Sudden Death in Patients with Myocardial Infarction and Left Ventricular Dysfunction, Heart Failure, or Both
Scott D. Solomon, M.D., Steve Zelenkofske, D.O., John J.V. McMurray, M.D., Peter V. Finn, M.D., Eric Velazquez, M.D., George Ertl, M.D., Adam Harsanyi, M.D., Jean L. Rouleau, M.D., Aldo Maggioni, M.D., Lars Kober, M.D., Harvey White, D.Sc., Frans Van de Werf, M.D., Ph.D., Karen Pieper, M.S., Robert M. Califf, M.D., Marc A. Pfeffer, M.D., Ph.D., for the Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators
Background The risk of sudden death from cardiac causes is increasedamong survivors of acute myocardial infarction with reducedleft ventricular systolic function. We assessed the risk andtime course of sudden death in high-risk patients after myocardialinfarction.
Methods We studied 14,609 patients with left ventricular dysfunction,heart failure, or both after myocardial infarction to assessthe incidence and timing of sudden unexpected death or cardiacarrest with resuscitation in relation to the left ventricularejection fraction.
Results Of 14,609 patients, 1067 (7 percent) had an event amedian of 180 days after myocardial infarction: 903 died suddenly,and 164 were resuscitated after cardiac arrest. The risk washighest in the first 30 days after myocardial infarction —1.4 percent per month (95 percent confidence interval, 1.2 to1.6 percent) — and decreased to 0.14 percent per month(95 percent confidence interval, 0.11 to 0.18 percent) after2 years. Patients with a left ventricular ejection fractionof 30 percent or less were at highest risk in this early period(rate, 2.3 percent per month; 95 percent confidence interval,1.8 to 2.8 percent). Nineteen percent of all sudden deaths orepisodes of cardiac arrest with resuscitation occurred withinthe first 30 days after myocardial infarction, and 83 percentof all patients who died suddenly in the first 30 days did soafter hospital discharge. Each decrease of 5 percentage pointsin the left ventricular ejection fraction was associated witha 21 percent adjusted increase in the risk of sudden death orcardiac arrest with resuscitation in the first 30 days.
Conclusions The risk of sudden death is highest in the first30 days after myocardial infarction among patients with leftventricular dysfunction, heart failure, or both. Thus, earlierimplementation of strategies for preventing sudden death maybe warranted in selected patients.
Sudden death is a catastrophic complication of acute myocardialinfarction.1 Although many patients who die from an acute myocardialinfarction do so before reaching the hospital, those admittedremain at substantial risk for ventricular arrhythmias. Thatrisk is greatest in the first few hours, declines rapidly thereafter,and is influenced by the extent of myocardial injury, recurrentischemia, electrolyte abnormalities, and other factors.2,3 Thesuccess of coronary care units in the 1960s was, in part, relatedto the early identification and treatment of life-threateningarrhythmias that occurred in the setting of an acute myocardialinfarction. Though the risk of sudden death is believed to decreaserapidly after infarction, the extent and time course of thischange in risk have not been well studied, especially sincethe use of coronary reperfusion, beta-blockers, and angiotensin-converting–enzymeinhibitors has become widespread.
Reduced left ventricular function is a major risk factor fordeath, including sudden death, after myocardial infarction.4,5This observation has led to trials of implantable cardioverter–defibrillators(ICDs) in patients with a low left ventricular ejection fractionafter infarction.6 The Multicenter Unsustained Tachycardia Trial(MUSTT) demonstrated the benefit of an ICD in patients withcoronary artery disease, a left ventricular ejection fractionof 40 percent or less, and inducible sustained ventricular tachycardia.7The Multicenter Automatic Defibrillator Implantation Trial II(MADIT-II)8 further showed a benefit of empirical ICD therapyin patients with a left ventricular ejection fraction of 30percent or less one month or more after myocardial infarction.Although these studies enrolled few patients within six monthsafter they had had a myocardial infarction, the results arereflected in the current American College of Cardiology–AmericanHeart Association guidelines for the management of acute myocardialinfarction,9 which recommend the implantation of an ICD onemonth or more after myocardial infarction in patients with aleft ventricular ejection fraction of 30 percent or less andin those with a left ventricular ejection fraction of 40 percentor less and additional evidence of electrical instability. Incontrast, the recently reported Defibrillator in Acute MyocardialInfarction Trial (DINAMIT)10 did not show that the implantationof an ICD 6 to 40 days after myocardial infarction reduced therisk of death in patients with a left ventricular ejection fractionof 35 percent or less and reduced heart-rate variability. Nevertheless,the risk of sudden death in the early period after myocardialinfarction remains high and has not been well studied in themodern era.11 To better delineate the early and later risk ofsudden death after myocardial infarction and the associationof these risks with the left ventricular ejection fraction,we studied patients enrolled in the Valsartan in Acute MyocardialInfarction Trial (VALIANT).
Methods
VALIANT was a randomized, controlled trial of treatment withvalsartan, captopril, or both in 14,703 patients with a firstor subsequent acute myocardial infarction complicated by heartfailure, left ventricular systolic dysfunction, or both.12 Patientswere enrolled between December 1998 and June 2001. All patientshad an ejection fraction of no more than 40 percent or clinicalor radiologic evidence of heart failure complicating their myocardialinfarction. For this analysis, we excluded 94 patients becausethey had already received an ICD before randomization. All patientsgave written informed consent, and the research protocol wasapproved by the appropriate review boards. The details of thepatient population and the protocol, including inclusion andexclusion criteria, have been reported previously.12
A central adjudication committee reviewed all deaths and episodesof cardiac arrest with resuscitation in a blinded fashion, usingsource documentation provided by the site investigators. Deathswere classified as having cardiovascular or noncardiovascularcauses, and deaths from cardiovascular causes were further classifiedas sudden or due to myocardial infarction, heart failure, stroke,or another cardiovascular cause. Sudden death was explicitlydefined as death that occurred "suddenly and unexpectedly" ina patient in otherwise stable condition and included witnesseddeaths (with or without documentation of arrhythmia) and unwitnesseddeaths if the patient had been seen within 24 hours before deathbut had not had premonitory heart failure, myocardial infarction,or another clear cause of death. Cardiac arrest with resuscitationwas defined as cardiac arrest from which a patient regainedconsciousness and subsequent cognitive function, even briefly.
The median duration of follow-up was 24.7 months. Sudden deathsand episodes of cardiac arrest with resuscitation were combinedfor this analysis. The left ventricular ejection fraction wasdetermined before randomization (a median of five days aftermyocardial infarction) at the clinical site in 11,256 patients:echocardiography was used in 9095, radionuclide ventriculographyin 272, and contrast ventriculography in 1889. The analysisof the incidence and timing of sudden death included all patientsand was related to the left ventricular ejection fraction inthe subgroup of patients for whom information on the ejectionfraction was available: 3852 with an ejection fraction of 30percent or less, 4998 with an ejection fraction of 31 to 40percent, and 2406 with an ejection fraction of more than 40percent.
The rates of sudden death were assessed by dividing the eventsin each period by the number of person-days of exposure andare expressed as the percentage per month. Baseline clinicalcharacteristics were compared with the use of Student's t-testfor continuous variables and the chi-square test for categoricalvariables. The risk of sudden death associated with each decreaseof 5 percentage points in the left ventricular ejection fractionwas assessed in a Cox proportional-hazards model, with adjustmentfor all known baseline covariates.
Results
Of 14,609 patients, 1067 (7 percent) had an event: 903 patientsdied suddenly, and 164 were resuscitated after cardiac arrest.For 643 of the 1067 patients (60 percent), this was the firstcardiovascular event after enrollment. Five patients who wereresuscitated after cardiac arrest died on the day of resuscitation.The median time to sudden death or cardiac arrest with resuscitationwas 180 days after myocardial infarction (interquartile range,50 to 428). Of the 164 patients who were resuscitated, 108 (66percent) were alive at six months and 93 (57 percent) were aliveat the end of the trial. As compared with surviving patientswithout events, patients who died suddenly or had cardiac arrestwith resuscitation were significantly older; had higher baselinesystolic and diastolic blood pressures, baseline heart rate,and Killip class; had a lower left ventricular ejection fraction;were more likely to have a history of diabetes or hypertension;and were less likely to have been treated with reperfusion therapy,amiodarone, or beta-blockers (Table 1). The differences betweenpatients who died suddenly or were resuscitated after cardiacarrest and those who died of other causes were much less clinicallyapparent.
Table 1. Baseline Characteristics of the Patients, According to the Outcome.
During the first 30 days after myocardial infarction, 126 patientsdied suddenly and 72 patients were resuscitated after cardiacarrest (representing 19 percent of all patients with such eventsduring the trial), for an event rate of 1.4 percent per month(95 percent confidence interval, 1.2 to 1.6 percent). Eighty-threepercent of sudden-death events from which the patients werenot resuscitated occurred after hospital discharge. Of the patientswho were resuscitated during the first 30 days after myocardialinfarction, 74 percent were alive at 1 year. Event rates andthe cumulative incidence of events during various periods inthe study are shown in Table 2. The rate of sudden death orcardiac arrest with resuscitation decreased precipitously duringthe first year, declining to 0.14 percent per month (95 percentconfidence interval, 0.11 to 0.18 percent) after year 2.
Table 2. Event Rate and Cumulative Incidence of Events during Follow-up.
Figure 1 shows the Kaplan–Meier estimates of the rateof sudden death or cardiac arrest with resuscitation accordingto the left ventricular ejection fraction in patients in whomthe ejection fraction was measured. The increased early incidenceof these events was most apparent among patients with an ejectionfraction of 30 percent or less: the incidence rate during thefirst 30 days was 2.3 percent per month (95 percent confidenceinterval, 1.8 to 2.8 percent) (Figure 1 and Figure 2). Of the156 sudden deaths or episodes of cardiac arrest with resuscitationthat occurred during the first 30 days, 85 occurred among the3852 patients with an ejection fraction of 30 percent or less(54 percent; 1 percent of all patients with a known left ventricularejection fraction). Of the 3852 patients with an ejection fractionof 30 percent or less, 399 (10 percent) died suddenly or hadcardiac arrest with resuscitation during the trial, as comparedwith 295 of the 4998 patients with an ejection fraction of 31to 40 percent (6 percent) and 119 of the 2406 patients withan ejection fraction of more than 40 percent (5 percent). Amongthe patients with a known left ventricular ejection fraction,49 percent of all sudden deaths or cardiac arrests with resuscitationoccurred in patients with an ejection fraction of 30 percentor less, and this proportion remained relatively constant throughoutfollow-up.
Figure 1. Kaplan–Meier Estimates of the Rates of Sudden Death or Cardiac Arrest with Resuscitation, According to the Left Ventricular Ejection Fraction (LVEF).
The analysis was restricted to patients for whom data on LVEF were available.
Figure 2. Rate of Sudden Death or Cardiac Arrest with Resuscitation over the Course of the Trial in the Three Categories of Left Ventricular Ejection Fraction (LVEF).
The analysis was restricted to patients for whom data on LVEF were available. The average rate (percentage per month) is shown at the midpoint of each period.
Among the 399 patients with an ejection fraction of 30 percentor less who died suddenly or had cardiac arrest with resuscitation,85 (21 percent) did so during the first 30 days after myocardialinfarction, as compared with 50 of 295 such patients with anejection fraction of 31 to 40 percent (17 percent) and 21 of119 such patients with an ejection fraction of more than 40percent (18 percent). Nevertheless, even among patients withan ejection fraction of more than 40 percent, the rate of suddendeath or cardiac arrest with resuscitation was more than sixtimes as high in the first month as after one year. Althoughthe incidence of sudden death or cardiac arrest with resuscitationdeclined markedly over time in all groups, the relative riskof these events remained two to three times as high as amongpatients with a left ventricular ejection fraction of 30 percentor less as among patients with an ejection fraction of morethan 40 percent, although overall, the absolute rate after twoyears was substantially lower than during the early period.When the left ventricular ejection fraction was considered asa continuous variable, each decrease of 5 percentage pointsin the ejection fraction was associated with a 21 percent increasein the risk of sudden death or cardiac arrest with resuscitationduring the first 30 days after myocardial infarction (hazardratio, 1.21; 95 percent confidence interval, 1.10 to 1.30),after adjustment for all known baseline covariates.
Discussion
The results of our analysis confirm that patients with leftventricular dysfunction, heart failure, or both after myocardialinfarction are at high risk for sudden death or cardiac arrestwith resuscitation. The absolute risk is greatest in the earlyperiod after myocardial infarction and among patients with thelowest ejection fraction and declines significantly over time,reaching a steady state at approximately one year. The riskwas increased despite the fact that all patients, accordingto the study design, were receiving inhibitors of the renin–angiotensinsystem and the majority were receiving beta-blockers and aspirin.
Several measures may identify patients at highest risk for suddendeath in the first year after myocardial infarction.3,13,14These are an assessment of the frequency or severity of arrhythmia,including the incidence of premature ventricular contractions,nonsustained ventricular tachycardia, dispersion of the QT interval,and late potentials on signal-averaged electrocardiograms; measuresof autonomic function; and the results of invasive electrophysiologicaltesting.15,16,17 The left ventricular ejection fraction, anindependent risk factor for sudden death, is currently the mostwidely used and robust clinical determinant of risk after infarctionand has become the basis for determining a patient's eligibilityfor ICD therapy.9 However, it is poor at distinguishing betweenpatients who will die from arrhythmia and those who will dieof other cardiovascular causes.18 In VALIANT, patients who diedsuddenly were similar to those who died of other causes. Othercauses of death included pump failure, recurrent myocardialinfarction, procedure-related causes, other cardiac causes,and noncardiac causes, which were relatively rare in this population.Baseline characteristics that were associated with an increasedrisk of death from other causes were also associated with anincreased risk of sudden death. Our inability to distinguishpatients who died suddenly from those who died of other causesmay reflect our lack of more sophisticated measures of the riskof arrhythmia in this study.
The other key determinant of the risk of sudden death is thetime after myocardial infarction. The absolute risk of suddendeath is highest in the first year after myocardial infarction.Our data suggest that this risk is greatest within the firstweek after myocardial infarction and falls rapidly within thefirst month. The increased early rate of sudden death was highestamong patients with the lowest left ventricular ejection fraction,but the high incidence was not restricted to patients with thelowest left ventricular ejection fraction. Indeed, the incidenceof sudden death in the group with the highest ejection fractionwas greater in the first 30 days than was the incidence of suddendeath in the group with the lowest ejection fraction after 90days. Moreover, patients who died suddenly or had cardiac arrestwith resuscitation were in clinically stable condition and manyhad recently been discharged from the hospital. Thus, to preventsudden death after infarction, the ideal strategy must alsotake into account patients with a better-preserved left ventricularejection fraction (more than 40 percent).
The discriminatory effect of the left ventricular ejection fractionappears to be greatest in the first six months after myocardialinfarction. Among patients who survived beyond one year, theannualized rate of sudden death was still highest in the groupwith the lowest left ventricular ejection fraction but was fairlysimilar among the three ejection-fraction groups, although therelative risk remained higher in the groups with a lower ejectionfraction. This observation, however, should be tempered by thefact that patients who survive are already at lower risk. Also,ventricular function was measured relatively early after infarction,and in some patients, substantial recovery of ventricular functionmay have occurred with a concomitant decrease in the risk ofsudden death. An additional decline in the left ventricularejection fraction may occur over time, and the risk of suddendeath at a particular time after myocardial infarction is morelikely to be related to the ejection fraction at that time thanto the ejection fraction in the periinfarction period.
Although our findings suggest that a strategy of treating agreater proportion of patients early and focusing on those witha low left ventricular ejection fraction later might be themost efficient approach to minimizing the risk of sudden deathafter myocardial infarction, the recently reported DINAMIT showedno benefit of implanting an ICD 6 to 40 days after myocardialinfarction in patients with an ejection fraction of 35 percentor less and evidence of reduced heart-rate variability.10 Indeed,in that trial, a decrease in the rate of death from arrhythmiawas offset by an increase in the rate of death from other causes.19The DINAMIT findings thus did not provide support for the useof early ICD therapy in a high-risk population after myocardialinfarction and underscore the fact that patients at increasedrisk for sudden death from arrhythmia are also at increasedrisk for death from other causes.
Although it is difficult to reconcile the absence of a benefitin DINAMIT with the substantially increased risk of sudden deathwe observed in the early post-infarction period, there werea number of important differences between the two studies. AlthoughDINAMIT enrolled patients with a lower overall left ventricularejection fraction than did VALIANT, the average time to enrollmentwas 18 days after myocardial infarction — 13 days laterthan the average enrollment date in VALIANT — and thus,DINAMIT may have selected for patients already at lower riskfor sudden death. Moreover, at 7.2 percent per year, the overallmortality rate was lower in DINAMIT than in VALIANT. Althoughthe rate of death from arrhythmia in the DINAMIT control groupwas similar to the rate of sudden death in VALIANT (3.5 percentand 3.7 percent per year, respectively), the true rate of deathfrom arrhythmia in our study may have been much higher, sinceonly unexpected deaths were categorized as sudden, thereby excludingpatients with fatal arrhythmia in the setting of myocardialinfarction or pump failure. Alternatively, DINAMIT, with only120 deaths, may have been statistically underpowered to demonstratea clinically important difference between groups, an interpretationthat would suggest the need for additional studies of ways toprevent sudden death from arrhythmia in the early period afterinfarction.
It remains unclear whether therapies targeted at a high-riskpopulation soon after infarction would reduce the risk of suddenunexpected death, but our data provide a rationale for consideringearly-intervention strategies, including short-term therapies,in selected patients at risk. This is supported by the factthat the majority of our patients (74 percent) who were resuscitatedduring the first 30 days were alive at 1 year. In addition,although our data suggest that the overall risk of sudden deathor cardiac arrest with resuscitation increases with a decreasingleft ventricular ejection fraction, even in patients with anejection fraction of more than 40 percent, the risk of suddendeath or cardiac arrest with resuscitation was six times ashigh in the first 30 days as at 1 year, suggesting a potentialrole for early short-term intervention, even in lower-risk patients.For example, if all sudden deaths could be prevented, a strategyof treating everyone for 30 days and only those with a leftventricular ejection fraction of 30 percent or less beyond 30days in the VALIANT study would potentially have prevented orpostponed 507 deaths, as compared with 317 deaths with the useof the currently recommended strategy of treating only thosewith an ejection fraction of 30 percent or less beyond 30 days.This approach may not be practical on the basis of current ICDtechnology, but such an approach might be practical and cost-effectivein the future, although it must be noted that current Medicareregulations do not allow for payment for ICD therapy before40 days after myocardial infarction.6
A number of limitations of this analysis should be noted. First,the left ventricular ejection fraction was measured locally,not centrally, although local estimation of the ejection fractionis used to make clinical decisions. Second, some patients identifiedas having died suddenly may have died from causes such as aorticdissection, pulmonary embolism, stroke, and especially, reinfarction;in the case of reinfarction, sudden death may still be due toarrhythmia.20 Also, since our definition of sudden death specifiedprior stability, we may have excluded many deaths from arrhythmiathat occurred in the setting of myocardial infarction or heartfailure. Finally, although our data may help guide interventionalstrategies that reduce risk, we did not assess the efficacyof such strategies.
In summary, we demonstrated that the risk of sudden death ishighest soon after myocardial infarction — particularlyduring the first 30 days. This risk is greatest among patientswith the lowest left ventricular ejection fraction (30 percentor less), but even patients with a high ejection fraction (morethan 40 percent) are at substantially increased risk in theearly post-infarction period, as compared with the subsequentrisk, and the discriminatory effect of the left ventricularejection fraction declines over time. Although it is not knownwhether early ICD therapy would reduce these risks, taken inthe context of recent data demonstrating the benefits of ICDtherapy in high-risk patients,21 our data suggest the need toconsider implementing strategies to prevent sudden death inselected patients before the time recommended by current guidelines.
Supported by a grant from Novartis Pharmaceuticals.
Source Information
From the Cardiovascular Division, Brigham and Women's Hospital, Boston (S.D.S., P.V.F., M.A.P.); Novartis Pharmaceuticals, East Hanover, N.J. (S.Z.); the Department of Cardiology, Western Infirmary, Glasgow, Scotland (J.J.V.M.); Duke University Medical Center, Durham, N.C. (E.V., K.P., R.M.C.); University of Wurzburg, Wurzburg, Germany (G.E.); the National Center for Health Services, Budapest, Hungary (A.H.); the University of Montreal, Montreal Heart Institute, Montreal (J.L.R.); Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy (A.M.); the Department of Cardiology, Rigshospitalet, Copenhagen (L.K.); the Department of Cardiology, Green Lane Hospital, Auckland, New Zealand (H.W.); and Leuven Coordinating Center, Leuven, Belgium (F.V.W.).
Address reprint requests to Dr. Solomon at the Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at ssolomon{at}rics.bwh.harvard.edu.
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Sudden Death in Patients with Myocardial Infarction
Pitt B., the EPHESUS Investigators , Zijlstra F., van der Horst I. C.C., Khera A., Levine B. D., Jacobs A. G., Solomon S. D., Califf R. M., Pfeffer M. A., the VALIANT Investigators , Buxton A. E.
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A correction has been published: N Engl J Med 2005;353(7):744.
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