“Please implant a defibrillator in my patient”: It's déjà vu all over again

Abstract

“Please implant a defibrillator in my patient,” Dr. Zipes recalled.1Zipes D.P. Implantable cardioverter-defibrillator Lifesaver or a device looking for a disease?.Circulation. 1994; 89: 2934-2936Crossref PubMed Google Scholar Should the answer be “sure” for every patient who meets a guideline criterion for implantable cardioverter-defibrillator (ICD) implantation?2Epstein A.E. DiMarco J.P. Ellenbogen K.A. et al.ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices).J Am Coll Cardiol. 2008; 51: e1-e62Abstract Full Text Full Text PDF PubMed Scopus (1286) Google Scholar Are all patients with a left ventricular ejection fraction (LVEF) ≤30% the same? Might not one patient feel fulfillment about life and accept the reality of death, whereas another has a desire to fulfill personal obligations and want all potentially life-prolonging therapy applied?3Erikson E. Identity: Youth and Crisis. Norton, New York, NY1968Google Scholar We have heard the request before. As Yogi Berra said after watching Mickey Mantle and Roger Maris repeatedly hit back-to-back home runs, “It's déjà vu all over again.”4Bera Y. Yogi Berra official website.http://www.yogiberra.com/yogi-isms.htmlGoogle ScholarStevenson et al5Stevenson L.W. Hellkamp A.S. Leier C.V. et al.Changing preferences for survival after hospitalization with advanced heart failure.J Am Coll Cardiol. 2008; 52: 1702-1708Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar elegantly demonstrated how our perceptions of patients' desires do not necessarily match. In a trade-off analysis, patients were asked “Would you prefer living 2 years in your current state of health or living 1 day in excellent health?” To those of us used to bell-shaped curves, the results were surprising: rather than a normal distribution, the responses were bimodal and polarized at either end of the spectrum. My take-home message is that patients need to be asked what they want, especially when an intervention is prophylactic and burdened by potential risks.To discuss the pros and cons of primary prevention ICD implantation, the risks and benefits of therapy need to be known by the person discussing the procedure and understood by the patient and his or her family. The benefits of primary-prevention ICD therapy are well known and easy to discuss. More complicated are the nuances of explaining relative and absolute risk, risk-benefit ratios, and the impact of comorbidities.The concept of risk stratification is not new. Our literature is rich with attempts using techniques such as signal-averaged electrocardiography, T-wave alternans, and heart rate variability,6Goldberger J.J. Cain M.E. Hohnloser S.H. et al.American Heart Association/American College of Cardiology/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death.Circulation. 2008; 118: 1497-1518Crossref PubMed Scopus (268) Google Scholar and for cardiac resynchronization therapy, scar burden, and dyssynchrony.7Bleeker G.B. Kaandorp T.A.M. Lamb H.J. et al.Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy.Circulation. 2006; 113: 969-976Crossref PubMed Scopus (655) Google Scholar Singly, none have panned out, and combinations have been variably reliable. Buxton et al8Buxton A.E. Lee K.L. Hafley G.E. et al.Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease Lessons from the MUSTT study.J Am Coll Cardiol. 2007; 50: 1150-1157Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar used the Multicenter Unsustained Tachycardia Trial (MUSTT) database to develop a risk stratification scheme for both overall and arrhythmic mortality. Although most of the variables used can be assessed at the bedside, electrophysiology study was required. Furthermore, MUSTT included only patients with coronary artery disease (CAD), left ventricular dysfunction, and nonsustained ventricular tachycardia. From the MADIT II study, Goldenberg et al identified 5 variables that predict outcome in patients also with CAD postinfarction, including New York Heart Association class >II, age >70 years, blood urea nitrogen >26 mg/dl, QRS duration >120 ms, and atrial fibrillation at baseline. Patients with none or >3 of these risk factors and patients with a creatinine >2.5 mg/dl or blood urea nitrogen >50 mg/dl derived no benefit.9Goldenberg I. Vyas A.K. Hall W.J. et al.Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.J Am Coll Cardiol. 2008; 51: 288-296Abstract Full Text Full Text PDF PubMed Scopus (465) Google ScholarIn the background of these prior data, Kramer et al developed another risk stratification model to predict individuals who may not only not benefit but also die within 1 year of ICD implantation.10Kramer D.B. Friedman P.A. Kallinen L.M. et al.Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators.Heart Rhythm. 2012; 9: 42-46Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The score, with its acronym PACE, incorporated peripheral arterial disease (P), age ≥70 years (A), creatinine ≥2.0 mg/dl (C), and LVEF ≤20% (E). Patients with a risk score ≥3 had a >4-fold excess 1-year mortality compared with patients with a risk score <3. The report importantly re-emphasizes the possibility of risk stratification and that it may be further refined. Furthermore, the population is representative of that which we see in practice: as in so many trials, the mean age was 65 years, about 80% were male, primary prevention accounted for 75% of the implantations, 60% had CAD, and 31% received cardiac resynchronization devices. Unlike the analyses from MUSTT8Buxton A.E. Lee K.L. Hafley G.E. et al.Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease Lessons from the MUSTT study.J Am Coll Cardiol. 2007; 50: 1150-1157Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar and MADIT II,9Goldenberg I. Vyas A.K. Hall W.J. et al.Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.J Am Coll Cardiol. 2008; 51: 288-296Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar patients with nonischemic heart disease are represented. Follow-up time was reasonable, 3.1 years, and most importantly a new risk factor was identified: peripheral vascular disease (PVD). Finally, the power of chronic kidney disease is yet again demonstrated.11Cannizzaro L.A. Piccini J.P. Patel U.D. Hernandez A.F. Device therapy in heart failure patients with chronic kidney disease.J Am Coll Cardiol. 2011; 58: 889-896Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In short, not only does LVEF take the stage, but other influences on patient survival now join the cast.Despite these strengths, the report has limitations, many addressed by the investigators. First, in the absence of a control group, we cannot know whether those individuals with high risk scores derive less benefit (after all, over 80% lived for a year despite comorbidities), no benefit, or are actually harmed by ICD therapy. Recall the work of Myerburg et al, showing that without an active control group, these outcomes cannot be differentiated.12Myerburg R.J. Mitrani R. Interian A. Castellanos A. Interpretation of outcomes of antiarrhythmic clinical trials.Circulation. 1998; 97: 1514-1521Crossref PubMed Scopus (176) Google Scholar Second, because ICD benefit increases with time, why should an ice-pick measurement made in time predict events years thereafter?13Goldenberg I. Gillepsie J. Moss A.J. et al.Long-term benefit of primary prevention with an implantable cardioverter-defibrillator.Circulation. 2010; 122: 1265-1271Crossref PubMed Scopus (185) Google Scholar Third, because the National Death Index was used to determine survival, mortality may have been underestimated. Finally, PVD was defined as that requiring intervention or the presence of claudication. We do not know whether asymptomatic PVD would perform as well as a risk stratifier.At the end of the day, what are we to do with this information? Is it enough to change practice? Will this or any risk-stratification scheme ever be adopted? How much harm or benefit is needed to justify or withhold a recommendation for ICD therapy? Do we not implant ICDs in the elderly, those with atrial fibrillation, and even women (who may derive less benefit than men)? Would you not implant an ICD in a patient with a high PACE score? Indeed, the investigators say that they would not use the score as a basis for recommending against ICD implantation in an otherwise appropriate candidate.This report is important because it takes us to the bedside and puts us on the spot asking are we doing the right thing by worshiping at only the LVEF altar. It signifies that prediction modeling can be done, and cries for the need for prospective data and research in this area. This is important not only for our patients, but also for society; and, if we do not do this work, others will force criteria for ICD indications upon us and our patients. Although it may seem outrageous, why not consider a trial in which very-high-risk patients receive a device, and the device is by randomization programmed on or off? In populations of patients excluded from clinical trials, for example those with end-stage renal disease, there are virtually no randomized clinical trial data showing benefit and there is ample evidence for the contrary.11Cannizzaro L.A. Piccini J.P. Patel U.D. Hernandez A.F. Device therapy in heart failure patients with chronic kidney disease.J Am Coll Cardiol. 2011; 58: 889-896Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar We have precedents for implanting devices and doing operations like this. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, we learned that about 30% of the effect of cardiac resynchronization therapy is placebo-mediated,14Abraham W.T. Fisher W.G. Smith A.L. et al.Cardiac resynchronization in chronic heart failure.N Engl J Med. 2002; 346: 1845-1853Crossref PubMed Scopus (4171) Google Scholar in the Multicenter Study of Pacing Therapy for Hypertrophic Cardiomyopathy (M-PATHY) we learned that implantation of a DDD pacemaker programmed to a short AV delay is not beneficial for patients with obstructive hypertrophic cardiomyopathy,15Maron B.J. Nishimura R.A. McKenna W.J. et al.Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy.Circulation. 1999; 99: 2927-2933Crossref PubMed Scopus (428) Google Scholar and in neurosurgery we learned that intracerebral fetal cell transplantation for Parkinson disease does not improve outcomes.16Kim S.Y.H. Frank S. Holloway R. Zimmerman C. Wilson R. Kieburtz K. Science and ethics of sham surgery A survey of Parkinson disease clinical researchers.Arch Neurol. 2005; 62: 1357-1360Crossref PubMed Scopus (63) Google ScholarWe live in an era in which resources are limited, we are scrutinized, and honesty and openness are essential. I think we have great opportunities to advance care for our patients and give them precise and accurate advice on what they can expect from ICD therapy. I also think that combinations of metrics offer the greatest chance for success, and that simpler ones have the greatest chance to be accepted. However, to get to this point we need to not rest on existing data, not fear that new studies may decrease implantation rates, and not rationalize that we will not enroll and randomize patients because of referral pressures and worry that studying patients about whom we have little data jeopardizes their outcome. Recall how wrong we were about treating PVCs with antiarrhythmic drugs,17Epstein A.E. Hallstrom A.P. Rogers W.J. et al.Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: the original design concept of the Cardiac Arrhythmia Suppression Trial (CAST).JAMA. 1993; 270: 2451-2455Crossref PubMed Scopus (163) Google Scholar the Vineberg procedure for angina,18Cobb L.A. Thomas G.I. Dillard D.H. Merendino K.A. Bruce R.A. An evaluation of internal-mammary-artery ligation by a double-blind technic.N Engl J Med. 1959; 260: 1115-1118Crossref PubMed Scopus (411) Google Scholar and estrogen therapy for CAD.19The Coronary Drug Project Research GroupThe Coronary Drug Project: findings leading to discontinuation of the 25-mg/day estrogen group.JAMA. 1973; 226: 652-657Crossref PubMed Scopus (397) Google Scholar The opportunities are ours. We know what we need to do. “Please implant a defibrillator in my patient,” Dr. Zipes recalled.1Zipes D.P. Implantable cardioverter-defibrillator Lifesaver or a device looking for a disease?.Circulation. 1994; 89: 2934-2936Crossref PubMed Google Scholar Should the answer be “sure” for every patient who meets a guideline criterion for implantable cardioverter-defibrillator (ICD) implantation?2Epstein A.E. DiMarco J.P. Ellenbogen K.A. et al.ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices).J Am Coll Cardiol. 2008; 51: e1-e62Abstract Full Text Full Text PDF PubMed Scopus (1286) Google Scholar Are all patients with a left ventricular ejection fraction (LVEF) ≤30% the same? Might not one patient feel fulfillment about life and accept the reality of death, whereas another has a desire to fulfill personal obligations and want all potentially life-prolonging therapy applied?3Erikson E. Identity: Youth and Crisis. Norton, New York, NY1968Google Scholar We have heard the request before. As Yogi Berra said after watching Mickey Mantle and Roger Maris repeatedly hit back-to-back home runs, “It's déjà vu all over again.”4Bera Y. Yogi Berra official website.http://www.yogiberra.com/yogi-isms.htmlGoogle Scholar Stevenson et al5Stevenson L.W. Hellkamp A.S. Leier C.V. et al.Changing preferences for survival after hospitalization with advanced heart failure.J Am Coll Cardiol. 2008; 52: 1702-1708Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar elegantly demonstrated how our perceptions of patients' desires do not necessarily match. In a trade-off analysis, patients were asked “Would you prefer living 2 years in your current state of health or living 1 day in excellent health?” To those of us used to bell-shaped curves, the results were surprising: rather than a normal distribution, the responses were bimodal and polarized at either end of the spectrum. My take-home message is that patients need to be asked what they want, especially when an intervention is prophylactic and burdened by potential risks. To discuss the pros and cons of primary prevention ICD implantation, the risks and benefits of therapy need to be known by the person discussing the procedure and understood by the patient and his or her family. The benefits of primary-prevention ICD therapy are well known and easy to discuss. More complicated are the nuances of explaining relative and absolute risk, risk-benefit ratios, and the impact of comorbidities. The concept of risk stratification is not new. Our literature is rich with attempts using techniques such as signal-averaged electrocardiography, T-wave alternans, and heart rate variability,6Goldberger J.J. Cain M.E. Hohnloser S.H. et al.American Heart Association/American College of Cardiology/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death.Circulation. 2008; 118: 1497-1518Crossref PubMed Scopus (268) Google Scholar and for cardiac resynchronization therapy, scar burden, and dyssynchrony.7Bleeker G.B. Kaandorp T.A.M. Lamb H.J. et al.Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy.Circulation. 2006; 113: 969-976Crossref PubMed Scopus (655) Google Scholar Singly, none have panned out, and combinations have been variably reliable. Buxton et al8Buxton A.E. Lee K.L. Hafley G.E. et al.Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease Lessons from the MUSTT study.J Am Coll Cardiol. 2007; 50: 1150-1157Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar used the Multicenter Unsustained Tachycardia Trial (MUSTT) database to develop a risk stratification scheme for both overall and arrhythmic mortality. Although most of the variables used can be assessed at the bedside, electrophysiology study was required. Furthermore, MUSTT included only patients with coronary artery disease (CAD), left ventricular dysfunction, and nonsustained ventricular tachycardia. From the MADIT II study, Goldenberg et al identified 5 variables that predict outcome in patients also with CAD postinfarction, including New York Heart Association class >II, age >70 years, blood urea nitrogen >26 mg/dl, QRS duration >120 ms, and atrial fibrillation at baseline. Patients with none or >3 of these risk factors and patients with a creatinine >2.5 mg/dl or blood urea nitrogen >50 mg/dl derived no benefit.9Goldenberg I. Vyas A.K. Hall W.J. et al.Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.J Am Coll Cardiol. 2008; 51: 288-296Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar In the background of these prior data, Kramer et al developed another risk stratification model to predict individuals who may not only not benefit but also die within 1 year of ICD implantation.10Kramer D.B. Friedman P.A. Kallinen L.M. et al.Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators.Heart Rhythm. 2012; 9: 42-46Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar The score, with its acronym PACE, incorporated peripheral arterial disease (P), age ≥70 years (A), creatinine ≥2.0 mg/dl (C), and LVEF ≤20% (E). Patients with a risk score ≥3 had a >4-fold excess 1-year mortality compared with patients with a risk score <3. The report importantly re-emphasizes the possibility of risk stratification and that it may be further refined. Furthermore, the population is representative of that which we see in practice: as in so many trials, the mean age was 65 years, about 80% were male, primary prevention accounted for 75% of the implantations, 60% had CAD, and 31% received cardiac resynchronization devices. Unlike the analyses from MUSTT8Buxton A.E. Lee K.L. Hafley G.E. et al.Limitations of ejection fraction for prediction of sudden death risk in patients with coronary artery disease Lessons from the MUSTT study.J Am Coll Cardiol. 2007; 50: 1150-1157Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar and MADIT II,9Goldenberg I. Vyas A.K. Hall W.J. et al.Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction.J Am Coll Cardiol. 2008; 51: 288-296Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar patients with nonischemic heart disease are represented. Follow-up time was reasonable, 3.1 years, and most importantly a new risk factor was identified: peripheral vascular disease (PVD). Finally, the power of chronic kidney disease is yet again demonstrated.11Cannizzaro L.A. Piccini J.P. Patel U.D. Hernandez A.F. Device therapy in heart failure patients with chronic kidney disease.J Am Coll Cardiol. 2011; 58: 889-896Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In short, not only does LVEF take the stage, but other influences on patient survival now join the cast. Despite these strengths, the report has limitations, many addressed by the investigators. First, in the absence of a control group, we cannot know whether those individuals with high risk scores derive less benefit (after all, over 80% lived for a year despite comorbidities), no benefit, or are actually harmed by ICD therapy. Recall the work of Myerburg et al, showing that without an active control group, these outcomes cannot be differentiated.12Myerburg R.J. Mitrani R. Interian A. Castellanos A. Interpretation of outcomes of antiarrhythmic clinical trials.Circulation. 1998; 97: 1514-1521Crossref PubMed Scopus (176) Google Scholar Second, because ICD benefit increases with time, why should an ice-pick measurement made in time predict events years thereafter?13Goldenberg I. Gillepsie J. Moss A.J. et al.Long-term benefit of primary prevention with an implantable cardioverter-defibrillator.Circulation. 2010; 122: 1265-1271Crossref PubMed Scopus (185) Google Scholar Third, because the National Death Index was used to determine survival, mortality may have been underestimated. Finally, PVD was defined as that requiring intervention or the presence of claudication. We do not know whether asymptomatic PVD would perform as well as a risk stratifier. At the end of the day, what are we to do with this information? Is it enough to change practice? Will this or any risk-stratification scheme ever be adopted? How much harm or benefit is needed to justify or withhold a recommendation for ICD therapy? Do we not implant ICDs in the elderly, those with atrial fibrillation, and even women (who may derive less benefit than men)? Would you not implant an ICD in a patient with a high PACE score? Indeed, the investigators say that they would not use the score as a basis for recommending against ICD implantation in an otherwise appropriate candidate. This report is important because it takes us to the bedside and puts us on the spot asking are we doing the right thing by worshiping at only the LVEF altar. It signifies that prediction modeling can be done, and cries for the need for prospective data and research in this area. This is important not only for our patients, but also for society; and, if we do not do this work, others will force criteria for ICD indications upon us and our patients. Although it may seem outrageous, why not consider a trial in which very-high-risk patients receive a device, and the device is by randomization programmed on or off? In populations of patients excluded from clinical trials, for example those with end-stage renal disease, there are virtually no randomized clinical trial data showing benefit and there is ample evidence for the contrary.11Cannizzaro L.A. Piccini J.P. Patel U.D. Hernandez A.F. Device therapy in heart failure patients with chronic kidney disease.J Am Coll Cardiol. 2011; 58: 889-896Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar We have precedents for implanting devices and doing operations like this. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, we learned that about 30% of the effect of cardiac resynchronization therapy is placebo-mediated,14Abraham W.T. Fisher W.G. Smith A.L. et al.Cardiac resynchronization in chronic heart failure.N Engl J Med. 2002; 346: 1845-1853Crossref PubMed Scopus (4171) Google Scholar in the Multicenter Study of Pacing Therapy for Hypertrophic Cardiomyopathy (M-PATHY) we learned that implantation of a DDD pacemaker programmed to a short AV delay is not beneficial for patients with obstructive hypertrophic cardiomyopathy,15Maron B.J. Nishimura R.A. McKenna W.J. et al.Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy.Circulation. 1999; 99: 2927-2933Crossref PubMed Scopus (428) Google Scholar and in neurosurgery we learned that intracerebral fetal cell transplantation for Parkinson disease does not improve outcomes.16Kim S.Y.H. Frank S. Holloway R. Zimmerman C. Wilson R. Kieburtz K. Science and ethics of sham surgery A survey of Parkinson disease clinical researchers.Arch Neurol. 2005; 62: 1357-1360Crossref PubMed Scopus (63) Google Scholar We live in an era in which resources are limited, we are scrutinized, and honesty and openness are essential. I think we have great opportunities to advance care for our patients and give them precise and accurate advice on what they can expect from ICD therapy. I also think that combinations of metrics offer the greatest chance for success, and that simpler ones have the greatest chance to be accepted. However, to get to this point we need to not rest on existing data, not fear that new studies may decrease implantation rates, and not rationalize that we will not enroll and randomize patients because of referral pressures and worry that studying patients about whom we have little data jeopardizes their outcome. Recall how wrong we were about treating PVCs with antiarrhythmic drugs,17Epstein A.E. Hallstrom A.P. Rogers W.J. et al.Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: the original design concept of the Cardiac Arrhythmia Suppression Trial (CAST).JAMA. 1993; 270: 2451-2455Crossref PubMed Scopus (163) Google Scholar the Vineberg procedure for angina,18Cobb L.A. Thomas G.I. Dillard D.H. Merendino K.A. Bruce R.A. An evaluation of internal-mammary-artery ligation by a double-blind technic.N Engl J Med. 1959; 260: 1115-1118Crossref PubMed Scopus (411) Google Scholar and estrogen therapy for CAD.19The Coronary Drug Project Research GroupThe Coronary Drug Project: findings leading to discontinuation of the 25-mg/day estrogen group.JAMA. 1973; 226: 652-657Crossref PubMed Scopus (397) Google Scholar The opportunities are ours. We know what we need to do. Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillatorsHeart RhythmVol. 9Issue 1PreviewCurrent guidelines do not recommend implantable cardioverter-defibrillator (ICD) implantation in patients with a life expectancy of <1 year. Better methods are needed for identifying patients at high risk for early mortality despite ICD therapy. Full-Text PDF