Are complications of implantable defibrillators under-estimated and benefits over-estimated?

It is ethically imperative that we are aware of the data, so that we can be honest with our patients . In a systematic review 1 of 12 randomized controlled trials (RCTs) accounting for a total of 8516 patients with left ventricular (LV) systolic dysfunction (regardless of whether the patients had heart failure symptoms), 86% of whom had New York Heart Association (NYHA) class II or III symptoms, implantable cardioverter defibrillators (ICDs) reduced all-cause mortality by 20% (95% CI, 10–29); the reduction in total mortality was largely due to a 54% relative reduction of sudden death. In the same review, ICDs reduced all-cause mortality by 46% (95% CI, 32–57) in 11 observational cohort studies with contemporaneous control groups for a total of 9450 patients. In the observational studies, the mean left ventricular ejection fraction (LVEF) ranged from 0.19 to 0.46. The observational studies demonstrated a reduced frequency of non-cardiac death in ICD recipients (RR, 0.74). The fact that the controlled observational studies demonstrated a reduced frequency of non-cardiac death in ICD recipients suggests that clinicians select healthier patients for ICD insertion, and this probably accounts for the larger apparent benefit from ICDs on all-cause mortality in observational studies than in RCTs. This beneficial effect exists regardless of whether a patient has a history of haemodynamically apparent ventricular arrhythmias (primary or secondary prevention) or an ischaemic cause. However, in RCTs, LVEF ranged from 0.21 to 0.28 in the primary prevention trials and from 0.32 to 0.46 in the secondary prevention trials. While there was a definite survival benefit in patients with a history of ventricular tachyarrhythmias (HR = 0.77 95% CI 0.65–0.91) and in those in NYHA class II or III (HR = 0.81 95% CI 0.69–0.95), a post hoc meta-regression using aggregate trial data from 12 RCTs showed no significant association with reduced mortality for patients with class I symptoms ( P = 0.13) and for patients in class NYHA IV ( P = 0.62) who showed even a non-significant increased mortality ratio (HR = 1.27 0.68–2.37). The evidences of efficacy of ICD therapy are indisputable. Probably very few other therapies are supported by so a large number of trials. Nevertheless, are we aware of the complications as well of the benefit? And are we sure that we are interpreting correctly these evidences? In a systematic review, 1 death associated with implantation of ICDs occurred during 1.2% (95% CI, 0.9–1.5) of procedures and occurred mainly in patients with LV dysfunction; mechanical complications occurred in 5.3% (CI, 4.6–6.2). The implantation success rate and safety of ICDs were similar in clinical practice and RCTs. Among 30 984 Medicare patients, 2 overall 10.8% of patients suffered one or more complications during the hospital stay in which their ICD was implanted. The overall complication rate of ICDs was similar to that of cardiac resynchronization therapy-defibrillator (CRT-D) devices. In a systematic review, 1 the frequency of post-implantation complications per 100 patient-years included 1.4 (CI, 1.2–1.6) device malfunctions, 1.5 (CI, 1.3–1.8) lead problems, and 0.6 (CI, 0.5–0.8) site infections. These figures were similar to those observed in Medicare patients. 2 Rates of inappropriate discharges was surprisingly high, being 19.1 per 100 patient-years (CI, 16.5–22.0) in RCTs and 4.9 per 100 patient-years (CI, 4.5–5.3) in observational studies. 1 These shocks are commonly due to double counting, oversensing, ectopy, and supraventricular tachycardias, ranging from sinus tachycardia to atrial fibrillation. 3 The occurrence of ICD shocks have consistently been demonstrated to be associated with a subsequent significant decrease in perceived general health, physical and emotional functioning, and psychological well-being. 1 , 4 , 5 Aside from morbidity, these shocks may have attendant lethal risks as patients receiving inappropriate shocks in the SCD-HeFT study 6 , 7 were at higher risk for death (HR = 1.97) as well those in the MADIT II 8 (HR = 2.29). It has been postulated that the negative inotropic consequences of the shock itself could increase the risk of death, especially when the patient receives multiple shocks owing to oversensing or ongoing supraventricular tachycardia. 7 The insertion of the device may be directly or indirectly proarrhythmic. 3 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. Additionally, local lead effects with mechanical irritation and late fibrosis may be a potential mechanism for ventricular tachycardia. 3 The long-term reliability of ICD leads has become an increasing concern. In a study, 9 15% leads failed during the follow-up. The estimated lead survival rates at 5 and 8 years after implantation were 85 and 60%, respectively. The annual failure rate increased progressively with time after implantation and reached 20% in 10-year-old leads ( P 30% were 48% of the total 13 152 ICD implants. In a homogeneous subgroup of 825 consecutive patients who received an ICD implant for primary prevention, 17 29% of the patients had an EF value between 31 and 35% and 9% had >35%; moreover, 12% of the patients were in NYHA class I. Many RCTs had peculiar inclusion criteria that were not considered in the recommendations of the guidelines. For example, in COMPANION, 18 inclusion criteria included also an acute episode of heart failure during last year requiring hospitalization which was not utilized in the guidelines. In DINAMIT, 19 the post-MI patients had not only an EF of 18 months) from their myocardial infarction but not in those who were implanted before 18 months. A screening log was not available and patients were not consecutive, so some data are missed which could help to understand how they were selected. Clinical trial results are difficult to replicate in the ‘real world’ practice. For example, in the recent MASTER trial, 21 in which the enrolled patients had to meet the MADIT-II indications, total mortality after 2.1 years of follow-up was 10.2% whereas the corresponding mortality after 2 years in the original MADIT 2 trial was 16%. ‘Appropriate’ ICD shocks do not equal necessary. An examination of RCTs 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. 3 Thus, ICD therapies may not be a surrogate for sudden cardiac death, as many episodes may have been non-sustained non-fatal events. This suggests that a distinction needs to be made between shocks that are appropriate and shocks that are necessary. In the DINAMIT trial, 17 the prevention of arrhythmic death with ICDs (HR = 0.42) was counterbalanced by excess death from non-arrhythmic etiologies (HR = 1.75). In the MADIT II study, 22 the mortality rate of patients receiving therapy for ventricular fibrillation was over 50% at 2 years. The most common cause of death among patients who received any ICD shock was progressive heart failure. The authors speculated that successful abortion of sudden cardiac death merely shifted the mode of death to pump failure. Furthermore, in the SCD-HeFT trial, 7 an appropriate ICD shock was associated with a significant increase in the subsequent risk of death from all causes. This relationship was independent of other covariates that are predictive of the outcome and was seen both in patients with ischaemic heart disease and in those with non-ischaemic heart disease. Although the response by physicians to ICD shocks is commonly a sense of relief that sudden death was averted, these findings highlight the need for a more thoughtful consideration of this patient group, directed in particular at a reassessment of the therapeutic options that might modify the prognosis. 7 Most patients currently implanted with an ICD never receive a therapeutic discharge but are exposed to the risks of ICDs outlined in this report. For example, in MADIT II trial, 22 77% of patients did not receive appropriate shocks during 21 months and in SCD-HeFT trial, 7 79% did not receive appropriate shocks at 5 years (annual rate of 5.1% of appropriate shocks). Similarly, three quarters to two-thirds of ICD recipients in the observational studies received no therapeutic ICD discharges. This suggests that many patients with current indications for ICD implantation may not benefit from this invasive therapy and that better risk stratification is needed to optimize patient selection and the cost-effectiveness of this therapy Current guidelines recommend ICD therapy in patients with a low EF. However, the benefit of the ICD in the low EF population may not be uniform. The development of risk stratification tools to identify who should (and should not) get an ICD is clearly a research priority. Since ICD insertion cannot be considered as an ‘insurance policy’, the decision to implant should be taken based on a careful risk-benefit evaluation. It is hopeful that future trials should focus on risk-benefit stratification and that future guidelines should consider to base their recommendations not only on crude cut-off, mainly based on values of EF, but rather on criteria of increasing probability of efficacy. What do we know at present at regard? In general, the patients most likely to benefit are probably those who are not too sick (because they will die despite intensive management) nor those too well (because they will thrive without treatment). In more scientific terms, this might be called the optimal treatment window. There is evidence of greater benefit among patients with overt heart failure and with EF values that are closer to 25%; the benefit is less, if any, for those with EF closer to 35%. Risk stratification has been mainly evaluated in post-myocardial infarction patients without a history of ventricular fibrillation or tachycardia (primary prevention). A guide to identify patients with systolic dysfunction likely to benefit from an ICD after a myocardial infarction is shown in Table 1 . Because ICDs were not associated with mortality benefits when implanted at the time of bypass surgery, within 40 days of a myocardial infarction, or within 6 months of coronary revascularization, to delay ICD implantation after acute coronary events or coronary revascularization is appropriate. 1 Five clinical factors were associated with a higher risk of death in the MADIT 2 trial. 23 These are New York Heart Association functional class II or more, age ≥70 years, BUN ≥26 mg/dL (creatinine ≥1.3), QRS duration ≥0.12 s, and atrial fibrillation. Crude mortality rates in the conventional group were 8 and 28% in patients with 0 and ≥1 risk factors, respectively. Defibrillator therapy was associated with a 49% reduction in the risk of death ( P = 0.001) among patients with one or two risk factors, whereas no ICD benefit was identified in patients with no risk factors and in those with a higher score. Thus, a U-shaped pattern for ICD efficacy in the low EF population was observed, with pronounced benefit in intermediate risk patients and attenuated efficacy in lower and higher risk subsets. Patients with EF higher than 35% after a myocardial infarction are not currently considered to be candidates for ICD implantation. For patients with ejection fractions in the range of 30–40%, a reassessment of ventricular function every 6–12 months is prudent. 24 For patients with EF between 25 and 35%, additional factors should be considered. Within this range, there is some evidence of greater benefit among patients with EF that are closer to 25%, and less, if any, benefit for those with EF closer to 35%. Modifying factors include symptomatic heart failure or a history of heart failure, documented non-sustained or inducible ventricular tachycardia, history of atrial fibrillation, and a prolonged duration of the QRS interval. For patients with none of these modifying factors, implantation of an ICD may be deferred, particularly when the EF is in the range of 30–35%. Decision-making involving patients in this category should include a discussion with the patient and his or her referring physician to gauge their preferences. Finally, patients with EF of 25% or less should generally be considered suitable candidates, even in the absence of the modifying factors. 24 A guide to identify patients likely to benefit from an ICD as primary prevention after a myocardial infarction Wide QRS Atrial fibrillation NYHA class II or more, age ≥70 years, BUN ≥26 mg/dL (creatinine ≥1.3) None of these ≥3 of these or BUN >50 mg/dL (serum creatinine >2.5 mg/dL) Induced VT EF deterioration over time Wide QRS Atrial fibrillation NYHA class II or more, age ≥70 years, BUN ≥26 mg/dL (creatinine ≥1.3) None of these ≥3 of these or BUN >50 mg/dL (serum creatinine >2.5 mg/dL) Induced VT EF deterioration over time A guide to identify patients likely to benefit from an ICD as primary prevention after a myocardial infarction Wide QRS Atrial fibrillation NYHA class II or more, age ≥70 years, BUN ≥26 mg/dL (creatinine ≥1.3) None of these ≥3 of these or BUN >50 mg/dL (serum creatinine >2.5 mg/dL) Induced VT EF deterioration over time Wide QRS Atrial fibrillation NYHA class II or more, age ≥70 years, BUN ≥26 mg/dL (creatinine ≥1.3) None of these ≥3 of these or BUN >50 mg/dL (serum creatinine >2.5 mg/dL) Induced VT EF deterioration over time There are also data to support the concept that non-invasive risk stratification techniques may be useful to improve the selection of the patients who might or might not benefit from an ICD. Among these, microvolt T-wave alternans, signal-averaged ECG (SAECG), short-term heart rate variability (HRV), heart rate turbulence are the most common techniques. However, in a recent consensus expert document, their clinical utility to guide selection of ICD therapy has been considered not yet demonstrated and further evidence from proper randomized trials is advocated. 25 After that statement, a prospective substudy of SCD-HeFT trial was unable to confirm the usefulness of T-wave alternans either among patients with ischaemic or non-ischaemic causes of left ventricular systolic dysfunction. 21 Conversely, the ABCD trial, 26 performed in patients with ischaemic cardiomyopathy (LVEF <0.40) and non-sustained ventricular tachycardia was able to identify a subgroup—with either non-inducibility of sustained ventricular tachycardia during an electrophysiological study and absence of T-wave alternans—that was at very low risk of arrhythmic events during 1 year follow-up (2 vs. 12% of that with both tests positive). Implantable cardioverter defibrillator (ICD) therapy has clearly been shown to be effective in aborting sudden arrhythmic death and consequently reducing total mortality. However, the extent to which 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. Many patients with current indications for ICD implantation may not benefit from this invasive therapy and a better risk stratification is needed to optimize patient selection. 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.