Risk stratification for sudden death in patients with coronary artery disease

CONTEMPORARY REVIEW

Risk stratification for sudden death in patients with coronary artery disease Alfred E. Buxton, MD From the Department of Cardiology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island. Although age-adjusted death rates of cardiovascular disease have declined over the past 2 decades, approximately half of cardiovascular deaths still occur suddenly and unexpectedly.1,2 The survival rate from out-of-hospital cardiac arrest is only 5%. Therein lies the rationale for prospective identification of patients at risk for cardiac arrest and institution of prophylactic therapy. In order to perform risk stratification intelligently, we must understand the mechanisms responsible for sudden cardiac arrest (SCA). Because SCA is the end result of an assortment of processes and mechanisms, a variety of tests is necessary to identify patients possessing the substrate for the various mechanisms. This article reviews the evolution and current status of risk stratification for sudden death in patients with coronary artery disease. We will review individual risk factors for evidence supporting a potential cause-and-effect relation with SCA. The test we use to evaluate this possibility is to ask whether the relative risk (RR) for SCA exceeds the RR for total cardiac mortality or non-SCA. If the data demonstrate risk for SCA elevated out of proportion to total mortality risk, we term this a specific relation. On the other hand, if patients possessing a given risk factor demonstrate risk for SCA increased proportionate to (or less than) total cardiac mortality risk, this suggests merely an association that may occur because one is identifying a population of patients with more advanced disease (and therefore at similarly increased risk for sudden and nonsudden cardiac death). The importance of this relation is as follows. Risk factors that demonstrate risk for SCA increased out of proportion to total mortality risk in theory should identify patients who derive significantly more survival benefit from the implantable cardioverter-defibrillator (ICD) than do risk factors associated with proportional increases in SCA and total mortality. KEYWORDS Implantable defibrillator; Sudden cardiac death; Cardiac arrest; T-wave alternans; Electrophysiologic test; Baroreflex sensitivity; Heart rate turbulence; Heart rate variability; Ventricular tachycardia; Ventricular fibrillation (Heart Rhythm 2009;6:836 – 847) Address reprint requests and correspondence: Dr. Alfred E. Buxton, Rhode Island Hospital, 2 Dudley Street, Suite 360, Providence, Rhode Island 29905. E-mail address: [email protected]. (Received August 17, 2008; accepted February 6, 2009.)

The significance of this relation was exemplified in a recent publication demonstrating that a significant proportion of patients at increased total mortality risk do not benefit from ICD therapy because of competing nonsudden death risks.3 In the accompanying tables, note for each risk factor the values for RR of SCA versus total cardiac mortality. We also will review the applicability of risk factors to individual patients and the prevalence of positive results. Past reviews have made much of the relatively low positive predictive value of many risk factors. I believe this limitation has been overemphasized. The observed positive predictive value of a variable will be influenced by the duration of follow-up. Most studies have used a relatively brief follow-up, usually 1 to 2 years. However, discovery that patients possess risk factors associated with sudden death does not necessarily mean they will experience cardiac arrest within the next 1 to 2 years. Thus, in order to judge the true positive predictive value of a test, longer follow-up is required than has been used in most studies. This then raises the issue of how long studies should report follow-up. If a test is not repeated but the condition progresses, the test results may no longer be valid. The optimal follow-up time and/or how often tests should be repeated are important unanswered questions.

Pathology of sudden cardiac death Autopsy studies of sudden death victims reveal two groups with coronary disease. Approximately two thirds have coronary atherosclerosis with a recent plaque rupture or erosion resulting in acute coronary thrombosis. A second group consists of patients with evidence of prior myocardial infarction (MI) but no acute coronary thrombosis. Healed infarction is found in at least one fourth of cases. Combinations of these two are also seen. Another significant pathologic finding is the frequent presence of left ventricular hypertrophy (LVH).1

Epidemiologic characteristics Population-based studies have delineated a number of important characteristics of SCA victims. They have shown that cardiac arrest is the initial manifestation of heart disease in approximately 50% of cases.4 Such patients are more likely to have single-vessel coronary disease and normal or

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Buxton

Risk Stratification for Sudden Death in Patients with CAD

mildly abnormal left ventricular systolic function than cardiac arrest victims with prior MI. Second, although heart failure increases risk for both sudden and nonsudden death, a history of heart failure is present in only approximately 10% of arrest victims.4 Third, although low ejection fraction (EF) identifies patients at increased risk for cardiac arrest, the majority of sudden deaths occur in patients with EF ⬎30%.4,5 Regarding MI, 6% of patients in the Maastricht study showed evidence of an acute infarct following cardiac arrest, and 66% had a history of MI a median of 9 years before the arrest.4,5 Thus, pathologic and epidemiologic data suggest a model of sudden death composed of two major patient groups. In one group, an acute ischemic episode or infarction precipitates cardiac arrest. Most individuals have normal or mildly reduced systolic ventricular function prior to the event. The second group is composed of patients with previous MI and varying degrees of left ventricular dysfunction. Pathologic characteristics of the infarction as well as compensatory changes in noninfarcted myocardium form the substrate for arrhythmias independent of recurrent ischemia. The autopsy data suggest a larger role for acute ischemic events than the population-based surveys, which probably are due to selection bias in the postmortem studies.

Mechanistic considerations Although acute ischemia may trigger tachyarrhythmia or bradyarrhythmias at any stage in the course of coronary disease, in patients with prior MI, multiple potential mechanisms for cardiac arrest exist. Reentrant circuits formed as a result of fibrosis on the border of MI form a common substrate for ventricular tachycardia, but other mechanisms, such as triggered activity in scar tissue or in nonscar hypertrophied myocardium, also may be relevant. In patients with heart failure, alteration in action potential characteristics as well as neurohormonal factors may contribute to a variety of ventricular tachyarrhythmias. Finally, it is important to remember that bradyarrhythmias, including heart block, as well as electromechanical dissociation contribute to SCA, although they seem to account for a minority of events.

Role of ischemia/coronary anatomy Multivessel coronary disease has been demonstrated both by invasive angiography and more recently by computed tomography to be related to all-cause mortality of patients with coronary disease.6,7 Of note, although coronary anatomy is associated with outcome, functional assessment for ischemia seems to be superior for prognostication.6 Pathologic and epidemiologic studies emphasize the importance of searching for potential ischemia in MI survivors. At this time we have no practical way to identify persons in the general population at risk for myocardial ischemia. In addition, we have no way to identify persons likely to develop ventricular fibrillation (VF) should acute myocardial ischemia occur. Population-based studies demonstrating the importance of a family history of sudden death

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suggest that genetic testing might play a role in risk stratification in the future.8

Evolution of postinfarction risk stratification Spontaneous ventricular ectopy and nonsustained ventricular tachycardia Recognition of the need for risk stratification dates to the 1960s when large-scale studies of patients with acute MI first began. It was noted that a significant fraction of patients experienced sudden death after discharge from the hospital following recovery from acute MI. In the 1960s, when the coronary care unit with continuous electrocardiographic (ECG) monitoring first came into being, VF was recognized as the most common arrhythmia precipitating cardiac arrest in the early phases of acute MI. Based upon observations that VF was frequently preceded by a marked increase in spontaneous ventricular ectopy (ventricular premature depolarizations) and episodes of nonsustained ventricular tachycardia (NSVT), it was assumed that detection of such arrhythmias prior to hospital discharge would predict postdischarge sudden death. Starting in the 1970s, studies began to correlate factors that predicted subsequent cardiac arrest. Many studies established an association among ventricular premature depolarizations, NSVT, and subsequent cardiac mortality, both sudden and nonsudden.9 Most studies show that the RR of nonsudden death or total mortality exceeds the RR of SCA in patients with frequent ectopy or NSVT, but there is significant overlap in all (Table 1). Thus, patients with frequent ectopy or NSVT are at similarly increased risk for sudden and nonsudden death. Equally important is the finding that frequent ectopy or NSVT is insensitive, failing to identify 47% to 94% of SCA victims (Table 1). An important finding established by early studies as well as some recent analyses of patients receiving contemporary treatment (i.e., reperfusion therapy during the acute phase, beta-adrenergic blocking agents, and angiotensin-converting enzyme inhibitors after MI) is the fact that the single period of highest risk for total and arrhythmic mortality is the first 6 months after acute MI.10 After the first year post-MI, there appears to be a relatively quiescent period of relatively low rates of sudden death. Earlier studies in the pre-reperfusion era suggested low rates of sudden death over follow-up periods as long as 8 years. However, recent studies suggest a second peak (plateau?) 4 to 10 years after acute MI.4,11 At least two mechanisms may explain these observations. The later occurrence of sudden death may result from delayed ventricular remodeling resulting in the creation or activation of reentrant ventricular tachycardia (VT) circuits on the infarct border. Other delayed sudden deaths likely result from the effects of heart failure developing late after MI.

Ejection fraction Multiple studies evaluating survival of patients following MI established a clear relationship between reduced EF and increased mortality.9,12 EF behaves as a continuous vari-

HR ⫽ hazard ratio; NA ⫽ not available; NSVT ⫽ nonsustained ventricular tachycardia; RR ⫽ relative risk; SCA ⫽ sudden cardiac arrest; VPD ⫽ ventricular premature depolarization. Note: The analysis depicted in this and subsequent tables is restricted to studies with ⱖ100 patients, in which data for relative risk or hazard ratio for both sudden death (and/or arrhythmic events) and total/cardiac mortality were provided. The majority of studies entailed follow-up of 1–2 years. With the exception of references to MUSTT (Tables 2 and 3, Buxton) and most studies of T-wave alternans (Table 5, Chow, Gold), all studies were performed in patients with recent (⬍1 month) myocardial infarction. Arrhythmic events include sudden death, resuscitated cardiac arrest, and sustained ventricular tachycardia.

Anderson, Circulation 1978;50:890 Kleiger, Circulation 1981;63:64 Bigger, Am J Cardiol 1981;48:815 Bigger, Circulation 1984;69:250 Maggioni, Circulation 1993;87:312 Hohnloser, J Am Coll Cardiol 1999;33:1895 La Rovere, Circulation 2001;103:2072 Huikuri, J Am Coll Cardiol 2003;42:652 Mäkikallio, Eur Heart J 2005;26:762 1.5 3.6 5 2.7 1.2 2.6 NA 2.9 2.8 (HR) 7 30 12 11 6.8 9 13.4 5 NA 22/15 26/13 63/44 89/54 256/84 15/17 43/30 59/22 113/52

53 31 25 30 13 12 NA 24 21

2.3 1.0 2.5 6.6 1.4 1.4 NA 4 3.3 (HR)

Mukharji, Am J Cardiol 1984;54:31 Maggioni, Circulation 1993;87:312 Hohnloser, J Am Coll Cardiol 1999;33:1895 Andresen, J Am Coll Cardiol 1999;33:131 Mäkikallio, Eur Heart J 2005;26:762 3.2 1.6 1.1 3.7 3.8 (HR) 15/ⱖ10 VPDs per hour 20/ⱖ10 VPDs per hour NA/ⱖ10 VPDs per hour ⱖ20 VPDs hour NA/⬎10 VPDs per hour

Frequent VPDs 532 8,552 325 657 2,130 NSVT 198 289 428 766 8,552 325 1,071 675 2,130

66/29 256/84 15/17 69/32 113/52

53 42 6 NA NA

3.0 2.2 0.4 1.8 2.4 (HR)

Reference No. endpoints (cardiac deaths/SCD–arrhythmic events)

Prevalence (%)/arrhythmia type

Sensitivity (SCA or arrhythmic events) (%)

RR (SCA or arrhythmic events)

RR (nonsudden death or cardiac mortality)

Heart Rhythm, Vol 6, No 6, June 2009

Study size (no. patients)

Table 1

Relation of spontaneous ventricular arrhythmias to total mortality and sudden cardiac arrest risk

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able, with gradually increasing mortality risk until EF declines to 40% and then markedly increasing risk for values ⬍40%. No study has demonstrated that reduced EF is specifically related to sudden death. That is, as left ventricular EF declines, risk of SCA and total mortality each increases proportionately. A consistent finding, with one recent exception, is the RR for nonsudden death or total mortality exceeding the RR for SCA (Table 2). Another limitation of EF is its poor sensitivity (Table 2). In studies that enrolled all patients after MI, patients with EF ⬍30% to 35% account for no more than 50% of SCA (see Epidemiologic Characteristics). Thus, EF is a good marker of risk for total mortality. However, the value of EF does not provide insight into how patients are likely to die (sudden vs nonsudden). Therefore, assignment of ICD therapy based on EF alone cannot be cost effective.

Programmed stimulation Subsequently, several different avenues of investigation into potential predictors of sudden death developed. First came observations that although VF is the most common rhythm recorded initially in out-of-hospital cardiac arrest victims, VT is responsible for a significant minority of cases. Monomorphic VT may precipitate cardiac arrest itself, or it may degenerate into VF. The realization that sustained monomorphic VT (usually due to intramyocardial reentry) is responsible for initiation of cardiac arrest in a great number of post-MI patients led to investigation of potential markers of the substrate for reentrant VT. The first to be evaluated was programmed stimulation (electrophysiologic study [EPS]). A series of studies from Australia, Japan, and the United States all showed a link between inducible sustained monomorphic VT and subsequent sudden cardiac death.9 Risk was not equal for all induced arrhythmias. Patients with inducible VT having very short cycle lengths (⬍250 ms) had significantly lower likelihood of cardiac arrest than did patients with VT having cycle length ⬎250 ms. Likewise, most data suggest that induced polymorphic VT and VF are not associated with high risk for cardiac arrest or sudden death. Other small studies suggested that the risk in patients with EF ⬎40% was significantly lower, even in the presence of inducible VT. A consistent finding in these studies is that RR for SCA exceeds RR for nonsudden death for patients with inducible VT (Table 3). These studies led to a multicenter randomized clinical trial evaluating the utility of EPS in risk stratifying as well as guiding antiarrhythmic therapy (both pharmacologic and implantable defibrillator), the Multicenter UnSustained Tachycardia Trial (MUSTT). This trial of 2,202 patients established that the presence of inducible sustained VT in patients with EF ⱕ40% was associated with significantly increased total mortality as well as risk of sudden death. Note that the difference in RR for SCA versus total mortality is much less in MUSTT than in prior studies, and RR for SCA exceeded RR for nonsudden death only for patients with EF 30% to 40% in MUSTT, not for patients with EF ⬍30% (Table 3). It seems likely that this lesser

Buxton

Table 2

Relation of EF to total mortality and sudden cardiac arrest risk Study size (no. patients)

No. endpoints (cardiac deaths/arrhythmic events)

Prevalence (EF ⬍ cutoff value) (%)

Sensitivity (SCA or arrhythmic events) (%)

RR (SCA and/or arrhythmic events)

RR (nonsudden death or cardiac mortality)

Reference

40 40 40 35 35 30* 40 30 40 30† 35

532 416 361 579 325 1,791 675 968 322 2,343 2,130

66/29 47/24 34/19 42/26 15/17 760/372 59/22 20/12 22/24 104/55 113/52

34 26 26 25 16 50 23 5 35 5 11

72 46 71 35 41 59 45 50 50 22 33

4.6 2.5 4.8 1.6 3.8 1.7 2.9 22.3 1.9 (HR) 5.3 4.5 (HR)

3.7 3.7 5.2 4.9 5.0 1.5 4.4 17.9 1.8 (HR) 15.6 7.2 (HR)

Mukharji, Am J Cardiol 1984;54:31 Farrell, J Am Coll Cardiol 1991;18:687 Richards, Circulation 1991;83:756 Copie, J Am Coll Cardiol 1996;27:270 Hohnloser, J Am Coll Cardiol 1999;33:1895 Buxton, Circulation 2002;106:2466* Huikuri, J Am Coll Cardiol 2003;42:652 Bauer, Eur Heart J 2005;26:755 Exner, J Am Coll Cardiol 2007;50:2275† Bauer, Eur Heart J 2008; Online access Dec 23, 2008 Mäkikallio, Eur Heart J 2005;26:762

EF ⫽ ejection fraction. Other abbreviations as in Table 1. *Trial enrolled only patients with EF ⱕ40%. †Trial enrolled only patients with EF ⬍50%.

Table 3

Risk Stratification for Sudden Death in Patients with CAD

EF cutoff

Relation of programmed electrical stimulation results to total mortality and sudden cardiac arrest risk§

Study size (no. patients)

No. endpoints (cardiac deaths/arrhythmic events)

Maximum no. of extrastimuli in stimulation protocol

Prevalence inducible VT (%)

Sensitivity (SCA or arrhythmic events) (%)

RR (SCA or arrhythmic events)

RR (nonsudden cardiac death)

Reference

403 100 361 1,209 86 492 146 1,791 1,791

22/27 10/10 34/19 77/49 17/11 34/22 27/9 296/140 464/232

2 3 5 4 or 2 (20mA) 3 2-3 2 3 3

20 37 9 6 22 20 15 32 32

52 80 58 29 55 69 44 37 28

5.1 5.7 15.2 6.3 4 4.2 4.5 2.0 1.4

3.7 0.61 5.6 3.3 1.5 2.5 1.1 1.5 1.3

Denniss, Circulation 1986;74:731 Wilber, Circulation 1990;82:350 Richards, Circulation 1991;83:756§ Bourke, J Am Coll Cardiol 1991;18:780 Bhandari, Am Heart J 1992;124:87‡ Brembilla-Perot, Int J Cardiol 1995;49:55 Andresen, J Am Coll Cardiol 1999;33:131 Buxton, Circulation 2002;106:2466*§ Buxton, Circulation 2002;106:2466†§

MI ⫽ myocardial infarction; NSVT ⫽ nonsustained ventricular tachycardia; VT ⫽ ventricular tachycardia. CCU ⫽ coronary care unit. Other abbreviations as in previous tables. *MUSTT patients with EF 30%– 40%. †MUSTT patients with EF ⬍30%. ‡Study included only patients with recent “high-risk” MI (CHF, recurrent ischemia in CCU, NSVT). §Study restricted to patients with prior MI, EF ⱕ40%, and spontaneous NSVT.

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840 difference between RR for SCA and nonsudden death in MUSTT results from the fact that only patients with EF ⱕ40% were enrolled.13 The sensitivity of inducible VT for predicting SCA has ranged from 28% (in patients with EF ⬍30%) to 80% (Table 3). All the studies evaluating the predictive utility of EPS were conducted in the era when use of beta-blockers after MI was suboptimal. For example, in MUSTT, only 35% of noninducible patients received betaadrenergic blocking agents, and only 72% were treated with angiotensin-converting enzyme inhibitors. It seems likely that with current pharmacologic therapy of patients with heart failure and reduced EF, the sudden death rate would be significantly lower in noninducible patients. A substudy of MUSTT examined the interaction between EF and the predictive power of EPS.14 Patients with EF ⬍30% are more likely to have heart failure than are patients with EF ⬎30%. The presence of heart failure may result in sudden death by mechanisms other than monomorphic VT. Thus, one might expect greater predictive utility of EPS in patients with EF ⬎30%. In fact, in this analysis, untreated patients without inducible VT, whose EF was 30% to 40%, experienced only an 8% incidence of arrhythmic death or cardiac arrest over 2-year follow-up, versus 15% risk for patients with EF was ⬍30%. Similar results were obtained recently by the Alternans Before Cardioverter Defibrillator (ABCD) trial (David Rosenbaum, MD, Personal Communication, June 2008). Thus, EPS can discriminate between patients at relatively high risk versus low risk for sudden death. However, used in isolation, the sensitivity is inadequate, especially in patients with EF ⬍30%. The clinical utility of EPS is limited by its invasive nature. Thus, it is not suitable as an initial screening test but probably is more valuable when used in patients having equivocal results after noninvasive testing as a means for avoiding ICD placement in those unlikely to benefit significantly. Of note, EPS does not carry a number of limitations associated with other risk stratification tests. It can be performed in patients with frequent ventricular ectopy and atrial fibrillation as well as in patients who are paced. Furthermore, EPS does not require that patients be able to exercise.

Signal-averaged ECG The second test developed to detect the substrate for reentrant VT was the signal-averaged ECG (SAECG), a noninvasive technique for detecting small areas of slowly conducting myocardium. The prognostic value of SAECG has been examined in multiple studies of acute MI survivors.9 A majority of these studies were performed prior to widespread adoption of modern reperfusion therapy for acute MI and appropriate use of pharmacologic therapy such as betablockers. Thus, the results of those studies may not be directly applicable to current practice, in part because reperfusion therapy during acute MI appears to attenuate the formation of late potentials.15 However, this study used a much stricter definition of late potential than used by most other studies, thereby resulting in a much lower percentage of patients having abnormal SAECG. The sensitivity for

Heart Rhythm, Vol 6, No 6, June 2009 prediction of arrhythmic events has ranged from 22% to 75%, with follow-up ranging from 6 to 24 months (Table 4).9 The negative predictive value has been very good, averaging over 90%. Thus, SAECG has performed well in identifying low-risk patients.9 The specificity for prediction of sudden death appears to be low. With the exception of one older study, every analysis has shown RR for nonsudden death exceeds RR for SCA in patients with an abnormal SAECG (Table 4).16 The likely explanation for this finding is that more extensive infarctions are associated with more extensive areas of slow conduction detected by the SAECG. In addition, patients with more extensive conduction slowing detected by SAECG may be more at risk for sustained hemodynamically stable monomorphic VT that does not precipitate SCA. SACEG has limitations. It is better at predicting risk of VT than VF. Normal standards for patients with bundle branch block or ventricular pacing have not been established (prior studies have excluded such patients). However, SAECG can be used in patients who are in atrial fibrillation, in contrast to use of T-wave alternans, baroreflex sensitivity, and heart rate variability.

T-wave alternans More recently, a third modality reflecting the arrhythmic substrate for prediction of sudden death risk has been evaluated, the presence of microvolt T-wave alternans (TWA). TWA describes alterations in the amplitude of the T wave on alternate beats, usually at modestly increased heart rates (105–110 bpm) elicited by exercise or atrial pacing. The development of TWA results from abnormal intracellular calcium handling. In contrast to SAECG (which measures abnormalities of ventricular activation), TWA measures abnormalities of repolarization. Initial clinical studies of TWA demonstrated that abnormal degrees of TWA correlate with inducible VT in patients who presented with spontaneous sustained VT or cardiac arrest as well as in patients who had never experienced spontaneous tachyarrhythmias. A series of studies then reported that abnormal TWA indicates significantly increased mortality risk as well as risk of arrhythmic events. A metaanalysis of these studies indicated abnormal TWA was associated with a fourfold increased risk for arrhythmic events and a negative predictive value of at least 95%.17 The positive predictive values were far more variable, depending on the characteristics of the study populations (pretest probability). For example, the positive predictive value in three studies of post-MI patients was only 6. In contrast, the positive predictive value in two studies of patients with heart failure attributed to coronary disease was 30! Several large multicenter studies of TWA that have been completed paint a different picture of the potential clinical utility of TWA. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators analyzed the relation of TWA testing to the endpoints of sudden death, sustained VT, and “appropriate” defibrillator discharge in a subset of almost 500 patients.18 The results of the TWA test did not predict the occurrence of composite events. Likewise, the

Breithardt, Eur Heart J 1986;7(Suppl A):127 Denniss, Circulation 1986;74:731 Richards, Circulation 1991;83:756 Gomes, Circulation 2001;104:436 Huikuri, J Am Coll Cardiol 2003;42:652 Bauer, Eur Heart J 2005;26:755 fQRSd ⫽ filtered QRS duration; SAECG ⫽ signal-averaged electrocardiogram. Other abbreviations as in previous tables.

0.4 5.8 7.0 1.9 4.8 2.4 3.6 5.3 4.4 1.9 4.8 2.4 75 65 57 67 46 22 8/13 22/27 34/19 341/230 59/22 20/12 132 306 361 1,268 675 968

45 26 NA 44 10 9

Sensitivity (SCA or arrhythmic events) (%) Prevalence (prolonged fQRSd) (%) No. endpoints (cardiac deaths/ SCD–arrhythmic events) Study size (no. patients)

Relation of SAECG results to total mortality and sudden cardiac arrest risk

RR (SCA and/or arrhythmic events)

RR (nonsudden cardiac death)

Reference

Risk Stratification for Sudden Death in Patients with CAD

Table 4

Buxton

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Microvolt T-Wave Alternans Testing For Risk Stratification of Post MI Patients (MASTER) study, a prospective study of patients with prior MI and left ventricular EF ⱕ30% who received an implanted defibrillator, found that the TWA test results did not influence the frequency of the composite endpoint of arrhythmic death or “appropriate” defibrillator shock over 3-year follow-up.19 Finally, the ABCD trial has been completed recently.20 This study enrolled 566 patients with coronary disease, left ventricular EF ⱕ40%, and spontaneous NSVT. The trial was designed to test the hypothesis that TWA is equivalent to EPS in predictive value. Most patients in the trial received implanted defibrillators, so the endpoint was a composite of sudden death or “appropriate” defibrillator discharge. After median follow-up of 1.9 years, the two tests predicted the composite endpoint with similar frequency. The accuracy of TWA appeared superior to that of EPS at 1-year follow-up, but at 2 years, EPS was superior. Of note, there was only 45% concordance between the results of the two tests. As a consequence, patients with negative results on both tests had significantly lower event rates than did patients with only one test positive. Patients with positive results on both tests had significantly more events than patients having only one test positive. Thus, it appears that TWA testing and EPS measure different aspects of the substrate for ventricular tachyarrhythmias, and their use is complementary. Based on the results of studies to date, it is difficult to asses the specificity of TWA to predict arrhythmic death for several reasons. The majority of studies to date have examined patients with markedly reduced EF. In these patients the risk of nonarrhythmic cardiac death probably is equal to the risk for arrhythmic death, and when advanced heart failure is present, the cause of death is difficult to judge. This nature of the patient populations enrolled in the studies may explain the similarity in RR for SCA and total mortality in most of the TWA studies (Table 5). Many of the studies evaluating TWA report only mortality or arrhythmic events, not both. A Japanese study that evaluated TWA in patients with EF ⱖ40% after a recent MI provides interesting data.21 TWA was performed an average of 48 days post-MI. More than 1,000 patients were enrolled and were followed an average of 32 months. Very few nonarrhythmic deaths occurred. Eighteen (1.8%) patients died suddenly. The frequency of indeterminate TWA testing was low in comparison to previous reports, only 9%. No patients with indeterminate test results experienced an arrhythmic event. TWA was positive in 18% of patients, and this result was associated with a hazard ratio of 19.7 for arrhythmic events. Arrhythmic events occurred in ⬍1% of patients with negative TWA but in 9% of patients with positive TWA. The investigators did not provide data on total cardiac mortality, but it seems likely that in the study population of patients with EF ⱖ40% a majority of the cardiac deaths would have been sudden. Therefore, it seems likely that, in this study, the RR for SCA would have exceeded the RR for nonsud-

ICD ⫽ implantable cardioverter-defibrillator; TWA ⫽ T-wave alternans. Other abbreviations as in previous tables. *Trial enrolled only patients with prior MI and EF ⱕ30%. All patient received ICD (detection criteria programmed uniformly). Arrhythmic events included “appropriate” ICD discharges. †Data presented are based on analysis of test results performed 10 –14 weeks after MI (results of tests performed 2– 4 weeks after MI did not predict outcomes). ‡SCD-HeFT substudy results include patients with nonischemic cardiomyopathy. All patients had EF ⱕ35%. §Trial included only patients with EF ⱖ40%. ¶Trial included patients with remote MI, and many received ICDs. This analysis is confined to patients who did not receive ICDs. All patients had EF ⱕ35%.

NA 1.7 2.4 1.5 2.2 19.7 (HR) 3 2.9 1.4 1.2 17/18 74/38 22/24 81 59/70 1,041 376 322 490 575

TWA TWA TWA TWA TWA

abnormal nonnegative nonnegative abnormal nonnegative

17 52 58 37 63

83 76 83 65 69

RR (nonsudden cardiac death or total cardiac mortality) RR (SCA and/or arrhythmic events) Sensitivity (SCA or arrhythmic events) (%) Prevalence abnormal TWA (%) Parameter measured No. endpoints (cardiac deaths/arrhythmic events) Study size (no. patients)

Relation of TWA results to total mortality and sudden cardiac arrest risk Table 5

Ikeda, J Am Coll Cardiol 2006;48:2268§ Chow, J Am Coll Cardiol 2006;49:50¶ Exner, J Am Coll Cardiol 2007;50:2275† Gold, Circulation 2008;118:2022‡ Chow, J Am Coll Cardiol 2008;52:1607*

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Reference

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den death in patients with abnormal TWA tests. Thus, in patients with relatively preserved EF after acute MI, the results of TWA testing may provide very useful prognostic information. Limitations of TWA include the fact that it cannot be measured in the presence of atrial fibrillation or frequent ventricular ectopy. Measurement of TWA requires that the patient be able to exercise to increase the sinus rate to ⬎105 bpm, although atrial pacing has been used to increase the heart rate (but then the test is no longer noninvasive). Of note, indeterminate results carry prognostic significance equal to that of positive results for total mortality. This is not surprising because the factors that cause indeterminate TWA (failure to increase sinus rate, frequent ectopy) are known indicators of adverse prognosis. As a result, many studies have analyzed outcomes by combining patients with positive and indeterminate tests. Although that may result in greater statistical power to detect differences in outcome, one can question the value of a test in which indeterminate results carry equal weight as positive test results. One could derive the same information provided by an indeterminate result during a standard exercise test, without the added expense required to perform the TWA test. Furthermore, reduced exercise capacity and frequent ectopy during exercise are not specific markers of risk for arrhythmic events.

Markers of autonomic nervous system function A second class of risk markers utilizes evaluation of autonomic nervous system function. Autonomic tone traditionally has been thought to be a modulator between triggers of ventricular tachyarrhythmias and the underlying substrate. Multiple studies have correlated relative excess of sympathetic tone (or deficient parasympathetic tone) with increased mortality post-MI as well as increased propensity for VF during acute ischemia. Sympathetic–parasympathetic balance has been measured by a number of parameters. The first to be evaluated was heart rate variability (HRV), the amount of beat-to-beat variation in resting sinus rate over time. HRV has been expressed in various ways, derived from both short-term (2- to 8-minute) and long-term (24-hour) ECG recordings. Most data are based on 24-hour recordings. HRV directly measures autonomic effects on sinus node function but is assumed to reflect effects on the ventricles. HRV may be expressed as time-domain variables (variations on the standard deviation of R-R intervals) or frequency-domain variables. Most studies suggest similar prognostic ability for both. The fundamental principle underlying these analyses is that higher-frequency, beat-tobeat variation in heart rate results from respiratory cycles, with increased HRV reflecting greater relative degrees of parasympathetic tone. Details of technical aspects and physiologic mechanisms underlying HRV measurement have been reviewed.22 Multiple studies have documented an association between reduced HRV and increased mortality after acute MI.23 The majority show no significant difference in RR for SCA versus total mortality (Table 6). When HRV has been compared to other autonomic markers, it has

843

not performed as well for prediction of sudden death risk.22 The prognostic utility of HRV was compared to baroreflex sensitivity in the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) study, which followed almost 1,300 patients with recent (⬍1 month) MI. Among patients with EF ⬍35%, abnormal HRV was statistically significantly associated with increased arrhythmic event risk, but its actual discrimination was not very high.24 In a Finnish registry of 700 patients with acute MI, HRV tested within 2 weeks failed to differentiate patients who subsequently died suddenly from survivors as well as from those who died nonsuddenly. However, HRV did distinguish those patients who died nonsuddenly from survivors.11

Farrell, J Am Coll Cardiol 1991;18:687 Bigger, Circulation 1996;93:2142 Copie, J Am Coll Cardiol 1996;27:270 Hohnloser, J Am Coll Cardiol 1999;33:1895 La Rovere, Circulation 2001;103:2072† Huikuri, J Am Coll Cardiol 2003;42:652 Camm, Circulation 2004;109:990* Mäkikallio, Eur Heart J 2005;26:762

Reference

Risk Stratification for Sudden Death in Patients with CAD

6.7 1.9 6.9 5.5 1.3 2.3 1.4 2.6 (HR) HRV ⫽ heart rate variability. Other abbreviations as in previous tables. *Study included only patients with EF 15%–35%. †Relative risks refer only to patients with EF ⬍35%.

32.4 2.1 2.7 4.1 4.1 2.4 1.3 2.4 (HR) 92 NA 75 53 36 5.5 45 NA 47/24 88/68 42/26 15/17 43/30 59/22 158/92 113/52 416 715 579 325 1,071 675 1,690 2,130

27 36 50 22 15 NA 28 NA

Sensitivity (SCA or arrhythmic events) (%) Prevalence (abnormal HRV) (%) No. endpoints (cardiac deaths/SCA–arrhythmic events) Study size (no. patients)

Relation of HRV results to total mortality and sudden cardiac arrest risk

RR (SCA and/or arrhythmic events)

RR (nonsudden cardiac death or total cardiac mortality)

Baroreflex sensitivity

Table 6

Buxton

A second variable reflecting autonomic balance evaluated is baroreflex sensitivity (BRS), the normal reflex decrease in heart rate in response to an increase in blood pressure. Lesser degrees of reduction of heart in response to increase in blood pressure reflect relative excess of sympathetic tone. BRS has also been expressed by measure of heart rate turbulence (HRT), the derangement in sinus rate following a ventricular premature depolarization.25 In the ATRAMI study, abnormal BRS was highly predictive of both sudden and nonsudden death, primarily in patients with EF ⱕ35%.24 However, whether BRS is specifically linked to excess SCA risk (using comparison of RR for SCA vs non-SCA) is not clear. In ATRAMI, RR for SCA was more than twofold greater than the RR for non-SCA risk in patients with abnormal BRS (Table 7).24 However, in no other study did the RR for SCA significantly exceed the RR for non-SCA. In a prospective Finnish study of patients with MI, BRS failed to distinguish among survivors and those who died, both sudden and nonsuddenly.11 The difference in results between ATRAMI and the Finnish study may be related in part to use of beta-blocking agents: only 20% of patients in ATRAMI received beta-blockers versus 95% of patients in the Finnish trial. An Italian study assessed BRS in 244 patients with EF ⬎35% tested 30 to 40 days post-MI and followed for an average of 5 years.26 Cardiovascular death occurred in 5.7% and was significantly related to impaired BRS but not EF (mean EF 54%). The 5-year cardiovascular mortality in the 14% of patients who demonstrated impaired BRS was 26% versus only 2.4% in the group without impaired BRS. The high event rate in patients with impaired BRS (even though EF was ⬎35% in all patients in this study) is noteworthy. One factor is pertinent to earlier evaluations and may explain the observed limitations of autonomic function and TWA testing in predicting sudden death—the time at which testing was performed after MI. In the case of ATRAMI and the Finnish post-MI study,11,24 autonomic function was evaluated within 2 weeks after the event. The Risk Estimation Following Infarction, Noninvasive Evaluation (REFINE) study explored the influence of time after MI on predictive utility of a variety of markers, including HRV, BRS, HRT, SAECG, TWA, and EF.27 In REFINE, 322 patients

BRS ⫽ baroreflex sensitivity; HRT ⫽ heart rate turbulence; SAF ⫽ severe autonomic failure (presence of abnormal HRT ⫹ abnormal deceleration capacity); TS ⫽ turbulence slope. Other abbreviations as in previous tables. *Relative risks refer only to patients with EF ⬍35%. †Study included only patients with EF ⬍50% after MI.

6.7 (HR) 4.6 (HR) 113/52 2,130

TS

NA

56

2.8 1.3 3.3 4.0 14.4 6.7 1.9 4.1 4.5 5.8 73 4.5 38 25 27 15 NA 14 8 6 43/30 59/22 22/24 22/24 104/55 1,071 675 322 322 2,343

BRS BRS (⬍3.0) HRT BRS (⬍3.1) SAF

RR (nonsudden cardiac death) RR (SCA or arrhythmic events) Sensitivity (SCA or arrhythmic events) (%) Prevalence (abnormal test) (%) Parameter measured No. endpoints (cardiac deaths/SCD–arrhythmic events) Study size (no. patients)

Relation of BRS and HRT results to total mortality and sudden cardiac arrest risk Table 7

La Rovere, Circulation 2001;103:2072* Huikuri, J Am Coll Cardiol 2003;42:652 Exner, J Am Coll Cardiol 2007;50:2275† Exner, J Am Coll Cardiol 2007;50:2275† Bauer, Eur Heart J 2008; Online access December 23, 2008 Mäkikallio, Eur Heart J 2005;26:762

Heart Rhythm, Vol 6, No 6, June 2009

Reference

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were tested twice: 2– 4 weeks after MI and again 10 –14 weeks after MI. Median follow-up was almost 4 years. None of the tests performed 2– 4 weeks post-MI predicted sudden or nonsudden death (note that the value for abnormal BRS used in this study was not the standard cutoff). In contrast, abnormal results on BRS, HRT, and TWA 10 –14 weeks after MI each predicted total mortality as well as sudden death or cardiac arrest. Abnormal HRV and SAECG tests were not predictive. The results of late testing did not provide evidence that any of the tests identified patients whose risk for arrhythmic events exceeded their total mortality risk (Tables 2, 5, and 7). Thus, the results of REFINE suggest that risk stratification using currently available methodology should be delayed ⬎1 month after MI. Furthermore, although assessment of autonomic function seems able to identify patients at risk for both sudden and nonsudden cardiac death, the mechanism(s) underlying this relation is not clear. Whether relative excess sympathetic tone plays a role in promoting only VF resulting from acute ischemia or if it also facilitates occurrence of reentrant VT also remains to be defined.

Role of conventional ECG To this point we have discussed tests that exploit specific aspects of the presumed substrates for VT/VF, the triggers for the arrhythmic substrate, or autonomic modulators of the interactions between substrate and triggers. However, there is obvious appeal in the value of simpler markers. A number of characteristics of the standard 12-lead ECG have been examined for their utility as risk markers, including bundle branch block, QRS duration, and LVH. In addition, measures of dispersion and duration of repolarization have been proposed, including QT duration, dispersion of QT interval (difference between longest and shortest QT intervals measured on 12-lead ECG), and QT-interval variability. The association among more advanced coronary disease, poorer left ventricular function, and QRS duration is well documented.12,23 The MUSTT Investigators found that left bundle branch block as well as nonspecific intraventricular conduction delay (IVCD), but not right bundle branch block, were associated with increased total mortality risk.28 Although the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) found that patients with very wide QRS complexes (⬎150 ms) seemed to derive more benefit from ICD therapy than patients with less wide QRS complexes,29 no other study has found evidence that the RR for SCA exceeds the RR for total mortality in patients with bundle branch block or wider QRS duration.12,23,28 In addition, the MUSTT Investigators found no link between bundle branch block and inducible monomorphic VT.28 Furthermore, in a large study of patients who received ICDs for both primary and secondary prevention, QRS duration and bundle branch block were not associated with the occurrence of ventricular tachyarrhythmias.30 QRS duration might correlate with local areas of slowed intraventricular conduction. However, other factors, such as ventricular mass, contribute to QRS duration. In addition, although slow conduction is one requisite to establish reentry,

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Risk Stratification for Sudden Death in Patients with CAD

the circuits responsible for monomorphic VT after MI need occupy only very small areas of myocardium, which may not be reflected in prolongation of the surface QRS. In summary, the weight of evidence supports the idea that prolonged QRS duration and bundle branch block reflect more advanced degrees of ventricular dysfunction. As such, their presence is associated with increased total mortality but no specific predilection to VT/VF. Although LVH is known to be associated with sudden death, the ECG is not the optimal tool for identifying patients with LVH. It is especially interesting in light of these facts that a substudy of MUSTT found LVH on the ECG was not only independently associated with sudden death, but that the RR for SCA was increased more than the RR for total mortality in patients with LVH.28 It is also noteworthy that LVH had a negative association with inducible VT, suggesting that LVH predisposes to sudden death by mechanisms other than reentrant VT. The unique association between LVH (detected by echocardiogram) and SCA in patients with coronary disease was reinforced in a broadbased study of patients with chronic coronary disease but no recent MI.31 In this study too, the RR for SCA in patients with increased left ventricular mass exceeded the RR for total mortality. LVH on the ECG has been linked to sudden death in hypertensive patients without previously manifest cardiac disease. Given the significant overlap between hypertension and coronary disease, these observations are not surprising. Thus, LVH as a risk factor for sudden death after MI warrants further investigation. ECG measures of the absolute duration of myocardial repolarization as well as dispersion in the duration of repolarization have been examined. Schwartz et al12 reported that the QT interval is longer in a small cohort of patients with MI (2 months to 6 years earlier) than matched controls. These investigators also noted a relation between QT interval prolongation and sudden death over a 10 year follow-up. The link between QT prolongation and sudden death is especially striking in that all deaths in this study were said to represent sudden death, suggesting a specific relation between QT duration and ventricular arrhythmias in the post-MI setting. Schwartz’s observations were partly replicated in an examination of data from the Beta-Blocker Heart Attack Trial (BHAT).12 In that study, total but not causespecific mortality was related to QT interval. Variation in QT interval over time also has been correlated with occurrence of sudden death. A 10-minute Holter recording performed upon entry to MADIT-II demonstrated that patients who subsequently developed spontaneous VT or VF detected by ICD exhibited a greater degree of variation in measured QT.32 Likewise, Schwartz reported significantly greater degrees of QT variability measured on standard ECGs over a period of months in patients who died suddenly after MI.12 These preliminary observations appear promising and warrant further investigation. A number of studies have examined the relation between QT dispersion

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and survival, but no consistent relation between QT dispersion and arrhythmic event has been observed.12 In summary, a number of standard ECG parameters have been examined for potential utility as risk stratification tools in patients with coronary disease and prior MI. Although several parameters correlate with both total mortality and sudden death, with the exception of LVH, and QT variability none has demonstrated a specific correlation with sudden death.

Importance of multiple risk factors A number of studies have examined the interactions between multiple risk stratification techniques. These studies can be grouped into those that evaluated patients with recent MI and those that evaluated patients with remote MI. Studies of patients with recent MI date to the 1980s, including studies evaluating the relation between SAECG and EF.23 The ATRAMI study examined the interaction among EF, HRV, BRS, and NSVT.24 In a study of 850 patients with recent MI, Ikeda et al33 evaluated the relation between EF and TWA. The ABCD trial documented an important interaction between TWA and EPS in patients with EF ⱕ40%.20 Finally, the REFINE study obtained similar results when various autonomic markers were combined with markers of arrhythmia substrate and EF.27 In each case, the results were remarkably similar. Patients with no or only one risk factor (e.g., low EF, only abnormal SAECG, BRS, or TWA) have had a relatively low risk for events. Patients with more than one risk factor have progressively increasing risk for mortality as well as arrhythmic death. It is impossible to ignore this pattern, and these observations must be accounted for in designing future risk stratification algorithms. Another finding that reinforces the importance of incorporating multiple risk factors into decisions to implant ICDs can be seen from examination of the tables. No single risk factor possesses adequate sensitivity for prediction of SCA. Thus, a paradox exists wherein it is desirable to find combinations of risk factors that will identify individuals at significantly increased risk. Unfortunately, requiring the presence of multiple risk factors in an individual will reduce the number of patients who qualify for ICD therapy, thereby compromising the sensitivity of any algorithm. Overcoming these limitations will require balancing sensitivity and specificity in risk stratification algorithms. Two recent studies have demonstrated practical ways to incorporate multiple risk factors in to risk stratification algorithms. A multivariable analysis of factors influencing survival of untreated patients in MUSTT was used to construct prediction algorithms.34 The model uses clinical (historical) variables—ECG, EF, EPS—to construct a prediction of the 2-year risk of total mortality or sudden death. The model predicts that patients with EF ⱕ30% but no other risk factor have a 2-year sudden death risk of 1% to 3% and total mortality of 5% to 6%. However, for patients with multiple risk variables, such as inducible VT or symptomatic heart failure, total mortality and sudden death risk increase to

846 10% to 20%. Thus, once again, we find that patients with only single risk factors, such as low EF, are not at high risk. Analysis of the MADIT-II data resulted in a multivariate model for predicting ICD benefit using NYHA class, atrial fibrillation, QRS duration, age, and blood urea nitrogen.35 In this study, very high-risk and low-risk patients did not benefit from the ICD, whereas patients at intermediate risk did benefit from the ICD. Very high-risk patients were defined by creatinine ⱖ2.5 and/or blood urea nitrogen ⱖ50 as well as those with ⱖ3 risk factors on multivariable analysis. In addition to the high-risk groups defined, survival was not improved in patients possessing none of the risk factors. The ICD improved survival in patients with one or two risk factors. Note that none of the variables in this model relate directly to risk markers for arrhythmic deaths. Rather, they identify patients with more advanced cardiac disease. Thus, these variables mark patients in whom nonarrhythmic risk factors compete with arrhythmias to cause death. This model is likely to be useful in patients with advanced ventricular dysfunction, which is characteristic of the MADIT-II study population. It will not be useful in a population without severe ventricular dysfunction, in which patients likely have a very low prevalence of heart failure, renal dysfunction, etc.

Putting it all together Several key points should be apparent from this discussion. First, sudden death is not one entity. Rather, it is the end product of a variety of processes. Owing to the variety of mechanisms, no single test will identify all patients at risk. Second, mechanisms of sudden death and markers to identify patients at risk are influenced by whether patients receive reperfusion therapy at the time of acute MI. In part, this probably relates to the degree of recovery of ventricular function after the acute event and whether clinical heart failure develops. However, other differences may result from reperfusion at the time of acute MI, and subsequent arrhythmia substrates may differ between patients depending on whether reperfusion occurs. Third, a consistent theme over the past 2 decades is that patients possessing only single risk factors are at relatively low risk. Risk increases markedly when more than one factor is present. The corollary of this is that not all patients identified by a given risk factor are identical, that is, some patients with reduced EF have heart clinical failure, or left bundle branch block, or inducible VT, and all of these factors modulate the initial risk. Fourth, markers of total mortality risk are not identical to markers for arrhythmic death. There is no doubt that EF is an excellent marker for total mortality risk but is of limited utility in predicting the mode of death (sudden vs nonsudden). It is the latter that we must focus on if ICDs are to be used cost-effectively. Thus, for patients with EF ⱕ30%, two additional requirements must be met to utilize ICDs efficiently. First, additional risk factors should be present to identify those at risk for tachyarrhythmic events. Second, factors likely to contribute to nonarrhythmic mortality should be absent.

Heart Rhythm, Vol 6, No 6, June 2009 Another broad issue that must be addressed is when should testing be performed initially after MI, and when should it be repeated. Results from the REFINE study suggest it is best to wait 2 to 3 months after acute MI before performing risk stratification. It would seem reasonable (in the absence of data) to retest every 2 years in apparently stable patients to detect potential changes in substrate, regardless of which tests appear to have the highest yield.

Future of risk stratification It is imperative that we refocus our efforts, but not on finding additional subgroups in which we can show a reduction in mortality with prophylactic therapy (e.g., patients with low EF). Rather, we must take a global view of the problem of sudden death and ask how can we have the greatest impact. Most studies to date have focused on patients with markedly reduced EF. This group currently accounts for only 10% to 15% of MI survivors. We must turn our efforts to the group in which the majority of sudden deaths occur: patients with EF ⬎30% after MI.4 The multivariable risk modeling studies suggest ways to integrate clinical characteristics with more specific tests of arrhythmic risk in order to more accurately classify individual risk for sudden death and potential ICD benefit.3,34 These models require prospective validation before they can be applied in practice. They are likely to be useful in designing algorithms to guide risk stratification in patients with very low EF. They will be less useful in patients with higher EF because such patients will have a lower prevalence of comorbid conditions (renal failure, heart failure) that figure prominently in the published models. We expect that markers more directly linked to arrhythmias (TWA, EPS, SAECG) should be more functional in patients with better preserved EF. An even greater challenge that constitutes part of this “whole picture” view of the problem of sudden death relates to identification of patients for whom cardiac arrest is the first manifestation of coronary disease. The screening base for this problem obviously is much broader because such patients have no history of MI. It seems likely that acute severe ischemic events are responsible for the majority of these events. This group might benefit from examination of genetic markers of membrane ion channel mutations that predispose to VT/VF when unmasked by ischemia or other stressors, as well as variants of adrenergic receptors that link arrhythmia triggers and the underlying substrate.26

Acknowledgments I thank Drs. Derek Exner and Heikki Huikuri for providing data from their studies that were not reported in the original publications.

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