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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?”
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),
Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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 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)
Variable
Value
Age (years)
43 ± 14
Males
215 (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
I
95 (33%)
II
129 (45)
III
63 (22%)
Electrocardiographic findings
Sinus rhythm
270 (94%)
Left bundle branch block
95 (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 fraction
0.45 ± 0.16
Left ventricular ejection fraction
0.29 ± 0.09
Mitral regurgitation area at echocardiography >4 cm2 (4-chamber view)
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
Variable
First Evaluation
Second Evaluation
p Value
Age (years)
46 ± 13
Males
120 (74%)
Duration of heart failure (months)
14 ± 23
Heart rate at rest (beats/min)
81 ± 17
71 ± 13
<0.001
Systolic blood pressure (mm Hg)
124 ± 16
127 ± 18
0.035
New York Heart Association class
<0.001
I
0 (0%)
65 (40%)
II
105 (65%)
78 (48%)
III
57 (35%)
16 (10%)
IV
0 (0%)
3 (2%)
I–II
105 (65%)
144 (89%)
<0.001
Electrocardiographic findings
Sinus rhythm
151 (93%)
149 (92%)
1
Left bundle branch block
70 (43%)
58 (36%)
0.007
Echocardiographic findings
Indexed left ventricular end-diastolic Diameter (mm)
38 ± 5
36 ± 6
<0.001
Indexed left ventricular end-diastolic volume (ml)
119 ± 37
102 ± 35
<0.001
Right ventricular area shortening fraction
0.44 ± 0.17
0.47 ± 0.14
0.053
Left ventricular ejection fraction
0.24 ± 0.06
0.35 ± 0.11
<0.001
Mitral regurgitation area at echocardiography >4 cm2 (4-chamber view)
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
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 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 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.
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
Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
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.
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.
Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade.
Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance.
Incidence of left ventricular function improvement after primary prevention ICD implantation for non-ischaemic dilated cardiomyopathy: a multicentre experience.
To date, the proportion and prognosis of such patients remain unknown, because most published studies evaluated either patients already receiving optimal medical treatment
Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
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
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.
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
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
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.
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
; 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
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.
References
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.
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.
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.
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).
The role of implantable cardioverter defibrillator for primary vs secondary prevention of sudden death in patients with idiopathic dilated cardiomyopathy.
Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade.
Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance.
Incidence of left ventricular function improvement after primary prevention ICD implantation for non-ischaemic dilated cardiomyopathy: a multicentre experience.
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%.
Restrictive filling pattern: mitral E wave deceleration time ≤120 ms or mitral E wave deceleration time <150 ms associated with E/A ratio ≥2.
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