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European Journal of Heart Failure 2002 4(3):297-304; doi:10.1016/S1388-9842(01)00202-1
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© 2002 European Society of Cardiology

Dissociation between hemodynamic changes and symptom improvement in patients with advanced congestive heart failure

Monica R. Shaha,*, Vic Hasselblada, Sandra S. Stinnetta, Judith M. Kramera, Steven Grossmanb, Mihai Gheorghiadec, Kirkwood F. Adams, Jr.d, Karl Swedberge, Robert M. Califfa and Christopher M. O'Connora

a Duke Clinical Research Institute P.O. Box 17969, Durham, NC 27715, USA
b Glaxo Wellcome, Inc. P.O. Box 13398, Research Triangle Park, NC 27709, USA
c Department of Cardiology Northwestern University Medical Center, 250 East Superior Street #524, Chicago, IL 60611, USA
d Department of Medicine University of North Carolina at Chapel Hill, 333 Burnett Womack, Chapel Hill, NC 27599, USA
e Department of Cardiology and Thoracic Surgery, Ostra University Sahlgrenska Hospital, SE-416 85 Göteborg, Sweden

* Corresponding author. Tel.: +1-919-668-8776; fax: +1-919-668-7057. E-mail address: shah0013{at}mc.duke.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Background: Changes in hemodynamic measures often serve as surrogate end points in efficacy trials for advanced heart failure, although there are few objective data to support this practice.

Aims: We compared changes in hemodynamic variables vs. changes in symptoms of decompensated heart failure in patients enrolled in a randomized trial.

Methods: We studied 201 patients with New York Heart Association (NYHA) class IIIb or IV heart failure and ejection fraction ≤25% for ≥3 months. Patients underwent continuous monitoring by pulmonary-artery catheter during inpatient drug administration. We assessed the relations of changes in hemodynamic variables (baseline minus final measure) to changes at 2 weeks in congestive heart failure symptoms, NYHA class, Yale Dyspnea-Fatigue Index (YDFI) score, and distance achieved in a 6-min walk.

Results: No hemodynamic measure significantly predicted either symptom score or NYHA classification. Mean pulmonary artery pressure and pulmonary capillary wedge pressure did show some relation to change in YDFI score in univariable, but not multivariable, analysis. No hemodynamic measure correlated significantly with changes in distance achieved in the 6-min walk test.

Conclusion: We noted no significant association between improved hemodynamics and improved symptoms in patients with advanced heart failure. Other measures may need to be evaluated as surrogate end points in future trials.

Key Words: Hemodynamic measures • Surrogate end points • Advanced heart failure

Received January 30, 2001; Revised June 18, 2001; Accepted August 14, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
Therapies for congestive heart failure may be assessed by their ability to improve symptoms and prolong life. Although a number of studies have raised concerns about the validity of hemodynamic measures as surrogate end points, the decision to pursue definitive, outcomes-based trials in heart failure often remains based on preliminary data from Phase II studies that demonstrate the impact of an agent on hemodynamics. This approach reflects the assumption that decompensated heart failure is primarily a hemodynamic disorder and that improved hemodynamic measures can predict improved symptoms in patients with this disease. This may seem intuitively correct, but few objective data exist to show how changes in hemodynamic measures relate to improvements in symptoms.

The present study was undertaken to investigate the relationship between various measures of dyspnea and changes in hemodynamic variables on pulmonary-artery catheterization. The goal of this analysis was to identify which hemodynamic measure(s) best predicts improvement in patient-reported heart-failure symptoms and physician-determined New York Heart Association (NYHA) class. We also assessed the relations between improvement in hemodynamic variables and changes in the distance traversed on the 6-min walk test.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
2.1. Study procedures
The Flolan International Randomized Survival Trial (FIRST) was a randomized, placebo-controlled trial that evaluated the effect of epoprostenol on morbidity and mortality in patients with advanced heart failure [1]. The trial was stopped early due to excess mortality in the epoprostenol group. The FIRST population consisted of 471 patients with NYHA class IIIb or IV heart failure and an ejection fraction ≤25% for at least 3 months. Patients were required to be receiving loop diuretics, digitalis glycosides, and angiotensin-converting enzyme (ACE) inhibitors.

After providing informed consent, patients who met the clinical criteria underwent a battery of non-invasive tests, including evaluation of heart failure symptoms, functional impairment, determination of NYHA class, and a 6-min walk test. We evaluated heart-failure symptoms with a symptom score that included assessments of dyspnea, orthopnea, and fatigue. Each symptom was scored as 0 (absent) or 1 (present); thus the composite symptom score ranged from 0 to 3. The Yale Dyspnea-Fatigue Index (YDFI) was used to evaluate the level of functional impairment and the magnitude and pace of tasks that cause dyspnea and fatigue [2]. For functional impairment, scores range from 0 (very severe) to 4 (none); for the magnitude of tasks that cause dyspnea and fatigue, 0 (symptomatic at rest) to 4 (symptomatic with extraordinary activity); and for the pace of tasks that cause dyspnea and fatigue, 0 (symptomatic at rest) to 4 (all activities performed at normal pace). Thus the composite YDFI score can range from 0 (severely limited) to 12 (no limitation).

Physicians determined the NYHA class using standard definitions [3]. The 6-min walk test was conducted as described by Guyatt et al. [4]. A 65-foot course was marked in a corridor and a chair was placed at each end. Patients were instructed to cover as much ground as possible in the allotted period of 6 min. Patients could stop and rest during the test but were instructed to resume walking as soon as they felt able to do so. After 6 min had elapsed, patients were instructed to stop walking, and the total distance walked was measured to the nearest meter or foot.

After completion of the non-invasive tests, medications were held for 8 h. Patients then underwent pulmonary-artery catheterization to measure hemodynamic variables (the ‘baseline’ measurement). To be eligible for the trial, patients were required to have a cardiac index ≤2.2 l min–1 m–2 and a pulmonary capillary wedge pressure (PCWP) ≥15 mmHg. Patients who met hemodynamic criteria were then randomly assigned to receive epoprostenol or placebo, with other standard therapy.

2.2. Medical regimens
Patients assigned to epoprostenol underwent a 24-h dose–titration phase that included continuous central hemodynamic monitoring. An epoprostenol infusion of 2 ng kg–1 min–1 was started and maintained for 15 min before any additional physiological measurements were taken. The epoprostenol dose was then increased by an increment of 2 ng kg–1 min–1 every 15 min until dose-limiting adverse effects developed, such as hypotension, tachycardia, or significant symptoms. Before discharge, patients assigned to epoprostenol had a permanent, indwelling central venous catheter implanted for the infusion, and each received extensive training to ensure that the infusion could be maintained at home.

Investigators titrated vasodilators to doses found to prolong survival in previous randomized trials. Vasodilator therapy could include ACE inhibitors, or hydralazine and nitrates. Diuretic doses were also optimized in both groups.

2.3. Hemodynamic data collection
Clinical and dose–titration data were recorded on standard forms for all patients. Heart rate, mean arterial pressure, pulmonary-artery systolic pressure (PASP), pulmonary-artery diastolic pressure (PADP), mean pulmonary-artery pressure (PAP), right atrial pressure (RAP), cardiac index and output, and PCWP were recorded after every 2 ng kg–1 min–1 increase in the dose of epoprostenol during the 24-h drug titration phase. The ‘final’ hemodynamic measurements used in this analysis were the last recorded during this period.

2.4. Follow-up
Patients returned for clinical assessment 2 weeks after randomization. At this visit, assessments for heart-failure symptoms, NYHA class, YDFI score, and 6-min walk test were repeated. The incidence of death or readmission also was captured at 1 year.

2.5. Statistical methods
We included patients for analysis if they had been randomized to epoprostenol and had baseline and final hemodynamic data available. Descriptive statistics were produced for hemodynamic, clinical, and demographic variables. Differences in continuous variables were assessed with the t-test. Differences in categorical variables and proportions were assessed using the Pearson chi-square test.

‘Change’ was defined for all variables as the baseline minus the final measure of the variable. Changes in symptom score and NYHA class were dichotomized into categorical variables because of the small range of these scales: a decrease of ≥1 point or class vs. a decrease of <1 point or class. We first used univariable logistic regression to assess the relations of changes in hemodynamic measures to changes in symptom score and in NYHA class. All hemodynamic variables then were placed in a multivariable logistic regression model that included age, sex, ejection fraction, and etiology of heart failure. Variables were selected in a stepwise fashion.

Changes in YDFI score and the 6-min walk test were assessed as continuous variables. First, we performed univariable linear regression analysis of the change in each hemodynamic variable vs. the change in YDFI score and the change in 6-min walk distance. This was followed by a multivariable linear regression analysis that included all hemodynamic variables and age, sex, ejection fraction, and etiology of heart failure. The analyses were performed using the methods described above.

Finally, we compared the rate of death or readmission at 1 year by improvement in symptom score, NYHA class, YDFI score, and distance achieved in the 6-min walk test. The investigation conforms with the principles outlined in the Declaration of Helsinki.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Acknowledgments
 References
 
3.1. Baseline characteristics
In all, 235 patients were randomized to receive epoprostenol. We deleted 34 patients from the analysis because of missing hemodynamic values. As shown in Table 1, the remaining cohort of 201 patients had advanced heart failure. Their median ejection fraction was 17%. In addition, 93% of patients had a symptom score of 3, and 59% were identified as having NYHA class IV. The median YDFI score at baseline was 2, and the median distance covered on the 6-min walk was 186 m. Baseline filling pressures were markedly elevated in this group with a median RAP of 10 mmHg, a median PAP of 37 mmHg, and a median PCWP of 24 mmHg (Table 2). The cardiac index was also compromised at baseline, with a median value of 1.8 l min–1 m–2.


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  		Table 1 Baseline characteristics

 


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  		Table 2 Baseline and final hemodynamic measures

 
3.2. Relations of changes in hemodynamics to improvement in symptoms
In univariable analysis, there was no hemodynamic parameter that was significantly associated with an improved symptom score at 2 weeks (Table 3). Changes in PCWP and PAP, the hemodynamic variables hypothesized to be the most important determinants of an improved symptom score, did not show even a trend towards significance. The median decline in PCWP in the patients whose symptom score improved was 4 mmHg compared with 5 mmHg in those whose score did not improve. The corresponding decreases in PAP were 6 and 5.5 mmHg, respectively.


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  		Table 3 Univariable relations of change in hemodynamic measures to change in symptom score

 
Similar results were seen when assessing changes in hemodynamic parameters relative to NYHA class (Table 4). Again, there were no trends towards significance for any of the hemodynamic measures. The median reduction in PCWP was identical (4 mmHg) whether the NYHA class had improved or not. The median increase in the cardiac index for patients with an improved NYHA class was 0.91 l min–1 m–2 vs. 0.78 l min–1 m–2 for patients with no improvement.


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  		Table 4 Univariable relations of change in hemodynamic measures to change in NYHA class

 
Changes in the mean PAP, however, correlated weakly but significantly with improvement in YDFI score in univariable analysis (correlation coefficient, 0.16; 95% CI, 0.01–0.30; P=0.05) (Table 5). There also was a non-significant trend toward improvement in YDFI score with changes in PCWP (correlation coefficient, 0.11; 95% CI, –0.04 to 0.28; P=0.14). No other hemodynamic changes correlated significantly with improvement in YDFI score. When PAP was placed in a multivariable model, however, that also included age, sex, etiology of heart failure, and ejection fraction, it was no longer significant.


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  		Table 5 Univariable relations of change in hemodynamic measures to change in Yale Dyspnea-Fatigue Index score

 
Reductions in RAP, PAP, and PCWP, and increases in the cardiac index, did not correlate significantly with greater distances achieved in the 6-min walk test (Table 6).


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  		Table 6 Univariable relations of change in hemodynamic measures to change in distance achieved in a 6-min walk

 
3.3. Improvement in symptoms in relation to outcomes
Improvements in symptom score and NYHA class at 2 weeks were not associated with fewer adverse outcomes at 1 year (Fig. 1). The median reduction in YDFI score was greater in patients who survived without readmission, but this difference was not statistically significant (Fig. 2). The median increase in the 6-min walk distance at 2 weeks was actually greater in patients who died or were readmitted; but again, this difference was not statistically significant (Fig. 3).


Figure 1
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  		Fig. 1 Incidence of death or readmission at 1 year by improvement in symptom score (left) and NYHA class (right) at 2 weeks. P=0.22 for symptom score; P=0.13 for NYHA class, patients with vs. without improvement.

 


Figure 2
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  		Fig. 2 Improvement in Yale Dyspnea-Fatigue Index score at 2 weeks among patients who died or were readmitted within 1 year vs. those who survived without readmission. P=0.24, survivors vs. non-survivors.

 


Figure 3
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  		Fig. 3 Improvement in distance achieved on a 6-min walk test at 2 weeks among patients who died or were readmitted within 1 year vs. those who survived without readmission. P=0.24, survivors vs. non-survivors.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Acknowledgments
 References
 
Reductions in filling pressures and increases in cardiac contractility are often assumed to correlate with improvements in symptoms. Thus many physicians use increases in the cardiac output and index, and reductions in the RAP, PCWP, and PAP, to guide treatment in patients with advanced heart failure and to show the efficacy of new therapies for this population. Our results, however, show that improvements in hemodynamic measures may not correspond with sustained improvements in symptoms as evaluated by symptom score, Yale Dyspnea-Fatigue Index, and NYHA class. Improvement in hemodynamic variables likewise did not correspond with better performance on a 6-min walk test. The only hemodynamic measure that was even minimally associated with improved symptoms at 2 weeks was the mean PAP in conjunction with the YDFI score, but this result had a very small correlation coefficient with wide confidence intervals. This finding also was not reproducible with the other assessments of heart-failure symptoms.

4.1. Hemodynamics as surrogate end points for quality of life
The results of this analysis may be interpreted in several ways. First, these observations suggest that hemodynamic variables are not adequate surrogate end points for congestive symptoms, an important aspect of quality of life for patients with heart failure. Although improvements in hemodynamic variables may show the physiological effects of a therapy, this may not necessarily translate into a favorable effect on symptoms over a longer period. Measures other than hemodynamic function are needed to test whether a drug will make patients feel better or increase their ability to deal with physically demanding activities of daily living.

Furthermore, improvement in hemodynamic function may be only one mechanism for the improvement in dyspneic symptoms; other physiological mechanisms may need to be incorporated to identify a correlation. Other, non-cardiac factors that may be important in producing the sensation of breathlessness include mechanical dysfunction of the respiratory muscles, impaired perceptions of changes in airflow resistance, increased inspiratory neuromuscular drive, and skeletal muscle deconditioning [5–7].

In this analysis, the median value for the decline in PCWP was 4 mmHg in the group that had improved symptoms. This raises a question about whether a minimum threshold of change in hemodynamic parameters is needed before significant improvement in symptoms can even be appreciated. Even though using greater increments of change in hemodynamic parameters in the present analysis increases the odds ratio of improved symptoms, as measured by symptom score, NYHA class and YDFI score, it also widens the confidence interval around this ratio. Thus, the significance of the relations between changes in hemodynamics and symptoms is not increased.

It may be that an analysis of a large group of patients who received drugs that produced more dramatic hemodynamic changes would demonstrate stronger relations between hemodynamic parameters and congestive symptoms.

Another reason that we found no strong correlation between hemodynamics and improved exertional symptoms may have been that quality-of-life variables were assessed at 2 weeks after randomization rather than at discharge. Hemodynamic changes may not have been sustained over this period for several reasons, including irregular patient compliance with medications, dietary indiscretions, and tolerance to epoprostenol. A counterpoint to this argument, however, is that the FIRST pilot study showed sustained hemodynamic values at 12 weeks with continuous drug administration via infusion pump [8].

Other studies have shown that improvements in hemodynamics do not always correlate with quality-of-life outcomes. For example, comparison of two recently completed Phase III trials of an endothelin receptor antagonist demonstrates that marked improvements in hemodynamic parameters in one study were not accompanied by significant improvement in congestive symptoms in the parallel trial [9,10]. In addition, a recent trial of milrinone showed no favorable effect of the drug on readmissions at 60 days, an important quality-of-life outcome [11]. There were also no significant differences between the drug and placebo groups in the Heart Failure Score, Visual Analog Scale, and the Subjective Health Status Questionnaire [11], the three assessments of heart-failure symptoms used in this trial. Previous controlled trials with vasodilators such as minoxidil, flosequinan, and calcium channel blockers have also demonstrated discordance between hemodynamic improvement and symptoms or exercise tolerance [12–16]. In addition, Phase II and III studies of positive inotropic agents have produced conflicting results for quality-of-life outcomes. There was no benefit on readmissions in earlier trials of vesnarinone or milrinone, despite hemodynamic improvements [17,18]. Although vesnarinone did have a positive short-term effect on the Minnesota Living with Heart Failure Questionnaire score, this effect was not significant at 26 weeks [17]. Finally, an analysis by Wilson et al. showed no relationship between the PCWP at peak exercise and the YDFI and the Borg Dyspnea Scale scores [19].

4.2. Limitations of quality-of-life measures
The other interpretation of the dissociation between hemodynamics and symptoms is that the quality-of-life instruments used in this study did not adequately capture all the data necessary to detect changes in heart-failure symptoms. The instruments may have lacked sufficient reliability (the ability to consistently discriminate between subjects) and adequate responsiveness (the ability to detect changes in response to interventions) [20]. Thus, although patients may have improved symptomatically with decreases in filling pressures and increases in cardiac contractility, the changes may not have been identified due to the measurement properties of the instruments. That improvements in symptom score, YDFI, and NYHA class did not translate into a lower rate of death or readmission may indicate that the instruments themselves were insensitive to changes in symptoms [21]. Alternatively, it may suggest that improvement in symptoms may not correlate with prevention of discrete events.

These points underscore the importance of prospective identification of quality-of-life end points in heart-failure clinical trials and evaluation with the same rigor currently applied to end points such as death, readmission, and myocardial infarction. In trials of advanced heart failure, it may be important to give health-related quality-of-life assessments the same priority as death, because one of the main goals in this population is the palliation of incapacitating symptoms.

4.3. Future directions for heart-failure clinical trials
This analysis shows a dissociation between improvements in hemodynamics and symptom status, as measured by three quality-of-life instruments and an exercise test. The inconsistencies between hemodynamic changes, symptoms, and exercise capacity illustrate some of the problems in the selection of appropriate outcomes for heart-failure trials. This analysis shows the challenges of viewing the syndrome of congestive heart failure as primarily a hemodynamic disorder and the limitations of using changes in hemodynamic variables alone as end points in Phase II trials [22]. These findings likewise show the difficulty in using hemodynamic measures alone to guide medical therapy designed to improve symptoms, the primary short-term goal in the care of patients with advanced heart failure.

The dissociation between hemodynamics and other pathophysiologic concepts in heart failure has emerged over the last decade based on the experience from clinical trials [23,24]. The lack of correlation between improvements in hemodynamics and changes in quality-of-life measures emphasizes the importance of using various types of end points for Phase II trials of new heart-failure therapies. To evaluate the full range of effects of a treatment, objective assessments (such as hemodynamics, exercise capacity, and biomarkers) should be used with quality-of-life instruments. This approach yields a comprehensive assessment of drug effects. In addition, the dissociation between hemodynamics and symptoms emphasizes the problems in using surrogate end points as definitive evidence of the efficacy of drugs. It also underscores the importance of conducting large outcome trials before drawing conclusions about the safety and efficacy of drugs for heart failure.

The results of this study have several clinical implications. First, investigators should not assume that improvements in hemodynamics and cardiac function correspond to improvements in heart-failure symptoms. These observations emphasize the fact that the symptoms of heart failure cannot be fully explained by hemodynamic derangements and that factors such as obesity, impaired endothelium-dependent vasodilation, and skeletal-muscle deconditioning and atrophy also may play an important role [25,26]. These other factors also may need modification to improve symptoms. In addition, better quality-of-life instruments may be needed to detect the effects of drugs on major symptoms of heart failure.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Acknowledgments
 References
 
Amelioration of symptoms and improvement in life expectancy are the dual goals of treatment in patients with heart failure. Drugs that improve quality of life over survival may have a place in the armamentarium for patients with advanced disease. For effective evaluation of these drugs in Phase II studies, we need more refined instruments to measure symptom end points and better methods for their validation.

The relationship between hemodynamics and symptoms may not be as direct as had been assumed, and hemodynamic variables may not be adequate surrogate end points to evaluate the effect of drugs on quality of life. Further analyses of databases that include information about hemodynamics and congestive symptoms should be pursued in order to learn more about the relations between these parameters. Such data would help clinicians better understand how to select and titrate therapy for patients with decompensated heart failure. This information would also allow clinical investigators to design more rigorous Phase II trials of new treatments for advanced heart failure.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
References
 
The FIRST trial was funded by a grant from Glaxo Wellcome, Inc., Research Triangle Park, North Carolina.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Acknowledgments
 References
 

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R. Fincke, J. S. Hochman, A. M. Lowe, V. Menon, J. N. Slater, J. G. Webb, T. H. LeJemtel, G. Cotter, and SHOCK Investigators
Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: A report from the SHOCK trial registry
J. Am. Coll. Cardiol., July 21, 2004; 44(2): 340 - 348.
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