Cardiac resynchronization therapy landmark trials

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Cardiac resynchronization therapy Microchapters




Landmark Trials


Pathophysiologic Basis for CRT


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]


The landmark trials which have led to the acceptance of CRT as a non-pharmacological treatment approach for heart failure enrolled a select group of patients including those with normal sinus rhythm and a QRS duration greater than or equal to 0.15 seconds. A QRS duration greater than or equal to 0.12 seconds has been used as a marker of risk for dyssynchrony and a criterion for selection of patients for CRT. These landmark trials have shown a reduction in mortality of 24% to 36%, a 30% decrease in hospitalization, improved 6 minute walk test, improved NYHA class, and an increase in peak oxygen consumption.

Landmark Trials

It has been speculated that a prolonged QRS duration is associated with dysynchronous activation of the ventricular myocardium. There are two sources of dysynchrony:

1. Interventricular dyssynchrony: The dyssynchronous contraction between the left ventricle and the right ventricle and

2. Intraventricular dyssynchrony: The dyssynchronous contraction within the left ventricle itself.

Left ventricular mechanical dyssynchrony has been shown to occur independent of the QRS duration by echocardiographic parameters (predominantly tissue Doppler and speckle tracking imaging), which measure inter and intra left ventricular conduction delay. By such parameters, nearly half of the heart failure patients with normal QRS duration have evidence of mechanical dyssynchrony and one fifth of heart failure patients with QRS duration greater than or equal to 0.15 seconds reveal no evidence of mechanical dyssynchrony[1][2]. It has also been shown that mechanical dyssynchrony measured by echocardiographic techniques is predictive of cardiac events in heart failure patients independent of their QRS duration[2]. Therefore, using QRS duration, which is an electrical measure of conduction delay may not be the most reliable marker of ventricular dyssynchrony.

Despite the potential benefits among patients with dyssynchrony identified on echocardiography who have amnimially prolonged QRS, the RethinQ[3] trial failed to show any benefit from CRT in heart failure patients with a NYHA class 3, left ventricular ejection fraction less than or equal to 35%, narrow QRS duration(less than or equal to 0.13 seconds) with mechanical dyssynchrony as measured by tissue Doppler imaging and M-mode echocardiography. One of the major limitations of this tril was the selection criteria for mechanical dyssynchrony. Currently, there are several studies underway which are looking at different echocardiographic techniques to more accurately identify intra left ventricular mechanical dyssynchrony. Until a feasible, convenient, reproducible and accurate technique to measure mechanical intra left ventricular dyssynchrony is identified, QRS duration will remain a surrogate measure of dyssynchrony in selecting patients for CRT. CRT in responders can reverse the above mentioned hemodynamic abnormalities to a certain extent with associated clinical and functional benefit.

Efficacy in Clinical Trials

PATH-CHF[4], MUSTIC SR[5][6], MUSTIC AF[7], MIRACLE[8], COMPANION[9], CARE-HF[10], MIRACLE-ICD[11], CONTAK-CD[12], RHYTHM-ICD and HOBIPACE[13] landmark trials demonstrated the following beneficial effects of CRT:

  1. Reduced mortality (24% to 36% benefit)
  2. Reduced hospitalizations (30% decrease)
  3. Improved 6 minute walk test (50 to 70 meter increase)
  4. Improved 105 -point Minnesota scale (greater than or equal to 10 point reduction of heart failure symptoms)
  5. Improved NYHA class
  6. Increase in peak oxygen consumption


  1. Bader H, Garrigue S, Lafitte S, Reuter S, Jaïs P, Haïssaguerre M; et al. (2004). "Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients". J Am Coll Cardiol. 43 (2): 248–56. PMID 14736445.
  2. 2.0 2.1 Cho GY, Song JK, Park WJ, Han SW, Choi SH, Doo YC; et al. (2005). "Mechanical dyssynchrony assessed by tissue Doppler imaging is a powerful predictor of mortality in congestive heart failure with normal QRS duration". J Am Coll Cardiol. 46 (12): 2237–43. doi:10.1016/j.jacc.2004.11.074. PMID 16360052.
  3. Beshai JF, Grimm RA, Nagueh SF, Baker JH, Beau SL, Greenberg SM; et al. (2007). "Cardiac-resynchronization therapy in heart failure with narrow QRS complexes". N Engl J Med. 357 (24): 2461–71. doi:10.1056/NEJMoa0706695. PMID 17986493.
  4. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P; et al. (1999). "The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study". Am J Cardiol. 83 (5B): 130D–135D. PMID 10089855.
  5. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C; et al. (2001). "Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay". N Engl J Med. 344 (12): 873–80. doi:10.1056/NEJM200103223441202. PMID 11259720.
  6. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S; et al. (2002). "Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study". J Am Coll Cardiol. 40 (1): 111–8. PMID 12103264.
  7. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P; et al. (2002). "Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation". Eur Heart J. 23 (22): 1780–7. PMID 12419298.
  8. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E; et al. (2002). "Cardiac resynchronization in chronic heart failure". N Engl J Med. 346 (24): 1845–53. doi:10.1056/NEJMoa013168. PMID 12063368. Review in: ACP J Club. 2002 Nov-Dec;137(3):82
  9. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T; et al. (2004). "Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure". N Engl J Med. 350 (21): 2140–50. doi:10.1056/NEJMoa032423. PMID 15152059. Review in: ACP J Club. 2004 Nov-Dec;141(3):60
  10. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L; et al. (2005). "The effect of cardiac resynchronization on morbidity and mortality in heart failure". N Engl J Med. 352 (15): 1539–49. doi:10.1056/NEJMoa050496. PMID 15753115. Review in: ACP J Club. 2005 Sep-Oct;143(2):29
  11. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B; et al. (2003). "Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial". JAMA. 289 (20): 2685–94. doi:10.1001/jama.289.20.2685. PMID 12771115.
  12. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA; et al. (2003). "Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias". J Am Coll Cardiol. 42 (8): 1454–9. PMID 14563591.
  13. Kindermann M, Hennen B, Jung J, Geisel J, Böhm M, Fröhlig G (2006). "Biventricular versus conventional right ventricular stimulation for patients with standard pacing indication and left ventricular dysfunction: the Homburg Biventricular Pacing Evaluation (HOBIPACE)". J Am Coll Cardiol. 47 (10): 1927–37. doi:10.1016/j.jacc.2005.12.056. PMID 16697307.

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