STATE-OF-THE-ART PAPER
A Critical Appraisal of Implantable Cardioverter-Defibrillator Therapy for the Prevention of Sudden Cardiac Death
Roderick Tung, MD*,
Peter Zimetbaum, MD and
Mark E. Josephson, MD
Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Manuscript received March 24, 2008;
revised manuscript received May 19, 2008,
accepted May 27, 2008.
* Reprint requests and correspondence: Dr. Roderick Tung, Division of Cardiology, David Geffen School of Medicine at UCLA, BH-307 CHS, 10833 Le Conte Avenue, Los Angeles, California 90095 (Email: RTung{at}mednet.ucla.edu).
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Abstract
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The indications for implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death have rapidly expanded over the past 10 years. Clinical trial data have quickly been implemented into guidelines without critical reassessment of the strengths and limitations of the evidence. ICD therapy has inherent risks including infection, unnecessary shocks, potential for proarrhythmia, device malfunction, highly publicized manufacturer advisories, and procedural complications, which can adversely affect morbidity and quality of life. A reappraisal of the benefits and potential hazards of ICD therapy will enable physicians to a have a more mutually informed and balanced dialogue with their patients.
Key Words: defibrillator • trials • sudden death • proarrhythmia • cost-effectiveness
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Abbreviations and Acronyms
| | CI = confidence interval | | CRT = cardiac resynchronization therapy | | EF = ejection fraction | | HR = hazard ratio | | ICD = implantable cardioverter-defibrillator | | NYHA = New York Heart Association | | VF = ventricular fibrillation | | VT = ventricular tachycardia |
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Since the first descriptions of external defibrillation in the 1960s and the first human implantable cardioverter-defibrillator (ICD) in 1980 by Mirowski (1), the paradigm for the prevention of sudden cardiac death shifted away from both antiarrhythmic drug and ablative strategies. After the publication of the AVID (Antiarrhythmics Versus Implantable Defibrillators) trial (2) for secondary prevention, ICD therapy has been tested in broader and lower-risk primary prevention populations, transforming it from a restricted "last resort" to a broad-reaching pre-emptive therapy. In the past 15 years, the annual insertion of ICDs has increased by 20-fold (3).
While the high stakes and unpredictable nature of sudden cardiac death justifiably provoke fear and uncertainty, emotional factors should not outweigh scientific evidence. ICD therapy, priced up to $30,000 per device, has attendant costs. The principle of nonmaleficence necessitates weighing any lifesaving benefit against the potential for harm, in the form of unnecessary shocks, procedural complications, infection, device malfunction, manufacturer recalls, and possible proarrhythmia.
We offer a critical review of the ICD literature that challenges the appropriateness of current practice patterns and guidelines for ICD insertion on the grounds that: 1) the clinical benefit has been overestimated by clinical trials; 2) the adverse effects on morbidity, quality of life, and the potential for proarrhythmia have been underestimated; and 3) the unfavorable cost-effectiveness of ICD therapy is understated.
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Have We Overestimated the Clinical Benefits of ICD Therapy?
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Stacking the deck: antiarrhythmic drugs as "control" arm and beta-blocker inequity.
With the exception of the SCD-HeFT (Sudden Cardiac Death Heart Failure Trial) (4), CASH (Cardiac Arrest Study Hamburg) (5), and MUSTT (Multicenter Unsustained Ventricular Tachycardia Trial) studies (6), the patients in ICD trials randomized to the "control" arm received antiarrhythmic drug therapy. While significant differences between randomized groups may be attributed to the superiority of the active treatment tested, the possibility of an inferior performance in the "control" arm, worse than that of placebo, must not be overlooked. Although there was a prevailing sentiment that randomizing patients to placebo was unethical, not a single randomized prospective trial has demonstrated improved overall mortality from antiarrhythmic therapy. In fact, several signals that are of concern that suggest increased mortality from antiarrhythmic therapy when compared with placebo have been seen in recent trials.
The potential for harm from antiarrhythmic therapy has been historically well documented in trials like the CAST (Cardiac Arrhythmia Suppression Trial) and SWORD (Survival with Oral D-Sotalol Trial) studies (7,8). The propafenone active treatment arm had to be discontinued in the CASH study due to a 61% increase in mortality at 11 months (5).
In the MADIT I (Multicenter Automatic Defibrillator Implantation Trial) study (9), patients in the control group had a 10% higher mortality rate if they were taking amiodarone at 1 month (36% amiodarone vs. 26% no amiodarone).
In 2 trials of ICD with "placebo" control groups, antiarrhythmic therapy performed worse than standard therapy. In the SCD-HeFT study, amiodarone was significantly worse than placebo (hazard ratio [HR]: 1.44, 95% confidence interval [CI]: 1.05 to 1.97, p = 0.01) in the pre-specified New York Heart Association (NYHA) functional class III patients. However, this trend was not seen in the overall study. In the MUSTT trial, patients that were randomized to electrophysiologic-guided antiarrhythmic therapy had worse outcomes than those who were randomized to no antiarrhythmic therapy (Fig. 1). No formal comparison was commented upon, despite a 10% absolute increased incidence of death at 5 years.
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Figure 1 Antiarrhythmic Therapy Can Perform Worse Than Placebo
Inferior performance of antiarrhythmic therapy compared with control group in the SCD-HeFT (Sudden Cardiac Death Heart Failure Trial) trial New York Heart Association functional class III patients (top) and the MUSTT (Multicenter Unsustained Ventricular Tachycardia Trial) trial (bottom). CI = confidence interval; EPG = electrophysiology-guided; ICD = implantable cardioverter-defibrillator.
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Beta-blocker utilization, which has been demonstrated to reduce arrhythmic and all-cause mortality in the post-myocardial infarction and chronic systolic dysfunction settings, can affect the outcome of ICD trials. First, higher utilization of beta-blockade decreases overall event rates, which diminishes the power of a study to demonstrate benefit from ICD therapy if the sample size is not increased. Furthermore, if patients randomized to ICD were disproportionately treated with higher rates of beta-blockade, overall benefit seemingly from ICD would be accentuated. This indeed was the case in 3 of the 4 trials that have proven significant survival benefit with ICDs (Table 1).
Trials in secondary prevention: reconsidering the AVID, CIDS (Canadian Implantable Defibrillator Study), and CASH trials.
The AVID trial (2) is the only trial to demonstrate statistically significant mortality reduction from ICD therapy in secondary prevention. Randomizing 1,016 patients with resuscitated ventricular fibrillation (VF), sustained ventricular tachycardia (VT) with syncope, or symptoms with an ejection fraction (EF) <40% to either ICD or predominantly amiodarone-based antiarrhythmic therapy, the study was prematurely discontinued due to a 9% absolute increase in death in the antiarrhythmic group at 18 months (24.0% vs. 15.8%, p = 0.02). Although statistical adjustments were attempted, it is difficult to overlook the >3-fold utilization of beta-blockers in the ICD group (38.1% vs. 11.0% at 1 year) and the 5% higher incidence of atrial fibrillation and NYHA functional class III heart failure in the antiarrhythmic group as additive confounding variables that amplified net clinical benefit in favor of ICD therapy. Moreover, clinical benefit was not observed in patients with an EF >35% and <20% (10).
While the number needed to treat in this trial was 11 ICD implants to save 1 life, the unadjusted improvement in mean survival was only 0.21 year, or 2.6 months (31 vs. 29 months). This small difference was reduced by 15% when adjustments were made for heart failure and EF. This modest prolongation of life was valued at $85,522 (11), which included the untoward costs of the 4% absolute increase in rehospitalizations in the ICD group (60% vs. 56%, p = 0.04).
Two smaller randomized trials, the CIDS (12) and CASH (5) trials, failed to demonstrate statistically significant reductions in mortality with ICD therapy for secondary prevention. These findings occurred despite similar inequities of beta-blockade therapy in ICD patients in the CIDS trial, with significantly higher event rates (44.4% in the CASH trial, 29.6% in the CIDS trial, and 24.0% in the AVID trial in control arms) and longer follow-up (57 months in the CASH trial, 36 months in the CIDS trial, and 18 months in the AVID trial). By current clinical trial standards, these trials, which did not meet conventional statistical significance, may not pass muster with the Food and Drug Administration.
These nonsignificant trends in favor of ICD therapy prompted a meta-analysis that showed a significant difference in mortality in favor of ICD (13). With a combined follow-up period of 6 years, patients with defibrillators lived only 4.4 months longer than those treated with antiarrhythmic therapy, and all statistically significant differences were nonsustained, narrowing at 4 years toward negligible after 6 years. As seen in the AVID trial, patients with an EF >35% did not experience survival benefit from ICD therapy. In summary, the benefit of ICD for aborting death in selected high-risk patients is consistent but modest across these 3 trials.
Primary prevention in ischemic cardiomyopathy.
The frequently quoted MADIT I study is ironically one of the smallest ICD trials to date (n = 196). Inclusion criteria required an EF of <35% and prior myocardial infarction with inducible sustained VT, which could not be suppressed with procainamide (9). Although ICD therapy did improve survival by 23% over conventional therapy (74% amiodarone utilization) at 5 years, more of these deaths were spared from nonarrhythmic, noncardiac, and unknown causes (n = 14) than from arrhythmic death (n = 10), when compared with that seen with conventional therapy. While misclassification is a possibility, this implausible improvement in mortality may have been the result of a statistical aberration due to small sample size.
The results of the MADIT I study are not generalizable to current medical practice for several reasons. While beta-blockers (8% conventional vs. 26% ICD at discharge) and angiotensin-converting enzyme inhibitors (55% conventional vs. 60% ICD at discharge) were used more frequently in ICD patients at 1 month, the overall low rate of medication administration is not in compliance with current post-myocardial infarction treatment guidelines. Data from patients that were screened and excluded were not available; therefore, the denominator for this highly selected population remains unknown. Additionally, there are no data on those patients who were suppressible with procainamide. Lastly, induction of sustained ventricular arrhythmias and procainamide suppression is rarely performed in current practice, and this feature may have been important for identifying patients more likely to experience adverse events (mortality rate 39%).
The larger MADIT II study, enrolling 1,232 patients with coronary artery disease and an EF <30%, demonstrated a 5.6% absolute mortality benefit (19.8% vs. 14.2%) at 20 months in patients receiving ICDs (14). This difference, the smallest difference seen in any statistically significant ICD trial, was likely attenuated by the equivalent high rate of beta-blockade (70%) and low rates of amiodarone therapy in both groups (13% ICD vs. 10% control group). An unexpected 5% absolute increase in hospitalizations for new or worsened congestive heart failure was seen in the ICD group (19.9% vs. 14.9%). Of note, only one-third of the patients were followed for 2 years at the time the study was stopped.
Side effects of device therapy: reprogramming the mode of death.
While acknowledging that the task of classifying death is fraught with problems, studies that attempt to differentiate between modes of death provide interesting insights. The AVID and MADIT II studies did not attempt to classify the exact mechanism of death in the original publications, and the MADIT I study suggested that ICD therapy not only prevented arrhythmic death, but also was a biologically implausible panacea for all causes of death. While an ICD cannot be expected to reduce nonarrhythmic deaths, it should be expected to not increase the incidence of nonarrhythmic deaths as a side effect. This was not the case in both the CABG Patch (Coronary Artery Bypass Graft-Patch) and DINAMIT (Defibrillators in Acute Myocardial Infarction Trial) studies.
The CABG Patch trial randomized 900 patients with an EF <35% with abnormal signal-averaged electrocardiograms to the epicardial ICD or control group at the time of coronary artery bypass grafting (15). No demonstrable mortality benefit was seen in patients receiving adjunctive ICD therapy, and many have attributed this finding to the favorable effects of revascularization on arrhythmic substrates. Although no randomized trials have evaluated the effects of revascularization on ventricular arrhythmias, observational studies suggest that revascularization has no effect on sustained monomorphic VT or VF in association with prior infarction or depressed EF (16,17). The incidence of arrhythmic death in the CABG Patch trial was indeed significantly reduced (29% control group vs. 15% ICD, p = 0.024), but an unexpected increase in death from other causes in patients randomized to ICD therapy led to an overall neutral effect (HR: 1.07, 95% CI: 0.81 to 1.42). A high incidence of death was seen in the first 30 days, and procedural device-related morbidity was seen with a significantly higher incidence of sternal and wound infections, which may have been due to the usage of surgically implanted epicardial patches and longer operative times (18).
A similar phenomenon was seen in the more recently published DINAMIT trial, which examined the role of ICDs in 674 patients 6 to 40 days status post-acute myocardial infarction with an EF of <35% and impaired autonomic tone (19). The prevention of arrhythmic death with ICDs (HR: 0.42, 95% CI: 0.22 to 0.83, p = 0.009) was counterbalanced by excess death from nonarrhythmic etiologies (HR: 1.75, 95% CI: 1.11 to 2.76, p = 0.02). The authors speculated that successful abortion of sudden cardiac death merely shifted the mode of death to pump failure. The potential for causal harm from ICD shocks was suggested by a substudy that showed the increased risk from nonarrhythmic death to be confined only to those that received ICD discharges.
This signal of increased nonarrhythmic deaths in both trials cannot be ignored as either an undesirable byproduct of ICD therapy or merely a shift into a competing mode of exit. In the case of heart failure, one could argue that death from pump dysfunction is substantially more morbid than sudden arrhythmic death.
Discordance between evidence and guidelines in the post-myocardial infarction setting.
The 2006 recommendations for primary prevention ICD in patients with post-myocardial infarction left ventricular dysfunction aggregates heterogeneous trial data into a final EF cutoff of <40% (20). While one can recognize the difficulty of synthesizing trials with different inclusion criteria, not a single trial has utilized an EF cutoff of 40% with the exception of the MUSTT trial, which was not a defibrillator trial but rather a trial of risk stratification using electrophysiologic study. This liberal cutoff may be a movement in the wrong direction, as the average EFs in these trials were substantially lower than the inclusion cutoffs. The average EF for patients enrolled in the AVID, MADIT I, MADIT II, SCD-HeFT, and MUSTT studies was 27%. Accordingly, the recently updated 2008 guidelines for device-based therapy abandoned an all-encompassing EF cutoff in favor of trial-specific inclusion criteria (21). As mentioned previously, the high-risk selection of drug-refractory VT induced at electrophysiologic study in the MADIT I (39% mortality at 2 years) and MUSTT (32% mortality at 5 years) studies is not incorporated in these guidelines.
The optimal timing of defibrillator insertion after myocardial infarction remains unresolved. The findings of the DINAMIT study contradict the inferences from the VALIANT (Valsartan in Acute Myocardial Infarction Trial) study (22), which showed that patients with reduced systolic function were at the highest risk for sudden cardiac death in the first 30 days after myocardial infarction. While guidelines have adopted a 40-day blanking period from the DINAMIT study, a gap in data exists from the immediate to chronic setting, as the majority of patients in the MADIT I and II studies were enrolled outside of 6 months after myocardial infarction (75% and 88%, respectively). The mean interval from index myocardial infarction in the MADIT II study was 6.7 years. A bimodal distribution of risk was suggested by the time-dependent benefit of ICD in the MADIT II study, which found benefit only for remote events outside of 18 months that persisted out to 15 years after index myocardial infarction (23).
The upper boundary of risk with advanced age must be tempered by rationality, as patients over the age of 80 years were appropriately excluded from the MADIT I study. While they remain at highest risk for sudden cardiac death, comprising over 65% of 465,000 out-of-hospital deaths in 1999 (24), routine insertion in elderly patients who would otherwise qualify for ICD is philosophically debatable. Although there was no age cutoff in the SCD-HeFT and MADIT II studies for enrollment, the median age of patients in the SCD-HeFT study was 61 years, and mean age in the MADIT II study was 64 ± 10 years.
Nonsignificance in nonischemics.
Despite the inclusion of the nonischemic etiologies into class I ICD primary prevention recommendations, not a single trial has demonstrated a statistically significant mortality benefit from ICD therapy in this group. The CAT (Cardiomyopathy Trial) (EF <30%, n = 104) and the AMIOVIRT (Amiodarone Versus Implantable Cardioverter Defibrillator Trial) studies (EF <35% with nonsustained VT, n = 103) were both terminated prematurely due to futility (25,26). The largest and only prospective trial of exclusively nonischemic patients was the DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) trial, which randomized 458 patients with EF <36% and nonsustained VT to standard medical therapy or single-chamber ICD (27). The primary end point of all-cause mortality failed to reach statistical significance at 29 months (14.1% control group vs. 7.2%, p = 0.08). The low event rates in this study may be attributed to the low usage of amiodarone in the control group and high equitable rates of beta-blockers (85%) and angiotensin-converting enzyme inhibitors (95%) as background therapy.
The SCD-HeFT study was the largest primary prevention defibrillator trial to date (4). With a combination of ischemic (52%) and nonischemic (48%) etiologies, 2,521 patients with an EF <35% and class II to III heart failure were randomized to conventional medical therapy, amiodarone, or ICD therapy. Compared with placebo, ICD therapy reduced all-cause mortality from 29% to 22% at 45 months (p = 0.007). Pre-specified subgroup analysis was performed by NYHA functional class and etiology, and due to 6 interim analyses of the data, the level of significance was a more stringent p value of 0.023. Neither ischemic nor nonischemic subgroups met statistical significance (p = 0.05 and 0.06, respectively). Interestingly, benefit from ICD was seen only in NYHA functional class II patients (HR: 0.54, 95% CI: 0.4 to 0.74, p < 0.001), and amiodarone was harmful when compared with placebo in patients with NYHA functional class III (HR: 1.44, 95% CI: 1.05 to 1.97, p = 0.01). In accordance with statistical dictum, subgroup analysis should be hypothesis-generating, rather than guideline-concluding. The nonsignificant benefit in nonischemic cardiomyopathy subgroup analysis was implemented into guidelines, and lack of benefit in NYHA functional class III patients was left out. The inconclusive nature of the data mentioned in the preceding text calls the class I, level B estimate of certainty into question for this population.
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Have We Underestimated the Risks of ICD?
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ICD shocks: "appropriate" does not equal necessary.
In a perfect world, ICD therapy would treat only the events that were imminently and inevitably fatal. However, clinical trial experience has revealed that up to 25% of patients receive inappropriate ICD shocks (28). These shocks are commonly due to double counting, oversensing, ectopy, and supraventricular tachycardias, ranging from sinus tachycardia to atrial fibrillation (Fig. 2). ICD shocks have consistently been demonstrated to reduce overall quality of life and increase the incidence of depression and anxiety while obligating strict driving restrictions. Aside from morbidity, these shocks may have attendant lethal risks, as patients receiving inappropriate shocks in the SCD-HeFT study were at higher risk for death (HR: 1.97, 95% CI: 1.29 to 3.01) (29).
An examination of randomized trials for primary and secondary prevention has shown that the number of appropriate shocks consistently exceeds the sudden death and overall mortality rate in the control group (28) (Fig. 3). Kadish et al. (27) reported twice as many events in the ICD arm of the DEFINITE trial when compared with the control arm (32 shocks/1 death, ICD vs. 15 arrhythmic deaths, control arm) (30). Two plausible explanations have been proposed to explain this phenomenon. First, ICD therapies may not be a surrogate for sudden cardiac death, as many episodes may have been nonsustained nonfatal events. This suggests that a distinction needs to be made between shocks that are appropriate and shocks that are necessary. Alternatively, insertion of the device may be directly or indirectly proarrhythmic. There are numerous speculated mechanisms by which an ICD may promote arrhythmogenesis including device malfunction, induction of arrhythmias from inappropriate shocks, pacemaker-facilitated triggers, and reversal of activation wavefronts from epicardial resynchronization increasing dispersion of refractoriness (31–35). Additionally, local lead effects with mechanical irritation and late fibrosis may be a potential mechanism for VT (Fig. 4).
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Figure 3 Appropriate Shocks Outnumber Control Arrhythmic Mortality in 6 of 7 Trials
AMIOVIRT = Amiodarone Versus Implantable Cardioverter Defibrillator Trial; AVID = Antiarrhythmics versus Implantable Defibrillators trial; DEFINITE = Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation trial; DINAMIT = Defibrillators in Acute Myocardial Infarction Trial; ICD = implantable cardioverter-defibrillator; MADIT II = Multicenter Automatic Defibrillator Implantation Trial II; MUSTT = Multicenter Unsustained Ventricular Tachycardia Trial; SCD-HeFT = Sudden Cardiac Death Heart Failure Trial. Adapted from Germano et al. (28).
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Figure 4 Proarrhythmia From Local Lead Effects?
Patient A presented with slow ventricular tachycardia initially, and rapid ventricular tachycardia induced in the laboratory was successfully pace terminated from the right ventricular catheter directly adjacent to the implantable cardioverter-defibrillator lead with paced morphology identical to tachycardia. Patient B presented with 28 implantable cardioverter-defibrillator shocks, and the closest pace map was from the right ventricular catheter adjacent to the implantable cardioverter-defibrillator lead in the apex.
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Pacing hazards.
Recently, Sweeney et al. (36) analyzed the intracardiac initiation sequence of 1,356 VT/VF episodes from the PainFree Rx II and EnTrust trials and found pacing-associated short-long-short sequences at the onset of 21% to 35% of all episodes. They also found sudden-onset initiations that occurred during pacing in 29.8% of the episodes analyzed. The short-long-short sequences were further broken down into pacing-permitted and pacing-facilitated onsets with a higher rate of the former in managed ventricular pacing and VVI modes when compared with those in DDD. This study suggests that normal pacing system operation might constitute an important mechanism of device proarrhythmia. A smaller double crossover study demonstrated that the cessation of backup pacing in patients with previous pacing-facilitated VT-VF eliminated VT-VF recurrences when compared with those that had backup pacing increased to a lower rate of 60 beats/min (37).
The precipitation of ventricular arrhythmias immediately after cardiac resynchronization therapy (CRT) has been reported. Extreme examples of VT storm that are only alleviated immediately after the discontinuation of left ventricular pacing have been seen (38). Cardiac resychronization with epicardial coronary sinus lead implantation reverses the typical transmural activation sequence, delaying endocardial depolarization and repolarization. Dispersion of refractoriness and heterogeneity in conduction patterns has been demonstrated to be arrhythmogenic in animal models (39). In the recent CARE-HF (Cardiac Resynchronization Heart Failure) trial, which demonstrated improvement in all-cause mortality from resynchronization, there was a higher incidence in sudden death in patients receiving CRT (35.4% vs. 31.7%) (40). A similar signal was seen in the COMPANION (Companion of Medical Therapy, Pacing and Defibrillation in Heart Failure) trial, with a 2% higher incidence of sudden death (7.8% vs. 5.8%) in the CRT arm when compared with that in the control arm (41). This may be the reverse phenomenon of shifting modes of death as seen in the DINAMIT study. A recent meta-analysis of 14 trials, however, did not suggest any excess risk of sudden death from CRT (risk ratio: 1.07; 95% CI: 0.79 to 1.46) despite a prior contrary suggestion seen on an analysis performed 3 years earlier by the same authors (HR: 1.99, 95% CI: 0.95 to 4.16). An additional meta-analysis demonstrated a neutral effect despite a slightly higher rate of sudden cardiac death in the CRT arm (6.4% vs. 5.9%) (42,43).
Hardware malfunction.
Despite advances in ICD system design and manufacturing, devices remain imperfect. Structural failure of an implanted device has tremendous adverse effects on patient morbidity, both medically and psychologically. Inappropriate sensing due to conductor or insulation fracture, sensing lead adapter failure, loose set screws, or frank dislodgement can lead to oversensing of electrical noise with resultant inappropriate shocks. Kleemann et al. (44) reported on the suboptimal reliability of over 20 lead models over a 13-year period. Overall, 148 (15%) of 990 ICD leads failed during follow-up, with estimated survival rates of 85% and 60% at 5 and 8 years after implantation, respectively.
In 2001, Maisel et al. (45) reported a recall rate of 16.4 per 100 person-years, with 54% for hardware malfunctions and 41% for programming malfunctions. In 2005, all 3 of the major ICD manufacturing companies (St. Jude Photon/Atlas, Guidant Ventak Prizm/Contak Renewal, Medtronic Marquis) issued advisories on the potential for ICD malfunction. Not unexpected, the public scrutiny of defibrillator recalls from 2005 brought the rampant insertion rate of ICDs to a screeching halt. Yet in the aftermath of this, the highly publicized recall of the Sprint Fidelis (Medtronic Inc., Minneapolis, Minnesota) lead was issued last October. The higher rates of lead fracture (2.3% to 6.7% at 30 months) led to more media-provoked mass hysteria as about 268,000 patients worldwide were at risk (46,47). Patients experiencing a lead complication are at risk for inappropriate shocks and ICD storm due to sensing of electrical noise (48) (Fig. 5). Five deaths linked to lead fracture-induced proarrhythmia were reported in the initial advisory.
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Figure 5 Lethal Proarrhythmia
Inappropriate shocks for electrical noise in a primary prevention implantable cardioverter-defibrillator recipient with a Sprint Fidelis lead. The sixth and final shock induced ventricular fibrillation (VF). EGM = electrogram.
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While the impact of recalls on patients is multiple and overt, the burden upon physicians must not be overlooked as there is little guidance on how to manage the "at-risk" population. Routine explantation is seldom advised, and individual cases are left up to the physician's discretion by the device companies. Several experienced centers reported a high rate of major complications (1.2% to 7.3%) from replacement of devices under advisory, ranging from reoperation to pocket infections, hematomas, and even death (49–52). From these data, the morbidity and mortality of replacing a device must not be underestimated.
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Have We Overestimated the Cost-Effectiveness of ICD Therapy?
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Sanders et al. (53) estimated the cost-effectiveness of ICD therapy for primary prevention based on 8 randomized controlled trials. At a cost between $34,000 to $70,200 per quality-adjusted life year, the authors performed a sensitivity analysis that showed a cost-effectiveness ratio below $100,000 assuming that the benefit of ICD persisted after 7 years. The projected life extension was 1.0 to 2.99 quality-adjusted life years based on the 6 trials showing benefit. This Markov model assumed an ICD efficacy based on only the 6 trials that demonstrated benefit and assumed a generator replacement every 5 years. The specific assumptions to account for hospitalizations, recurrent shocks, and lead replacement were not elaborated.
An analysis of the SCD-HeFT study found significant interaction between NYHA functional class and ICD therapy and no incremental benefit despite higher costs in patients with NYHA functional class III heart failure. Furthermore, incremental cost-effectiveness ratio was under $100,000 only after a sensitivity analysis extrapolated the time 3 years beyond the trial follow-up ($127,503 per life-year saved at 5 years, $88,657 per life-year saved at 8 years) (54). In the United Kingdom, a comprehensive review by Buxton et al. (55) concluded that the utilization scheme was not cost-effective, with a mean-discounted ICD cost of  70,900 over a 20-year horizon for a mean gain of 1.24 years. Assuming a persistent treatment effect, the cost per life year was estimated at 32,000 (55).
The multivariable calculus of cost-effectiveness analysis is heavily dependent on start-up cost estimates, projected follow-up care, and a fundamental assumption of persistent treatment effect. Reynolds et al. (56) reported a 10.8% early complication rate in Medicare patients undergoing ICD insertion, associated with a mean cost of $42,184 and mean stay of 4.7 days. The assumption that ICD therapy has a persistent effect on late survival has not been supported by data. In a meta-analysis of secondary prevention trials, convergence of the survival curves for ICD and control arms was seen at 4 years (14). Furthermore, patients that receive appropriate ICD shocks appear to have a declining prognosis. Eleven percent of patients in the SCD-HeFT trial who received a single shock died within 24 h, and the average life expectancy thereafter was 1 year (29). In the MADIT II study, the mortality rate of patients receiving therapy for VF was over 50% at 2 years (57).
Based on the previously mentioned overestimation of ICD efficacy and the underestimation of "real-world" complication rates, which leads to increased costs, the published time-extrapolated cost-effectiveness analyses are hypothetical "best-case scenario" estimates. A cost-effectiveness analysis based on the actual MADIT II study population within the study time frame supports this assertion. ICD therapy was associated with a 3-fold higher rate of hospitalizations, and the average survival gain was 2 months. Because of this modest benefit, the incremental cost-effectiveness ratio was an astounding $235,000 per year of life saved, unadjusted for quality of life. The cost-effectiveness approached the accepted range of $50,000 to $100,000 only when the data were extrapolated to 12 years (58). A similar unfavorable finding was reported from the CIDS trial in secondary prevention, with life extension of 2.8 months priced at $213,543 per unadjusted year of life saved (59).
While many analyses attempt to adjust cost-effectiveness for quality of life, there are many intangible impacts on psychological well-being that cannot be made mathematically. While many patients are comforted by having a "safety net," ICD-specific fears including fear of death, shock, and public embarrassment are commonly experienced by recipients. In one study, symptoms of anxiety and depression persisted in 40% to 63% of defibrillator recipients at 1 year (60). Psychiatric studies have found that the aversive classical conditioning and dysfunctional cognition that occurs in defibrillator shock recipients makes them a prototypical model for anxiety development (61,62). The adverse psychological effects of increasing shock frequency has been clearly demonstrated in the quality-of-life analysis from the AVID, CIDS, and DEFINITE trials (63–65).
As current guidelines are being broadened to include lower-risk groups with lower event rates, the cost-effectiveness will become even less favorable. In the case of primary prevention in nonischemic patients, a 20% appropriate shock rate approximates a 10% necessary life-saving therapy rate. Therefore, 90% of patients that do not experience life-saving shocks are still exposed to the costs and risks of device-related complications. A distinction between therapeutic efficacy and efficiency needs to be recognized.
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Conclusions
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ICD therapy has clearly been shown to be effective in aborting sudden arrhythmic death. However, the extent to how much this capability, which modestly prolongs life, outweighs potential adverse effects on morbidity, quality of life, and the mode of death is less clear. ICD insertion is unlike an "insurance policy," as patients who do not benefit from device therapy are still exposed to procedural and device-related complications. The intent of clinical trials and future research should help physicians refine their selection of patients who are most likely to derive benefit and avoid harm from ICD therapy. However, some of the current guidelines appear to have been implemented based on trials with nonsignificant p values and outdated practice standards. The obligation to adhere to guidelines appears to have paradoxically dulled our discriminatory senses as clinicians.
With modern medicine, less emphasis has been placed on the physician-patient dialogue where concerns and expectations are freely exchanged. Physicians should understand that choosing longevity with potential tradeoffs in device-related complications and quality of life is a personal decision that must be individually tailored to patient preference. The process of obtaining informed consent from patients mandates and pre-supposes that physicians, first, are fully informed of the risks and benefits of the therapy that they are offering. It is ethically imperative that we are honest with the data, so that we can be honest with our patients.
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Footnotes
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Dr. Josephson has received educational grants and honoraria from Medtronic.
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References
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E. J. Rashba
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D. S. Rosenbaum
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A. E. Epstein
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Abstract
Have We Overestimated the...