American Heart Journal
Volume 147, Issue 2 , Pages 190-192, February 2004

Training trials in heart failure: Time to exercise restraint?

  • David J Whellan, MD, MHS

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • Corresponding Author InformationReprint requests: David J. Whellan, MD, MHS, Duke Clinical Research Institute, PO Box 17969, Room 7442, North Pavilion, Durham, NC 27715, USA.
    • ,
  • Christopher M O'Connor, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Ileana Pina, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA

Article Outline

 

Heart failure is the only cardiovascular disorder growing in prevalence in the United States. Currently, >4.9 million Americans live with the disease, and 550,000 new cases are diagnosed each year.1 Many patients with heart failure have a poor quality of life, much of which is attributable to reduced exercise tolerance.2 Although pharmacologic treatment is the cornerstone of the treatment of heart failure patients, recent attempts to advance the therapy for heart failure patients beyond ACE inhibitors, β-blockers, digoxin, and eplerenone have not been successful.3, 4, 5 In response to these setbacks, the medical community's attention has turned to other strategies, including devices and lifestyle strategies such as exercise training.

Clinicians have been reluctant to recommend exercise to patients with heart failure for a number of years. The poor relationship between resting indices of ventricular function (eg, ejection fraction) and indices of exercise capacity (eg, oxygen uptake [Vo2]) is widely known. In addition, early studies and education perpetuated the idea that exercise could exacerbate symptoms and actually be deleterious to patients with heart failure.6, 7, 8 Cardiac rehabilitation programs in the 1970s excluded patients with impaired ventricular function due to concerns of risks and worsening symptoms. One study by Jugdutt et al reported worsening of left ventricular dilatation postinfarction.9 This single study has not been reproduced by others, but has nonetheless left a negative impression among clinicians and influenced their reluctance to recommend exercise for their patients.

Over the past 12 years, investigators have conducted 14 randomized, controlled clinical trials.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 These 14 studies were prospective randomized designs involving patients with class II or III ischemic and nonischemic heart failure. The training involved bicycle ergometers or walking. The exercise intensity equivalent had a range of 50% to 70% peak Vo2. Participants exercised 3 to 7 times per week in a supervised setting or in the home. These studies have consistently shown improvements in physiologic measurements such as peak Vo2, autonomic function, plasma norepinephrine levels, 6-minute walk test, and quality-of-life parameters, though these studies may have preselected patients who were able to perform these activities and whose severity of heart failure allowed them to do so. Other factors may have led to selection of patients who could attend sessions regularly and were not hampered by frequent admissions for heart failure exacerbations. None of the studies enrolled enough patients to properly evaluate the impact of exercise training on mortality or hospitalization.

The study by Corvera-Tindel et al in this issue of the Journal sought to determine the effect of low-intensity exercise in the home setting on functional status and exercise parameters.24 This is the largest home-based study involving walking as a modality for exercise, and it has the advantage of being particularly applicable to the elderly, since home-based walking involves no special equipment. The study was relatively short, lasting only 12 weeks, and involved an intensive home nursing component (weekly for the first 6 weeks and biweekly the second 6 weeks). Even with this level of follow-up, adherence was only 65% in the training group at the end of the study; the most significant dropout occurred in the first 6 weeks, when follow-up was the most intensive. It would be interesting to know why participants discontinued this low-intensity training program.

Although the primary end point was positive, in many respects this was a neutral study. The results showed no significant difference between the intervention and control groups in exercise capacity measured by peak Vo2. There was a small but not significant increase in ventilatory threshold, and a trend towards increased exercise duration. For those patients completing the study (n = 62), there was improvement in the 6-minute walking test only after adjustment for ejection fraction. Global ratings of symptoms were also improved, but there was no difference in the more extensive and detailed instruments.

The lack of improvement in the majority of end points may reflect the dose of exercise administered. The exercise prescription of 40% maximal heart rate during the first 6 weeks and 65% the second 6 weeks is significantly less than the intensity used in most previous training studies, and may have been inadequate to achieve a training effect. The 14 randomized controlled trials show that exercise training at 60% to 70% heart rate reserve 5 to 7 times per week for more than 30 minutes is needed to achieve physiologic evidence of a training effect. One could view this study as a phase I dosing study; low-intensity exercise training appears to be inadequate to achieve significant changes in the intermediate clinical end points of exercise performance or quality of life. It will be interesting to see how this level of training intensity affects other end points that are known to improve with more intensive types of training, such as heart rate variability and neurohormone levels.

Small studies such as this actually can be misleading. With no significant representation of women or the very elderly, the current study provides no broad information on the stated target population of heart failure patients. In addition to the demographic disparity, important imbalances between the study groups include minority representation, left ventricular ejection fraction, the type of cardiomyopathy, and history of substance abuse. These imbalances in baseline characteristics often occur in small studies; unfortunately, the totality of these imbalances in baseline characteristics could significantly influence the primary and secondary end points, a problem that is addressed with larger sample sizes.25, 26

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Implications for future exercise training trials 

One of the important limitations in exercise training trials is the inability to conduct a blinded study. However, precautions can be taken. For instance, the evaluators can be blinded to treatment allocations when assessing physiologic parameters and administering the quality-of-life instruments and 6-minute walk test. Surveys of clinical investigators in this field reflect that the overwhelming majority of clinicians believe that exercise will be beneficial in this patient population. Blinded end point assessment is therefore critical to maintaining the scientific integrity of the study.

Perhaps one of the greatest challenges in exercise training trials is distinguishing the exercise component from the other types of interventions patients may receive as a result of their participation. Many cardiac rehabilitation centers where these supervised training studies take place include other lifestyle training, such as stress reduction courses and diet classes. Participants have an opportunity to interact with staff and bring worsening symptoms to their attention, which may trigger a call to their physician. Due to the nature of exercise training interventions, participants in the training arm of these studies undoubtedly receive these additional interventions to a greater extent. Investigators need to carefully track educational and medical interventions that may be differentially applied to the exercise group. If, for example, patients had greater diuretic use, greater angiotensin-converting enzyme inhibitor and β-blocker titration, and greater weight reductions, could the differential surveillance of symptoms rather than the exercise training have resulted in the improved clinical outcomes?

The statistical methodology used in small exercise-training trials should be standardized. For example, using a completer analysis alone places the intervention in the best possible light. Both intention-to-treat and completer analysis should be done in all trials of this magnitude. Furthermore, methods for using missing or incomplete data should be described, particularly when it occurs in follow-up.

In spite of this encouraging study and past studies, there are gaps in our knowledge about the role of exercise training in heart failure. Will all groups of patients benefit in a similar manner if compliance is adequate? Are there groups that should not exercise at all (eg, patients with a primary valvular etiology for heart failure)? What is the minimum amount of intensity that will create an increase in functional capacity? Which muscle groups should be trained? Will the benefits of a small trial including a drop in cardiac events translate to a larger population in a controlled, randomized setting? Can hospitalizations for heart failure be prevented or length of stay shortened if the patient were in a better state of physical conditioning? Will patients with preserved systolic function benefit as well? These are only a few of the important questions that remain to be answered in the field of exercise training and heart failure.

In summary, further small-scale clinical trials of exercise training in heart failure are no longer warranted. In fact, one could conclude that there is no further valuable information to be obtained, and question whether it is ethically appropriate to continue to randomize patients in such studies. Although these studies continue to show positive results for endpoints such as cardiopulmonary exercise test values, 6-minute walk exercise duration, and quality-of-life indicators, they provide no evidence that exercise training is safe or improves clinical outcomes such as mortality or hospitalization for the broader heart failure population. We have learned from experience that interventions that improve putative surrogate end points do not necessarily improve mortality and hospitalizations.27

In an attempt to answer these questions and concerns regarding exercise training of patients with heart failure, the National Heart, Lung, and Blood Institute has funded the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) study. HF-ACTION is a multi-center trial that will randomize 3000 patients with New York Heart Association class II to IV heart failure and ejection fraction of 35 or less to either exercise training or usual care. The primary aim of HF-ACTION is to determine the long-term safety and effectiveness of exercise training in patients with New York Heart Association class II to IV heart failure. Second, it will attempt to measure change in quality of life for patients participating in the exercise program with sufficient power to comment on quality-of-life changes and cost to the health care system. Third, the study will attempt to validate the putative surrogate markers that have been used in small-scale studies such as peak Vo2, exercise duration, 6-minute walk test changes, and quality-of-life indices. Fourth, HF-ACTON will assess the effects of exercise training on societal costs.

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References 

  1. American Heart Association . Heart disease and stroke statistics—2003 update. Dallas (Tex): American Heart Association; 2002;
  2. Weinberger M, Oddone EZ, Henderson WG. Does increased access to primary care reduce hospital readmissions?. N Engl J Med. 1996;334:1441–1447
  3. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101–13
  4. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE study spell the end for non-selective endothelin antagonism in heart failure?. Int J Cardiol. 2002;85:195–197
  5. Coletta AP, Clark AL, Banarjee P, et al.  Clinical trials update (RENEWAL (RENAISSANCE and RECOVER) and ATTACH). Eur J Heart Fail. 2002;4:559–561
  6. Hellerstein HK, Hornsten TR, Goldbarg A, et al.  The influence of active conditioning upon subjects with coronary artery disease. CMAJ. 1967;96:758–759
  7. McHenry MM. Medical screening of patients with coronary artery disease (criteria for entrance into exercise conditioning programs). Am J Cardiol. 1974;33:752–756
  8. Ferguson RJ, Petitclerc R, Choquette G, et al.  Effect of physical training on treadmill exercise capacity, collateral circulation and progression of coronary disease. Am J Cardiol. 1975;34:764–769
  9. Jugdutt BI, Michorowski BL, Kappagoda CT. Exercise training after anterior Q wave myocardial infarction (importance of regional left ventricular function and topography). J Am Coll Cardiol. 1988;12:362–372
  10. Coats AJ, Adamopoulos S, Meyer TE, et al.  Effects of physical training in chronic heart failure. Lancet. 1990;335:63–66
  11. Coats AJ, Adamopoulos S, Radaelli A, et al.  Controlled trial of physical training in chronic heart failure (exercise performance, hemodynamics, ventilation, and autonomic function). Circulation. 1992;85:2119–2131
  12. Koch M, Douard H, Broustet JP. The benefit of graded physical exercise in chronic heart failure. Chest. 1992;101(5 Suppl):S231–235
  13. Belardinelli R, Georgiou D, Scocco V, et al. Low intensity exercise training in patients with chronic heart failure. J Am Coll Cardiol 1995;26:975_82
  14. Hambrecht R, Niebauer J, Fiehn E, et al.  Physical training in patients with stable chronic heart failure (effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles). J Am Coll Cardiol. 1995;25:1239–1249
  15. Kiilavuori K, Toivonen L, Naveri H, et al.  Reversal of autonomic derangements by physical training in chronic heart failure assessed by heart rate variability. Eur Heart J. 1995;16:490–495
  16. Keteyian SJ, Levine AB, Brawner CA, et al.  Exercise training in patients with heart failure (a randomized, controlled trial). Ann Intern Med. 1996;124:1051–1057
  17. Kiilavuori K, Sovijarvi A, Naveri H, et al.  Effect of physical training on exercise capacity and gas exchange in patients with chronic heart failure. Chest. 1996;110:985–991
  18. Keteyian SJ, Brawner CA, Schairer JR, et al.  Effects of exercise training on chronotropic incompetence in patients with heart failure. Am Heart J. 1999;138:233–240
  19. Wielenga RP, Huisveld IA, Bol E, et al.  Exercise training in elderly patients with chronic heart failure. Coron Artery Dis. 1998;9:765–770
  20. Willenheimer R, Erhardt L, Cline C, et al.  Exercise training in heart failure improves quality of life and exercise capacity. Eur Heart J. 1998;19:774–781
  21. Belardinelli R, Georgiou D, Cianci G, et al.  Randomized, controlled trial of long-term moderate exercise training in chronic heart failure (effects on functional capacity, quality of life, and clinical outcome). Circulation. 1999;99:1173–1182
  22. Hambrecht R, Gielen S, Linke A, et al.  Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure (a randomized trial). JAMA. 2000;283:3095–3101
  23. McKelvie RS, Teo KK, Roberts R, et al.  Effects of exercise training in patients with heart failure (the Exercise Rehabilitation Trial (EXERT)). Am Heart J. 2002;144:23–30
  24. Corvera-Tindel T, Doering LV, Woo MA, et al. Effects of a home walking exercise program on functional status and symptoms in heart failure. Am Heart J 2004;147:339–46
  25. Fleming TR, DeMets DL. Surrogate endpoints in clinical trials (are we being misled?). Ann Intern Med. 1996;125:605–613
  26. Lee KL, McNeer JF, Starmer CF, et al.  Clinical judgment and statistics (Lessons from a simulated randomized trial in coronary artery disease). Circulation. 1980;61:508–515
  27. O'Connor CM, Gattis WA, Ryan TJ. The role of clinical nonfatal end points in cardiovascular phase II/III clinical trials. Am Heart J. 2000;139:S143–154

PII: S0002-8703(03)00649-5

doi:10.1016/j.ahj.2003.09.008

American Heart Journal
Volume 147, Issue 2 , Pages 190-192, February 2004

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