A 55-year-old woman presented to your clinic for a follow-up. She was diagnosed with nonischemic cardiomyopathy diagnosed9 months ago after she presented to the emergency department (ED) with New York Heart Association (NYHA) class IV heart failure (HF) symptoms. Coronary angiography then revealed no obstructive coronary artery disease (CAD). Echocardiogram at the time of her initial evaluation revealed moderately dilated left ventricle, and global hypokinesis with an ejection fraction of 20%, with no gross valvular abnormalities. Cardiac magnetic resonance imaging (MRI) showed midwall fibrosis consistent with nonischemic cardiomyopathy. During her clinic visit, she reported symptoms of effort intolerance and exertional dyspnea with mild exertion. She denied resting or exertional chest pain. An echocardiogram at the time of her visit showed left ventricular ejection fraction (LVEF) of 25%. Her current medications include carvedilol 25 mg twice daily, lisinopril 10 mg twice daily, aldactone 25 mg by mouth once a day, Lipitor 80 mg by mouth once daily, Aspirin (ASA) 81 mg by mouth once daily, and Plavix 75 mg by mouth once daily. Electrocardiogram showed normal sinus rhythm, left bundle branch block with QRS duration of 155 ms. Blood Pressure is 90/60 mm Hg and heart rate is 70 beats per minute. Her cardiovascular examination was unremarkable.
Cardiac resynchronization therapy (CRT) is a device-based treatment for HF that emerged over the last few decades to be a major contributor to reducing morbidity and mortality. The concept of this therapy is to restore synchronous activation of both ventricles in select patients who had evidence of prolonged depolarization evident by prolongation of the QRS segment on the surface electrocardiogram (ECG). Stimulation of the right ventricle is achieved with the standard transvenous leads used in traditional pacemakers and implantable cardioverter defibrillators (ICDs). Early CRT systems required thoracotomy and epicardial left ventricular (LV) lead placement by open surgical approach. This practice was replaced by a transvenous approach in which implantation of the LV lead is achieved by cannulation of the coronary sinus and targeting a lateral or posterior branch. Given the recent advancement in lead and delivery system technologies, the transvenous approach has become the standard technique worldwide. The epicardial technique is still used but reserved for patients with difficult venous anatomy or suboptimal target vessels.
Cardiac dyssynchrony has deleterious effects on the heart’s performance as a pump. It can occur between the left and right ventricles and within the left ventricle itself.1 A left bundle-branch blockade (LBBB) with prolongation of the QRS duration ≥120 ms has been used as a universal measure of electrical dyssynchrony in most clinical trials. LBBB is present in approximately one-third of HF patients in whom the septum is activated earlier than the lateral or posterior walls, resulting in paradoxical septal motion and ineffective contraction (Figure 31-1). Furthermore, dyssynchronous contraction increases LV end-systolic and end-diastolic volumes and reduces diastolic filling. Because the onset of LV contraction is delayed, the LV contraction occurs simultaneously with atrial contraction, which leads to reduction in preload and systolic mitral regurgitation through inadequate leaflet closure.
Figure 31-1
The top 12-lead electrocardiogram (ECG) illustrates normal sinus rhythm with left bundle-branch block and QRS width of 200 ms. The bottom 12-lead ECG is the same patient after cardiac resynchronization therapy (CRT). It illustrates atrial-sensed biventricular stimulation; note that the paced QRS complex has narrowed significantly from the baseline in response to CRT. (Reproduced with permission from Fuster V, Walsh RA, Harrington RA. Hurst’s The Heart. 13th ed. New York, NY: McGraw-Hill Education; 2011. Figure 43-19.)
CRT benefits can be divided into acute and chronic changes that account for the improvement in patients’ symptoms and reduction in HF mortality. Acute CRT benefits include favorable hemodynamic changes such as improved LV systolic function through increased slope of dP/dt and increased stroke volume.2
Chronic CRT benefits include restoring normal cardiac chamber size, and reduction in LV end-systolic and end-diastolic volumes with subsequent improvement in ejection fraction.3 CRT is also capable of producing biventricular pacing that is well synchronized with the atrial activation, which reinstates earlier activation of the left ventricle, restores diastolic filling time, and increases stroke volume. Restoring atrioventricular (AV) delay will also cause reduction in mitral regurgitation and subsequent improvement in LV systolic function. Restoring delays in electrical consequences contributes to the immediate improvement in mitral regurgitation; however, an intermediate and long-term improvement has been observed and is thought to be related to restoring normal chamber geometry seen with chronic CRT.
The common long-term benefits seen in responders to CRT is the reverse remodeling of ventricular dilatation, which can be detected within 3 months of CRT4 and confirmed by several large randomized-controlled trials (Table 31-1).
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The CRT concept was first studied in the early 1990s. Since then, 8 large randomized clinical trials with more than 4000 patients enrolled were completed and established the benefits of CRT in reducing HF’s morbidity and mortality with or without an ICD (Table 31-2).
| Trial | Randomization | Patients | Mean Follow-up | NYHA | LVEF Inclusion Criteria | QRS Inclusion Criteria | Primary Endpoint | Secondary Endpoint | Intervention Group Better? |
|---|---|---|---|---|---|---|---|---|---|
| MUSTIC-SR (2001) | CRT-P/Med crossover | 29/29 | 3 | II, III, IV | ≤35% | ≥150 ms | 6 MWT | NYHA, quality of life, peak VO2, MR, LV improvement, hospitalization, mortality | Yes |
| PATH-CHF (2002) | RV/LV/CRT-P crossover | 41 | 12 | III, IV | NA | ≥150 ms | 6 MWT, peak VO2 | NYHA, quality of life, hospitalization | Yes |
| MIRACLE (2002) | CRT-P/Med | 228/225 | 6 | III, IV | ≤35% | ≥130 ms | NYHA, 6 MWT, quality of life | Peak VO2, LVEDD, MR, LVEF, CCR | Yes |
| MIRACLE (2003) | CRT-D/ICD | 187/182 | 6 | III, IV | ≤35% | ≥130 ms | NYHA, 6 MWT, quality of life | Peak VO2, LVV, MR, LVEF, CCR | Yes |
| CONTAK-CD (2003) | CRT-D/ICD | 245/245 | 6 | II, III, IV | ≤35% | ≥120 ms | NYHA, 6 MWT, quality of life | LVV, LVEF, CCR | Yes |
| COMPANION (2004) | CRT-D/CRT-P/ICD | 617/595/308 | 15 | III, IV | ≤35% | ≥120 ms | All-cause mortality or hospitalization | Cardiac mortality | Yes/yes |
| MIRACLE-ICD II (2004) | CRT-D/ICD | 85/101 | 6 | II | ≤35% | ≥130 ms | Peak VO2 | NYHA, quality of life, 6-MWT, LVV, LVEF, CCR | No, but several secondary were met |
| CARE-HF (2005) | CRT-P/Med | 409/404 | 29 | III, IV | ≤35% | ≥120 ms | All-cause mortality or cardiovascular hospitalization | NYHA, quality of life, LVEF, LVESV, HF hospitalization | Yes |
| REVERSE (2008) | CRT-P/ICD | 419/191 | 12 | I, II | ≤40% | ≥130 ms | CCR | LVESVi | No, but secondary was met |
| MADIT-CRT (2009) | CRT-D/ICD | 1089, 739 | 29 | I, II | ≤30% | ≥130 ms | All-cause mortality or HF hospitalization | LVESV, LVEDV, LVEF | Yes |
| RAFT (2010) | CRT-D/ICD | 894/904 | 40 | II, III, IV | ≤30% | ≥120 ms | All-cause mortality or HF hospitalization | Cardiac death, nonfatal HF hospitalization | Yes |
The Pacing Therapies for Congestive Heart Failure (PATH-CHF) trial5 was the earliest randomized CRT trial. It studied the acute hemodynamic effects of CRT. PATH-CHF showed that LV and biventricular pacing formed significant acute hemodynamic benefits when compared to right ventricular (RV) pacing alone.
The Multisite Stimulation in Cardiomyopathy (MUSTIC) study6 was a single-blind randomized crossover study that evaluated the safety and efficacy of CRT in moderate HF. The study had a normal sinus rhythm (SR) arm and an atrial fibrillation (AF) arm and enrolled patients with NYHA class III HF and QRS >150 ms. In each arm, patients were randomized to 3 months of biventricular pacing or the control, followed by a 3-month crossover period, and final programming at 6 months to their preference. The primary endpoint of exercise capacity measured by 6-minute walk test (6MWT) and peak oxygen consumption on metabolic exercise test was significantly improved in both arms who received active CRT. Secondary endpoints of quality of life and NYHA functional class were also significantly improved with active CRT. Fewer hospitalizations were seen with biventricular pacing during a 12-month follow-up period. MUSTIC was the first trial to show clinical benefits with CRT but it was not a mortality trial.
The Multicenter InSync Randomized Clinical Evaluation (MIRACLE)7,8 was the first prospective double-blind randomized trial that evaluated the benefits of CRT in severe HF patients. It was larger than PATH-CHF and MUSTIC and enrolled patients with NYHA class III and ambulatory class IV HF who were on optimal medical therapy. Patients had to be in normal sinus rhythm (SR) and dyssynchrony was defined as QRS durations ≥130 ms. Patients were assigned to 6 months of biventricular pacing or the control arm of medical therapy alone. Primary endpoints of NYHA class and 6MWT improved significantly with CRT, compared to the control group. There was also statically significant improvement in ejection fraction, oxygen consumption (peak VO2), and exercise duration in the CRT arm. MIRACLE also demonstrated significant reduction in HF hospitalizations (P = 0.02) among those who received CRT. The study, however, was not powered to assess mortality.
MIRACLE-ICD9 was a separate trial intended to evaluate the safety and efficacy of devices that combined both CRT and ICD therapies. Patients were randomized to receiving ICD without CRT capacity (n = 182) versus CRT pacing combined with ICD therapies (n = 187). The study demonstrated improvement in quality of life and NYHA functional class at 6 months among patients who received CRT. Mortality at 6 months did not differ between the 2 groups and there was no proarrhythmic effect. The results of MIRACLE-ICD established the safety of combining CRT and ICD therapies.
The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial10 was designed to compare the risks of death and HF hospitalizations in patients who were prospectively randomized to receive medical therapy, resynchronized pacing, and defibrillation. CRT was delivered with and without defibrillator therapy to evaluate whether it had any additive benefits beyond the prevention of sudden cardiac death (SCD) through defibrillation. The trial included patients with NYHA class III and class IV HF on optimal medical therapy, LVEF ≤35%, QRS duration ≥120 ms, and no secondary prevention indication for ICD placement. Patients were randomized in a 1:2:2 ratio into 3 groups. The control group (n = 308) received optimal medical therapy only, group 2 (n = 617) received optimal medical therapy and CRT device without defibrillator capabilities, and group 3 (n = 595) received optimal medical therapy and a CRT device with ICD function.
There was significant (20%) decrease in all-cause mortality and all-cause hospitalizations in both CRT groups compared to the control group. All-cause mortality alone was significantly reduced by 36% in patients receiving CRT with an ICD (P < 0.003) and trended toward a significant reduction of 24% in patients who received CRT alone (P = 0.06), when compared to the control group.
The COMPANION trial was the first to show survival benefits of combined CRT and defibrillator therapies. It also demonstrated that prophylactic ICD therapy would be beneficial in nonischemic cardiomyopathy before the SCD-HeFT trial, as nearly half of the randomized patients had a nonischemic etiology.
The COMPANION trial showed that CRT alone or in combination with defibrillator therapy would significantly reduce the risks of all-cause mortality and HF hospitalizations in patients with moderate to severe HF, reduced ejection fraction, and prolonged QRS. In order to clear any doubt in regards to the pure effect of CRT alone on the risk of death, the Cardiac Resynchronization Heart Failure (CARE-HF) trial11,12 was designed. CARE-HF was a multicenter randomized unblended study aimed to evaluate the net effects of CRT without a defibrillator on the risk of death in advanced HF (NYHA class III and class IV). Inclusion criteria included ejection fractions ≤35% if QRS duration was ≥150 ms. If the QRS duration was between 120 and 150 ms, patients had to meet 2 of 3 additional echocardiographic criteria for dyssynchrony: interventricular mechanical delay >40 ms, aortic preejection delay >140 ms, or delayed posterolateral activation. Patients assigned to the control group (n = 404) received optimal medical therapy and those assigned to the treatment arm received CRT devices without defibrillation capabilities (n = 409). One of the unique aspects of CARE-HF is that control patients did not receive a device implant. This helped illustrate the effect of CRT as a whole, incorporating potential risks related to the implant at procedures.
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