Expanding Indications for Cardiac Resynchronization Therapy to Treat Congestive Heart Failure

Cardiac resynchronization therapy (CRT) has been used clinically to treat patients with congestive heart failure (CHF) for almost a decade. Many patients with CHF have electrical conduction delay, as evidenced electrocardiographically by a prolonged QRS duration. In certain patients, this electrical conduction delay results in dyscoordinate contraction of the ventricular septum and left ventricular free wall, leading to decreased ventricular systolic function. CRT pacemakers (and defibrillators) resynchronize the ventricles by simultaneously pacing the right and left ventricles via a pacing lead in the coronary sinus branches.

"The initial randomized clinical trials demonstrated improved left ventricular systolic function, fewer hospitalizations for heart failure, and improved survival in patients randomly assigned to CRT compared with those who received medical therapy alone," says Brian D. Powell, M.D., an electrophysiologist at Mayo Clinic.

Approximately 70% of patients experience improvement in heart failure symptoms with CRT. Enrollment in previous trials was limited to patients with New York Heart Association (NYHA) class III-IV heart failure symptoms, QRS wider than 120 milliseconds, and ejection fraction (EF) less than 35%, on optimal medical therapy. Until recently, it was unknown if CRT would benefit patients with NYHA class I-II heart failure symptoms.

Many patients with NYHA class I-II symptoms meet criteria for placement of an implantable cardioverter-defibrillator (ICD) as primary prevention to lower their risk of sudden death.

Should these mildly symptomatic patients receive a CRT defibrillator (CRT-D) at the time of the primary prevention ICD placement if they have a wide QRS interval? Many of these patients eventually progress to NYHA III-IV symptoms over time. Should upgrading the device to a CRT-D be deferred until symptoms progress, or should the initial device be a CRT-D while their heart failure symptoms are mild? Two recently completed trials—MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) and REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction)—evaluated the effect of CRT on patients with minimal or mild CHF symptoms (NYHA class I-II).

Survival probability in the MADIT-CRT trial

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The larger MADIT-CRT trial randomized more than 1800 patients with EF less than 30%, QRS wider than 130 milliseconds, and NYHA class I-II to CRT-D or to standard ICD alone. Patients in the CRT-D group had a significant reduction in the combined endpoint of death or heart failure hospitalization (25% for the ICD group vs 17% for the CRT-D group; P=.001).

"The difference in the combined endpoint was primarily driven by fewer heart failure hospitalizations in the CRT-D group," according to Margaret M. Redfield, M.D., director of the Heart Failure Clinic at Mayo Clinic.

Heart failure risk by QRS duration

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The CRT-D group also had improved EF at follow-up compared with the ICD group. Subgroup analyses of both the MADIT-CRT and REVERSE trials suggested that patients with QRS wider than 150 milliseconds were more likely to benefit from CRT-D compared with an ICD alone.

Based on the results of these two trials, the US Food and Drug Administration approved a new indication for CRT-D for ischemic cardiomyopathy patients with NYHA class I or greater heart failure or for nonischemic cardiomyopathy with NYHA class II or greater, including all patients with EF less than 30%, QRS wider than 130 milliseconds, and left bundle branch block. The requirement of left bundle branch block was based on subgroup analysis. This new indication expands the use of CRT-D to patients with less symptomatic heart failure.

Do patients with CHF and narrow QRS benefit from CRT?
Initial single-center, nonrandomized case series reported improvement in left ventricular function in patients with CHF and narrow QRS who received CRT. The theory was that the QRS duration on electrocardiography may not accurately detect electrical dyssynchrony that may benefit from CRT.

This theory was primarily driven by the perception of ventricular dyssynchrony as measured by echocardiographic tissue velocity parameters. These parameters have since been found to be less reproducible and reliable than previously thought. Data from the PROSPECT (Predictors of Response to CRT) trial and the Mayo Clinic Cardiac Resynchronization Registry found that dyssynchrony as measured by echocardiography (tissue velocity, M-mode, pulsed wave Doppler) did not adequately correlate with patients' clinical improvement or improvement in ventricular function.

The RethinQ (Resynchronization Therapy in Normal QRS) trial randomized patients with NYHA class III symptoms, EF less than 35%, narrow QRS (<130 milliseconds), and echocardiographic evidence of dyssynchrony to receive an ICD alone or CRT-D. There was no significant difference in the primary endpoint of improvement in peak oxygen consumption at 6 months. At this time, there is no conclusive evidence to support the use of CRT in patients with a narrow QRS duration of less than 120 milliseconds.

In summary

Patients with EF less than 35%, QRS wider than 120 milliseconds, and NYHA III-IV CHF symptoms on optimal medical therapy should be considered for CRT. Recent randomized studies support expanding the use of CRT for patients with NYHA class I-II symptoms, EF less than 30%, and QRS wider than 130 milliseconds.