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Editorials |

Translating the Benefits of Cardiac Resynchronization Therapy Widely and Wisely: Challenges Remain FREE

Carl R. Reynolds, MD; and Mariell Jessup, MD
[+] Article and Author Information

From University of Pennsylvania School of Medicine, Philadelphia, PA 19104.


Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0281.

Requests for Single Reprints: Mariell Jessup, MD, 2 East Perelman Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104; e-mail, jessupm@uphs.upenn.edu.

Current Author Addresses: Dr. Reynolds: 3400 Spruce Street, 8 Gates Building, Philadelphia, PA 19104.

Dr. Jessup: 2 East Perelman Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104.


Ann Intern Med. 2011;154(6):436-438. doi:10.7326/0003-4819-154-6-201103150-00314
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During the past 2 years, we have seen a rapid accumulation of evidence for the use of cardiac resynchronization therapy (CRT) in patients with milder symptoms of systolic heart failure. Previously, investigators studied patients whose quality of life was substantially compromised by the disease despite optimal medical therapy. In these trials, patients who received CRT felt better, had positive cardiac remodeling, and came to the hospital less than patients who did not receive this therapy (1). Ultimately, a mortality benefit of CRT was demonstrated in patients with New York Heart Association (NYHA) class III or ambulatory class IV heart failure (23). More recently, we have witnessed a recapitulation of the evidence of the benefits of CRT in patients with milder heart failure: The first studies that enrolled such patients showed reverse remodeling (46) and a reduction in heart failure hospitalizations (78). Data from RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial), published in 2010 (9), showed convincingly that CRT can reduce mortality in patients with mildly symptomatic heart failure as well.

Al-Majed and colleagues place an emphatic stamp on these recent findings with their meta-analysis in this issue (10). Pooling data from 2616 trial participants with NYHA class I or II symptoms, they show that CRT significantly reduces all-cause mortality (risk ratio, 0.80 [95% CI, 0.67 to 0.96]) and heart failure hospitalization (risk ratio, 0.69 [CI, 0.59 to 0.80]) for patients with milder heart failure. These benefits are equivalent to those seen in patients with more advanced heart failure. However, this meta-analysis also shows that that these less sick patients do not experience improvement in quality of life or 6-minute walk test times with CRT. In their conclusion, the investigators aptly observe that even as we close the book on one important question, we are left with numerous and even more vexing problems threatening the effective translation of this knowledge into responsible clinical practice.

For example, we know that CRT is efficacious in selected patients with heart failure who meet criteria for dyssynchrony, but up to 30% of patients in earlier trials of CRT have been nonresponders (1112). The European Society of Cardiology recently published its guideline for use of CRT in mild heart failure, outlining the evidence-based characteristics of patients most likely to respond. The guideline recommends that patients who are eligible for CRT have some heart failure symptoms—NYHA class greater than I, an ejection fraction of 0.35 or less, a QRS duration of 150 ms or greater, and sinus rhythm—despite maintenance of optimal medical therapy (13). This conservative approach is appropriate if we consider data beyond the inclusion criteria of REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) (6), MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) (8), and RAFT (9). In each of these trials, although patients with much shorter QRS intervals could have been enrolled, the mean QRS in patients who were randomly assigned was greater than 150 ms. In REVERSE, patients with an ejection fraction as high as 0.40 were included, but the mean ejection fraction was only 0.27. The patients who benefitted most demonstrably from CRT in these trials are probably not the ones near the inclusion cutoffs, an observation that has been described in the data on implantable cardioverter-defibrillator use for primary prevention of sudden cardiac death (14). Moreover, even the patients considered to have NYHA class I symptoms in REVERSE and MADIT-CRT were allowed to have had symptoms at some point before enrollment; RAFT did not include patients with NYHA class I symptoms.

Questions about other subgroups of patients with heart failure also persist. For example, atrial fibrillation is woefully underrepresented in these studies; in addition, patients with ischemic cardiomyopathy had less reverse remodeling than those with nonischemic cardiomyopathy in REVERSE (15), and women benefitted from CRT more than men in MADIT-CRT. Presence of left bundle branch block and age were independent predictors of clinical response in REVERSE (15). Given these complexities, it seems unwise to believe that the response rate to CRT in patients with milder heart failure will be any better than 60% if we are not very selective about which patients receive this therapy.

The critical lesson is that CRT, an effective therapy, can work in patients with mild heart failure, but it will not do so if it is applied haphazardly or if our current system of cardiac care is not organized to be able to correctly identify appropriate candidates. Indiscriminate interpretation of device-based guidelines has already been proved common with implantable cardioverter-defibrillators (16). Current device-based guidelines in the United States will soon be updated to include an indication for CRT in mild heart failure (17). How do we prevent overly enthusiastic physicians from prematurely implanting CRT in patients with a newly discovered depressed ejection fraction and a wide QRS complex? Optimal medical therapy continues to evolve alongside CRT, as evidenced by the recent EMPHASIS (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial (18). Many patients with mildly symptomatic heart failure in the upper end of the ejection fraction range might be spared device implantation by careful titration of a β-blocker, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and an aldosterone antagonist (18).

This may seem to be an overly pessimistic stance just as the medical community passes another milestone in device-based heart failure management. Our intention, however, is to highlight an oft-neglected part of medicine: namely, the translation of a new therapy to effective and cost-efficient care. In this field, technology has overrun our ability to use it judiciously. We need to develop effective systems of care, within individual practices and hospitals, to harness the power of evidence-based medicine (Figure). A good start would be to better define the influence of atrial fibrillation, etiology, QRS duration and morphology, ejection fraction, and sex on the response to CRT. Simply adopting an amalgam of inclusion criteria from the clinical trials would handicap the success of CRT in patients with mild heart failure and squander health care resources when we have little to spare.

Grahic Jump Location
Figure.
Device utilization in patients with mildly symptomatic heart failure.

The first 3 boxes show the progression to the next step of care; the information that flows from the third box, “Reassess EF and ECG and clinical status,” indicated a stepwise progression that is well supported by strong evidence from randomized, controlled trials. The dashed arrow indicates a step that has weak justification from current data. ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CRT-D = CRT with defibrillator; CRT-P = CRT with pacing only; ECG = electrocardiography; EF = ejection fraction; ICD = implantable cardioverter-defibrillator; NYHA = New York Heart Association.

* The 2008 American College of Cardiology/American Heart Association guidelines (17) stipulate that patients have NYHA class II symptoms and an EF ≤0.35 to be eligible for ICD implantation but allow patients with NYHA class I symptoms and concomitant EF ≤0.30 and ischemic cause (>40 d after myocardial infarction) to be eligible for this therapy.

Grahic Jump Location

References

Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. MIRACLE Study Group.  Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346:1845-53.
PubMed
CrossRef
 
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators.  Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350:2140-50.
PubMed
 
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators.  The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539-49.
PubMed
 
Abraham WT, Young JB, Leon AR, Adler S, Bank AJ, Hall SA, et al. Multicenter InSync ICD II Study Group.  Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004; 110:2864-8.
PubMed
 
Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA. et al.  Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003; 42:1454-9.
PubMed
 
Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C, REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group.  Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008; 52:1834-43.
PubMed
 
Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G, et al. REVERSE Study Group.  Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J Am Coll Cardiol. 2009; 54:1837-46.
PubMed
 
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. MADIT-CRT Trial Investigators.  Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009; 361:1329-38.
PubMed
 
Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al. Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators.  Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010; 363:2385-95.
PubMed
 
Al-Majed NS, McAlister FA, Bakal JA, Ezekowitz JA.  Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure. Ann Intern Med. 2011; 154:401-12.
 
Bax JJ, Gorcsan J 3rd.  Echocardiography and noninvasive imaging in cardiac resynchronization therapy: results of the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) study in perspective. J Am Coll Cardiol. 2009; 53:1933-43.
PubMed
 
McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM. et al.  Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA. 2007; 297:2502-14.
PubMed
 
Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J. et al.  2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur J Heart Fail. 2010; 12:1143-53.
PubMed
 
Myerburg RJ.  Implantable cardioverter-defibrillators after myocardial infarction. N Engl J Med. 2008; 359:2245-53.
PubMed
 
Linde C, Abraham WT, Gold MR, Daubert C, REVERSE Study Group.  Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study. J Am Coll Cardiol. 2010; 56:1826-31.
PubMed
 
Al-Khatib SM, Hellkamp A, Curtis J, Mark D, Peterson E, Sanders GD. et al.  Non-evidence-based ICD implantations in the United States. JAMA. 2011; 305:43-9.
PubMed
 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices).  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008; 117:350-408.
PubMed
 
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. EMPHASIS-HF Study Group.  Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
PubMed
 

Figures

Grahic Jump Location
Figure.
Device utilization in patients with mildly symptomatic heart failure.

The first 3 boxes show the progression to the next step of care; the information that flows from the third box, “Reassess EF and ECG and clinical status,” indicated a stepwise progression that is well supported by strong evidence from randomized, controlled trials. The dashed arrow indicates a step that has weak justification from current data. ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CRT-D = CRT with defibrillator; CRT-P = CRT with pacing only; ECG = electrocardiography; EF = ejection fraction; ICD = implantable cardioverter-defibrillator; NYHA = New York Heart Association.

* The 2008 American College of Cardiology/American Heart Association guidelines (17) stipulate that patients have NYHA class II symptoms and an EF ≤0.35 to be eligible for ICD implantation but allow patients with NYHA class I symptoms and concomitant EF ≤0.30 and ischemic cause (>40 d after myocardial infarction) to be eligible for this therapy.

Grahic Jump Location

Tables

References

Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. MIRACLE Study Group.  Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346:1845-53.
PubMed
CrossRef
 
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators.  Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350:2140-50.
PubMed
 
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators.  The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539-49.
PubMed
 
Abraham WT, Young JB, Leon AR, Adler S, Bank AJ, Hall SA, et al. Multicenter InSync ICD II Study Group.  Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004; 110:2864-8.
PubMed
 
Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA. et al.  Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003; 42:1454-9.
PubMed
 
Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C, REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group.  Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008; 52:1834-43.
PubMed
 
Daubert C, Gold MR, Abraham WT, Ghio S, Hassager C, Goode G, et al. REVERSE Study Group.  Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J Am Coll Cardiol. 2009; 54:1837-46.
PubMed
 
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. MADIT-CRT Trial Investigators.  Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009; 361:1329-38.
PubMed
 
Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al. Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators.  Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010; 363:2385-95.
PubMed
 
Al-Majed NS, McAlister FA, Bakal JA, Ezekowitz JA.  Meta-analysis: cardiac resynchronization therapy for patients with less symptomatic heart failure. Ann Intern Med. 2011; 154:401-12.
 
Bax JJ, Gorcsan J 3rd.  Echocardiography and noninvasive imaging in cardiac resynchronization therapy: results of the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) study in perspective. J Am Coll Cardiol. 2009; 53:1933-43.
PubMed
 
McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM. et al.  Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA. 2007; 297:2502-14.
PubMed
 
Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J. et al.  2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur J Heart Fail. 2010; 12:1143-53.
PubMed
 
Myerburg RJ.  Implantable cardioverter-defibrillators after myocardial infarction. N Engl J Med. 2008; 359:2245-53.
PubMed
 
Linde C, Abraham WT, Gold MR, Daubert C, REVERSE Study Group.  Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study. J Am Coll Cardiol. 2010; 56:1826-31.
PubMed
 
Al-Khatib SM, Hellkamp A, Curtis J, Mark D, Peterson E, Sanders GD. et al.  Non-evidence-based ICD implantations in the United States. JAMA. 2011; 305:43-9.
PubMed
 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices).  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008; 117:350-408.
PubMed
 
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. EMPHASIS-HF Study Group.  Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
PubMed
 

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