Author + information
- J. Malcolm O. Arnold, MD⁎ ( and )
- Liane Porepa, MD
- ↵⁎Reprint requests and correspondence:
Dr. J. Malcolm O. Arnold, Division of Cardiology, University of Western Ontario, Room C6-124D, University Hospital, LHSC, 339 Windermere Road, London, Ontario N6A 5A5, Canada
Linus Pauling first popularized this quest in his famous health book entitled How to Live Longer and Feel Better (1). Although not a physician nor a heart failure specialist, he identified 2 important endpoints in acute decompensated heart failure (ADHF): reduce mortality (live longer) and relieve dyspnea (feel better). Efforts to reduce mortality have driven the design and primary endpoints of many clinical trials, whereas symptom improvement is often a secondary or lower endpoint (2). However, dyspnea relief remains an important goal in ADHF (3,4).
ADHF is an important clinical syndrome affecting a growing and aging population. It accounts for approximately 100,000 hospitalizations/year in Canada and 1 million hospitalizations/year in the United States. In-hospital mortality is high as are post-discharge readmission and mortality rates. Patients in the ADHERE (Acute Decompensated Heart Failure National Registry) had a 4% in-hospital mortality, with a median length of stay of 4.3 days (5). In the EuroHeart Failure survey I, 16.9% of patients died on the index admission, 24.2% were readmitted within 12 weeks of discharge, and 13% died between admission and 12 weeks of follow-up (6). In the EuroHeart Failure survey II, in-hospital mortality was 8.1% in de novo heart failure, 9.1% for those in pulmonary edema, and 30.6% in cardiogenic shock (7). Randomized control trials inform the strong evidence base for the treatment of most cardiovascular conditions, but ADHF stands out because its management has previously been largely based on clinical experience and pathophysiological assumptions rather than randomized control data. Although our treatment of chronic heart failure has evolved substantially, clinical trial results in ADHF have been disappointing. Current medical guidelines for ADHF are based largely on consensus interventions that provide symptom relief (2).
Why has it been challenging to demonstrate a mortality benefit in ADHF therapies?
The demographic and clinical heterogeneity of the ADHF syndromes makes systematic evaluation challenging. None of the major ADHF trials in the last decade have achieved a mortality benefit, though improvements have been shown in other clinical outcomes such as hemodynamic parameters, shorter hospital stay, and dyspnea. Gaps in understanding the underlying pathophysiology of ADHF make it difficult to impact mortality with single therapeutic agents over a short time frame. Disconnects exist between the focus on acute symptoms during ADHF and the transition to chronic heart failure care, though programs exist to try and bridge that continuum of care.
Do we need to standardize our assessment of symptom relief in ADHF?
In light of the aforementioned challenges, a pragmatic approach would be to choose alternative clinically meaningful endpoints to assess interventions in ADHF. Is it sufficient to have a goal to make patients feel better? Dyspnea would appear to be the most relevant and important “feel better” outcome in ADHF and has recently been emphasized as a treatment priority (4,8). Dyspnea has been an endpoint (either coprimary or secondary) in the majority of ADHF trials over the last decade, using tools such the visual analogue (VA) or Likert scales. However, dyspnea is subjective, dynamic, difficult to quantify, and not amenable to blinding. Concerns over the lack of standardization of dyspnea as an important clinical endpoint has led to a consensus statement that “a standardized method with which to assess dyspnea is required for clinical trials of acute heart failure syndromes in order to ensure uniform collection of data on a key endpoint” (3). The criteria specified in the document are for an instrument that is accurate, reliable, and reproducible between and among observers.
In this issue of the Journal, Ezekowitz et al. (9) have responded to this “call to action.” They report the results of a substudy of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) clinical trial that enrolled 421 patients admitted with ADHF in whom peak expiratory flow rate (PEFR) was measured at baseline and 1, 6, and 24 h after randomization to nesiritide or placebo. The Dyspnea Index (DI) by Likert scale was also collected at 6 and 24 h. The authors hypothesized that PEFR would improve with ADHF treatment over the first 24 h and would correlate with the DI change and treatment effect. PEFR significantly increased at each time interval, and the change was modestly correlated to the DI. The concept of using pulmonary function testing to measure response to congestive heart failure treatment is not new. A 1983 study showed improved pulmonary function using serial measures of forced expiratory volume in 1 s (FEV1) and forced vital capacity in 28 patients admitted with heart failure (10). A previous review paper suggested serial measurement of lung function may be useful in tracking pulmonary expression of disease or response to therapy (11). An important component of the paper by Ezekowitz et al. (9) was correlating the pulmonary function test measure of PEFR with other previously validated measures of dyspnea (Likert and VA scale). Furthermore, linking dyspnea as a quantitative outcome to other important clinical endpoints, such as the 30-day mortality and heart failure re-hospitalization rates, was consistent with suggested developments of dyspnea measurements (4). PEFR, an effort-dependent measure of airflow limitation, was chosen for its portability and strong evidence base in the respiratory literature (12,13). In the cardiac literature, its utility as a diagnostic tool to differentiate cardiac versus respiratory dyspnea has been suggested in some smaller studies (14–16).
However, a number of questions arise
Can we assume that the test characteristics, as validated in the pulmonary population, are applicable to the heart failure population? Should we question whether a measurement of airflow limitation, determined mainly by large airway flow, is an oversimplification? The mechanism of dyspnea in ADHF is multifactorial and may be more complex than would be suggested by this assessment tool. Nonetheless, in the absence of complete physiological equanimity, a correlation was observed, and the potential utility of PEFR as an objective reflection of improvement in dyspnea was tested. Although its use as a diagnostic tool for ADHF has not been widely used, PEFR may have potential as a quantitative assessment tool for early response to treatment as demonstrated in this study.
Are PEFR measurements ready for routine clinical use?
For PEFR to be validated as an assessment tool in the ADHF population, more detailed information is needed. How long was the time from first symptoms or first acute medical intervention to first PEFR? Who specifically performed the PEFR tests (physician, nurse, allied health)? Was the patient allowed just 1 first attempt or multiple attempts to determine how reproducible the measurements were at each time interval? Was the patient in a standard supine or upright position? The authors also concluded that PEFR improved after nesiritide compared with placebo. However, the absolute difference of 7 liters in PEFR between nesiritide and placebo, although numerically statistically significant, is below the minimal clinically important difference of 18 l/min in asthma and 10 to 32 l/min in chronic obstructive pulmonary disease. Caution is also needed given the overall ASCEND-HF trial did not show significant improvement in dyspnea between nesiritide and placebo according to pre-specified statistical parameters. Nesiritide also has a direct bronchodilator effect, which begs the question as to whether this result reflects a known property of nesiritide (17).
There are alternative objective measures of dyspnea that could also be incorporated into future studies. The provocative dyspnea assessment scale is a threshold test that is felt to be more objective and sensitive to changes in dyspnea compared with the Likert or VA scale (3). In patients with milder symptoms, 47% had worsening dyspnea when placed in the supine position versus sitting upright in the URGENT-Dyspnoea study (Ularitide Global Evaluation in Acute Decompensated Heart Failure) (8). Other pulmonary function test components including FEV1, vital capacity, or forced expiratory flow at 50%, could also be compared as objective outcome measures in future studies (18,19). It would be important to correlate PEFR measurements with each of these measures, including additional clinical surrogates or hemodynamic parameters.
Should we pursue dyspnea as a standardized endpoint?
This is an important question to answer as it places the impact of this research in perspective. Some may argue that we already have interventions that provide dyspnea relief in ADHF, and it is more important to improve “hard outcomes.” The latter will require better pathophysiological understanding of ADHF and the development of new interventions. For patients, dyspnea remains a very important goal of therapy. A more objective measure of dyspnea improvement, such as PEFR, may facilitate assessment of current and new drugs in the critical first hours and days, and may help to identify drugs that have potential to improve some basic abnormalities in ADHF that might lead to improved acute outcomes. This paper is the largest study using PEFR as an objective measurement of dyspnea in ADHF that both reflects clinical improvement and correlates with the previously used dyspnea index. Although many details will need to be further elucidated, it serves as an excellent springboard for further study.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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- Why has it been challenging to demonstrate a mortality benefit in ADHF therapies?
- Do we need to standardize our assessment of symptom relief in ADHF?
- However, a number of questions arise
- Are PEFR measurements ready for routine clinical use?
- Should we pursue dyspnea as a standardized endpoint?