EDITORIAL
Programmed Stimulation for Risk Stratification for Postinfarction Sudden Cardiac Arrest: Why and How? MARK E. JOSEPHSON, M.D. From the Harvard Medical School, Harvard Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Prevention of sudden cardiac arrest due to ventricular tachyarrhythmias post-ST segment elevation, myocardial infarction has been an important, but yet unresolved, goal of physicians caring for patients with coronary artery disease. Sudden cardiac arrest is one of the most common causes of mortality in adults. Although the incidence of cardiac arrest appears to have decreased in the past decade, it still remains the single most common cause of death for inpatients per year. While earlier attempts to stratify patients at risk using ambient ectopy failed, a variety of noninvasive and invasive predictors have been proposed to select patients who are at increased risk for sudden cardiac arrest. These include the ejection fraction, baroreceptor responsiveness, heart rate variability, QT dispersion, turbulence, baroreceptor reflex, the signal average electrocardiogram, T-wave alternans, and programmed electrical stimulation.1,2 The vast majority of patients are truly unselective in their predictability for sudden cardiac arrest. They all predict total mortality and pari-passu sudden cardiac arrest. What is clear from all of these studies is that multiple risk factors need to be taken into consideration when dealing with developing a strategy to predict who is likely to die of an arrhythmic event and who therefore might benefit from an implantable cardioverter defibrillator (ICD). The MUSTT study, which used programmed stimulation, nonsustained ventricular tachycardia (VT), and an ejection fraction of ࣘ40 for entry, showed the most effective utilization of ICDs3,4 ; the number needed to treat to save a life using an ICD was three. In studies using ejection fraction with or without heart failure (MADIT II and SCDHeft),5,6 the number needed to treat was >10. Unfortunately, the attempt to make risk stratification easy by using only ejection fraction and, to a lesser degree, heart
Address for reprints: Mark E. Josephson, M.D., Harvard Medical School, Harvard Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] Received March 18, 2014; accepted March 24, 2014. doi: 10.1111/pace.12412
failure has resulted in the widespread use of ICDs in patients who were less likely to need them. The programmed stimulation has been the only test that reproducibly predicted sudden cardiac arrest.3,4,7–14 While T-wave alternans had been suggested to be a predictor of sudden cardiac arrest in the ABCD trial,9 it was not reproduced in SCDHeft.6 Even in the ABCD trial, the T-wave alternans predictability was not as good as the programmed stimulation and had no correlation with the results of programmed stimulation.9 Despite evidence over the last 30 years that programmed stimulation might be useful in predicting patients at risk of sudden cardiac arrest, the “invasive” nature of the procedure and the ease of implanting ICDs with only ejection fraction as risk stratification have moved the cardiology community away from electrophysiologic testing for risk stratification. While it is clear that restratification based on ejection fraction alone is imperfect,1,2 it remains the single most critical factor on which guidelines for ICD implantation are based. Besides the invasive nature of electrophysiologic studies, one of the important concerns that led to its limited use has been the negative predictive value of the procedure. This is interesting because the majority of early studies to predict risk of recurrent VT testing for restratification suggested that patients with no inducible VT had a lower recurrence rate and better prognosis than those with inducible VT.4,7–14 However, it was deemed imperfect because in some studies patients who had negative results for programmed stimulation died. For example, a major finding of the MUSTT study was that in 2 years, 12% of patients without inducible sustained VT experienced sudden cardiac arrest, whereas 18% with inducible VT randomized to no therapy (the control group) had cardiac arrest.3,4 For many people, this negative predictive value was not good enough. Coupled with the invasive nature of programmed stimulation, the use of this technique has all but vanished from the restratification strategies currently proposed today. In my opinion, it is illogical to assume that any predictive strategy would be 100% accurate in predicting a benign
©2014 Wiley Periodicals, Inc. PACE, Vol. 37
July 2014
791
JOSEPHSON
outcome, particularly in a progressive disease process such as coronary artery disease. This ignores the fact that programmed stimulation has been the only strategy that specifically predicted sudden cardiac arrest. However, undaunted by what was taking place in America, the electrophysiologists at Westmead Hospital in Sydney, Australia have been using programmed electrical stimulation to predict risk of sudden death for the last 30 years.7,8,11,13,14 The present report by Zaman et al.15 continued this strategy. In the past year, Zaman et al. also reported the long-term arrhythmia-free survival in patients with negative electrophysiology (EP) studies early postinfarction.8 They showed that patients with no inducible VT had a similar low event rate as a control population. The major limitations of that study were that many of these patients enrolled in the study had experienced their initial myocardial infarction, whereas much of the primary prevention ICD populations have experienced their myocardial infarction more than 3 years ago, reflecting a different population. The results of these studies, however, should not be ignored. One of the remaining questions related to the use of programmed stimulation that is addressed in the current article is related to the known variability of inducibility of VT with programmed stimulation. This brings up two issues related to the role of programmed stimulation. One is the nature of the protocol of programmed stimulation, and the second is the reproducibility of programmed stimulation and its impact on risk stratification. The present report from Zaman et al.15 partially addresses the reproducibility issue in the identical population recently reported in the same group.16 In contrast to the previous study, the data analyzed the results of electrophysiologic studies conducted in patients with ejection fractions less than 40% instead of 35% with heart failure (SCDHeft) and less than 30% without any heart failure requirement (MADIT II). This study expansion to 40% more closely mirrored the MUSTT population. In this study, programmed stimulation was performed for a median of 8 days postinfarction in 290 patients. The electrophysiologic study was negative in 70% and positive in 30%. What was different about this study was that programmed stimulation was repeated after a 5–10-minute waiting period. In both studies, the same patient protocol was used: the basic drive drain of 400 ms for eight beats was followed by one to four extrastimuli. The first extrastimulus was delivered at 300 ms in the beginning and reduced in 10-ms decrements until ventricular refractoriness was reached. The extrastimulus was then set at 10 ms above refractoriness; the third stimulus
792
again began at a coupling of 300 ms and decreased in 10-ms decrements until refractoriness was reached, and then as the third stimulus was set at 10 ms above refractoriness, and the fourth stimulus was delivered in the way similar to the third stimulus. This was continued until four extrastimuli were delivered. Of the 87 patients in whom a VT was induced, 58 (67%) patients had VT induced on the first stimulation protocol, and a third (29 patients) had VT only induced on the second round of programmed stimulation. Thus, a positive EP study was considered to be present if two rounds of programmed stimulation were able to induce monomorphic tachycardia. ICDs were implanted in the VT “positive” patients, and they were followed and compared with the group of patients who had negative EP studies after two rounds of programmed stimulation. What was interesting about the results of this study were patients who were only inducible on the second round had similar outcomes as those induced on the first round. At 3 years, the primary end point (cumulative incidence of death or arrhythmia) was significantly higher in EPpositive patients with VT induced on the second programmed stimulation round compared to those induced on the first programmed stimulation round (12.9 ± 5.6% vs 38.3 ± 9.7% of EPpositive patients induced by the first and second rounds of programmed stimulation, respectively). This was significantly higher than a primary end point seen in the negative EP study, which was 6.3 ± 1.9% of patients. In terms of arrhythmic events alone, 10 of the 58 patients with inducible VT on the first programmed stimulus round had an arrhythmic event (17.2%) and nine of the 29 patients (31%) with VT induced on the second round of programmed ventricular stimulation had an arrhythmic event. It is of interest that the mean cycle length of spontaneous VT in whom VT was induced in the first round was slightly longer than spontaneous VT in those patients in whom VT was induced on the second round (318 ± 35 ms vs 248 ± 31 ms). Only three patients with negative EP studies (1.5%) had an arrhythmic event. How can one interpret and put into use these results? First, the lack of reproducibility of programmed stimulation was confirmed as was the usefulness of repetition, previously noted by several investigators when studying patients presenting with sustained VT. It had been previously documented that there was immediate (single study) and day-to-day variability in the number of extrastimuli required to induce sustained VT.17–21 Morady’s group specifically found a 10% variability in VT induced with first, second, or third programmed ventricular stimulation induction.20,21 These studies,
July 2014
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PROGRAMMED STIMULATION FOR RISK STRATIFICATION
however, were in patients with known history of sustained VT, whereas this study was assessing people never having had a sustained VT who have early postinfarction and in whom programmed stimulation was being used for risk stratification for a primary prevention ICD. What then is the most appropriate stimulation protocol to use? In the current paper, the patients who had a positive study did not have a second round of programmed stimulation. What would have happened if it was negative? If so would the investigators then go on to do a third round and take the best two out of three? Or would they continue to do multiple rounds? How many rounds would actually be enough before one would be able to identify those patients at risk? What is clear, however, is that the incidence of sudden death in the patients who were noninducible after the second round of stimulation was incredibly small. This is remarkable. Perhaps adding a third round would have been even better, but it is hard to beat the low event rate seen in this study. Obviously the number of patients included in this single-center study is small and these results would need to be validated in a much larger population in different centers, so that it is accepted. The other question to be raised is what is the right protocol of programmed stimulation? In many of the earliest studies (MUSTT and MADIT) and in other studies of VT, the standard stimulation protocol involved one to three extrastimuli during multiple drive cycle lengths from at least two different pacing sites either in the right or left ventricle.3,4,9,19 Morady’s group showed that immediately using four extrastimuli could reduce the time of program stimulation and have similar sensitivity in studying patients with sustained VT for induction of any VT.20,21 The answer to the question which is the best protocol depends on the purpose of the study. If in fact the purpose of the study was to see whether someone has the potential for sustained monomorphic VT in order to say that the patient is at risk for sudden cardiac death, then the protocol does not matter. In that case using four extrastimuli, as done in this protocol, is fine. If one is using programmed stimulation to induce VT in order to guide ablation then neither of these protocols nor the protocols suggested by Morady are the most useful. The reason for this is that the site of stimulation and the mode of stimulation can yield different morphologies of VT that need to be targeted by ablation or surgery. In addition, our institution’s faculty has seen many patients in whom ventricular fibrillation is induced with three extrastimuli at one site and then the electrophysiology study is stopped.
PACE, Vol. 37
On the other hand, stimulation at a second site might induce a sustained tachycardia. Thus, in my opinion the safest way for the patient to be studied is to use single then double then triple extrastimuli at each cycle length and at each site: with a single extrastimulus first delivered at one site and then at the other site at a given drive cycle length, then changing the cycle length and again giving an extrastimulus before moving on to double extrastimuli at each site at a different cycle length and the same for triple extrastimuli. This is the longest stimulation protocol, but is safest for the patient and most likely to yield different tachycardia morphologies that might have to be targeted for ablation. If one is just going to utilize a sinus rhythm “substrate mapping” approach, one might never identify tachycardia that occur outside the area of abnormal electrograms (14% of our tachycardias in our initial studies in the mid-1980s)22 and certainly not identify patients who would have substrate removed from the subendocardium. The best way to decrease the extrastimuli again depends on what one is interested in. While de Buitleir et al20 suggest an initial rapid drive of 350 ms with four extrastimuli reduced in tandem, others, as in this study, suggest one then two then three then four extrastimuli are sequentially delivered. In our own protocols, we actually started at least 50 ms above the coupling interval that was refractory before beginning to add additional extrastimuli. When the additional extrastimuli failed to capture, we then reduced the prior extrastimulus. We did this because the known significant effects of changing the diastolic interval on refractory periods were encountered by subsequent extrastimuli. While this may not matter when one is doing risk stratification for primary prevention ICDs, it may have important implications on inducing sustained VT in patients in whom that arrhythmia has been present. This study,15 while intriguing, is limited by the low number of patients enrolled. But the results are still noteworthy. They bring up again the utility of a negative electrophysiology study in predicting good outcomes. If this result was reproduced in a larger randomized trial, programmed stimulation would once again be incorporated as one component of risk stratification. Application of such studies could reduce the use of ICDs in these patient populations, which could have a profound effect on national economy. Until the results of this and prior studies from Westmead are recognized by the cardiology community at large, and the insurance payers and government, programmed stimulation will continue to be ignored as a useful tool. However, in
July 2014
793
JOSEPHSON
the current era of changing health care economics, as well as the known complications of device implantation in patients who do not need them, further studies should be undertaken to see if the results of the Westmead group are reproducible.
If so, programmed stimulation would once again assume an important role in risk stratification, and electrophysiologic data, not ejection fraction or financial interest, will have a major impact on device usage.
References 1. Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS, Maron BJ, et al. American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: A scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrophysiology and Arrhythmias and Council on Epidemiology and Prevention. Circulation 2008; 118:1497– 1518. 2. Goldberger JJ, Basu A, Boineau R, Buxton AE, Cain ME, Canty M Jr., Chen P, et al. Risk stratification for sudden cardiac death: A plan for the future. Circulation 2014; 129:516–526. 3. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter unsustained tachycardia trial investigators. N Engl J Med 1999; 341:1882– 1890. 4. Buxton AE, Lee KL, Hafley GE, Wyse DG, Fisher JD, Lehmann MH, Pires LA, et al. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: An analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation 2002; 106:2466– 2472. 5. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877–883. 6. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, et al. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005; 352:225–237. 7. Bourke JP, Richards DA, Ross DL, Wallace EM, McGuire MA, Uther JB. Routine programmed stimulation in survivors of acute myocardial infarction for prediction of spontaneous ventricular tachyarrhythmias during follow-up; results, optimal stimulation protocol and cost-effective screening. J Am Coll Cardiol 1991; 18:780–788. 8. Zaman S, Sivangangabalan G, Narayan A, Thiagalingam A, Ross DL, Kovoor P. Outcomes of early risk stratification and targeted implantable cardioverter-defibrillator implantation after ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Circulation 2009; 120:194–200. 9. Constantini O, Hohnloser SH, Kirk MM, Lerman BB, Baker JH 2nd, Sethuraman B, Dettmer MM, et al. The ABCD (Alternans Before Cardioverter Defibrillator) trial: Strategies using t-wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol 2009; 53:471–479. 10. Huikuri HV, Raatikainen MJ, Moerch-Joergensen R, Hartikainen J, Virtanen V, Boland J, Anttonen O, et al. Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009; 30:689–698.
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11. Richards DA, Byth K, Ross DL, Uther JB. What is the best predictor of spontaneous ventricular tachycardia and sudden death after myocardial infarction? Circulation 1991; 83:756–763. 12. Schmitt C, Barthel P, Ndrepepa G, Schreieck J, Plewan A, Schomig A, Schmidt G. Value of programmed ventricular stimulation for prophylactic internal cardioverter-defibrillator implantation in postinfarction patients preselected by noninvasive risk stratifiers. J Am Coll Cardiol 2001; 37:1901–1907. 13. Denniss AR, Baaijens H, Cody DV, Richards DA, Russell PA, Young AA, Ross DL, et al. Value of programmed stimulation and exercise testing in predicting one year mortality after acute myocardial infarction. Am J Cardiol 1985; 56:431–435. 14. Denniss AR, Richards DA, Cody DV, Russell PA, Young AA, Cooper MJ, Ross DL, et al. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal averaged electrocardiograms of survivors of acute myocardial infarction. Circulation 1986; 74:731– 745. 15. Zaman S, Narayan A, Thiagalingam A, Sivagangabalan G, Thomas S, Ross D, Kovoor P. Significance of repeat programmed ventricular stimulation at electrophysiology study for arrhythmia prediction after acute myocardial infarction. Pacing Clin Electrophysiol 2014; 37:795–802. 16. Zaman S, Narayan A, Thiagalingam A, Sivagangablan G, Thomas S, Ross DL, Kovoor P. Long-term arrhythmia-free survival in patients with severe left ventricular dysfunction and no inducible ventricular tachycardia after myocardial infarction. Circulation 2014; 129:848–854. 17. Cooper MJ, Hunt LJ, Palmer KJ, Denniss AR, Richards DA, Uther JB, Ross DL. Quantitation of day to day variability in mode of induction of ventricular tachyarrhythmias by programmed stimulation. J Am Coll Cardiol 1988; 11:101–108. 18. Cooper MJ, Koo CC, Skinner MP, Mortensen PT, Hunt LJ, Richards DA, Uther JB, et al. Comparison of immediate versus day to day variability of ventricular tachycardia induction by programmed stimulation. J Am Coll Cardiol 1989; 13:1599–1607. 19. Ferrick KJ, Luce J, Miller S, Mercando AD, Kim SG, Roth JA, Fisher JD. Reproducibility of electrophysiologic testing during antiarrhythmic therapy for ventricular arrhythmias secondary to coronary artery disease. Am J Cardiol 1992; 69:1296–1299. 20. de Buitleir M, Morady F, DiCarlo LA Jr., Baerman JM, Krol RB. Immediate reproducibility of clinical and nonclinical forms of induced ventricular tachycardia. Am J Cardiol 1986; 58: 279–282. 21. Morady F, DiCarlo L, Winston S, Davis JC, Scheinman MM. A prospective comparison of triple extrastimuli and left ventricular stimulation in studies of ventricular tachycardia induction. Circulation 1984; 70:52–57. 22. Cassidy DM, Vassallo JA, Buxton AE, Doherty JU, Marchlinski FE, Josephson ME. The value of catheter mapping during sinus rhythm to localize site of origin of ventricular tachycardia. Circulation 1984; 69:1103–1110.
July 2014
PACE, Vol. 37
Programmed Stimulation for Risk Stratification for Postinfarction Sudden Cardiac Arrest: Why and How? MARK E. JOSEPHSON, M.D. From the Harvard Medical School, Harvard Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Prevention of sudden cardiac arrest due to ventricular tachyarrhythmias post-ST segment elevation, myocardial infarction has been an important, but yet unresolved, goal of physicians caring for patients with coronary artery disease. Sudden cardiac arrest is one of the most common causes of mortality in adults. Although the incidence of cardiac arrest appears to have decreased in the past decade, it still remains the single most common cause of death for inpatients per year. While earlier attempts to stratify patients at risk using ambient ectopy failed, a variety of noninvasive and invasive predictors have been proposed to select patients who are at increased risk for sudden cardiac arrest. These include the ejection fraction, baroreceptor responsiveness, heart rate variability, QT dispersion, turbulence, baroreceptor reflex, the signal average electrocardiogram, T-wave alternans, and programmed electrical stimulation.1,2 The vast majority of patients are truly unselective in their predictability for sudden cardiac arrest. They all predict total mortality and pari-passu sudden cardiac arrest. What is clear from all of these studies is that multiple risk factors need to be taken into consideration when dealing with developing a strategy to predict who is likely to die of an arrhythmic event and who therefore might benefit from an implantable cardioverter defibrillator (ICD). The MUSTT study, which used programmed stimulation, nonsustained ventricular tachycardia (VT), and an ejection fraction of ࣘ40 for entry, showed the most effective utilization of ICDs3,4 ; the number needed to treat to save a life using an ICD was three. In studies using ejection fraction with or without heart failure (MADIT II and SCDHeft),5,6 the number needed to treat was >10. Unfortunately, the attempt to make risk stratification easy by using only ejection fraction and, to a lesser degree, heart
Address for reprints: Mark E. Josephson, M.D., Harvard Medical School, Harvard Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: [email protected] Received March 18, 2014; accepted March 24, 2014. doi: 10.1111/pace.12412
failure has resulted in the widespread use of ICDs in patients who were less likely to need them. The programmed stimulation has been the only test that reproducibly predicted sudden cardiac arrest.3,4,7–14 While T-wave alternans had been suggested to be a predictor of sudden cardiac arrest in the ABCD trial,9 it was not reproduced in SCDHeft.6 Even in the ABCD trial, the T-wave alternans predictability was not as good as the programmed stimulation and had no correlation with the results of programmed stimulation.9 Despite evidence over the last 30 years that programmed stimulation might be useful in predicting patients at risk of sudden cardiac arrest, the “invasive” nature of the procedure and the ease of implanting ICDs with only ejection fraction as risk stratification have moved the cardiology community away from electrophysiologic testing for risk stratification. While it is clear that restratification based on ejection fraction alone is imperfect,1,2 it remains the single most critical factor on which guidelines for ICD implantation are based. Besides the invasive nature of electrophysiologic studies, one of the important concerns that led to its limited use has been the negative predictive value of the procedure. This is interesting because the majority of early studies to predict risk of recurrent VT testing for restratification suggested that patients with no inducible VT had a lower recurrence rate and better prognosis than those with inducible VT.4,7–14 However, it was deemed imperfect because in some studies patients who had negative results for programmed stimulation died. For example, a major finding of the MUSTT study was that in 2 years, 12% of patients without inducible sustained VT experienced sudden cardiac arrest, whereas 18% with inducible VT randomized to no therapy (the control group) had cardiac arrest.3,4 For many people, this negative predictive value was not good enough. Coupled with the invasive nature of programmed stimulation, the use of this technique has all but vanished from the restratification strategies currently proposed today. In my opinion, it is illogical to assume that any predictive strategy would be 100% accurate in predicting a benign
©2014 Wiley Periodicals, Inc. PACE, Vol. 37
July 2014
791
JOSEPHSON
outcome, particularly in a progressive disease process such as coronary artery disease. This ignores the fact that programmed stimulation has been the only strategy that specifically predicted sudden cardiac arrest. However, undaunted by what was taking place in America, the electrophysiologists at Westmead Hospital in Sydney, Australia have been using programmed electrical stimulation to predict risk of sudden death for the last 30 years.7,8,11,13,14 The present report by Zaman et al.15 continued this strategy. In the past year, Zaman et al. also reported the long-term arrhythmia-free survival in patients with negative electrophysiology (EP) studies early postinfarction.8 They showed that patients with no inducible VT had a similar low event rate as a control population. The major limitations of that study were that many of these patients enrolled in the study had experienced their initial myocardial infarction, whereas much of the primary prevention ICD populations have experienced their myocardial infarction more than 3 years ago, reflecting a different population. The results of these studies, however, should not be ignored. One of the remaining questions related to the use of programmed stimulation that is addressed in the current article is related to the known variability of inducibility of VT with programmed stimulation. This brings up two issues related to the role of programmed stimulation. One is the nature of the protocol of programmed stimulation, and the second is the reproducibility of programmed stimulation and its impact on risk stratification. The present report from Zaman et al.15 partially addresses the reproducibility issue in the identical population recently reported in the same group.16 In contrast to the previous study, the data analyzed the results of electrophysiologic studies conducted in patients with ejection fractions less than 40% instead of 35% with heart failure (SCDHeft) and less than 30% without any heart failure requirement (MADIT II). This study expansion to 40% more closely mirrored the MUSTT population. In this study, programmed stimulation was performed for a median of 8 days postinfarction in 290 patients. The electrophysiologic study was negative in 70% and positive in 30%. What was different about this study was that programmed stimulation was repeated after a 5–10-minute waiting period. In both studies, the same patient protocol was used: the basic drive drain of 400 ms for eight beats was followed by one to four extrastimuli. The first extrastimulus was delivered at 300 ms in the beginning and reduced in 10-ms decrements until ventricular refractoriness was reached. The extrastimulus was then set at 10 ms above refractoriness; the third stimulus
792
again began at a coupling of 300 ms and decreased in 10-ms decrements until refractoriness was reached, and then as the third stimulus was set at 10 ms above refractoriness, and the fourth stimulus was delivered in the way similar to the third stimulus. This was continued until four extrastimuli were delivered. Of the 87 patients in whom a VT was induced, 58 (67%) patients had VT induced on the first stimulation protocol, and a third (29 patients) had VT only induced on the second round of programmed stimulation. Thus, a positive EP study was considered to be present if two rounds of programmed stimulation were able to induce monomorphic tachycardia. ICDs were implanted in the VT “positive” patients, and they were followed and compared with the group of patients who had negative EP studies after two rounds of programmed stimulation. What was interesting about the results of this study were patients who were only inducible on the second round had similar outcomes as those induced on the first round. At 3 years, the primary end point (cumulative incidence of death or arrhythmia) was significantly higher in EPpositive patients with VT induced on the second programmed stimulation round compared to those induced on the first programmed stimulation round (12.9 ± 5.6% vs 38.3 ± 9.7% of EPpositive patients induced by the first and second rounds of programmed stimulation, respectively). This was significantly higher than a primary end point seen in the negative EP study, which was 6.3 ± 1.9% of patients. In terms of arrhythmic events alone, 10 of the 58 patients with inducible VT on the first programmed stimulus round had an arrhythmic event (17.2%) and nine of the 29 patients (31%) with VT induced on the second round of programmed ventricular stimulation had an arrhythmic event. It is of interest that the mean cycle length of spontaneous VT in whom VT was induced in the first round was slightly longer than spontaneous VT in those patients in whom VT was induced on the second round (318 ± 35 ms vs 248 ± 31 ms). Only three patients with negative EP studies (1.5%) had an arrhythmic event. How can one interpret and put into use these results? First, the lack of reproducibility of programmed stimulation was confirmed as was the usefulness of repetition, previously noted by several investigators when studying patients presenting with sustained VT. It had been previously documented that there was immediate (single study) and day-to-day variability in the number of extrastimuli required to induce sustained VT.17–21 Morady’s group specifically found a 10% variability in VT induced with first, second, or third programmed ventricular stimulation induction.20,21 These studies,
July 2014
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PROGRAMMED STIMULATION FOR RISK STRATIFICATION
however, were in patients with known history of sustained VT, whereas this study was assessing people never having had a sustained VT who have early postinfarction and in whom programmed stimulation was being used for risk stratification for a primary prevention ICD. What then is the most appropriate stimulation protocol to use? In the current paper, the patients who had a positive study did not have a second round of programmed stimulation. What would have happened if it was negative? If so would the investigators then go on to do a third round and take the best two out of three? Or would they continue to do multiple rounds? How many rounds would actually be enough before one would be able to identify those patients at risk? What is clear, however, is that the incidence of sudden death in the patients who were noninducible after the second round of stimulation was incredibly small. This is remarkable. Perhaps adding a third round would have been even better, but it is hard to beat the low event rate seen in this study. Obviously the number of patients included in this single-center study is small and these results would need to be validated in a much larger population in different centers, so that it is accepted. The other question to be raised is what is the right protocol of programmed stimulation? In many of the earliest studies (MUSTT and MADIT) and in other studies of VT, the standard stimulation protocol involved one to three extrastimuli during multiple drive cycle lengths from at least two different pacing sites either in the right or left ventricle.3,4,9,19 Morady’s group showed that immediately using four extrastimuli could reduce the time of program stimulation and have similar sensitivity in studying patients with sustained VT for induction of any VT.20,21 The answer to the question which is the best protocol depends on the purpose of the study. If in fact the purpose of the study was to see whether someone has the potential for sustained monomorphic VT in order to say that the patient is at risk for sudden cardiac death, then the protocol does not matter. In that case using four extrastimuli, as done in this protocol, is fine. If one is using programmed stimulation to induce VT in order to guide ablation then neither of these protocols nor the protocols suggested by Morady are the most useful. The reason for this is that the site of stimulation and the mode of stimulation can yield different morphologies of VT that need to be targeted by ablation or surgery. In addition, our institution’s faculty has seen many patients in whom ventricular fibrillation is induced with three extrastimuli at one site and then the electrophysiology study is stopped.
PACE, Vol. 37
On the other hand, stimulation at a second site might induce a sustained tachycardia. Thus, in my opinion the safest way for the patient to be studied is to use single then double then triple extrastimuli at each cycle length and at each site: with a single extrastimulus first delivered at one site and then at the other site at a given drive cycle length, then changing the cycle length and again giving an extrastimulus before moving on to double extrastimuli at each site at a different cycle length and the same for triple extrastimuli. This is the longest stimulation protocol, but is safest for the patient and most likely to yield different tachycardia morphologies that might have to be targeted for ablation. If one is just going to utilize a sinus rhythm “substrate mapping” approach, one might never identify tachycardia that occur outside the area of abnormal electrograms (14% of our tachycardias in our initial studies in the mid-1980s)22 and certainly not identify patients who would have substrate removed from the subendocardium. The best way to decrease the extrastimuli again depends on what one is interested in. While de Buitleir et al20 suggest an initial rapid drive of 350 ms with four extrastimuli reduced in tandem, others, as in this study, suggest one then two then three then four extrastimuli are sequentially delivered. In our own protocols, we actually started at least 50 ms above the coupling interval that was refractory before beginning to add additional extrastimuli. When the additional extrastimuli failed to capture, we then reduced the prior extrastimulus. We did this because the known significant effects of changing the diastolic interval on refractory periods were encountered by subsequent extrastimuli. While this may not matter when one is doing risk stratification for primary prevention ICDs, it may have important implications on inducing sustained VT in patients in whom that arrhythmia has been present. This study,15 while intriguing, is limited by the low number of patients enrolled. But the results are still noteworthy. They bring up again the utility of a negative electrophysiology study in predicting good outcomes. If this result was reproduced in a larger randomized trial, programmed stimulation would once again be incorporated as one component of risk stratification. Application of such studies could reduce the use of ICDs in these patient populations, which could have a profound effect on national economy. Until the results of this and prior studies from Westmead are recognized by the cardiology community at large, and the insurance payers and government, programmed stimulation will continue to be ignored as a useful tool. However, in
July 2014
793
JOSEPHSON
the current era of changing health care economics, as well as the known complications of device implantation in patients who do not need them, further studies should be undertaken to see if the results of the Westmead group are reproducible.
If so, programmed stimulation would once again assume an important role in risk stratification, and electrophysiologic data, not ejection fraction or financial interest, will have a major impact on device usage.
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July 2014
PACE, Vol. 37
![[Risk stratification for sudden cardiac death in ischemic heart disease. Programmed ventricular stimulation].](/assets/img/hold.png)
