Cardiac Resynchronization Therapy in Heart Failure 

Cardiac Resynchronization Therapy in Heart Failure – 7 Interesting Facts

1. CRT is a treatment option indicated to improve symptoms that has a demonstrable morbidity and mortality benefit for select patients with heart failure with LVEF 35% or less, NYHA class II to IV, LBBB morphology, and QRS duration of 150 milliseconds or greater who are in sinus rhythm
2. Resynchronization of portion of left ventricle that has delayed left ventricular activation is pathophysiologic basis for therapy; however, robust, objective measurement of left ventricular dyssynchrony and resynchronization is not yet standardized
3. Only approximately two-thirds of all implanted patients respond to therapy, and there is wide variability in the extent of left ventricular remodeling and improvement in LVEF, heart failure hospitalization, mortality, and quality of life
4. Appropriate patient selection is a fundamental step in CRT utilization
5. Consider clinical appropriateness as well as possible predictors of nonresponse, including myocardial scarring, absence of left ventricular dyssynchrony, and mitral regurgitation
6. Clinical practice guidelines differ on recommendations for specific patient subgroups, including those with QRS duration less than 150 milliseconds, those without LBBB, those with atrial fibrillation, and those who would benefit from implantable cardioverter-defibrillator placement
7. All patients under consideration for CRT should be engaged in shared decision-making discussions to assess goals of care to facilitate patient-centered management

Alarm Signs and Symptoms

• Perform urgent assessment if the following are present:
  • Swelling or bruising of implant site that worsens over time
    • May indicate hematoma
  • Warmth, drainage, or pain around incision site
    • May indicate infection
  • Chest pain, shortness of breath, lightheadedness, near syncope, or syncope
    • May indicate arrhythmia, pneumothorax, hemothorax, myocardial perforation, or exacerbation of heart failure
  • Acute rise in creatinine level
    • May indicate acute kidney injury
  • Persistent hiccups
    • May indicate phrenic nerve capture

Introduction

• Form of cardiac pacing used in patients with symptomatic heart failure, left ventricular systolic dysfunction, and dyssynchronous ventricular activation¹
• Aims to correct high-grade intraventricular conduction delay and dyssynchrony associated with systolic heart failure in appropriately selected patients
• Provides simultaneous or near-simultaneous electrical activation of left and right ventricles via a permanent pacemaker or implantable cardiac defibrillator by placing 1 lead in right ventricle and another lead in region of left ventricle (coronary sinus)
• Subsequent electrical resynchronization of the ventricular myocardium results in mechanical resynchronization of left and right ventricular contraction, which leads to improved cardiac function
• CRT (cardiac resynchronization therapy) has been associated with:²
  • Reduction in heart failure hospitalizations
  • Improved functional status and quality of life among patients with HFrEF (heart failure with reduced ejection fraction)
  • Reduced overall morbidity and mortality

Terminology

• Biventricular pacemakers use right and left ventricular activating leads, placed in right ventricle and coronary sinus, to allow for cardiac resynchronization⁴
• Electrical dyssynchrony describes the pathology whereby normal physiologic left ventricular electrical activation is lost, resulting in impaired cardiopulmonary status⁵
• Mechanical dyssynchrony describes the differences in timing of contraction or relaxation between either:
  • Left ventricle and right ventricle (ie, interventricular dyssynchrony)
  • Different myocardial segments of left ventricle (ie, intraventricular dyssynchrony)⁷
• Responder: patient who demonstrates benefit from implant and use of cardiac resynchronization pacing
  • Successful response can be defined as:⁹
    • Improved exercise capacity
    • Improved quality of life via standardized assessments
    • Improved NYHA (New York Heart Association) functional status by at least 1 class
    • Prevention of heart failure hospitalizations
    • Left ventricular reverse remodeling as assessed using echocardiography (decreased left ventricular volume and/or improved left ventricular ejection fraction [LVEF])
• Nonresponder: patient who does not demonstrate benefit from CRT
• Negative responder: patient whose clinical condition worsens (on basis of clinical metrics) after initiation of CRT
• Coronary sinus venography: imaging that anatomically defines coronary sinus via contrast material to identify acceptable locations for left ventricular lead
• Quadripolar leads: leads placed in coronary sinus with 4 electrodes that allow for numerous pacing configurations to optimize electrical activation, battery utilization, and phrenic nerve capture
• HFrEF: LVEF 40% or less¹⁰

Treatment

Approach to Treatment

• CRT involves pacing the left ventricle along with intrinsic conduction or right ventricular pacing to restore ventricular synchrony and thus improve left ventricular systolic function and clinical outcomes
• Patient selection is the fundamental first step to ensure patients have low risk of undergoing the procedure and high likelihood of benefit¹¹
• Guidelines from European Society of Cardiology, Canadian Cardiovascular Society, National Institute for Health and Care Excellence, Heart Rhythm Society, and American Heart Association/American College of Cardiology/Heart Failure Society of America all recommend CRT for patients with heart failure who have been treated with guideline directed medical therapy for at least 90 days, are at least 40 days post myocardial infarction (if applicable), and meet the following criteria: ¹⁰
  • LVEF 35% or less
  • LBBB (left bundle branch block) QRS morphology¹²
  • Symptomatic heart failure (NYHA class II-IV)
  • QRS duration of 150 milliseconds or greater
  • Sinus rhythm

Patient Selection

• Figure 1. CRT guidelines for patients with LVEF 35% or less based on NYHA class, QRS morphology, and QRS duration. Strength of recommendations are derived from each specific guideline based on the suggested interpretation provided. – *National Institute for Health and Care Excellence guidelines provide guidance on type of device rather than recommendation or evidence level.ACC, American College of Cardiology; AHA, American Heart Association; CCS, Canadian Cardiovascular Society; ESC, European Society of Cardiology; HFSA, Heart Failure Society of America; LBBB, left bundle branch block; NICE, National Institute for Health and Care Excellence; NYHA, New York Heart Association; ms, milliseconds.

• LVEF 35% or less is a key parameter for eligibility¹²
  • Majority of CRT clinical trials have restricted enrollment to patients with LVEF less than 35%; therefore, the body of evidence supporting its use is greatest for this patient population
  • Assessment of LVEF via echocardiography is reliable; however, it does not reliably assess for mechanical dyssynchrony
  • Absence of significant dyssynchrony has been associated with nonresponse to treatment
  • Although several imaging techniques to evaluate for dyssynchrony exist, their effectiveness and relationship to patient outcomes has not been adequately assessed in clinical trials
• Patients with LBBB QRS morphology have demonstrated the most consistent benefits from CRT compared with those without LBBB in numerous clinical trials¹²
  • It remains unclear whether patients with non–LBBB QRS morphology significantly benefit from CRT¹⁶
  • MADIT-CRT trial demonstrated that CRT had no benefit for NYHA class I to II patients without LBBB, and the 7-year follow-up analysis demonstrated increased mortality among these patents¹⁷
  • Clinical practice guidelines differ on recommendations for patients without LBBB
    • Guidelines from European Society of Cardiology, Canadian Cardiovascular Society, National Institute for Health Care and Excellence, and American Heart Association/American College of Cardiology/Heart Failure Society of America provide at least moderate support for CRT for patients with QRS intervals greater than 150 milliseconds, while recommendations diverge somewhat for patients with shorter QRS intervals (Figure 1)
• Patients with symptomatic heart failure (NYHA class II-IV) have consistently demonstrated improved outcomes with CRT compared with those with asymptomatic heart failure (NYHA class I)
  • In a meta-analysis of 14 randomized trials including 4420 patients (nearly all with NYHA class III-IV symptoms and mean QRS duration of 155-209 milliseconds), CRT:¹⁹
    • Increased the likelihood of symptomatic improvement by at least 1 NYHA class (59% versus 37%; relative risk, 1.6)
    • Reduced heart failure hospitalizations 37% and all-cause mortality 22%, primarily because of a lower risk of heart failure-related death (relative risk, 0.64)
  • Additional support comes from imaging data demonstrating that CRT improves LVEF and reduces left ventricular end-systolic volume
    • MIRACLE trials demonstrated that LVEF increased 3.6% in CRT patients versus 0.4% in controls, and left ventricular end-systolic volume decreased 25.6 mL compared with no change in controls at 6-month follow-up²⁰
  • While 2022 American Heart Association/American College of Cardiology and 2014 National Institute for Health and Care Excellence guidelines suggest that CRT may be considered in patients with NYHA class I symptoms, the 2017 Canadian Cardiovascular Society and 2021 European Society of Cardiology guidelines recommend it for patients with symptomatic heart failure (NYHA class II-IV)¹⁰
• Patients with QRS duration of 150 milliseconds or greater have stronger indications for CRT compared with those with shorter QRS duration; this is particularly true for patients who do not have LBBB morphology¹⁰
  • For patients with LBBB, multiple clinical trials including MADIT-CRT,²¹ REVERSE, and RAFT²² have demonstrated superior outcomes for patients with QRS intervals of 130 to 150 milliseconds compared with shorter QRS intervals
  • Among patients without LBBB morphology, there is conflicting evidence, with only those with longer QRS intervals demonstrating improved outcomes
    • RAFT trial demonstrated significant reduction in death and heart failure hospitalizations for patients with NYHA II to III and without LBBB block when QRS was greater than 160 milliseconds but potential adverse outcomes when QRS was less than 160 milliseconds²²
    • EchoCRT, a multicenter randomized controlled trial with 1680 patients, found that CRT increased mortality in patients without LBBB and with QRS less than 130 milliseconds based on cardiac imaging data²³
  • Clinical practice guidelines differ on recommendations for patients based on QRS duration, LBBB status, and NYHA classification
• Currently the strongest recommendations for CRT are for patients in sinus rhythm because most randomized clinical trials have been restricted to patients in sinus rhythm¹²
  • Patients with atrial fibrillation and other conduction abnormalities may benefit from CRT in specific scenarios but require additional consideration
• Additional considerations
  • Patients with the following are not appropriate candidates until their medical status improves:
    • Acutely decompensated heart failure
    • Dependence on inotropes
    • Unstable ventricular arrhythmias
  • Therapy is not indicated in patients who are not expected to survive for more than 1 year owing to their comorbidities or frailty¹⁰
  • When considering patients for CRT, use a patient-centered approach that considers risk-benefit of therapy and patient preferences¹²

Intraprocedural Considerations

• Left ventricular lead placement is an important step
  • Recommend coronary sinus venography to create a roadmap to guide lead selection and assist with navigation
  • Basal posterolateral lead locations have been associated with better CRT responses compared with apical locations
    • Apical lead position compared with nonapical lead positions (eg, basal or midventricular position) has been associated with increased risk for heart failure or death (MADIT-CRT) after adjustment for clinical covariates and increased risk for death²⁴
  • Successful left ventricular lead positioning requires knowledge of phrenic nerve course, as phrenic nerve capture is a frequent limitation of left ventricular epicardial pacing
    • Phrenic nerve capture results in patient experiencing a hiccuplike sensation that often requires changes in CRT programming or occasional lead repositioning
    • Intraprocedural left ventricle lead testing is recommended to assure an adequate safety margin for capture and avoidance of phrenic nerve stimulation
• Quadripolar pacing leads, consisting of 4 electrodes placed in coronary sinus, are the standard of care to allow for various electrical vectors of pacing and to facilitate optimized resynchronization and battery use/longevity
• Successful CRT implantation (eg, placement of left ventricle pacing lead) is now achieved in 90% of cases owing in part to increased CRT use, increased operator experience, and advancement in implant tools
• In patients where left ventricle endocardial leads cannot be placed in coronary sinus, alternative options exist:
  • Left ventricle surgical epicardial leads
  • Physiologic pacing via His bundle/left bundle pacing²⁵
  • Emerging technologies (ie, wireless left ventricle endocardial implants)

Nondrug and Supportive Care

• Preimplant patient education, including information about the indication for and function of CRT device and a follow-up plan, is recommended
• CRT optimization postimplant is an important step in ensuring patients derive maximal benefit from hardware²⁶
  • First step in optimization is ensuring maximal biventricular pacing
  • Studies vary with regards to a cutoff but are in general agreement that greater than 90% pacing portends greater benefit
• Beyond pacing percentage, electrical delays and synchrony can be adjusted, and various algorithms exist to optimize electrical and thus mechanical dyssynchrony
• ECG and echocardiographic optimization of device performance have both been studied to target optimal programming of CRT devices¹²
  • Further studies are needed to determine best target and optimization methodology; however, it is evident that close follow-up and routine adjustments are required

Drug Therapy

• CRT is one component in the complex management of HFrEF in addition to pharmacologic therapy
  • Patients with heart failure being considered for treatment with CRT must first demonstrate having received at least 90 days of optimal medical management for heart failure, including: ¹⁰
    • ACE inhibitor, angiotensin receptor blocker, or angiotensin receptor–neprilysin inhibitor
    • β-Blocker
    • Loop diuretics as needed
    • Mineralocorticoid receptor antagonist, if indicated, with persistently reduced LVEF less than 35%
    • Sodium-glucose cotransporter 2 inhibitor

Admission Criteria

• Most patients undergoing CRT system implantation should be observed in a hospital setting for postprocedure monitoring
• Postprocedure evaluation
  • Physical examination
    • Evaluate for hematoma around incision site
    • Monitor volume status and electrolyte levels
      • CRT may result in significant diuresis
  • Electrophysiologic evaluation
    • Monitor patient on telemetry for any postimplant rhythm disturbances as a proarrhythmic response can be seen on rare occasion
    • Obtain device interrogation performed by electrophysiologic team before hospital discharge to confirm maximal biventricular capture
    • Obtain surface ECG before hospital discharge
  • Perform chest radiography postprocedure to evaluate for pneumothorax
  • Perform 2D echocardiography before discharge if there is concern for postprocedural complication based on patient symptoms or clinical findings

Special Considerations

Atrial Fibrillation

• In patients with atrial fibrillation, rapid intrinsic conduction may reduce ability of CRT pacemaker to provide effective biventricular pacing
  • Adequate biventricular pacing may not occur in up to two-thirds of patients with atrial fibrillation, leading to a high nonresponse rate
• Moreover, observational data have demonstrated potential harm and increased mortality for patients with atrial fibrillation who undergo CRT²⁸
• There is a paucity of trial data for use of CRT in patients with atrial fibrillation as most studies involve patients in sinus rhythm
  • Subgroup analysis of RAFT trial is most robust demonstration, where there was no significant improvement shown in mortality, hospitalizations, 6-minute walk time, or quality of life among patients with heart failure and atrial fibrillation who underwent CRT¹²
  • Notably, most patients did not achieve adequate biventricular pacing
  • Patients with atrioventricular junction ablation were noted to have improved outcomes compared with those who did not undergo ablation
    • Use of atrioventricular nodal blocking agents has demonstrated similarly improved outcomes if greater than 90% biventricular capture is obtained¹²
• Nonresponse rates and overall outcomes are improved when patients receive pharmacotherapy with atrioventricular nodal blocking agents or are status post atrioventricular nodal ablation and subsequently achieve a high pacing percentage (greater than 90%)
• Guidelines from European Society of Cardiology, Canadian Cardiovascular Society, and American Heart Association/American College of Cardiology/Heart Failure Society of America provide moderate strength recommendations that patients with atrial fibrillation who otherwise meet CRT criteria should be considered if nearly 100% ventricular pacing is required or can be achieved
• Ongoing RAFT-PermAF trial is expected to provide more robust data on outcomes for patients with atrial fibrillation that can influence recommendations in the future²⁹

Indications for CRT Compared With Traditional Right Ventricular Pacing

• Standard right ventricular pacing has been associated with ventricular dyssynchrony and left ventricular remodeling leading to development of heart failure among patients with previously normal ejection fraction and those with HFrEF
• Analysis of secondary endpoints from MOST study demonstrated that standard right ventricular pacing is associated with an increased incidence of atrial fibrillation and new diagnosis of heart failure among patients previously in sinus rhythm and with normal ejection fraction
• BLOCK AF trial demonstrated that patients with mildly reduced ejection fraction (less than 50%) had improved composite outcomes of LVEF, heart failure events, and mortality with biventricular pacing over right ventricular pacing⁷
• Patients with right ventricular pacing who develop HFrEF with LVEF less than 35% may benefit from biventricular pacing and may be considered for an upgrade to CRT; however, further trial data demonstrating efficacy and outcomes are still needed¹²
• CRT is strongly recommended over right ventricular pacing for patients with LVEF less than 40% with atrial fibrillation and high-grade atrioventricular block or those who otherwise have an indication for ventricular pacing¹²

Implantable Cardioverter-Defibrillator and CRT

• No head-to-head trials have been held comparing heart failure outcomes among patients receiving CRT with pacing alone versus CRT with implantable cardioverter-defibrillator
• Although data obtained in multiple meta-analyses have demonstrated a reduction in heart failure mortality, questions remain regarding the independent association of CRT with implantable cardioverter-defibrillator with these improved outcomes
• 2021 European Society of Cardiology guidelines offer strong recommendations to use CRT with implantable cardioverter-defibrillator if patient meets criteria for implantable cardioverter-defibrillator and note that shared decision-making with patient should inform treatment strategy¹²

Follow-up

Monitoring

• Referral to CRT optimization clinic has been established as part of a multidisciplinary approach to heart failure disease management
• Multidisciplinary team that includes heart failure and electrophysiologic specialists should collaborate to ensure continued and optimized CRT response for these complex heart failure patients
• Remote device evaluation and management is the standard of practice in combination with at least annual in-person follow-up visits
• Remote device management includes 3 components:
  • Remote follow-up: full remote device interrogation
  • Remote monitoring: unscheduled transmission of alert events for clinician review
  • Patient-initiated follow-up: interrogations prompted by patient symptoms or complaints
• Clinical practice guidelines recommend combination of remote management approach and in-office visits every 12 months or more frequently as needed¹²

Complications

• Most recognized perioperative complications
  • Failure to successfully implant left ventricle lead
  • Pocket hematoma
  • Hemo- and/or pneumothorax
  • Coronary sinus dissection
  • Cardiac perforation or tamponade
  • Extracardiac stimulation
  • Left ventricle lead dislodgement, including loss of capture
  • Exacerbation of heart failure
  • Acute renal failure
  • Death
• Phrenic nerve capture is a complication of left ventricle lead movement, which results in symptomatic diaphragm movements that are often perceived by patient as hiccups
  • Proceed with electrical reprogramming to attempt to resolve
• Overall perioperative complication rates for pacemaker implant range from 4% to 5% at 30 days to 7% to 8% at 90 days¹²
• Rate of complications is higher among hospitals that perform a low volume of procedures¹²
• Patients who receive CRT as an upgrade from standard pacemaker compared with those with de novo CRT have a higher risk of mortality and myocardial perforation and need for revision¹²
• Many perioperative complications relate directly to patient selection and preparation as well as operative technique
  • Risk of complications increases with number of comorbid conditions¹²
  • Heart failure status must be optimized medically to avoid instances of acute perioperative decompensation
  • Death is rare perioperative complication and usually related to implant attempts in unstable patients
  • Patients with acutely decompensated heart failure, dependence on inotropes, or unstable ventricular arrhythmias are unacceptable candidates until their medical status is improved³⁰

Prognosis

• Randomized controlled trials have shown that CRT prolongs survival and reduces morbidity and mortality for approximately two-thirds of eligible patients undergoing CRT
  • Less than 5% will worsen (ie, negative responders)
  • Less than one-third have no clinical, hemodynamic, or mortality benefit (ie, nonresponders)¹⁹
• Clinical data have shown that female patients benefit more from CRT in comparison with male patients with regard to responder rate
  • Although CRT is not recommended for patients with narrow QRS complex, in a study of individual patient data, female patients demonstrated benefit from CRT with defibrillator at a shorter QRS duration compared with male patients³¹
  • Further study into sex differences is required to allow for better practice guidelines³¹
• Potential clinical contributors to suboptimal response
  • Absence of mechanical dyssynchrony¹²
  • Myocardial scarring¹²
    • Myocardial scar tissue is more resistant to reversal of remodeling than healthy tissue²⁷
  • Mitral regurgitation¹²
  • Right ventricular dysfunction without left ventricular dysfunction¹²
  • Not prescribed or not compliant with an evidence-based drug therapy or dietary recommendations
  • BMI of 30 kg/m² or more³²
  • Anemia (defined as hemoglobin level less than 11 g/dL for female patients and less than 12 g/dL for male patients)³³
• Potential electromechanical issues related to suboptimal response
  • Left ventricle lead malposition (mostly anteriorly)¹²
  • Underlying narrow QRS complex (less than 130 milliseconds)
  • Inefficient left ventricle filling due to suboptimal programming of atrioventricular timings
• Potential electrophysiologic and device issues related to suboptimal response¹²
  • Underlying arrhythmias are common (eg, atrial fibrillation, significant amount of supraventricular and ventricular ectopy), causing insufficient percentage of biventricular pacing (less than 90% of the time)

Referral

• After implant, referral to CRT optimization clinic protocol has been established as a component of multidisciplinary heart failure disease management programs
• While various models exist, heart failure and electrophysiologic specialists should collaborate to ensure continued and optimized CRT response for these patients

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