Cardiac Resynchronization Therapy

I. Cardiac Resynchronization Therapy: What every physician needs to know.

Cardiac resynchronization therapy (CRT), also known as biventricular (biV) pacing, is an important component of the total management of patients with heart failure and a wide QRS complex on an electrocardiogram (EKG). It has a growing track record of proven benefits with respect to patients’ symptoms and, most importantly, mortality. This makes CRT an essential, rather than an adjunct, aspect of heart failure care that must be considered in everyone who meets the criteria for therapy.

The pathophysiology of adverse outcomes with dyssynchrony is thought to be due to worsened pump efficiency, leading to left ventricular remodeling and increased metabolic expenditure. Functional mitral regurgitation can also result. By pacing the septal and free walls of the left ventricle, these issues can be overcome, leading to improved left ventricular (LV) function and remodeling.

II. Diagnostic Confirmation: Are you sure your patient needs CRT?

The indications for CRT are straightforward, such that patients meeting the following criteria should not be denied therapy except for compelling reasons:

1. Left ventricular ejection fraction (LVEF) less than or equal to 35%

2. QRS duration greater than or equal to 120 msec

3. New York Heart Association (NYHA) functional Class III or IV heart failure despite optimal medical therapy

These criteria apply to patients with either ischemic or nonischemic cardiomyopathy, and to patients in sinus rhythm or in atrial fibrillation. Furthermore, if the patient’s wide QRS is a result of actual or anticipated frequent right ventricular pacing, then CRT is a reasonable option for patients with NYHA functional Class I or II symptoms.

More recently, the indications for CRT have expanded further based on the landmark Multicenter Automatic Defibrillator Implantation Trial (MADIT)-CRT trial . In patients with milder heart failure (NYHA Class I-II), LVEF less than or equal to 30%, and QRS duration greater than or equal to 130 msec with a left-bundle-branch-block (LBBB) pattern, CRT is also indicated.

A. History Part I: Pattern Recognition:

The typical patient meeting criteria for CRT is any patient with heart failure, wide QRS on EKG, and severe (NYHA Class III-IV) symptoms, although the indications are expanding for patients with milder symptoms. NYHA Class III patients are limited to walking one block or one flight of stairs due to dyspnea on exertion, and can be symptomatic with their normal activities. NYHA Class IV patients experience dyspnea at rest.

Generally, patients that fall into these functional classes have frequent hospitalizations for heart failure decompensation. CRT has been shown to improve symptoms, as demonstrated by decreased NYHA class, decreased hospitalizations, increased 6-minute walking distance, increased scores on heart failure quality-of-life surveys, and decreased peak oxygen consumption.

B. History Part 2: Prevalence:

The 2011 AHA update reported a 2008 prevalence of heart failure of 2.4% in adults at least 20 years of age, with 670,000 incident cases in adults at least 45 years of age. There were 56,565 fatalities, with 990,000 hospital discharges in 2007. The total cost of the disease has been estimated at $39.2 billion.

The incidence is approximately 10 per 1,000 patients over the age of 65. Overall, at age 40, the lifetime risk of heart failure is 20%. White women have the lowest prevalence, at 1.8%. The prevalence in white men is 2.7%, increasing to 3.8% for black women and 4.5% for black men.

The most important risk factor for developing heart failure is hypertension, such that 75% of patients with heart failure had prior hypertension, with a doubled lifetime risk of heart failure for patients with BP >160/90 as compared to those <140/90. These figures demonstrate the scope of the problem of heart failure, as well as the potential broad benefits of therapies such as CRT.

C. History Part 3: Competing diagnoses that can mimic Heart Failure Requiring CRT.

1. Diastolic heart failure. Over half of patients with clinical heart failure have normal systolic function. Thus far, the focus of CRT investigation has been in patients with severely depressed systolic function. Recently, CRT has been shown to have benefit in diastolic dyssynchrony, such that the diastolic abnormality can be stronger than the systolic in predicting CRT success .

2. Right heart failure. Physical examination and echocardiography are instrumental in distinguishing this type of heart failure.

3. Primary lung disease. Patients with normal echocardiograms should be evaluated for lung pathology as a source of their cardiopulmonary symptoms.

D. Physical Examination Findings

The physical examination findings are those consistent with congestive heart failure and include:

1. Elevated jugular venous pressure.

2. Decreased carotid volumes.

3. Enlarged point of maximum impulse (PMI).

4. Audible or palpable third heart sound (S3).

5. Dullness to percussion or crackles on pulmonary auscultation.

6. Abdominal distention or pulsatile liver.

7. Peripheral edema.

8. Cool extremities, often a marker of advanced heart failure and/or acute decompensation leading to cardiogenic shock.

E. What diagnostic tests should be performed?

Diagnostic testing should include the following (not in specific order):

1. ECG. Determination of QRS duration and bundle-branch block morphology.

2. Echocardiography. It is important to evaluate left ventricular function, presence of wall motion abnormalities, degree of mitral regurgitation, as well as left ventricular dimensions.

3. Coronary angiography. Establishing the etiology of heart failure is critical. Patients with newly diagnosed congestive heart failure must undergo coronary angiography to rule out ischemia. In patients with known coronary disease and worsening left ventricular function, reassessment of the coronary anatomy for worsening or intervenable disease must be considered.

4. Evaluation and assessment of functional capacity. Subjective evaluation includes determination of NYHA functional class. Cardiopulmonary stress testing as well as the 6-minute walk test can give the clinician important objective baseline functional capacity and can be used to follow response to therapy. It should be noted that predicting response from these baseline parameters has not been established.

5. Quality of life scores. Quality of life scores have been used as endpoints in many of the clinical trials evaluating effectiveness of CRT.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no specific laboratory studies to use in determining candidacy for CRT; however, basic laboratory data, including complete blood count (CBC) and basic metabolic panel are important in patient workup and management. It is important to rule out anemia from chronic gastrointestinal (GI) losses as a cause of high output cardiac failure.

Biomarkers such as brain natriuretic peptide (BNP) are not only useful in the diagnosis of heart failure, but they are in the management of those with chronic disease. The evidence of its use has not been established. Serum creatinine should be checked prior to device implantation, as contrast venography of the coronary sinus is frequently performed. Other preoperative tests include a CBC to evaluate for leukocytosis or thrombocytopenia, and a coagulation profile, particularly in patients on systemic anticoagulation.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

1. Echocardiography to establish the LVEF.

2. Cardiac stress testing, preferably nuclear myocardial perfusion imaging with vasodilator stress in the setting of LBBB.

3. Coronary angiography, to rule out obstructive coronary artery disease (CAD), as an initial study or following abnormal stress testing, depending on the patient’s CAD risk profile and pretest probability.

(Please see section on diagnostic testing)

Coronary sinus venography

Device implantation requires coronary sinus venography to assess for appropriate branch targets. These are frequently performed in the left anterior oblique (LAO) projection to assess for favorable lateral positions. Right anterior oblique (RAO) images are also valuable in determining the degree to which a branch is in a basal versus apical position.

Example 1: A 40-year-old man with complete heart block, chronic right ventricular pacing, and development of severe left ventricular dysfunction referred for upgrade of a dual-chamber pacemaker to a CRT-D system.

LAO view of coronary sinus venogram. Note the temporary pacing wire required for this pacemaker-dependent patient’s revision and upgrade (Figure 1).

Figure 1.

RAO view of coronary sinus venogram (Figure 2).

Figure 2.

Final LAO lead position (Figure 3).

Figure 3.

Final RAO lead position (Figure 4).

Figure 4.

Example 2: A 52-year-old man with ischemic cardiomyopathy, severe LV dysfunction, and QRS duration over 130 msec, referred for CRT-D.

Occluded distal coronary sinus (Figure 5).

Figure 5.

Proximal available branch (Figure 6).

Figure 6.

CXR demonstrating final lead position (Figure 7).

Figure 7.

III. Management.

Systolic heart failure is a chronic disease, which requires lifelong comprehensive medical optimization and management. Patients will require routine device follow-up at 3-month intervals, which will include review of pacing sensing and thresholds, battery longevity, percentage of biventricular pacing, and review of arrhythmia detections.

Approximately 70% of patients who undergo device implantation will respond symptomatically to CRT. Some patients feel immediate benefit after CRT placement, commonly that their breathing or energy are noticeably different within the first day. Others will begin to notice changes upon resuming their daily activities at discharge, and may report benefit at their first postoperative follow-up visit. Cardiac remodeling may take weeks to months in others who ultimately will respond.

Patients that do not respond or those who have worsening of symptoms after an initial response will require the following evaluations:

1. Clinical Evaluation.

History and physical examination should be focused on symptoms of shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), and signs of decompensated heart failure. Optimization of medical therapy, ischemia evaluation, functional assessment (CPET, 6-MHW), and pulmonary function evaluation are important considerations. Repeat echocardiography should be performed to determine if patient is having worsening of left ventricular function or mitral regurgitation. Moreover, laboratory data including BNP, CBC, and basic metabolic panel must be reviewed.

2. Electromechanical Evaluation

A. Does the left ventricular lead capture the ventricle? Occasionally, left ventricular pacing thresholds may increase after device implantation, usually due to lead microdislodgement. Ongoing device checks will ensure that there is adequate pacing output for ventricular capture. Often a change in the left ventricular pacing configuration can lead to a better pacing threshold. If no acceptable threshold can be located, then a chest radiograph is required to evaluate for gross lead dislodgement, which would require reoperation for lead repositioning.

On occasion, no acceptable coronary sinus branch with adequate pacing thresholds can be located for endovascular lead placement. In these cases, the patient can be referred for surgical epicardial LV lead placement.

B. Is the patient truly receiving biventricular pacing? Evidence has shown that patients who receive pacing at least 93% of the time fare better than those with lesser degrees of pacing. A cursory check of the device’s pacing output will show the percentage of time the device delivers paced beats.

This does not mean, however, that the patient is receiving biventricular pacing for all of those beats. One common issue leading to falsely reassuring pacing counts is pseudofusion. This refers to delivered pacing spikes that do not effectively capture the heart due to intrinsic conduction faster than the programmed atrioventricular (AV) delay. Decreasing the AV delay can remedy this situation.

C. Does the device require timing optimization? There are several methods for pacing optimization in CRT devices. These focus on AV and interventricular (VV) timing.

The most commonly employed method for AV and VV optimization is based on echocardiographic parameters. Specifically, AV optimization can be achieved by using the pulsed-wave Doppler recording of mitral inflow to time pacing delivery for the end of atrial systole without allowing for diastolic mitral regurgitation. Alternatively, the aortic volume time integral (VTI) can be assessed at various AV delay values.

The VV timing can be optimized by assessing the aortic volume-time integral across a range of VV settings. Routine device programming based on these echocardiographic parameters has not been shown to improve CRT outcomes, but these may have some application in nonresponders. Newer optimization methods based on noninvasive cardiac outputs, electrocardiographic changes, and intracardiac electrogram analyses are also under investigation.

D. Is the left ventricular lead in an appropriate location? There are patients who fail to respond to CRT despite adequate LV capture and optimal device timing. Recent evidence has shown that more apical lead locations are associated with poorer CRT outcomes.

In other cases, LV scarring may contribute to ongoing mechanical dyssynchrony despite LV pacing. It is therefore important to perform echocardiographic evaluation of hemodynamics with and without biventricular pacing. If in fact the left ventricular lead is in a suboptimal position causing worsening hemodynamic effects, then LV pacing should be turned off. In such cases, lead repositioning versus surgical referral for epicardial lead placement may need consideration.

3. Device Evaluation

A. Arrhythmias including atrial fibrillation, and frequent atrial and ventricular ectopy may cause pacing counts less than 93%. Rate control with AV nodal blocking agents as well as antiarrhythmic therapy may need to be initiated to ensure adequate biventricular pacing.

Additionally, most devices offer options for ventricular triggering, such that sensed events in the right ventricle can trigger left ventricular pacing, thereby providing the patient with CRT. This can be particularly useful in patients with atrial fibrillation. Patients may need to be considered for AV nodal ablation when refractory to medical therapy.

B. Chronotropic competence is frequently overlooked in patients who are nonresponders to CRT. Evaluation of rate histograms is necessary to ensure that adequate heart rates are maintained during periods of increased physiologic need. Rate response algorithms should be optimized in patients with poor chronotropic response to activity.

A. Immediate management.

Immediate management postoperatively and predischarge includes:

1. Physical examination with careful attention to hemodynamic changes that could be related to complications including lead perforation resulting in cardiac tamponade, pneumothorax, and hemothorax.

2. Chest radiograph to rule out pneumothorax and document lead positions.

3. EKG should be performed to record morphology of biventricular pacing QRS complexes. These templates can be used in the future to compare pacing morphologies and assess left ventricular capture.

3. Device interrogation to ensure adequate sensing, thresholds, and absence of diaphragmatic stimulation.

4. Wound evaluation for signs and symptoms of possible infection.

B. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Laboratory tests to monitor response include CBC, BNP, and basic metabolic panel.

C. Long-term management.

As noted in the management section, specific attention is given to evaluation of patients that do not respond to therapy.

D. Common Pitfalls and Side-Effects of Management

1. Incomplete biV pacing (e.g., pseudofusion and frequent premature ventricular contractions [PVCs]). Regular device checks are required to assess for true CRT pacing, as well as the percentage of LV pacing, as outlined above.

2. Suboptimal medical management. Device-based therapy with CRT is complementary to ongoing optimal medical management of the patient’s heart failure. The mainstays of this treatment are afterload-reducing therapies (ACE inhibitors, ARBs, spironolactone, hydralazine with nitrates) and beta-blockers.

3. Development of arrhythmias. Patients with severe LV dysfunction are always at risk for atrial fibrillation, ventricular tachycardia, and other arrhythmias, which require ongoing vigilance. While patients with atrial fibrillation have been shown to have clinical benefit from CRT, the degree of benefit is less significant than in patients with sinus rhythm.

4. Worsening ischemia.

IV. Management with Co-Morbidities

1. Atrial fibrillation has been associated with an attenuated response to CRT. Recent evidence suggests that patients with longstanding, persistent atrial fibrillation fare better with AV node ablation than with pharmacologic AF rate control. Pharmacologic rhythm control strategies can also be useful in improving CRT delivery.

2. Ventricular arrhythmias are very frequent in patients with heart failure, which encompasses the CRT population. A patient with a device presenting with aborted sudden cardiac death (SCD) due to appropriate ICD firing requires full evaluation for decompensated heart failure and new ischemia. These patients frequently require antiarrhythmic drugs. Patients with monomorphic ventricular tachycardia may also be candidates for catheter ablation.

3. Patients with CRT-D devices whose heart failure progresses such that they require a left ventricular assist device (LVAD) placement represent a special CRT population. This is another emerging device-based therapy, the interactions of which with CRT-D and other ICDs are only now becoming apparent.

In our experiences with LVAD patients and ICDs, patients can remain asymptomatic of ventricular arrhythmias, including ventricular fibrillation (VF) for hours at a time. While it is generally thought that the LVAD overcomes the effect of the arrhythmia on the left ventricle, a common concern is that the right ventricle fails as a result of inadequate filling. In our experience, this has not been the case.

We, therefore, advocate extension of tachyarrhythmia therapies to very long detection times and allowing for many trials of antitachycardia pacing (ATP) prior to any shocks in these otherwise asymptomatic patients. Patients with shocks despite these settings should then strongly consider having their tachycardia therapies disabled altogether.

Prior to CRT implantation, all patients should be counseled on the risks and benefits of the procedure. The risks of device implantation include infection, bleeding, vascular injury, cardiac perforation, pericardial effusion, pneumothorax, and myocardial infarction, among others. Success rates of system implantation have been reported at 93%, with a 0.3% procedural mortality.

The device itself poses the risk of inappropriate shocks for a CRT-D device. Regarding CRT, patients need to be counseled that there is a 30 percent nonresponder risk, which can sometimes be addressed with programming.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

All patients undergoing permanent device implantation require prophylactic antibiotics. This can be a cephalosporin, although given the often frequent hospital exposure of these patients with heart failure or those patients undergoing a repeat procedure, the risk of methicillin-resistant infection is such that most CRT patients are likely to benefit from vancomycin.

B. What's the Evidence for specific management and treatment recommendations?

Epstein, AE, DiMarco, JP, Ellenbogen, KA. “ACC/AHA/HRS guidelines for device-based therapy”. Heart Rhythm. vol. 5. 2008. pp. e1-e62. (The ACC/AHA/HRS Guidelines for Device-Based Therapy provide a concise listing of CRT indications.)

Moss, AJ, Hall, W, Cannom, DS. “Cardiac-resynchronization therapy for the prevention of heart-failure events”. N Engl J Med. vol. 361. 2009. pp. 1329-38. (The MADIT-CRT trial demonstrated benefit from CRT for patients with NYHA Class I-II heart failure, thereby contributing to a broadening of the CRT-indicated population.)

Roger, VL, Go, AS, Lloyd-Jones, DM. “Heart disease and stroke statistics-2011 update: A report from the American Heart Association”. Circulation. vol. 123. 2011. pp. e18(This comprehensive report details the updated AHA statistics on heart disease.)

Shanks, M, Bertini, M, Delgado, V. “Effect of biventricular pacing on diatolic dyssynchrony”. J Am Coll Cardiol. vol. 56. 2010. pp. 1567-75. (This study illustrates the importance of diastolic dyssynchrony and its potential for predicting CRT response.)

Kerlan, JE, Sawhney, NS, Waggoner, AD. “Prospective comparison of echocardiographic atrioventricular delay optimization methods for cardiac resynchronization therapy”. Heart Rhythm. vol. 3. 2006. pp. 148-54. (This trial investigated CRT optimization using echocardiographic parameters to guide device programming.)

Singh, JP, Klein, HU, Huang, DT. “Left ventricular lead position and clinical outcome in the Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy (MADIT-CRT) Trial”. Circulation. vol. 123. 2011. pp. 1159-66. (This analysis of the MADIT-CRT population found suboptimal outcomes with apical positioning of the left ventricular lead in CRT.)

McAlister, FA, Ezekowitz, J, Hooton, N. “Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review”. JAMA. vol. 297. 2007. pp. 2502-14. (The morbidity and mortality benefits seen in prior CRT trials were reinforced with this systematic review).

Abraham, WT, Fisher, WG, Smith, AL. “Cardiac resynchronization in chronic heart failure”. N Engl J Med. vol. 346. 2002. pp. 1845-53. (The landmark MIRACLE trial helped to establish the benefits of biventricular pacing in patients with NYHA Class III-IV heart failure.)

Bristow, MR, Saxon, LA, Boehmer, J. “Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure”. N Engl J Med. vol. 350. 2004. pp. 2140-50. (The COMPANION trial showed a decreased combined death/hospitalization endpoint with CRT pacing, as well as improved mortality with CRT-defibrillators).

Cleland, JGF, Daubert, JC, Erdmann, E. “The effect of cardiac resynchronization on morbidity and mortality in heart failure”. N Engl J Med. vol. 352. 2005. pp. 1539-49. (The CARE-HF trial found improved morbidity, quality of life, and mortality with CRT.)

Daubert, C, Gold, MR, Abraham, WT. “Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction”. J Am Coll Cardiol. vol. 54. 2009. pp. 1837-46. (The REVERSE trial showed benefits of CRT in patients with mild heart failure symptoms of NYHA class I-II.)

Beshai, JF, Grimm, RA, Nagueh, SF. “Cardiac-resynchronization therapy in heart failure with narrow QRS complexes”. N Engl J Med. vol. 357. 2007. pp. 2461-71. (The RethinQ study did not find a significant benefit in patients with narrow QRS complexes and mechanical dyssynchrony based on echocardiographic parameters.)

Chung, ES, Leon, AR, Tavazzi, L. “Results of the predictors of response to CRT (PROSPECT) trial”. Circulation. vol. 117. 2008. pp. 2608-16. (None of the echo features studied in the PROSPECT trial provided robust information regarding CRT response.)

C. DRG Codes and Expected Length of Stay.

The relevant codes include the following:

222: Cardiac defib implant w cardiac cath w AMI/HF/shock w major complications and comorbidities (MCC)

223: Cardiac defib implant w cardiac cath w AMI/HF/shock w/o MCC

224: Cardiac defib implant w cardiac cath w/o AMI/HF/shock w MCC

225: Cardiac defib implant w cardiac cath w/o AMI/HF/shock w/o MCC

226: Cardiac defib implant w/o cardiac cath w MCC

227: Cardiac defib implant w/o cardiac cath w/o MCC

Most patients require overnight inpatient treatment with antibiotics and observation following CRT implantation to monitor for lead migration.

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