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From the mid-1980s through the late 1990s, great been made in improving heart failure clinical advances were made in the pharmacological status or outcomes with newer (investigational) management of chronic systolic heart failure. drug therapies, and heart failure morbidity and During that time, several drugs or drug com-mortality have remained high. In the year 2001, a binations were shown to substantially new era of implantable device therapies for the improve functional status and to reduce mor-treatment of heart failure began with the U.S. bidity and mortality in heart failure patients. Food and Drug Administration (FDA) approval of Since then, however, no additional gains have the first cardiac resynchronization therapy (CRT) device. Over the subsequent 4 years, implantable cardioverter defibrillators (ICDs) and combined CRT-ICD devices were also approved for the management of heart failure. In the former case, ICDs became indicated for the primary prevention of death in patients with heart failure and reduced ejection fractions, in addition to the previous secondary prevention indication for these devices. In the latter instance, combined CRTICD devices were shown to reduce morbidity and mortality in heart failure patients with ventricular dyssynchrony. In acknowledgement of the evidence-based benefits of these devices, the 2005 update to the American College of Cardiology/American Heart Association (ACC/AHA) heart failure guideline strongly supports, with Class I indications, the use of an ICD or CRT device in the management of eligible heart failure patients.1
Left ventricular assist devices (LVADs) represent another approved approach to treating highly selected patients with end-stage heart failure. These devices may be used as a bridge to cardiac transplant, as so-called destination (or permanent) therapy, or as means to support patients with reversible causes of heart failure temporarily as they recover left ventricular function. The use of an LVAD as a surgical approach to heart failure is discussed in Chap. 15. While not therapeutic per se, implantable devices that monitor physiological parameters such as patient activity level, heart rate variability, intrathoracic impedance, and/or hemodynamics have been developed. In some instances, these data are already available in currently implantable CRT and ICD devices. The exact utility of such device-based diagnostic or monitoring features is unknown and currently under investigation. Other promising novel implantable therapeutic devices are also under investigation for the treatment of heart failure. This chapter reviews the use of CRT and ICDs for the management of heart failure, discusses the potential utility of implantable heart failure monitoring devices, and previews some other investigational device therapies for heart failure.
VENTRICULAR DYSSYNCHRONY IN HEART FAILURE
Several conduction abnormalities are commonly seen in association with chronic heart failure. Among these are abnormalities of ventricular conduction such as bundle branch blocks that alter the timing and pattern of ventricular contraction so as to place the already failing heart at a further mechanical disadvantage. Specifically, these ventricular conduction delays produce suboptimal ventricular filling, a reduction in left ventricular contractility, prolonged duration of mitral regurgitation, and paradoxical septal wall motion.2–5 Collectively, these mechanical manifestations of altered ventricular conduction have been termed ventricular dyssynchrony. Classically, ventricular dyssynchrony has been defined by QRS duration ≥120 msec. By this definition, about one-third of patients with systolic heart failure have ventricular dyssynchrony.6,7 In addition to reducing the ability of the failing heart to eject blood, ventricular dyssynchrony has also been associated with increased mortality in heart failure patients.8–11
After several attempts during the mid-1990s to improve heart failure with pacing therapies, atrial-synchronized biventricular pacing emerged as the most promising approach for the treatment of ventricular dyssynchrony. This form of pacing therapy has come to be known as CRT. The history of CRT began with a single case report of encouraging results.12 Such favorable single-case experiences led to small observational studies evaluating the acute effects of biventricular pacing on hemodynamics and on other measures of cardiac performance.4,13 These studies provided additional support for the concept of CRT. Several uncontrolled or unblinded studies soon followed to further evaluate the acute and longer term effects of CRT on clinical status in heart failure patients.14–22 The results of these trials were equally encouraging, with patients demonstrating consistent and sustained improvement in exercise tolerance, quality of life, and New York Heart Association (NYHA) functional class. Finally, large-scale randomized controlled trials of CRT confirmed the beneficial effects of this therapy in heart failure patients with ventricular dyssynchrony.
RANDOMIZED CONTROLLED TRIALS OF CARDIAC RESYNCHRONIZATION THERAPY
More than 4000 patients have been evaluated in randomized single- or double-blinded controlled trials of CRT in heart failure. The following randomized controlled trials are considered among the landmark studies of CRT: the Multisite Stimulation in Cardiomyopathy (MUSTIC) studies, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, MIRACLE ICD, the CONTAK CD trial, the Cardiac Resynchronization in Heart Failure (CARE HF) trial, and the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial.23–32 To understand the clinical benefits, risks, and limitations of CRT with or without an ICD, these studies will be reviewed.
Multisite Stimulation in Cardiomyopathy Trials
The MUSTIC trials were designed to evaluate the safety and efficacy of cardiac resynchronization in patients with advanced heart failure, ventricular dyssynchrony, and either normal sinus rhythm or atrial fibrillation.23,24 They represent the first randomized single-blinded trials of CRT for heart failure. The first study involved 58 randomized patients with NYHA Class III heart failure, normal sinus rhythm, and QRS duration of at least 150 msec. All patients were implanted with a CRT device, and after a run-in period, patients were randomized in a single-blind fashion to either active pacing or to no pacing. After 12 weeks, patients were crossed over and remained in the alternate study assignment for 12 weeks. After completing this second 12-week period, the device was programmed to the patient’s preferred mode of therapy. The second MUSTIC study involved fewer patients (only 37 completers) with atrial fibrillation and a slow ventricular rate (either spontaneously or from radiofrequency ablation). A VVIR biventricular pacemaker and leads for each ventricle were implanted and the same randomization procedure described above was applied; however, biventricular VVIR pacing versus single site right ventricular VVIR pacing (rather than no pacing) were compared in this group of patients with atrial fibrillation.
The primary endpoints for MUSTIC were exercise tolerance assessed by measurement of peak VO2or the 6-minute hall walk test and quality of life determined using the Minnesota Living with Heart Failure questionnaire. Secondary endpoints included rehospitalizations and/or drug therapy modifications for worsening heart failure. Results from the normal sinus rhythm arm of MUSTIC provided strong evidence of benefit. The mean distance walked in 6 minutes was 23% greater with CRT than during the inactive pacing phase (P <0.001). Significant improvement was also seen in quality of life and NYHA functional class ranking. There were fewer hospitalizations during active resynchronization therapy. The atrial fibrillation group evaluated in MUSTIC demonstrated similar improvements, although the magnitude of benefit was slightly less.
Multicenter InSync Randomized Clinical Evaluation
MIRACLE was the first prospective, randomized, double-blind, parallel-controlled clinical trial designed to evaluate the merits of CRT and to further elucidate potential mechanisms of action of CRT.25,26 Primary endpoints were NYHA class, quality of life score (using the Minnesota Living with Heart Failure questionnaire), and 6minute hall walk distance. Secondary endpoints included assessments of a composite clinical response, cardiopulmonary exercise performance, neurohormone and cytokine levels, QRS duration, cardiac structure and function (as determined by echocardiography), and a variety of measures of worsening heart failure and combined morbidity and mortality.
The MIRACLE trial was conducted between 1998 and 2000. Four hundred and fifty-three patients with moderate to severe symptoms of heart failure associated with a left ventricular ejection fraction ≤35% and QRS duration of at least 130 msec were randomized (double-blind) to cardiac resynchronization (n = 228) or to a control group (n = 225) for 6 months, while conventional therapy for heart failure was maintained.26 Compared with the control group, patients randomized to CRT demonstrated a significant improvement in quality of life score (–18 vs. –9 points, P = 0.001), 6-minute walk distance (+39 vs. +10 m, P = 0.005), NYHA functional class ranking (–1 vs. 0 class, P <0.001), treadmill exercise time (+81 vs. +19 seconds, P = 0.001), peak VO2 (+1.1 vs. +0.1 mL/kg/min, P <0.01), and left ventricular ejection fraction (LVEF) (+4.6% vs. –0.2%, P <0.001). Patients randomized to CRT demonstrated a highly significant improvement in a composite clinical heart failure response endpoint, compared to control subjects, suggesting an overall improvement in heart failure clinical status. In addition, when compared with the control group, fewer patients in the CRT group required hospitalization (8% vs. 15%) or intravenous medications (7% and 15%) for the treatment of worsening heart failure (both P <0.05). In the resynchronization group, the 50% reduction in hospitalization was accompanied by a significant reduction in length of stay, resulting in a 77% decrease in total days hospitalized over 6 months compared to the control group. The major limitation of the therapy was due to unsuccessful implantation of the device in 8% of patients. The results of this trial led to the U.S. FDA approval of the InSync system in August 2001, the first approved CRT system in America, allowing the introduction of CRT into clinical practice.
The MIRACLE trial also provided persuasive evidence supporting the occurrence of reverse left ventricular remodeling with chronic CRT. In the MIRACLE trial, serial Doppler echocardiograms were obtained at baseline 3, and 6 months in a subset of 323 patients.26,33 Cardiac resynchronization therapy for 6 months was associated with reduced end-diastolic and end-systolic volumes (both P <0.001), reduced left ventricular mass (P <0.01), increased ejection fraction (P <0.001), reduced mitral regurgitant blood flow (P <0.001), and improved myocardial performance index (P <0.001) as compared with control (Fig. 14-1). These effects are similar to those seen with b-blockade in heart failure but were seen in MIRACLE in patients already receiving b-blocker therapy.
Multicenter InSync-ICD Randomized Clinical Evaluation
The MIRACLE ICD study was designed to be almost identical to the MIRACLE trial. MIRACLE ICD was a prospective, multicenter, randomized, double-blind, parallel-controlled clinical trial intended to assess the safety and efficacy of a combined CRT-ICD system in patients with dilated cardiomyopathy (LVEF ≤35%, left ventricular end diastolic dimension [LVEDD] ≥55 mm), NYHA Class III or IV heart failure, ventricular dyssynchrony (QRS ≥130 msec), and an indication for an ICD. Primary and secondary efficacy measures were essentially the same as those evaluated in the MIRACLE trial, but also included measures of ICD function (including the efficacy of anti-tachycardia therapy with biventricular pacing).
Of 369 patients receiving devices and randomized, 182 were controls (ICD active, CRT inactive) and 187 were in the resynchronization group (ICD active, CRT active). At 6 months, patients assigned to active CRT had a greater improvement in median quality of life score (–17.5 vs. –11.0, P = 0.02) and functional class (−1 vs. 0 class, P = 0.007) than controls, but were no different than controls in the change in distance walked in 6 minutes (55 m vs. 53 m, P = 0.36).27 Peak oxygen consumption increased by 1.1 mL/kg/min in the resynchronization group versus 0.1 mL/kg/min in controls (P = 0.04), while treadmill exercise duration increased by 56 seconds in the CRT group and decreased by 11 seconds in controls (P = 0.0006). The magnitude of improvement was comparable to that seen in the MIRACLE trial, suggesting that heart failure patients with an ICD indication benefit as much from CRT as those patients without an indication for an ICD. The combined CRT-ICD device used in this study was approved by the FDA for use in NYHA Class III and IV systolic heart failure patients with ventricular dyssynchrony and an ICD indication in June 2002.
CONTAK CD
The CONTAK CD trial enrolled 581 symptomatic heart failure patients with ventricular dyssynchrony (QRS > 120 msec), and malignant ventricular tachyarrhythmias, who were all candidates for an ICD.28 Following unsuccessful implant attempts and withdrawals, 490 patients were available for analysis. The study did not meet its primary endpoint of a reduction in disease progression, defined by a composite endpoint of heart failure hospitalization, all-cause mortality, and ventricular arrhythmia requiring defibrillator therapies, although the trends were in a direction favoring improved outcomes with CRT. However, the CONTAK CD trial did demonstrate statistically significant improvements in peak oxygen uptake and quality of life in the resynchronization group compared to control subjects, although quality of life was improved only in NYHA Class III and IV patients without right bundle branch block. Left ventricular dimensions were also reduced, and LVEFs increased, as seen in other trials of CRT. Importantly, the improvement seen in peak VO2 with cardiac resynchronization was again comparable to that observed in the MIRACLE trial. Improvements in NYHA functional class were observed in NYHA Class III-IV patients. The CONTAK CD device was approved by the FDA for use in NYHA Class III and IV systolic heart failure patients with ventricular dyssynchrony and an ICD indication in May 2002.
Cardiac Resynchronization in Heart Failure Trial
The Cardiac Resynchronization in Heart Failure (CARE HF) trial was designed to evaluate the effects of resynchronization therapy without an ICD on morbidity and mortality in patients with NYHA Class III or IV heart failure and ventricular dyssynchrony.29,30 Eight hundred and nineteen patients with LVEFs of 35% or less and ventricular dyssynchrony defined as a QRS duration ≥150 msec or a QRS duration between 120 msec and 150 msec with echocardiographic evidence of dyssynchrony were enrolled in this randomized, unblinded controlled trial and followed for an average of 29.4 months.30 Four hundred and four patients were assigned to receive optimal medical therapy alone and 409 patients were randomized to optimal medical therapy plus resynchronization therapy alone. The risk of death from any cause or unplanned hospitalization for a major cardiac event, the primary endpoint analyzed as time to first event, was significantly reduced by 37% in the treatment group compared to control subjects (hazard ratio, 0.63; 95% confidence interval [CI], 0.51 to 0.77; P <0.001; Fig. 14-2). In the CRT group, 82 patients (20%) died during follow-up compared to 120 patients (30%) in the medical group, yielding a significant 36% reduction in all-cause mortality with resynchronization therapy (hazard ratio, 0.64; 95% CI, 0.48 to 0.85; P <0.002). Resynchronization therapy also significantly reduced the risk of unplanned hospitalization for a major cardiac event by 39%, all-cause mortality plus heart failure hospitalization by 46%, and heart failure hospitalization by 52%.
Begun in early 2000, COMPANION was a multicenter, prospective, randomized controlled clinical trial designed to compare drug therapy alone to drug therapy in combination with cardiac resynchronization in patients with dilated cardiomyopathy, an IVCD, NYHA Class III or IV heart failure, and no indication for a device.31,32 COMPANION randomized 1520 patients into one of three treatment groups in a 1:2:2 allocation: Group I (308 patients) received optimal medical care only, Group II (617 patients) received optimal medical care and the Guidant CONTAK TR (biventricular pulse generator), and Group III (595 patients) received optimal medical care and the CONTAK CD (combined heart failure/ bradycardia/tachycardia device). The primary endpoint of the COMPANION trial was a composite of all-cause mortality and all-cause hospitalization, measured as time to first event, beginning from time of randomization. Secondary endpoints included all-cause mortality and a variety of measures of cardiovascular morbidity. When compared to optimal medical therapy alone, the combined endpoint of mortality or heart failure hospitalization was reduced by 35% for patients receiving CRT and 40% for patients receiving CRT-ICD (both P <0.001). For the mortality endpoint alone, CRT patients had a 24% risk reduction (P = 0.060) and CRT-ICD patients experienced a risk reduction of 36% (P <0.003), when compared to optimal medical therapy. COMPANION confirmed the results of earlier resynchronization therapy trials in improving symptoms, exercise tolerance, and quality of life for heart failure patients with ventricular dyssynchrony. In addition, COMPANION showed for the first time the impact of CRT-ICD in reducing all-cause mortality.
LIMITATIONS OF CARDIAC RESYNCHRONIZATION THERAPY
The success rate for placement of a transvenous cardiac resynchronization system has ranged from about 88–92% in clinical trials. Thus, some patients undergoing an implant procedure will not receive a functioning system using this approach. Implant-related complications are similar to those seen with standard pacemakers and defibrillators, with the additional risk of dissection or perforation of the coronary sinus. This is a rare event but may lead to substantial morbidity and even mortality in heart failure patients.
Despite the results of randomized controlled CRT trials, some patients do not respond to this therapy. The nonresponder rate for cardiac resynchronization therapy appears to be about 25%, a rate that is similar to the nonresponder rate for heart failure drug therapies. A variety of factors have been proposed as contributing to the nonresponder rate associated with CRT including suboptimal left ventricular lead placement, suboptimal atrioventricular (AV) and interventricular (VV) timing, ventricular scar, and heart failure disease progression. One identifiable cause of poor response is loss of resynchronization. A specific programming sequence should be performed in the clinic to determine capture thresholds and document that left ventricular capture is present. Lead dislodgement or a change in capture threshold may result in the loss of left ventricular pacing and thus the beneficial effects of CRT may also be lost. It is also possible that left ventricular lead placement and pacing thresholds are fine but resynchronization is lost for other reasons. For example, anything that frequently or consistently inhibits left ventricular stimulation can effectively inhibit CRT. If the AV interval is too long and the patient’s intrinsic PR conduction inhibits biventricular pacing, deterioration may occur. The AV interval may have been programmed appropriately but accelerated intrinsic AV conduction could result in loss of effective biventricular pacing. This is commonly seen when atrial fibrillation occurs, resulting in a rapid ventricular response competing with biventricular pacing. Frequent premature ventricular contractions may also inhibit ventricular pacing output. While follow-up of the device itself and battery life are similar to that seen for contemporary dual-chamber pacemakers and defibrillators and generally managed by an implanting physician, heart failure specialists, general cardiologists, and primary care providers should possess the knowledge required to recognize the aforementioned limitations of resynchronization therapy and troubleshoot them.
INDICATIONS FOR CARDIAC RESYNCHRONIZATION THERAPY IN HEART FAILURE PATIENTS
The 2005 ACC/AHA heart failure guideline proposes a Class I indication for CRT.1 Patients with LVEF ≤35%, normal sinus rhythm, and NYHA functional Class III or ambulatory Class IV symptoms despite recommended optimal medical therapy and who have ventricular dyssynchrony should receive CRT, unless contraindicated. Currently, the guideline defines ventricular dyssynchrony as a QRS duration of at least 120 msec. However, echocardiography appears to be a promising way to define ventricular dyssynchrony in the future, so that a newer definition of ventricular dyssynchrony may one day prevail. This is being studied in the Predictors of Responsiveness to CRT (PROSPECT) trial.34 Other ongoing trials of CRT are evaluating the usefulness of this therapy in NYHA Class I and II patients and in patients with narrow QRS durations but with echocardiographic evidence of ventricular dyssynchrony.
SUDDEN CARDIAC DEATH IN HEART FAILURE
Patients with heart failure and left ventricular systolic dysfunction are at increased risk for sudden cardiac death (SCD).35,36 Sudden cardiac death is the leading cause of mortality in patients with heart failure and occurs at a rate of six-to-nine times that is seen in the general population. A randomized controlled trial of b-blockade in heart failure demonstrated that patients with NYHA Class II or III symptoms die most frequently as a result of SCD.37 This study estimated the proportion of total mortality attributable to SCD at 64% and 59% for NYHA Class II and III patients, respectively. In contrast, the major cause of death in Class IV patients was worsening heart failure.
Given this high incidence of SCD in heart failure, it was easy to hypothesize that an ICD used as prophylactic therapy would reduce total mortality by reducing the incidence of SCD. A series of recently completed and published studies have confirmed this notion.38–43 These studies focused mainly on patients with coronary artery disease and left ventricular dysfunction and more recently on those patients with left ventricular systolic dysfunction of any cause.
RANDOMIZED CONTROLLED TRIALS OF IMPLANTABLE CARDIOVERTER DEFIBRILLATORS IN HEART FAILURE
Several early studies including the Multicenter Automatic Defibrillator Implantation Trial (MADIT), the Coronary Artery Bypass Graft (CABG)-Patch trial, and the Multi-center Unsustained Tachycardia Trial (MUSTT) supported the benefit of prophylactic ICD implantation.38–40 The landmark trials establishing a role for ICDs as primary prevention of mortality in heart failure patients are MADIT II, the Prophylactic Defibrillator Implantation in Patients with Nonischemic Dilated Cardiomyopathy (DEFINITE) trial, and the National Institutes of Health sponsored Sudden Cardiac Death-Heart Failure Trial (SCD-HeFT).41–43
Multicenter Automatic Defibrillator Implantation II Trial
MADIT II, a randomized controlled trial, was prospectively designed and powered to assess the survival benefit of ICDs in a population of post-MI patients with reduced ejection fractions (<30%). Importantly, this trial included no arrhythmic markers such as nonsustained or inducible ventricular tachycardia for inclusion. A total of 1232 patients were randomly assigned in a 3:2 ratio to receive an ICD (742 patients) or conventional medical therapy (490 patients). During an average follow-up of 20 months, the all-cause mortality rates were 19.8% in the conventional therapy arm and 14.2% in the ICD group (31% relative risk reduction, P = 0.016).41 The effect of ICD therapy on survival was similar in subgroup analyses stratified according to age, gender, ejection fraction, NYHA class, and the QRS interval. Moreover, b-blocker utilization was 72% in these patients and was well balanced between the ICD and conventional therapy groups.
Of note, the majority of patients enrolled into MADIT II were classified in NYHA Class II or III. Class IV patients were excluded and the Class I cohort was relatively small. The average left ventricular ejection fraction was 23%. These findings suggest that heart failure patients with mild-tomoderate symptoms and moderate-to-severe reductions in LVEF may benefit the most from a prophylactic ICD. Moreover, in contrast to MADIT I, where the survival benefit of ICD therapy was seen early post-randomization, the survival benefit observed in MADIT II began approximately 9 months after the device was implanted. The authors suggested that this difference may be due to a lower-risk population enrolled in MADIT II, the absence of arrhythmia as risk stratification for entry, and/or the use of more aggressive medical treatment. Regardless of the explanation, this observation may be important when considering the timing of device placement in eligible patients.
Prophylactic Defibrillator Implantation in Patients with Nonischemic Dilated Cardiomyopathy Trial
While MADIT II enrolled exclusively post-MI patients with an ischemic cause of left ventricular systolic dysfunction and heart failure, the DEFINITE trial was the first randomized trial of primary prevention therapy with an ICD in nonischemic cardiomyopathy patients.42 Such patients also exhibit high rates of SCD; however, until recently, there has been little consensus regarding the management of SCD risk in such patients. This may be due, in part, to limitations in objective risk assessment, in that no invasive or noninvasive testing procedure has been shown to accurately determine which nonischemic heart failure patient is likely to die suddenly. Also clouding the picture were older observations suggesting that the prophylactic administration of an antiarrhythmic agent, amiodarone, might prolong survival in nonischemic cardiomyopathy patients.44
The DEFINITE trial was a prospective evaluation of 458 patients with nonischemic dilated cardiomyopathy. Entry criteria included an ejection fraction of ≤35%, a history of symptomatic heart failure, and the presence of ambient arrhythmias defined as an episode of nonsustained ventricular tachycardia or at least 10 premature ventricular contractions per 24-hour period on continuous ambulatory electrocardiographic monitoring. Two hundred and twenty-nine patients were randomized to each arm of the study to receive either an ICD and standard medical therapy or standard medical therapy alone. Compliance with medical therapy was excellent and included an angiotensin-converting enzyme inhibitor (ACE-I) in 86% of the cohort and a b-blocker in 85%. The patients were followed for a mean of 29 ± 14.4 months with a primary endpoint of all-cause mortality.
There were 68 deaths reported in DEFINITE, 28 in the ICD group, and 40 in the standard therapy group. The implantation of an ICD yielded a nonsignificant 35% reduction in death from any cause (hazard ratio, 0.65; 95% CI, 0.4 to 1.06; P = 0.08) and significantly reduced the risk of sudden death by a remarkable 80% (hazard ratio, 0.20; 95% CI, 0.06 to 0.71; P = 0.006). In the subgroup of NYHA Class III patients, all-cause mortality was significantly decreased in the ICD arm (hazard ratio, 0.37, 95% CI 0.15 to 0.90; P = 0.02).
Although this study was underpowered and did not reach statistical significance with respect to the primary endpoint of all-cause mortality for the entire randomized cohort, the results demonstrated a strong trend toward a survival advantage for patients receiving an ICD. It is worth mentioning that the all-cause mortality reduction seen in DEFINITE was 35%, a value that is strikingly similar to the 31% relative risk reduction observed in the ischemic population studied in MADIT II. The statistical power of DEFINITE was affected by a low rate of SCD in both groups, which may be related to aggressive utilization of ACE-I and b-blockade in this trial.
Sudden Cardiac Death-Heart Failure Trial
The results of the SCD-HeFT trial, published in 2005, have had a substantial impact on current practice and reimbursement guidelines for ICDs.43 This landmark randomized controlled trial enrolled 2521 patients from 148 mostly American centers between 1997 and 2001. Patients with NYHA Class II (70%) or III (30%) heart failure and reduced LVEF (≤35%; mean about 25%) of either ischemic or nonischemic etiology were eligible for the study. SCD-HeFT was a three-arm trial, comparing treatment with an ICD to amiodarone and placebo. Specifically, SCD-HeFT addressed the following issues in heart failure treatment: (1) whether or not empirical amiodarone therapy saved lives in well-treated NYHA Class II and III heart failure patients with no arrhythmic indication for the drug and (2) whether or not a prophylactic ICD saved lives in such patients with heart failure from either an ischemic or nonischemic cause.
In SCD-HeFT, patients received standard heart failure therapy, if tolerated, which included an ACE-I or angiotensin receptor blocker (85%), b-blocker (69%), and aldosterone antagonists (19%), compatible with guidelines recommendations at the time the study was conducted. The median follow-up was 45.5 months. Importantly, the cohort was equally divided between ischemic and nonischemic causes of heart failure, allowing an important subgroup analysis of these cohorts to be done.
Mortality rates in the ICD, amiodarone, and placebo groups were 17.1%, 24%, and 22.3% at 3 years and 28.9%, 34.1%, and 35.9%, respectively, at 5 years. The ICD was associated with a statistically significant 23% reduction in all-cause mortality compared to placebo (hazard ratio 0.77; 97.5% CI, 0.62 to 0.96, P = 0.007). Outcomes on amiodarone were not significantly different from placebo across all subgroups (hazard ratio 1.06; 97.5% CI, 0.86 to 1.30) (Fig. 14-3). Similar degrees of benefit were noted in patients with ischemic (21% mortality reduction) and nonischemic (27% mortality reduction) heart failure, thus confirming the findings of MADIT II and DEFINITE, respectively. The SCD-HeFT trial provides the most robust evidence to date supporting the prophylactic use of an ICD in patients with NYHA Class II and III systolic heart failure of virtually any cause.
INDICATIONS FOR PROPHYLACTIC IMPLANTABLE CARDIOVERTER DEFIBRILLATOR IMPLANTATION IN HEART FAILURE PATIENTS
The 2005 ACC/AHA heart failure guideline endorses Class I indications for the use of an ICD as primary prevention of all-cause mortality in well-treated NYHA Class II and III patients with LVEFs of less than or equal to 30% and either ischemic or nonischemic cardiomyopathy.1 There is a Class IIa indication for such patients with ejection fractions of 31–35%. The reasoning behind these separate indications stems from the fact that MADIT II and SCD-HeFT used different ejection fraction criteria for enrollment. In any event, patients with moderate-to-severe left ventricular systolic dysfunction and NYHA Class II or III heart failure should receive an ICD, unless they have a poor chance of survival (<1 year) related to some comorbidity or a contraindication to the implantation or use of this device.
LEVERAGING IMPLANTABLE DEVICES TO MONITOR HEART FAILURE
Implantable devices can provide substantial physiological information about heart failure patients. Such information may be useful in evaluating heart failure clinical status and/or in predicting episodes of heart failure decompensation. If these devices are reliable in the latter sense, the use of this information may improve heart failure outcomes by reducing the risk of worsening heart failure. For example, many implantable CRT and ICD devices can provide information on atrial heart rate and rhythm, ventricular heart rate and rhythm, patient activity level, heart rate variability (HRV), and in some cases, intrathoracic impedance, which has been proposed as a measure of lung “wetness.”
Many implantable devices record an activity trend, providing an objective record of the number of hours per day that patients are physically active. The activity level may serve as a useful teaching and reinforcement tool to both the patient and family about the importance and level of activity. Since exercise intolerance is a manifestation of worsening heart failure, a decrease in patient activity level may provide one clue to disease progression or decompensation. This measurement may be viewed as complimentary to the patient history and, perhaps, more objective. In fact, patients may reduce their activity level without conscious recognition, until their heart failure becomes overtly decompensated. The objective measure of activity may have predictive value for worsening heart failure and is currently under investigation.
Heart rate variability reflects the balance between sympathetic and parasympathetic nervous system activity in the heart, with a decrease in HRV serving as a marker of increased sympathetic and decreased parasympathetic tone.45 An analysis from Adamson et al. showed that HRV diminished in the days to weeks leading up to a hospitalization for worsening heart failure, suggesting that decreases in HRV may predict episodes of worsening heart failure.46 This idea is biologically plausible, given our understanding of the changes in the neurohormonal milieu that occur as heart failure worsens. Specifically, sympathetic activation has been viewed as a hallmark of worsening heart failure, consistent with the findings of decreased HRV preceding decompensation.
Since most patients with decompensation exhibit pulmonary congestion due to an elevated left ventricular filling pressure, indirect measurement of lung water or direct measurement of left ventricular filling pressure or its surrogate may be useful in managing heart failure patients on an outpatient basis. Implantable devices can monitor fluid status by assessing changes in intrathoracic impedance. Electrical impedance can be determined between the ICD lead residing within the right ventricle and the device generator or “can.” Using this approach, electrical impedance is measured across the lung, from the tip of the lead to the generator. The principle that is exploited is quite simple: water conducts electricity better than air, so increasing lung water is associated with a decrease in electrical impedance. Using this technique, electrical impedance may be assessed multiple times throughout the day and followed for changes over time. In a small study of 33 patients, intrathoracic impedance changes demonstrated the ability to predict hospitalizations for decompensated heart failure 10–14 days in advance of the event.47 The challenge for clinicians is knowing how to react to this information, especially in the absence of signs or symptoms of congestion.
Thus, additional studies are underway to better understand the use and potential of this approach. Finally, a new generation of even more sophisticated implantable monitoring devices is under investigation. These devices allow continuous or intermittent assessment of hemodynamics, generally focused on the direct measurement or estimation of left-sided filling pressure.
OTHER INVESTIGATIONAL IMPLANTABLE DEVICES FOR THE TREATMENT OF HEART FAILURE
Another electrical approach to heart failure currently under investigation has been called cardiac contractility modulation or CCM.48 This investigational implantable device delivers an intermittent electrical impulse to the heart during the absolute refractory period of the ventricle. While the mechanism of action of CCM is incompletely understood, it may be thought of as a form of electrical conditioning of the heart whereby electrically medicated changes in myocyte calcium handling improve contractility. This improvement in contractility occurs in association with a reduction in myocardial oxygen consumption, suggesting improved efficiency of the heart.49 This favorable relationship between myocardial contractility and work has been associated with improved outcomes for other heart failure therapies, such as CRT. A large-scale randomized controlled trial of CCM is underway. Other implantable heart failure devices are in preclinical and clinical evaluation. Among these are cardiac support devices (CSDs) that provide either passive or elastic ventricular restraint that may favorably affect functional status and remodeling. While these are surgically implanted devices, minimally invasive techniques have been developed for their deployment. An investigational ventricular partitioning device now under study attempts to replicate the effects of surgical ventricular restoration (SVR; discussed in Chap. 15) surgery, using a less invasive catheter-based approach to deployment. Nonimplantable devices are also being used or investigated for the treatment of heart failure. A discussion of these devices is beyond the scope of this chapter.
SUMMARY
The device era for heart failure management is upon us, ushered in by the routine use of CRT and primary prevention ICDs. Specifically, CRT is intended for patients with ventricular dyssynchrony and moderate-to-severe heart failure. Substantial experience suggests that it is safe and effective, with patients demonstrating significant improvement in clinical symptoms, functional status, exercise capacity, and outcomes. The beneficial effects of CRT on ventricular structure and function have also been demonstrated. Prophylactic implantation of an ICD is also now of proven benefit in heart failure patients, specifically in those with NYHA Class II and III disease. Emerging implantable monitoring technologies may improve our ability to avoid episodes of heart failure decompensation. Other investigational devices may add incremental benefit to the treatment of heart failure, using novel approaches to improving cardiac structure, function, and/or energetics.
REFERENCES
1. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: summary article. Circulation. 2005;112:1825–1852 and J Am Coll Cardiol. 2005;46:1116–1143.
2. Xiao HB, Brecker SJ, Gibson DG. Effects of abnormal activation on the time course of the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J. 1992;68:403–407.
3. Littmann L, Symanski JD. Hemodynamic implications of left bundle branch block. J Electrocardiol. 2000;33(Suppl):115–121.
4. Saxon LA, Kerwin WF, Cahalan MK, et al. Acute effects of intraoperative multisite ventricular pacing on left ventricular function and activation/ contraction sequence in patients with depressed ventricular function. J Cardiovasc Electrophysiol. 1998;9:13–21.
1. Kerwin WF, Botvinick EH, O’Connell JW, et al. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol. 2000;35:1221–1227.
2. Farwell D, Patel NR, Hall A, et al. How many people with heart failure are appropriate for biventricular resynchronization? Eur Heart J. 2000;21:1246–1250.
3. Aaronson KD, Schwartz JS, Chen TM, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667.
4. Xaio HB, Roy C, Fujimoto S, et al. Natural history of abnormal conduction and its relation to prognosis in patients with dilated cardiomyopathy. Int J Cardiol. 1996;53:163–170.
5. Unverferth DV, Magorien RD, Moeschberger ML, et al. Factors influencing the one-year mortality of dilated cardiomyopathy. Am J Cardiol. 1984;54:147–152.
6. Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduction delay: a prognostic marker in chronic heart failure. Int J Cardiol. 1999;70:171–178.
7. Brophy JM, Deslauriers G, Rouleau JL. Long-term prognosis of patients presenting to the emergency room with decompensated congestive heart failure. Can J Cardiol. 1994;10:543–547.
8. Cazeau S, Ritter P, Bakdach S, et al. Four chamber pacing in dilated cardiomyopathy. PACE. 1994;17:1974–1979.
9. Foster AH, Gold MR, McLaughlin JS. Acute hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg. 1995;59:294–300.
10. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol. 1996;19:1748–1757.
11. Blanc JJ, Etienne Y, Gilard M, et al. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation. 1997;96:3273–3277.
12. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol. 1998;32:1825–1831.
13. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacingin patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999; 99:1567–1573. |
