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How Can Optimization of Medical Treatment Avoid Unnecessary Implantable Cardioverter-Defibrillator Implantations in Patients With Idiopathic Dilated Cardiomyopathy Presenting With “SCD-HeFT Criteria?”

Published:December 19, 2011DOI:https://doi.org/10.1016/j.amjcard.2011.10.033
      To assess the proportion and long-term outcomes of patients with idiopathic dilated cardiomyopathy and potential indications for implantable cardioverter-defibrillator before and after optimization of medical treatment, 503 consecutive patients with idiopathic dilated cardiomyopathy were evaluated from 1988 to 2006. A total of 245 patients (49%) satisfied the “Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) criteria,” defined as a left ventricular ejection fraction of ≤0.35 and New York Heart Association (NYHA) class II-III on registration. Among these, 162 (group A) were re-evaluated 5.4 ± 2 months later with concurrent β-blockers and angiotensin-converting enzyme inhibitor use. Of the 162 patients, 50 (31%) still had “SCD-HeFT criteria” (group A1), 109 (67%) had an improved left ventricular ejection fraction and/or New York Heart Association class (group A2), and 3 (2%) were in NYHA class IV. Of the 227 patients without baseline “SCD-HeFT criteria” (left ventricular ejection fraction >0.35 or NYHA class I), 125 were evaluated after 5.5 ± 2 months. Of these 227 patients, 13 (10%) developed “SCD-HeFT criteria” (group B1), 111 (89%) remained without “SCD-HeFT criteria” (group B2), and 1 (1%) had worsened to NYHA class IV. The 10-year mortality/heart transplantation and sudden death/sustained ventricular arrhythmia rate was 57% and 37% in group A1, 23% and 20% in group A2 (p <0.001 for mortality/heart transplantation and p = 0.014 for sudden death/sustained ventricular arrhythmia vs group A1), 45% and 41% in group B1 (p = NS vs group A1), 16% and 14% in group B2 (p = NS vs group A2), respectively. In conclusion, two thirds of patients with idiopathic dilated cardiomyopathy and “SCD-HeFT criteria” at presentation did not maintain implantable cardioverter-defibrillator indications 3 to 9 months later with optimal medical therapy. Their long-term outcome was excellent, similar to that observed for patients who had never met the “SCD-HeFT criteria.”
      Since the publication of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and the DEFibrillators In Non-Ischemic cardiomyopathy Treatment Evaluation Trial (DEFINITE),
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • Domanski M.
      • Troutman C.
      • Anderson J.
      • Johnson G.
      • McNulty S.E.
      • Clapp-Channing N.
      • Davidson-Ray L.D.
      • Fraulo E.S.
      • Fishbein D.P.
      • Luceri R.M.
      • Ip J.H.
      Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.
      • Anderson K.P.
      • Calkins H.
      • Hoch D.
      • Goldberger J.
      • Shalaby A.
      • Sanders W.E.
      • Schaechter A.
      • Levine J.H.
      Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      the treatment with implantable cardioverter-defibrillator (ICD) for the primary prevention of sudden death (SD) has been extended to patients with nonischemic idiopathic dilated cardiomyopathy (IDC), who have a left ventricular (LV) ejection fraction (EF) of ≤0.35 and who are classified as New York Heart Association (NYHA) functional class II or III (“SCD-HeFT criteria,” class I indication, level of evidence B). The appropriate timing for ICD implantation, however, is still uncertain.
      • Epstein A.E.
      • DiMarco J.P.
      • Ellenbogen K.A.
      • Estes III, N.A.
      • Freedman R.A.
      • Gettes L.S.
      • Gillinov A.M.
      • Gregoratos G.
      • Hammill S.C.
      • Hayes D.L.
      • Hlatky M.A.
      • Newby L.K.
      • Page R.L.
      • Schoenfeld M.H.
      • Silka M.J.
      • Stevenson L.W.
      • Sweeney M.O.
      • Smith Jr, S.C.
      • Jacobs A.K.
      • Adams C.D.
      • Anderson J.L.
      • Buller C.E.
      • Creager M.A.
      • Ettinger S.M.
      • Faxon D.P.
      • Halperin J.L.
      • Hiratzka L.F.
      • Hunt S.A.
      • Krumholz H.M.
      • Kushner F.G.
      • Lytle B.W.
      • Nishimura R.A.
      • Ornato J.P.
      • Page R.L.
      • Riegel B.
      • Tarkington L.G.
      • Yancy C.W.
      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) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons.
      Current guidelines suggest that an ICD should be considered in addition to medical therapy,
      • Epstein A.E.
      • DiMarco J.P.
      • Ellenbogen K.A.
      • Estes III, N.A.
      • Freedman R.A.
      • Gettes L.S.
      • Gillinov A.M.
      • Gregoratos G.
      • Hammill S.C.
      • Hayes D.L.
      • Hlatky M.A.
      • Newby L.K.
      • Page R.L.
      • Schoenfeld M.H.
      • Silka M.J.
      • Stevenson L.W.
      • Sweeney M.O.
      • Smith Jr, S.C.
      • Jacobs A.K.
      • Adams C.D.
      • Anderson J.L.
      • Buller C.E.
      • Creager M.A.
      • Ettinger S.M.
      • Faxon D.P.
      • Halperin J.L.
      • Hiratzka L.F.
      • Hunt S.A.
      • Krumholz H.M.
      • Kushner F.G.
      • Lytle B.W.
      • Nishimura R.A.
      • Ornato J.P.
      • Page R.L.
      • Riegel B.
      • Tarkington L.G.
      • Yancy C.W.
      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) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons.
      but many patients are treated without evidence-based indications, mainly because of newly diagnosed heart failure and before treatment optimization.
      • Al-Khatib S.M.
      • Hellkamp A.
      • Curtis J.
      • Mark D.
      • Peterson E.
      • Sanders G.D.
      • Heidenreich P.A.
      • Hernandez A.F.
      • Curtis L.H.
      • Hammill S.
      Non-evidence-based ICD implantations in the united states.
      In our study, we evaluated the proportion of patients with and without potential indications for ICD implantation at presentation and the long-term prognosis of patients with initial ICD indications but who improved after optimization of medical treatment. Finally, we compared the long-term outcome of “improved” patients to those maintaining “SCD-HeFT criteria” and those who never met “SCD-HeFT criteria.”

      Methods

      In our study, we evaluated all patients with IDC who were not taking β blockers and had data recorded in the Heart Muscle Disease Registry of Trieste, Italy, from January 1, 1988 to April 30, 2006. After our first assessment, optimization of medical treatment was achieved with β blockers, if tolerated, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers at the highest tolerated dosage. Although the data were retrospectively analyzed, the patients were prospectively included in the Registry, and follow-up visits were regularly scheduled, according to the policy of our institution, after about 6 months during the first year and every 12 months afterwards. For the purpose of the present analysis, patients with NYHA class IV, those who died before a second evaluation and patients with a second evaluation performed >9 months after the first visit were excluded from the study population.
      The patients were usually referred to our center by general practitioners or by primary or secondary care hospitals. Those already taking ACE inhibitors were included, because these drugs were usually started earlier, by general practitioners, since the late 1980s.
      A physical examination, 12-lead electrocardiogram, transthoracic echocardiogram, exercise stress test, 24-hour Holter monitoring, and invasive hemodynamic study were performed. All patients >35 years old underwent coronary angiography to exclude significant coronary artery stenosis (>50% in a major vessel). Until 1996, the patients routinely underwent endomyocardial biopsy to exclude active myocarditis.
      • Aretz H.T.
      Myocarditis: the Dallas criteria.
      Thereafter, biopsies were performed only in those patients presenting with recent (<6 months) onset of heart failure and/or clinical history suggestive of active myocarditis. The diagnosis of IDC was made when the LVEF was decreased (<0.50) in the absence of any other known cause of cardiac disease. In the present analysis, only patients evaluated after 1988 were included. This date was chosen because since that year, according to the policy of our institution, β blockers (metoprolol or, later, carvedilol) have been tested and started in all tolerating patients.
      Medical treatment of IDC was considered optimal when the maximum tolerated dose of β blockers and ACE inhibitors was administered. To achieve this condition, low doses of β blockers were tested and slowly uptitrated to the highest dosage tolerated within 2 to 3 months. ACE inhibitors were introduced and/or the dosages increased before the second evaluation. The daily dosage of ACE inhibitors and β blockers reached at the second evaluation were reported as enalapril and carvedilol equivalents, respectively.
      • Poole-Wilson P.A.
      • Swedberg K.
      • Cleland J.G.
      • Di Lenarda A.
      • Hanrath P.
      • Komajda M.
      • Lubsen J.
      • Lutiger B.
      • Metra M.
      • Remme W.J.
      • Torp-Pedersen C.
      • Scherhag A.
      • Skene A.
      Carvedilol or Metoprolol European Trial Investigators
      Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol European trial (COMET): randomised controlled trial.
      Antialdosterone agents were given only for potassium-sparing intent and, after the publication of the Randomized Aldactone Evaluation Study (RALES),
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • Cody R.
      • Castaigne A.
      • Perez A.
      • Palensky J.
      • Wittes J.
      Randomized Aldactone Evaluation Study Investigators
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
      to patients with persisting severe heart failure despite the optimization of medical treatment.
      Amiodarone was administered in the presence of frequent and/or symptomatic ventricular or supraventricular arrhythmias. No other antiarrhythmic drugs were given.
      According to the guidelines available before 2006
      • Gregoratos G.
      • Abrams J.
      • Epstein A.E.
      • Freedman R.A.
      • Hayes D.L.
      • Hlatky M.A.
      • Kerber R.E.
      • Naccarelli G.V.
      • Schoenfeld M.H.
      • Silka M.J.
      • Winters S.L.
      • Gibbons R.J.
      • Antman E.M.
      • Alpert J.S.
      • Gregoratos G.
      • Hiratzka L.F.
      • Faxon D.P.
      • Jacobs A.K.
      • Fuster V.
      • Smith Jr, S.C.
      ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to update the 1998 pacemaker guidelines).
      and our internal policy,
      • Zecchin M.
      • Di Lenarda A.
      • Proclemer A.
      • Faganello G.
      • Facchin D.
      • Petz E.
      • Sinagra G.
      The role of implantable cardioverter defibrillator for primary vs secondary prevention of sudden death in patients with idiopathic dilated cardiomyopathy.
      the patients were not treated with an ICD for primary prevention during the first year after diagnosis. The patients with previous major ventricular arrhythmias (MVA) were excluded from the analysis.
      The patient population was divided into 2 prespecified groups. Group A included those who satisfied the “SCD-HeFT criteria” and group B, those with a LVEF >0.35 and/or NYHA class I on presentation. According to the response to medical treatment, patients belonging to groups A and B were further divided into 4 subgroups:
      • Group A1
        patients with “SCD-HeFT criteria” both on presentation and at the second evaluation
      • Group A2
        patients with “SCD-HeFT criteria” on presentation but with a LVEF >0.35 and/or NYHA class I at the second evaluation
      • Group B1
        patients with a LVEF >0.35 and/or NYHA class I on presentation but with “SCD-HeFT criteria” after 6 months
      • Group B2
        patients with a LVEF >0.35 and/or NYHA class I both on presentation and at the second evaluation
      The primary end point of the study was the long-term total death/heart transplantation (D/HT) and sudden death/sustained ventricular arrhythmia (SD/MVA) rate. Urgent HT was considered for patients with refractory heart failure requiring inotropic treatment and/or mechanical support. SD was defined as an immediate death or a death occurring within 1 hour after the onset of symptoms or during sleep in patients with stable NYHA functional class I to III. MVA was defined as ventricular fibrillation/flutter or a sustained ventricular tachycardia (hemodynamically unstable or lasting >30 seconds) or appropriate ICD interventions (for ventricular tachycardia with a rate >185 beats/min).
      The study design, data analysis, and reporting were performed according to the “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) guidelines.
      • Vandenbroucke J.P.
      • von Elm E.
      • Altman D.G.
      • Gøtzsche P.C.
      • Mulrow C.D.
      • Pocock S.J.
      • Poole C.
      • Schlesselman J.J.
      • Egger M.
      STROBE Initiative
      Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.
      The study was performed in accordance with the guidelines set by the Declaration of Helsinki
      • Rickham P.P.
      Human experimentation: code of ethics of the world medical association Declaration of Helsinki.
      and with the local legal requirements.
      All values are reported, as appropriate, as the mean ± SD or number and percentage. Repeated measures of continuous variables were compared by paired t test. For binary variables, the McNemar test was used. Survival curves were calculated according to the Kaplan-Meier method, and the comparison between curves was performed with the log-rank test. All results were considered as statistically significant when p <0.05. The entire analysis was performed using the Statistical Package for Social Sciences package, version 13.0 (SPSS, Chicago, Illinois).

      Results

      From January 1, 1988 to April 30, 2006, 503 consecutive patients were recorded in the Heart Muscle Disease Registry of Trieste, Italy (see flow diagram in Figure 1) . About ½ of patients satisfied the “SCD-HeFT criteria” at the first evaluation.
      Figure thumbnail gr1
      Figure 1Study population and effect of medical treatment optimization on “SCD-HeFT criteria” (LVEF ≤0.35 and NYHA functional class II or III) evaluated 3 to 9 months after enrollment. Proportion of patients treated with β blockers and ACE inhibitors described for each group. ACEi = ACE inhibitors.
      Of the 245 patients with baseline “SCD-HeFT criteria,” 9 (4%) had died (4 suddenly, 2%) before the second evaluation and 162 were fully re-evaluated 3 to 9 months (mean 5.4 ± 2) later (group A).
      Of the 227 patients with a LVEF >0.35 and/or NYHA class I (group B), 4 (2%) had died (all suddenly) before the second evaluation and 125 were fully re-evaluated 3 to 9 months (mean 5.5 ± 2) later (group B). Thus, the study population (group A plus group B patients) included 287 patients. The clinical and laboratory findings of the study population at the first evaluation are summarized in Table 1.
      Table 1Characteristics of population at first presentation (n = 287)
      VariableValue
      Age (years)43 ± 14
      Males215 (75%)
      Body surface area (m2)1.87 ± 0.23
      Duration of heart failure (months)11 ± 21
      Heart rate at rest (beats/min)79 ± 15
      Systolic blood pressure (mm Hg)125 ± 15
      New York Heart Association class
       I95 (33%)
       II129 (45)
       III63 (22%)
      Electrocardiographic findings
       Sinus rhythm270 (94%)
       Left bundle branch block95 (33%)
      Echocardiographic findings
       Indexed left ventricular end-diastolic diameter (mm)37 ± 5
       Indexed left ventricular end-diastolic volume (ml)108 ± 38
       Right ventricular area shortening fraction0.45 ± 0.16
       Left ventricular ejection fraction0.29 ± 0.09
       Mitral regurgitation area at echocardiography >4 cm2 (4-chamber view)115 (40%)
       Restrictive filling pattern
      Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      95 (33%)
      Holter findings (number of nonsustained ventricular tachycardia/24 hours)4 ± 25
      Exercise stress test (functional capacity [W])104 ± 41
      Drug therapy
       Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker132 (46%)
       β Blockers0 (0%)
       Digoxin195 (68%)
       Diuretics164 (57%)
       Amiodarone26 (9%)
      low asterisk Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      In 172 patients (74 with baseline SCD-HeFT criteria and 98 with a LVEF >0.35 and/or NYHA class I at baseline), a second full evaluation was performed >9 months later and they were excluded from the analysis (Figure 1). At the first evaluation, these patients, compared to the study population, showed a slightly greater LVEF (0.33 ± 0.09 vs 0.29 ±0.09; p <0.001), lower end-diastolic diameter (35.5 ± 5 vs 37.5; p = 0.003), and less frequent LV restrictive filling pattern (in 23% vs 33%; p = 0.041). No differences were found concerning the demographic and clinical features, symptoms or duration of heart failure. Long-term survival was not different comparing these patients and the study population (data not shown).
      ACE inhibitors or angiotensin receptor blockers were given to 46% of the study population before our first evaluation and to 91% of patients at the second evaluation (reaching an enalapril-equivalent dose of 22 ± 13 mg/day). At the second evaluation, β blockers were tolerated in 85% of patients, reaching a mean carvedilol-equivalent dosage of 51 ± 26 mg/day.
      In both group A and B patients, a significant improvement occurred in the LV systolic and diastolic function and LV dimensions (Table 2, Table 3), as well as a reduction in the heart rate and nonsustained ventricular arrhythmias. The improvement was more evident in patients with baseline SCD-HeFT characteristics (group A; Table 2).
      Table 2Comparison between baseline (first evaluation) and 3 to 9 months of follow-up (second evaluation) in group A (n = 162) patients
      VariableFirst EvaluationSecond Evaluationp Value
      Age (years)46 ± 13
      Males120 (74%)
      Duration of heart failure (months)14 ± 23
      Heart rate at rest (beats/min)81 ± 1771 ± 13<0.001
      Systolic blood pressure (mm Hg)124 ± 16127 ± 180.035
      New York Heart Association class<0.001
       I0 (0%)65 (40%)
       II105 (65%)78 (48%)
       III57 (35%)16 (10%)
       IV0 (0%)3 (2%)
       I–II105 (65%)144 (89%)<0.001
      Electrocardiographic findings
       Sinus rhythm151 (93%)149 (92%)1
       Left bundle branch block70 (43%)58 (36%)0.007
      Echocardiographic findings
       Indexed left ventricular end-diastolic Diameter (mm)38 ± 536 ± 6<0.001
       Indexed left ventricular end-diastolic volume (ml)119 ± 37102 ± 35<0.001
       Right ventricular area shortening fraction0.44 ± 0.170.47 ± 0.140.053
       Left ventricular ejection fraction0.24 ± 0.060.35 ± 0.11<0.001
       Mitral regurgitation area at echocardiography >4 cm2 (4-chamber view)86 (53%)52 (32%)<0.001
       Restrictive filling pattern
      Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      70 (43%)26 (16%)<0.001
      Holter findings (number of nonsustained ventricular tachycardia/24 hours)4 ± 171 ± 2<0.001
      Exercise stress test findings (functional capacity [W])95 ± 33101 ± 370.013
      Drug therapy
       Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker66 (41%)154 (95%)<0.001
       β Blockers0 (0%)141 (87%)<0.001
       Enalapril equivalent dosage (mg/day)Not known27 ± 13//
       Carvedilol equivalent dosage (mg/day)053 ± 28//
       Digoxin146 (90%)146 (90%)1
       Diuretics123 (76%)125 (77%)1
       Amiodarone15 (9%)15 (9%)1
      low asterisk Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      Table 3Comparison between baseline (first evaluation) and 3- to 9-month follow-up (second evaluation) in group B (n = 125) patients
      VariableFirst EvaluationSecond Evaluationp Value
      Age (years)40 ± 14
      Males94 (75%)
      Duration of heart failure (months)6 ± 16
      Heart rate at rest (beats/min)77 ± 1269 ± 11<0.001
      Systolic blood pressure (mm Hg)127 ± 15126 ± 160.523
      New York Heart Association class1
       I94 (75%)92 (74%)
       II24 (19%)28 (22%)
       III8 (6%)4 (3%)
       IV0 (0%)1 (1%)
       I–II118 (94%)120 (96%)0.727
      Electrocardiographic findings
       Sinus rhythm120 (96%)116 (93%)0.375
       Left bundle branch block25 (20%)25 (20%)1
      Echocardiographic findings
       Indexed left ventricular end-diastolic Diameter (mm)35 ± 533 ± 5<0.001
       Indexed left ventricular end-diastolic volume (ml)96 ± 3685 ± 34<0.001
       Right ventricular area shortening fraction0.50 ± 0.140.49 ± 0.120.578
       Left ventricular ejection fraction0.36 ± 0.080.41 ± 0.11<0.001
       Mitral regurgitation area at echocardiography >4 cm2 (4-chamber view)26 (21%)20 (16%)0.286
       Restrictive filling pattern
      Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      20 (16%)10 (8%)0.092
      Holter findings (number of nonsustained ventricular tachycardia/24 hours)6 ± 321 ± 70.008
      Exercise stress test findings (functional capacity [W])121 ± 43124 ± 390.326
      Drug therapy
       Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker63 (50%)108 (86%)<0.001
       β Blockers0 (0%)103 (82%)<0.001
       Enalapril equivalent dosage (mg/day)Not known23 ± 13
       Carvedilol equivalent dosage (mg/day)063 ± 29
       Digoxin73 (58%)70 (56%)0.688
       Diuretics41 (33%)36 (29%)0.424
       Amiodarone11 (9%)11 (9%)1
      low asterisk Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
      The effects of optimization of medical treatment in the subgroups A1, A2, B1, and B2 are shown in Figure 1. The proportion of patients treated with ACE inhibitors and β blockers before and after 3 to 9 months in the 4 subgroups was not significantly different.
      The mean follow-up of the study population (n = 287) was 110 ± 63 months. During this period, 51 patients (18%) died, 28 (10%) suddenly, and 31 (11%) underwent HT because of refractory heart failure; 40 patients (17%) underwent ICD implantation for primary prevention (26% of patients in group A1, 14% in group A2, 46% in group B1, and 12% of patients in group B2, p = 0.02). Cardiac resynchronization therapy was added for 18 patients with ICD. Nonfatal sustained ventricular tachycardia or ventricular fibrillation successfully treated with an ICD was observed in 13 patients (33% of those with an ICD). The 10-year D/HT and SD/MVA incidence (Figure 2, Figure 3) was as follows:
      • 57% and 37% in patients with baseline “SCD-HeFT criteria” at both the first and the second evaluation (group A1)
      • 23% and 20% in patients with baseline “SCD-HeFT criteria” at the first but not the second evaluation (group A2; p <0.001 for D/HT and p = 0.014 for SD/MVA vs group A1; the main clinical characteristics of the patients with SD/MVA in this subgroup are listed in Table 4)
        Table 4Main clinical/laboratory characteristics evaluated at 3 to 9 months in 19 patients from A2 group
        SCD-HeFT criteria at presentation but improved on medical treatment, with SD/MVAs during follow-up.
        VariableValue
        Age (years)46 ± 13
        Males19 (100%)
        New York Heart Association class
         I17 (89%)
         II2 (11%)
         III–IV0 (0%)
        Left ventricular ejection fraction0.35 ± 0.08
        Left ventricular ejection fraction ≤0.358 (42%)
        Indexed left ventricular end-diastolic Diameter (mm)34 ± 6
        Indexed left ventricular end-diastolic volume (ml)99 ± 35
        Left bundle branch block8 (42%)
        Nonsustained ventricular tachycardia (>1/24 hours)10 (53%)
        β Blockers19 (100%)
        Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker19 (100%)
        low asterisk SCD-HeFT criteria at presentation but improved on medical treatment, with SD/MVAs during follow-up.
      • 45% and 41% in patients developing “SCD-HeFT criteria” only at the second evaluation (group B1; p = NS vs group A1 for D/HT and SD/MVA)
      • 16% and 14% in patients without “SCD-HeFT criteria” neither at the first nor the second evaluation (group B2; p = NS vs group A2 for D/HT and SD/MVA)
      Figure thumbnail gr2
      Figure 2Long-term survival free from HR rate in 4 groups: A1, baseline “SCD-HeFT criteria” both at first and second evaluation; A2, baseline “SCD-HeFT criteria” at first but not at second evaluation; B1, patients developing “SCD-HeFT criteria” only at second evaluation; and B2, patients without “SCD-HeFT criteria” at first or second evaluation. A1 versus A2, p <0.001; A1 versus B1, p = 0.18; A2 versus B2, p = 0.10.
      Figure thumbnail gr3
      Figure 3Long-term survival free from SD/MVA rate in 4 groups (A1, baseline “SCD-HeFT criteria” at both first and second evaluation; A2, baseline “SCD-HeFT criteria” at first but not second evaluation; B1, patients developing “SCD-HeFT criteria” only at second evaluation; B2, patients without “SCD-HeFT criteria” at first or second evaluation. A1 versus A2, p = 0.014; A1 versus B1, p = 0.8; A2 versus B2, p = 0.6.

      Discussion

      Our study emphasizes how important is the optimization of medical treatment in patients initially presenting with ICD indications and that ICD implantation can be unnecessary for many of them.
      According to a recent report from the United States, 22.5% of patients with an ICD did not meet the evidence-based criteria for implantation, because of newly diagnosed heart failure
      • Al-Khatib S.M.
      • Hellkamp A.
      • Curtis J.
      • Mark D.
      • Peterson E.
      • Sanders G.D.
      • Heidenreich P.A.
      • Hernandez A.F.
      • Curtis L.H.
      • Hammill S.
      Non-evidence-based ICD implantations in the united states.
      in most cases (62%). In patients with impaired LV function and heart failure symptoms, the ICD can significantly reduce mortality,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • Domanski M.
      • Troutman C.
      • Anderson J.
      • Johnson G.
      • McNulty S.E.
      • Clapp-Channing N.
      • Davidson-Ray L.D.
      • Fraulo E.S.
      • Fishbein D.P.
      • Luceri R.M.
      • Ip J.H.
      Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      but economical issues, the risk of complications, and the inappropriate shock rate (in ≤25% of patients) should also be considered.
      • Epstein A.E.
      • DiMarco J.P.
      • Ellenbogen K.A.
      • Estes III, N.A.
      • Freedman R.A.
      • Gettes L.S.
      • Gillinov A.M.
      • Gregoratos G.
      • Hammill S.C.
      • Hayes D.L.
      • Hlatky M.A.
      • Newby L.K.
      • Page R.L.
      • Schoenfeld M.H.
      • Silka M.J.
      • Stevenson L.W.
      • Sweeney M.O.
      • Smith Jr, S.C.
      • Jacobs A.K.
      • Adams C.D.
      • Anderson J.L.
      • Buller C.E.
      • Creager M.A.
      • Ettinger S.M.
      • Faxon D.P.
      • Halperin J.L.
      • Hiratzka L.F.
      • Hunt S.A.
      • Krumholz H.M.
      • Kushner F.G.
      • Lytle B.W.
      • Nishimura R.A.
      • Ornato J.P.
      • Page R.L.
      • Riegel B.
      • Tarkington L.G.
      • Yancy C.W.
      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) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons.
      • Tung R.
      • Zimetbaum P.
      • Josephson M.E.
      A critical appraisal of implantable cardioverter-defibrillator therapy for the prevention of sudden cardiac death.
      Many patients with severe LV dysfunction and heart failure symptoms can improve their clinical condition after the optimization of medical treatment, especially with β blockers.
      • Hall S.A.
      • Cigarroa C.G.
      • Marcoux L.
      • Risser R.C.
      • Grayburn P.A.
      • Eichhorn E.J.
      Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade.
      • Metra M.
      • Nodari S.
      • Parrinello G.
      • Giubbini R.
      • Manca C.
      • Dei Cas L.
      Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance.
      • Verma A.
      • Wulffhart Z.
      • Lakkireddy D.
      • Khaykin Y.
      • Kaplan A.
      • Sarak B.
      • Biria M.
      • Pillarisetti J.
      • Bhat P.
      • Di Biase L.
      • Constantini O.
      • Quan K.
      • Natale A.
      Incidence of left ventricular function improvement after primary prevention ICD implantation for non-ischaemic dilated cardiomyopathy: a multicentre experience.
      • DiLenarda A.
      • Gregori D.
      • Sinagra G.
      • Lardieri G.
      • Perkan A.
      • Pinamonti B.
      • Salvatore L.
      • Secoli G.
      • Zecchin M.
      • Camerini F.
      The Heart Muscle Disease Study Group
      Metoprolol in dilated cardiomyopathy: is it possible to identify factors predictive of improvement?.
      To date, the proportion and prognosis of such patients remain unknown, because most published studies evaluated either patients already receiving optimal medical treatment
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • Domanski M.
      • Troutman C.
      • Anderson J.
      • Johnson G.
      • McNulty S.E.
      • Clapp-Channing N.
      • Davidson-Ray L.D.
      • Fraulo E.S.
      • Fishbein D.P.
      • Luceri R.M.
      • Ip J.H.
      Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      or patients not fully treated with β blockers.
      • Grimm W.
      • Christ M.
      • Bach J.
      • Müller H.H.
      • Maisch B.
      Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg cardiomyopathy study.
      The main results of the present study are: first, about 50% of patients observed at our institution had SCD-HeFT characteristics at the first assessment. Second, 2/3 of the patients with a baseline LVEF of ≤0.35 and NYHA functional class II-III improved and thus did not maintain “SCD-HeFT criteria” 5.5 months after starting β blockers and increasing ACE inhibitor treatment. Finally, the long-term total and sudden mortality were similar in the “improved” patients (group A2) and in those already presenting without “SCD-HeFT criteria” (group B2), suggesting that ICD implantation should not be performed in most patients with low LVEF and heart failure symptoms before optimization of medical treatment.
      Four patients (2%) died suddenly before a second evaluation; however, during the same period, a similar risk of SD was present in patients without baseline “SCD-HeFT criteria,” confirming the difficulty of stratifying the risk of SD at first evaluation. Not a negligible proportion of patients with “SCD-HeFT criteria” at enrollment but not after optimization of treatment died suddenly or developed major ventricular arrhythmias during follow-up. These patients were considered asymptomatic for heart failure and/or had a LVEF >0.35 at the second evaluation (Table 4) and, therefore, were not eligible for ICD implantation. However, the stratification using the NYHA classification is subjective and often inaccurate
      • Raphael C.
      • Briscoe C.
      • Davies J.
      • Ian Whinnett Z.
      • Manisty C.
      • Sutton R.
      • Mayet J.
      • Francis D.P.
      Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure.
      and an underestimation of symptoms in some patients cannot be excluded. In addition, in 8 of these patients (42%), the LVEF was still ≤0.35, and 10 (53%) had nonsustained ventricular tachycardia at Holter monitoring and could have been considered at greater risk according to the published data.
      • Zecchin M.
      • Di Lenarda A.
      • Gregori D.
      • Merlo M.
      • Pivetta A.
      • Vitrella G.
      • Sabbadini G.
      • Mestroni L.
      • Sinagra G.
      Are nonsustained ventricular tachycardias predictive of major arrhythmias in patients with dilated cardiomyopathy on optimal medical treatment?.
      According to some investigators, ICD implantation should not be delayed in patients with heart failure symptoms and severe LV dysfunction. Data from the DEFINITE study
      • Kadish A.
      • Schaechter A.
      • Subacius H.
      • Thattassery E.
      • Sanders W.
      • Anderson K.P.
      • Dyer A.
      • Goldberger J.
      • Levine J.
      Patients with recently diagnosed nonischemic cardiomyopathy benefit from implantable cardioverter-defibrillators.
      suggest that early ICD implantation (<9 months or even <3 months) can be more beneficial than implantation in patients with a more remote diagnosis. In contrast, the Cardiomyopathy Trial
      • Bänsch D.
      • Antz M.
      • Boczor S.
      • Volkmer M.
      • Tebbenjohanns J.
      • Seidl K.
      • Block M.
      • Gietzen F.
      • Berger J.
      • Kuck K.H.
      Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the cardiomyopathy trial (CAT).
      did not show any benefit in patients with a recent onset of IDC (<9 months; median duration of symptoms, 3 months) treated with an ICD.
      There is no doubt that patients with severe LV dysfunction, as a group, can benefit from an ICD when implanted immediately after diagnosis. However, the choice of treating all these patients with an ICD without any delay could be questionable, both from the clinical and economical viewpoint. Finally, the risk of complications in nonevidence-based implants could be greater.
      • Al-Khatib S.M.
      • Hellkamp A.
      • Curtis J.
      • Mark D.
      • Peterson E.
      • Sanders G.D.
      • Heidenreich P.A.
      • Hernandez A.F.
      • Curtis L.H.
      • Hammill S.
      Non-evidence-based ICD implantations in the united states.
      An improvement of most clinical and functional parameters can be expected, especially in patients with moderate to severe left ventricular impairment, after optimization of medical treatment.
      The analysis was performed in about 60% of all patients recorded in the Registry, because some patients, usually because of geographic reasons, were evaluated >9 months after the first assessment. Our choice of considering a reassessment within 9, but >3, months after the first evaluation is supported by the published data
      • Al-Khatib S.M.
      • Hellkamp A.
      • Curtis J.
      • Mark D.
      • Peterson E.
      • Sanders G.D.
      • Heidenreich P.A.
      • Hernandez A.F.
      • Curtis L.H.
      • Hammill S.
      Non-evidence-based ICD implantations in the united states.
      and our experience
      • Pinamonti B.
      • Zecchin M.
      • Di Lenarda A.
      • Gregori D.
      • Sinagra G.
      • Camerini F.
      Persistence of restrictive left ventricular filling pattern in dilated cardiomyopathy: an ominous prognostic sign.
      ; thus, ≤3 months could be inadequate for uptitration of drugs (especially β blockers) and waiting >9 months in high-risk patients could be unnecessary and potentially harmful, even if the benefit of β blockers can be evident >1 year
      • DiLenarda A.
      • Gregori D.
      • Sinagra G.
      • Lardieri G.
      • Perkan A.
      • Pinamonti B.
      • Salvatore L.
      • Secoli G.
      • Zecchin M.
      • Camerini F.
      The Heart Muscle Disease Study Group
      Metoprolol in dilated cardiomyopathy: is it possible to identify factors predictive of improvement?.
      after their introduction.
      In the present study, the effect of optimization of medical therapy was analyzed. However, about 50% of our population was already taking ACE inhibitors before our observation, usually just started from the referring physician, at our first observation, and the starting dosage was not always available.
      Our population included only patients with IDC; the results therefore should not be extended to patients with other causes of impaired LVEF, such as hypertension or ischemic heart disease.

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      Linked Article

      • Timing of Prophylactic Implantable Cardioverter-Defibrillator Implantation in Patients With Cardiomyopathy
        American Journal of CardiologyVol. 110Issue 1
        • Preview
          The recent study by Zecchin et al1 is an important contribution to the debate regarding the appropriate timing of prophylactic implantable cardioverter-defibrillator (ICD) implantation for patients with idiopathic dilated cardiomyopathy (DC). They have shown that with optimal medical therapy, 2/3 of patients with DC and “SCD-HeFT [Sudden Cardiac Death in Heart Failure] criteria” at presentation2 did not maintain ICD indications 3 to 9 months later. We wish to extend these observations by showing that even in patients with advanced heart failure and very low left ventricular ejection fractions (LVEFs), intensive medical management without ICD implantation can be associated with an exceptionally low 1-year mortality and, in many cases, with an improvement of the LVEF to >35%.
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