Europace Advance Access published online on October 17, 2007
Europace, doi:10.1093/europace/eum230
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Predictive value of programmed ventricular stimulation in patients with ischaemic cardiomyopathy: implications for the selection of candidates for an implantable defibrillator
Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy
Manuscript submitted 5 April 2007. Accepted after revision 24 September 2007.
* Corresponding author. Tel: +39 0382 503715; fax: +39 0382 503161. E-mail address: g.deferrari{at}smatteo.pv.it
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Abstract |
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Aims: The present study assessed the role of programmed ventricular stimulation (PVS) in risk stratification of patients with ischaemic cardiomyopathy (ICM), candidates for implantable cardioverter-defibrillator (ICD).
Methods and results: Consecutive patients with ICM and LVEF 
40% (n = 106, age 61 ± 7 years, LVEF 27 ± 7%) underwent PVS. This was considered positive in case of inducibility of monomorphic ventricular tachycardia (VT) with 3 extrastimuli; polymorphic VT, ventricular fibrillation (VF), and fast monomorphic VT (CL 230 ms) with 2 extrastimuli. Primary end-point was the combination of arrhythmic death and VF requiring ICD shock. Forty-nine patients (46%) were inducible at PVS; 74 (70%) were implanted with ICD. During a 24-month follow-up, the primary end-point occurred more frequently in positive PVS patients among the overall population, among patients with LVEF 30% (n = 80) and among patients with an ICD. The negative predictive value of PVS was 96% in each group. In the overall population, both PVS (HR 7.32, 95% CI 1.6–32) and LVEF (HR 4.59, 95% CI 1.6–13) predicted the primary end-point.
Conclusion: PVS may still have a role in predicting the arrhythmic risk in patients with ICM. A negative PVS identifies a subgroup with a very low risk of arrhythmic events even in patients with LVEF 30%.
Key Words: Cardiomyopathy, Electrophysiological study, Post-myocardial infarction, Risk stratification, Sudden death
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Introduction |
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The effectiveness of implantable cardioverter-defibrillator (ICD) in the prevention of sudden cardiac death and in the reduction of total mortality in patients with post-ischaemic cardiomyopathy has been largely established.1
–3 The implantation of prophylactic ICDs in all patients with ischaemic cardiomyopathy and low left ventricular ejection fraction (LVEF) has enormous costs. MADIT II results indicate the need to implant 18 patients with an ICD to save one life during 20 months of follow-up, suggesting the potential utility of good risk stratifications4–6 which can help in selecting patients at higher risk, who can benefit the most from an ICD, and patients at very low risk, in whom ICD implantation could be potentially withheld. Programmed ventricular stimulation (PVS) has long been considered to predict the risk of malignant arrhythmias in patients with a previous myocardial infarction (MI).7,8 Accordingly, it has been used in MADIT I to identify the best candidates for an ICD. The MUSTT trial and registry confirmed the prognostic value of PVS, although the negative predictive value of the test was found to be sub-optimal.9 More recently, a MADIT II sub-study10 has called into question the role of PVS, suggesting that it predicts the risk of ventricular tachycardia (VT) but not of ventricular fibrillation (VF). The concept that PVS has no present role in the risk stratification of these patients has been widely accepted also due to the inherent simplicity of directly implanting an ICD in all patients with LVEF 30%. The question whether EF 30% alone could be sufficient to identify appropriate candidates for ICD therapy is, nevertheless, still a matter of debate.11 |
Methods |
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Patient characteristics
Consecutive patients (n = 106) with ischaemic cardiomyopathy referred to the Electrophysiology Unit of our Department, from June 1998 to August 2004 for arrhythmic risk stratification represent the population of the study. Patients were included if they had an LVEF
40% and a previous MI. Patients were excluded if they had a previous cardiac arrest or sustained VT or if they had an MI or a cardiac revascularization within 30 days from enrolment. Patients characteristics are summarized in Table 1. Thirty-six percent of patients were on amiodarone, 55% on beta-blockers, and 11% on both drugs; none was treated with other anti-arrhythmic drugs. All patients gave written informed consent to the study.
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Programmed ventricular stimulation protocol
Therapy with amiodarone and beta-blockers was not discontinued. Programmed ventricular stimulation was conducted using 2 ms stimuli at twice diastolic threshold, 500 and 400 ms cycle length from both right ventricular apex and outflow tract. A maximum of three extrastimuli were delivered late in diastole and decremented by 10 ms intervals until refractoriness or to a minimum of 200 ms. If a given protocol caused the induction of a VT lasting
10 beats, the scanning was repeated starting from a coupling interval 30 ms longer than the index one and proceeding downwards.
The test was considered positive in case of reproducible induction of monomorphic VT with up to three extrastimuli, or of polymorphic VT, VF, and fast monomorphic VT (CL 230 ms) with up to two extrastimuli, according to MADIT I inducibility criteria.12
Follow-up and end-points
Patients were prospectively followed and the end-points were pre-specified. Patients were seen in the out-patient clinic 1 month after PVS and every 6 months thereafter. In case of patients implanted with a defibrillator, the device memory was interrogated at each visit and the stored electrograms were analysed: a ventricular arrhythmia faster than 200 bpm requiring ICD shock was defined as VF; a ventricular arrhythmia slower than 200 bpm was classified as VT; in case of acceleration of a ventricular arrhythmia in the VF zone by antitachycardia pacing, the index arrhythmia was considered VT.
Deaths were defined as cardiac or non-cardiac and the classification of Hinkle and Thaler13 modified as in the MUSTT study9 was used for coding the suspected mechanism of cardiac death (arrhythmic or non-arrhythmic).
The primary end-point of the study was the combination of arrhythmic death and VF requiring ICD shock. Secondary end-points were the combination of total mortality and VF requiring ICD shock and the combination of arrhythmic death and VF or VT requiring ICD intervention.
Statistical analysis
Results are presented as mean ± SD for continuous variables and as percent for categorical variables. Fisher's exact test and Student-t test were used to compare discrete and continuous variables, respectively. Kaplan–Meier estimates and logrank test were used to compare events occurrence during follow-up. Hazards ratio both at univariate and multivariate analysis was generated from Cox proportional hazards models. A P-value <0.05 was considered statistically significant.
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Results of programmed ventricular stimulation
During PVS, a monomorphic VT was reproducibly induced in 41 patients (38%) with up to three extrastimuli and a polymorphic VT or VF was induced in 8 patients (8%) with up to two extrastimuli. Therefore, 49 patients (46%) had a positive PVS according to the traditional MADIT I definition of inducibility.
Follow-up
Seventy-four patients (70%) were implanted with an ICD. The choice whether to implant an ICD was left to the clinical cardiologist taking care of the patients; ICD implantation was proposed to patients considered by the treating physician to be at high risk. In particular, 47 of 49 patients with positive PVS were implanted with an ICD (two patients refused). Additionally, 19 patients were implanted because of frequent episodes of non-sustained VT (in 18/19 cases in the presence of LVEF 30%); seven patients were implanted because of LVEF 30% in the absence of documented arrhythmias (following MADIT II criteria), and one patient because of a family history of sudden cardiac death. Overall, patients implanted and not implanted with an ICD were similar regarding age (60 ± 7 vs. 62 ± 8 years), LVEF (26 ± 7 vs. 28 ± 7%), NYHA class (2.3 ± 0.6 vs. 2.1 ± 0.6), and QRS duration (129 ± 29 vs. 133 ± 34 ms). Moreover, almost identical was the pharmacological treatment among the two groups; ACE-inhibitors in 78 and 84%, beta-blockers in 66 and 68%, amiodarone in 45 and 50% in implanted and non-implanted patients, respectively.
The type of ICD was chosen according to clinical characteristics of patients (60% single chamber, 16% dual chamber, 24% biventricular ICD). CRT-D devices were implanted in 10 patients with positive PVS (20%) and in 8 patients with negative PVS (14%, P = 0.442). The average percentage of paced beats was 8% among single chamber devices, 27% among dual chamber devices, and 98% among biventricular devices.
During a median follow-up of 24 months (range 1–71), 14 patients (13%) died: 12 due to end-stage heart failure while 2 patients died suddenly. Both cases of sudden death occurred among non-implanted patients: one patient had negative PVS and 24% LVEF, one positive PVS and 20% LVEF (he refused ICD implantation). Four patients (3.7%) underwent emergency heart transplantation, 12 patients (11%) had VF requiring ICD shock, and 10 (9%) had a VT treated with antitachycardia pacing or low-energy shock by the ICD.
End-points predictors
In the overall population of patients, those experiencing the predetermined composite end-point of arrhythmic death and VF requiring ICD intervention (n = 14, 13%) were similar to patients who did not experience an arrhythmic event in age, NYHA functional class, and QRS duration (Table 2).
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Patients with the primary end-point showed a lower LVEF compared with those with no events (21 ± 5 vs. 28 ± 8%, P = 0.003) and, notably, all patients had a baseline LVEF
30%. Twenty-four percent of patients with a positive PVS experienced the primary end-point, compared with 3.5% of patients with negative PVS (P = 0.002). Survival analysis confirmed the significantly worse outcome for patients with positive PVS (P = 0.002, Figure 1).
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At univariate analysis LVEF significantly predicted the primary end-point with a hazards ratio of 4.62 associated with a 10% LVEF decrease (95% CI: 1.58–13, P = 0.005). Programmed ventricular stimulation was also found to significantly predict the primary end-point with a hazards ratio of 7.2 (95% CI: 1.61–32, P = 0.009). Other clinical variables such as NYHA class, age, QRS duration, and beta-blockers or amiodarone use were unable to predict the primary end-point.
When PVS and LVEF were simultaneously entered in the model and adjusted for other baseline clinical variables (age, NYHA class, QRS duration, NSVT, beta-blockers, and amiodarone use), they were both independent predictors of the primary end-point (PVS: HR 7.32, 95% CI 1.63–32, P = 0.009 and LVEF: HR 4.59, 95% CI 1.56–13, P = 0.005).
Within the group of 74 patients implanted with an ICD, 23% of those with positive PVS experienced a primary end-point (in all cases an ICD shock on VF) compared with 3.5% of those with negative PVS (P = 0.04). Survival analysis confirmed the significantly (P = 0.03) worse outcome of patients with positive PVS. At multivariate analysis, both LVEF and PVS significantly predicted the incidence of VF in this group of patients (LVEF: HR = 4.52, 95%CI 1.45–14, P = 0.009 and PVS: HR = 8.3, 95% CI 1.07–64, P = 0.04). When considering single- and dual-chamber devices, the percentage of paced beats was similar among patients with vs. patients without the primary end-point.
Patients with depressed left ventricular function
All primary end-points occurred among patients with LVEF 30% confirming the prognostic role of depressed LV function. Among patients with an LVEF 30% (n = 80, 75%), 35% of patients with positive PVS experienced a primary end-point compared with 4.3% of those with negative PVS (P < 0.001). Survival analysis confirmed in this subgroup the worse outcome of patients with positive PVS (P < 0.001). At multivariate analysis, PVS was still an independent predictor of the primary end-point in this subgroup of patients (HR = 7.8, 95% CI 1.74–35, P = 0.007), whereas LVEF was not.
Diagnostic accuracy
Programmed ventricular stimulation had a relatively low positive predictive value in the entire population (24%), among patients with ICD (23%) and among patients with LVEF 30% (35%); likewise specificity resulted rather low in all three groups (60, 42, 66%, respectively). On the contrary, sensitivity was found to be good (86% both in the overall population and in the subgroup with LVEF 30%, 91% in the ICD group). The most remarkable result of the current study is that patients with a negative PVS were found to have a very low arrhythmic event rate, resulting in a negative predictive value that was found to be 96% in all three populations tested (general population, patients with implanted ICD, and patients with LVEF 30%).
Additional subgroups and influence of CRT-Don risk predictors
The analysis of several meaningful subgroups of patients is presented in Table 3. In all eleven subgroups, patients with positive PVS were found to have a significantly higher incidence of the primary end-point compared with negative PVS patients. Also, the test had a negative predictive value exceeding 95% in all subgroups.
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The question of the influence of CRT-D device implantation on the predictive role of PVS is particularly meaningful since CRT may convey an important potential protective effect against sudden death, particularly over the long-term, derived from reverse remodelling.14
In the present study, the primary end-point occurred in 13 out of 88 patients without CRT (14.7%) and in 3 out of 18 patients with CRT (16.7%). In the overall population of the study, when PVS, LVEF, and the presence of an implanted CRT were entered in the model, the following HRs were found: PVS 7.5 (95% CI 1.7–33, P = 0.003); LVEF 4.9 (95% CI 1.7–13, P = 0.005); CRT HR 0.4 (95% CI 0.07–2.2, P = 0.295). When patients with CRT-D were excluded, the HR related to a positive PVS in the remaining 88 patients was very high (15.8) and statistically significant (P = 0.008) as shown in Table 3. Within this subgroup, an additional multivariate analysis adjusting for LVEF and the other baseline clinical variables (age, NYHA class, QRS duration, NSVT, beta-blockers, and amiodarone) also resulted in a high and significant HR related to a positive PVS (HR = 18, P = 0.007).
Secondary end-points
Additional end-points were the combination of total mortality and VF requiring ICD shock and the combination of arrhythmic death, VF, and VT treated by the ICD.
The combined end-point of total mortality and VF requiring ICD shock was more frequent among patients with either positive PVS [32 vs. 14%, P = 0.02, relative risk (RR) 2.3] or LVEF 30% (29 vs. 3.8%, P < 0.01, RR 7.4).
Finally, the combined end-point of arrhythmic death, VF, and VT treated by the ICD occurred more frequently in patients with positive PVS both in the overall population (30 vs. 7%, P < 0.01, RR = 4.3; 95% CI 1.5–12) and in the subgroup with LVEF 30% (38 vs. 8.6%, P < 0.01, RR = 4.3; 95%CI 1.5–12).
Broader definition of inducibility
We also evaluated whether a broader ‘more aggressive’ definition of a positive PVS would decrease the number of false-negative tests and thus further increase the negative predictive value. For this purpose, PVS was considered positive in case of inducibility of monomorphic VT, polymorphic VT, and VF with 3 extrastimuli. With these criteria, 58% (rather than 46%) of patients were found to have a positive PVS.
Also, according to this broader definition of inducibility, significantly more patients with a positive vs. a negative PVS experienced the primary end-point of VF+sudden death in the overall population (19 vs. 4.5%, P = 0.03), among patients with LVEF 30% (25 vs. 6%, P = 0.03), and among patients implanted with ICD (18 vs. 7%, NS).
However, the use of these criteria did not reduce further the (already very low) number of false-negative tests, but simply increased the number of false-positive tests, thus reducing overall diagnostic accuracy.
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Discussion |
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The results of the present study are in agreement with the acknowledged role of depressed LV function in identifying high-risk subjects among ischaemic cardiomyopathy patients. The findings also suggest that programmed ventricular stimulation may still have a role in predicting the arrhythmic risk in this group of patients. More specifically, the study suggests that patients with negative PVS are at very low risk, independently of the presence of LV dysfunction.
Risk stratification and the selection of candidates for an implantable cardioverter-defibrillator
In the MADIT II trial, among patients with a previous MI and an LVEF of 30% or less, the ICD saved one life every 18 patients implanted, during the average follow-up of 20 months (slightly shorter than that of the present study). The identification of a variable showing a high negative predictive value that could identify low risk patients not to be implanted, among a population otherwise candidate to an ICD due to presence of depressed LV function, would lead to an increased cost-efficacy ratio.
Predictive role of programmed ventricular stimulation
Standard diagnostic criteria for a positive PVS were associated, in the present study, with a significant predictive capacity. Positive patients were found to have an incidence of a major arrhythmia of 24% during a 24-month follow-up, that increased to 35% among patients with depressed LV function. These data would lead to number-needed-to-treat values of 4.2 and 2.8, respectively. Patients with a negative PVS, on the other hand, had an incidence of a major arrhythmia of 3.5%. It should be emphasized that patients with a negative PVS were not a minority of the population, representing overall 54% of the patients.
The predictive value of a broader ‘more aggressive’ definition of inducibility was also assessed but it was found to increase the number of false-positive tests without decreasing the number of false-negative tests.
Overall, our results are at variance with the MADIT II substudy10 that suggests no role for PVS in the arrhythmic risk stratification in patients with previous MI and decreased LVEF.
MADIT II involved 76 centres and a standard PVS protocol was recommended in each centre, but not mandatory. In 21% of patients, PVS was not performed, while in 13% it was performed by means of the implanted defibrillator, thus permitting a single-site stimulation only.15 Overall 36% of patients were inducible.
The MUSTT investigators assessed the predictive role of PVS in patients with coronary artery disease and an LVEF 40%, by comparing the rate of arrhythmic events in patients with positive PVS randomized to no antiarrhythmic therapy with that of patients with negative PVS who were followed in a registry. Patients with no inducible ventricular arrhythmias showed a significantly lower rate of arrhythmic death and cardiac arrest, compared with non-inducible patients, thus indicating the usefulness of PVS in this population. The 2-year negative predictive value of PVS in the MUSTT trial was 88%, slightly less favourable than that found in the present study.
In the MUSTT trial, both LVEF and inducible VT were independent predictors of arrhythmic events,16 but positive PVS was associated with a higher hazards ratio compared with LVEF<30%. Furthermore, whereas depressed LV function did not discriminate between arrhythmic and non-arrhythmic death, PVS identified patients for whom the cause of death was more likely to be arrhythmic.
Therefore, our results on the predictive power of PVS appear different from the MADIT II report but similar to the MUSTT findings. Several factors may contribute to these differences.
First, the population of our study, similar to MUSTT, included patients with an a priori relatively high likelihood of arrhythmic end-points, due to the presence of many patients with non-sustained VT at Holter recording. No information is available regarding spontaneous ventricular arrhythmias in MADIT II patients.
Secondly, each centre that contributed to the MADIT II substudy enrolled only an average of three patients per year, thus suggesting the presence of a selection bias, whereas we studied consecutive patients referred for arrhythmic risk assessment. This population is more likely to represent post-MI patients with LV dysfunction as encountered in everyday clinical practice.
Thirdly, the protocol of PVS was very strictly followed in the present monocentric study, whereas this was unlikely to be the case in MADIT II patients, as mentioned earlier. Also, we performed PVS repeating carefully each protocol that caused the induction of non-sustained VT lasting 10 beats and this could justify both the higher percentage of PVS positive patients and the stronger negative predictive value.
Curiously, the definition of positive PVS in MADIT II was arbitrary17 and significantly different from that used by the same authors in MADIT I (and used by most studies, including the present one). When the ‘narrow’ definition of inducibility was used (more similar, but not identical to the traditional one), inducible patients did have a significantly higher probability of appropriate ICD therapy, even in the MADIT II substudy.10
Also, pharmacological treatment was rather comprehensive in the present study. Many arrhythmic end-points in patients with negative PVS (and thus no stable arrhythmic substrate) may depend on triggering conditions that may be particularly sensitive to antiadrenergic treatment.18 For instance, only 35% of patients received beta-blockers in the MUSTT registry, when compared with 67% of our patients. Additionally, 47% were on amiodarone and this may actually have increased the diagnostic accuracy of the test. The concept that patients with a VT that is induced at PVS and not suppressed by antiarrhythmic drugs are at, particularly high risk is well known and, as a matter of fact, has been used to select more severe patients in the MADIT I study.19 Thus, patients positive at PVS while on amiodarone are likely to be more prone to arrhythmic events and the test itself may prove to be more predictive.
Finally, as suggested by the accompanying editorial, the MADIT II substudy was not intended to address the mortality issue as a primary end-point; therefore the question whether ICD implantation in patients with negative PVS results in improved survival remains unanswered.17 This issue is critical because the identification of subgroups at different mortality risk within a substantially large population of potential candidates is both clinically and economically relevant.17
Other risk stratifications
Several studies have proposed predictors to identify candidates for an ICD among patients with ischaemic cardiomyopathy. Recently, among 177 MADIT II-like patients, a negative T-wave alternans (TWA), present in 32% of the population, was found to have a 96% negative predictive value for overall mortality.20 The finding that a test assessing substrate susceptibility for arrhythmias, as TWA,21 may provide a strong negative predictive value agrees with the present findings. Furthermore, the recently presented results of the ABCD trial demonstrated that both TWA and PVS have a high negative predictive value (95% at 1 year) in predicting the arrhythmic risk in a large population of patients with ischaemic cardiomyopathy.22
The analysis of autonomic markers may also help in this setting. Specifically, a preserved baroreflex sensitivity is associated with a reduced risk of VT23,24 as well as with a better haemodynamic tolerability, should the arrhythmia occur.25
Therefore, variables beyond LVEF may significantly help in optimizing the cost-to-benefit ratio for ICD implantation among post-MI patients at risk of arrhythmic events.
Potential limitations of the study
The population of the study was small, compared with multicentre trials.9,10 However, the event rate was relatively high allowing sufficient power for the overall population, although not in all possible subgroups.
The major limitation of the present study is that both patients with and without ICD were included and the primary end-point was defined as the composite of arrhythmic death and VF treated by the defibrillator. Although not all appropriate shocks delivered by the device may avoid a arrhythmic death, we believe that this is the most expected consequence of a ventricular arrhythmia faster than 200 bpm. Also, these end-points are commonly used in studies evaluating predictors among patients with reduced LVEF.26 Moreover, PVS was found to be a significant predictor also in the subgroup of patients with ICD. Finally, the high negative predictive value of PVS found in the current study is not substantially affected by the aforementioned limitation.
In the present study, the survival curves show very good separation between positive and negative PVS patients for over 4 years after the test. It may be reasonable to repeat PVS every 3–4 years to provide dynamic risk assessment as well as in the presence of a change in the clinical conditions of the patient, such as amiodarone discontinuation, occurrence of a further coronary event, or deterioration in left ventricular function.
Conclusion
Programmed ventricular stimulation may still have a role in arrhythmic risk stratification of patients with ischaemic cardiomyopathy. In particular, the present findings suggest that patients with a negative PVS may be at low arrhythmic risk, even if they have an LVEF < 30%, and thus may receive only a modest benefit from ICD therapy.
Conflict of interest: none declared.
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