxysmal nocturnal dyspnoea

Received June 1, 2005; Revised August 26, 2005; Accepted November 1, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 6. Conclusions
 References
 
Prognostic assessment and management strategies are currently driven more by objective measurements of left ventricular remodelling, exercise tolerance testing, and lately, blood levels of brain natriuretic peptide than by signs and symptoms (S&S). Therefore, the day-to-day assessments made by all medical practitioners have been sidelined in recent large-scale clinical trials.

The Valsartan Heart Failure Trial (Val-HeFT) was a trial in 5010 patients designed to assess the effect of adding valsartan, an angiotensin receptor blocker, to standard therapy on outcomes in patients with heart failure [1]. Approximately 25,000 histories and physical examinations were recorded at baseline and during follow-up observations. Our goal was to determine if information gained at the time of these point-of-care evaluations alone provided incremental evidence in determining prognosis and response to therapy. The analysis of individually graded S&S as predictors and therapeutic indicators has little precedence. Until the recent COMET study, which examined individual symptoms as prognostic indicators [2] clinical trials analysed symptoms in the aggregate New York Heart Association (NYHA) classification, and signs were rarely scrutinized as predictive markers [3].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Statistical methods
 4. Results
 5. Discussion
 6. Conclusions
 References
 
The Val-HeFT study was performed at 302 sites in 16 countries in Continental and Central Europe, Scandinavia, United Kingdom, Australia, South Africa, and the United States. 5010 patients with NYHA Class II-IV chronic heart failure, on standard therapy that may have included angiotensin-converting enzyme inhibitors (ACEI), beta blockers, aldosterone inhibitors, diuretics, and digitalis, were randomised into this placebo-controlled, double-blind trial to test the efficacy of the addition of valsartan. The primary endpoints were mortality and combined mortality and morbidity, defined as cardiac arrest with resuscitation, hospitalisation for heart failure or administration of intravenous inotrope or vasodilator without hospitalisation. The mean observation period was 23 months. The entry criteria included echocardiographic evidence of left ventricular remodelling, i.e., left ventricular internal end-diastolic diameter/body surface area (LVIDd/BSA) >2.9 cm/m2, and ejection fraction (EF) <40%. After randomisation patients were seen every 2 weeks for 2 months, then at 4, 6, and 9 months, and then quarterly. At each site, one or more physicians were designated to perform a review of symptoms and a physical examination on the same patients at each visit whenever possible. The investigation conformed to the principles outlined in the Declaration of Helsinki. All patients gave written consent for participation in the trial, which was approved by the institutional review board at each centre [4].


   3. Statistical methods
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
4. Results
 5. Discussion
 6. Conclusions
 References
 
Five symptoms and four signs of heart failure were individually graded (Table 1) by the site investigators and recorded at baseline and at every visit. The graded symptoms were grouped according to severity, and signs were grouped according to increasing number of signs observed. Treatment differences between valsartan and placebo across groups of S&S at baseline were evaluated by chi-square test. To examine the treatment effects on reducing the percentages of patients with more severe S&S groups at endpoint compared with baseline, a multivariate logistic regression analysis for ordered groups was performed on symptoms (absent to severe) and signs (0 to 4). To examine treatment differences over time, each of the S&S grades was normalised between best (0) and worst (1) and summed as an overall score for each patient. An analysis of covariance (ANCOVA) was adapted to analyse treatment differences from changes in the overall score from baseline to months 4, 12, 18, 24, 30, and at endpoint, adjusting for the overall score at baseline, site, and use of ACEI and beta blocker. Results were expressed as least squares means.


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  		Table 1 Signs and symptoms: grading and frequencies at baseline

 
The hazard ratios for heart failure hospitalisation (time to first heart failure hospitalisation) and for mortality were calculated for increasing severity of S&S groups in a univariate Cox model. Due to competing risks of heart failure hospitalisations and death, the analysis of first heart failure hospitalisation was performed including patients with prior deaths as being censored at the time of death. Kaplan-Meier curves for probabilities of avoiding hospitalisation and for surviving were constructed for the symptom groups. Differences among groups were assessed by the log-rank test.

Cox proportional hazard models for predicting mortality were developed to evaluate the contributions of symptoms and of signs to historical and physical (H&P) variables (age, sex, coronary heart disease, diabetes, background medications, study treatment, heart rate, blood pressure, and body mass index [BMI]), and to EF and LVIDd. Four nested models were compared by means of –2log L statistics and the likelihood ratio test was applied.


   4. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
5. Discussion
 6. Conclusions
 References
 
Patients enrolled in Val-HeFT were predominantly white, the average age was 63 years with a male/female distribution of 4/1. Most patients were either in NYHA Class II (62%) or III (36%). Primary aetiology of heart failure was coronary heart disease in 57%; 93% were on ACEI therapy and 35% were on beta blocker therapy. As the entry criteria included only patients with structural left ventricular remodelling, mean±standard deviation for LVIDd/BSA was 3.65±0.5 cm/m2 and for EF was 26.8±7.1%.

The most common symptoms were dyspnoea on effort and fatigue (Table 1). Rest symptoms, i.e., dyspnoea at rest, orthopnoea, and paroxysmal nocturnal dyspnoea, were less frequent but all were used to stratify patients by symptoms into absent, minimal, moderate, moderately severe, and severe. Signs of heart failure, although relatively infrequent, were also used to stratify severity (Table 2).


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  		Table 2 Definitions of groupings of signs and symptoms by severity and relative frequencies at baseline

 
At baseline, the distribution of patients across S&S groups was similar for valsartan and placebo. At endpoint, there were fewer valsartan patients with moderately severe or severe symptoms and more with minimal or no symptoms compared to placebo (P=0.037). Similar improvement in signs of heart failure were also observed for valsartan-treated patients compared to placebo, P=0.011 (Table 3). Treatment effects on overall score for S&S over time are illustrated in Fig. 1. At each time point the decrease in overall score, i.e., an improvement in S&S, was more favourable in the valsartan group, statistically significant at each time point except for month 24.


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  		Table 3 Signs and symptoms and treatment effects

 


Figure 1
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  		Fig. 1 Treatment effects on overall signs and symptoms score over time. Histobars are least squares mean±S.E.M. change from baseline. Changes were adjusted for baseline score, site and use of ACEI and beta blocker. ACEI=angiotensin-converting enzyme inhibitor.

 
From a univariate analysis, Table 4 summarises hazard ratios for first heart failure hospitalisation and mortality comparing the moderate, moderately severe, and severe symptom groups to the absent/minimal group. Similarly, the groups with 1, 2, 3, and 4 positive signs were compared to the group with absent signs. All S&S groups showed significantly increased risk compared to the lowest severity group except for the mortality comparison of patients with one heart failure sign vs. those with no heart failure signs. When moderately symptomatic patients were compared to patients with absent/minimal symptoms, the risk for the first heart failure hospitalisation was 32% greater (P=0.0006), and for mortality was 40% greater (P<0.0001). More pronounced risks were observed for the severely symptomatic patients in whom the hazard ratio for heart failure hospitalisation was 3.85 (95% CI, 2.61 to 5.67), and mortality was 3.79 (95% CI, 2.68 to 5.35). Kaplan-Meier curves (Fig. 2) demonstrated significant differences among symptom groups for the probabilities of not being hospitalised for heart failure for the first time, and for survival, P<0.0001. The separation of curves was most defined for the severe group with the separation for heart failure hospitalisation being clearly evident by 6 months, and for mortality, starting at 6 months.


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  		Table 4 Baseline signs and symptoms and risk of first hospitalisation for heart failure and mortality

 


Figure 2
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  		Fig. 2 a: Kaplan-Meier curves of symptom groups—probability of being event-free from first hospitalisation for heart failure. b: Kaplan-Meier curves of symptom groups—probability of survival.

 
Four nested multivariate Cox models were evaluated for mortality by adding the variables of each model to those of the previous model in the following sequence: 1) variables from the H&P examination; 2) EF and LVIDd; 3) symptoms; and 4) signs. Table 5 shows hazard ratios and chi-square values obtained in the last nested model. H&P characteristics were highly predictive, e.g., age, ischemic etiology, BMI, and use of diuretics. Of the echocardiographic measurements, LVIDd was more predictive than EF, with a ranking of statistical significance second only to age. With H&P and S&S in the analysis, EF was less predictive than symptoms, but more predictive than signs. The incremental predictive values of each model are illustrated in Fig. 3. The increments are expressed as chi-square values, 235, 295, 335, and 354, respectively. The addition of symptoms increases the chi-square value by 40, P<0.0001, and the addition of signs, 19, P<0.001. Therefore, both S&S were independently predictive and added significantly to the predictive model that already included echocardiographic variables with the contribution of symptoms being greater than signs in this heart failure population.


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  		Table 5 Hazard mortality risk of variables from the final multivariate Cox model for baseline history and physical examination, echocardiography, symptoms, and signs

 


Figure 3
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  		Fig. 3 Multivariate Cox models for mortality. Chi-square values for Cox models, including baseline H&P variables, the addition of baseline echocardiography (Echo=LVIDd+EF), symptoms, and lastly, signs. The addition of variables to the Cox models was evaluated by means of –2log L criterion, assuming a {chi}2(df) distribution. For df=2, increments of {chi}2(2)≥5.99 indicate that the variables added were statistically significant. When echo variables were added to the model already including H&P variables, {chi}2 increased by 60, P<0.0001, for symptoms group {chi}2(3)=40, P<0.0001; and for signs group {chi}2(4)=19, P<0.001. * denotes significant increments of {chi}2. Numbers below the curve are the {chi}2 values for each model. H&P=historical and physical; Echo=echocardiographic; LVIDd=left ventricular internal end-diastolic diameter; EF=ejection fraction.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
6. Conclusions
 References
 
Current strategies for managing heart failure are derived from the results of randomised clinical trials and subsequent guidelines. Primary endpoints that test the benefit of a new treatment usually include mortality and combinations of mortality and morbidity. Secondary endpoints that assess prognosis typically include quantitative laboratory variables. With the aim of putting the results from a trial into everyday context, we examined the relationship between S&S and outcome and treatment effects in Val-HeFT.

The study showed that S&S were related directly and independently to mortality and morbid events. In addition, S&S registered improvement by valsartan compared to placebo. At endpoint, a significant treatment effect was seen in the distributions among S&S strata, and over time, in the combined S&S overall score.

S&S were strongly predictive of hospitalisation and mortality. Even moderate compared to absent/minimal symptoms and two compared to no signs significantly increased the risk of hospitalisation for heart failure by 32% and 116%, respectively, and risk of mortality by 40% and 65%. Kaplan-Meier curves of symptom group strata demonstrated clear separation among the minimally, moderately, and severely symptomatic patients for first heart failure hospitalisation and mortality. Comparing hazard risk for mortality for all variables in the final multivariate risk model, the statistical significance of symptoms ranked between echocardiographic LVIDd and EF. Comparing the relative strengths for predicting outcomes, both S&S added significant increments of predictability even after accounting for strongly predictive demographic, historical, and echocardiographic variables.

Symptoms have long been graded in aggregate for convenience and by convention in the NYHA functional classification. As the entire spectrum from asymptomatic to the severely symptomatic is included, the classification is predictive of mortality [5]. Clinical trials recruit patients with heart failure sufficiently severe enough to detect a positive effect with new treatments. Examples of this risk to benefit relationship were four trials that selected only NYHA Class III and IV patients [6-9]. The results were compelling gains in survival and led to early termination of three of the trials.

The distribution of NYHA classes within a trial population can also influence the risk to benefit results. In the CHARM trial, candesartan generally had a less favourable effect on symptoms in the Preserved arm of the study than in the Alternative or Added studies, which was attributed to the different percentages of Class III-IV patients (39% in Preserved, 53% in Alternative and 76% in Added). However, in all three CHARM studies, the most symptomatic patients had the most improvement [10]. In using the NYHA classification to evaluate a given treatment compared to placebo, the change in class between baseline and endpoint has been analysed by measuring the frequencies of patients with improvement, worsening, or no change in NYHA classification. Previously published data from Val-HeFT [4] showed that valsartan induced a statistically significant improvement in NYHA class, as have trials with enalapril [6], metoprolol [11], spironolactone [9] and candesartan [10]. Thus, NYHA classification can detect changes in symptoms despite a low (56%) inter-observer reproducibility [12]. However, the classification probably detects serial change in individual patients less well than individual S&S. This hypothesis has not been tested.

A recently reported investigation from the COMET trial [2] was the first to consider individual symptoms of heart failure as prognostic markers in patients who were evenly distributed between NYHA Class II and III. Breathlessness, fatigue, and angina were self-reported on a 5-point scale, including effort and rest symptoms, and orthopnoea, on a yes-no scale. In a univariate analysis, worse scores for breathlessness, orthopnoea, and fatigue were significantly related to mortality, all-cause hospitalisation, and worsening heart failure. In a multivariate Cox regression analysis, including 16 baseline covariables, only breathlessness remained significantly predictive of mortality, risk ratio=1.14 (1.04-1.26), P=0.01 and all-cause hospitalisation, 1.09 (1.02-1.17), P=0.02, while fatigue remained predictive of worsening heart failure, 1.09 (1.02-1.17), P=0.02.

Signs have rarely been reported as trial endpoints. A study analysing signs as prognostic endpoints from SOLVD treatment data, found that jugular venous distension and third heart sound (S3) in a multivariate analysis were each independently predictive of risk for hospitalisation and death from heart failure [3]. Elevated jugular venous distension was present in 11%, and S3 in 24%, nearly identical to our findings (Table 1). The risk ratios for jugular venous distention+S3 were 1.17 (1.02-1.35) for all cause death, and 1.48 (1.28-1.66) for hospitalisation, less predictive than for our 2 positive signs (Table 4); however, the analyses differed by statistical adjustments and our analysis also included oedema and rales.

In this study, S&S groupings were derived from collective clinical experience, frequencies of S&S (Table 1), and the prognostic value of individual S&S (not shown). Heart failure progresses from symptoms on effort to symptoms at rest. Dyspnoea at rest and paroxysmal nocturnal dyspnoea were the most prognostic and associated with the highest risk ratios for mortality and morbidity. Some dyspnoea on effort (DOE) and fatigue were present in most patients, but were not prognostic until severe (+++/++++). Orthopnoea had the same risk ratio for outcomes as severe DOE and fatigue, but lower than paroxysmal nocturnal dyspnoea and rest dyspnoea. Therefore, orthopnoea appeared to be a transitional symptom between the minimally and severely symptomatic. The resultant symptom groupings reflected the course of heart failure, and the proof of concept was evident in the stepwise progression of symptom grouping with mortality in Table 6.


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  		Table 6 Distribution of patients and mortality percent by baseline NYHA class and symptom groups

 
The study revealed shortcomings of the NYHA classification that included misinterpretation by physicians as suggested by the patients in Class I, II and III who reported absent symptoms, and the ambiguity of classifying symptoms by either slight or marked limitation with physical activity as illustrated by the moderately symptomatic group being divided between Class II and III. The classification's emphasis on effort symptoms relies on physician interpretation and extrapolation especially in sedentary and elderly patients. The notable finding was that in all patients with some DOE and fatigue, the appearance of one rest symptom, usually orthopnoea, was associated with higher mortality (20.5%) compared to that of Class II (15%), but lower than that of Class III (26%). In this population consisting of 62% Class II subjects, the assessment of individual effort and rest symptoms identified a majority group (57%) of moderately symptomatic patients who were deteriorating more rapidly than had been appreciated.

The aims of this investigation were achieved. Information routinely obtained between physicians and patients in heart failure with structural disease was highly prognostic of outcomes. Stratification by individual S&S was independently and incrementally predictive of mortality and heart failure hospitalisation even after adjustment for demographic, historic, and echocardiographic variables. In a risk model that included all of the variables, symptoms were more prognostic of mortality than echocardiographic EF. An unexpected finding was that by focusing on individual symptoms, especially rest symptoms, 57% of the patients were stratified as moderately symptomatic with a mortality rate that fell between those in NYHA Class II and III patients.

Our grouping of S&S into strata is an aggregate term; however, unlike NYHA class, the groupings consist of grades and avoid any physician subjectivity and bias. The groupings were a post hoc convenience for analysis and were not used as tools of assessment as in the COMET study and with NYHA class. S&S remain the most basic and common clinical information solicited directly from patients, and the study delineated their strengths at predicting hospitalisation and death.

The potential significance of the study is the recognition that moderately symptomatic patients should be managed with greater anticipation and that the earlier detection of patients slipping into a riskier phase warrants more intensive treatment.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 6. Conclusions
References
 
From Val-HeFT data, S&S graded individually and grouped according to severity were highly predictive of heart failure hospitalisation and mortality, and were significantly improved by treatment with valsartan. Symptom strata graded by individual symptoms identified a group of patients between NYHA Class II and III with an intermediate mortality rate. Quantitative grading of individual signs and symptoms provides point-of-care markers of therapy and of outcome—without additional time or cost.


   Acknowledgements
 
The authors acknowledge valuable general assistance from Nora Aknay and a critical review of the manuscript from Allen Hester.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Statistical methods
 4. Results
 5. Discussion
 6. Conclusions
 References
 

  1. Cohn J.N., Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med (2001) 345:1667–1675.[Abstract/Free Full Text]
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  3. Drazner M.H., Rame J.E., Stevenson L.W., Dries D.L. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. N Engl J Med (2001) 345:574–581.[Abstract/Free Full Text]
  4. Cohn J.N., Tognoni G., Glazer R.D., Spormann D. Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure. J Card Fail (1999) 5:155–160.[CrossRef][Web of Science][Medline]
  5. Cowburn P.J., Cleland J.G., Coats A.J.S., Komajda M. Risk stratification in chronic heart failure. Eur Heart J (1998) 19:696–710.[Free Full Text]
  6. THE CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med (1987) 31:1429–1435.
  7. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  8. Packer M., Coats A.J., Fowler M.B., Katus H.A., Krum H., Mohacsi P. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  9. Pitt B., Zannad F., Remme W.J., Cody R., Castaigne A., Alfonso Perez. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study (RALES) Investigators. N Engl J Med (1999) 341:709–717.[Abstract/Free Full Text]
  10. O'Meara E., Solomon S., McMurray J., Pfeffer M., Yusuf S., Michelson E. Effect of candesartan on New York Heart Association functional class. Results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J (2004) 25:1920–1926.[Abstract/Free Full Text]
  11. Waagstein F., Bristow M.R., Swedberg K., Camerini F., Fowler M.B., Silver M.A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet (1993) 342:1441–1446.[CrossRef][Web of Science][Medline]
  12. Goldman L., Hashimoto B., Cook E.F., Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation (1981) 64:1227–1234.[Abstract/Free Full Text]

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