We evaluated the risk and timing of sudden death among high-risk patients after myocardial infarction (MI). Among survivors of acute MI with reduced left ventricular systolic function or heart failure, or both, the risk of sudden death from cardiac causes was highest in the first 30 days after MI. These findings indicate a need for early intervention to prevent sudden death during this vulnerable period.
Sudden and unexpected death is an all-too-common and devastating outcome for patients who have survived a myocardial infarction (MI) but have decreased systolic function.1 Myocardial infarction survivors face increased risk of ventricular arrythmia in the first 30 days after MI. The increased risk of sudden death peaks in the hours immediately after MI and declines rapidly thereafter.2,3 The first 30 days after MI, however, represent an especially dangerous period for survivors of MI with left ventricular dysfunction and indicates that there is a need for a better understanding of this increased risk.
The Valsartan in Acute Myocardial Infarction Trial (VALIANT) included 14,703 patients with MI complicated by left ventricular dysfunction or heart failure (left ventricular ejection fraction [LVEF] < 40%), or both, in a clinical, randomized, controlled study comparing the angiotensin-converting enzyme inhibitor captopril (Capoten) with the angiotensin receptor blocker valsartan (Diovan) or a combination of the two.4 Our analysis of the VALIANT data provided a more detailed understanding of the danger of sudden death in survivors of MI, specifically in relation to left ventricular function, and the time course and extent of increased risk in the early period after MI.
All patients in the VALIANT study had acute MI (first or subsequent) complicated by left ventricular dysfunction (LVEF < 40%) or heart failure, or both. Patients were treated with 160 mg of valsartan twice daily, 50 mg of captopril 3 times daily, or the combination of 50 mg of captopril 3 times daily plus 80 mg of oral valsartan twice daily. Deaths were categorized based on narratives and source documentation. We defined sudden death as death occurring suddenly and unexpectedly in an otherwise stable patient. Patients were followed up for a median of 24.7 months.
Patients and methods
For this analysis, we combined instances of sudden death and cardiac arrest with resuscitation. For 11,256 patients, LVEF was assessed at a median of 5 days after MI before patients were randomly assigned to treatment. All patients were evaluated for timing and incidence of sudden death. In the group of patients for whom we had data on LVEF, the timing and incidence of sudden death was correlated with LVEF. There were 2046 patients with an LVEF above 40%, 4998 with an LVEF of 31% to 40%, and 3852 with an LVEF of 30% or below. To ascertain sudden death rates, we divided the number of events in each period by the number of person-days of exposure. As shown in Table 1, this figure was represented as the percentage per month.
Seven percent of patients (n = 1067) had an event. There were 164 patients who had cardiac arrest with resuscitation and 903 patients who had sudden death. The median was 180 days after MI (interquartile range, 50-428 days) for time to cardiac arrest with resuscitation or sudden death.
Compared with patients who survived without events, sudden death patients or those who were resuscitated after cardiac arrest had higher Killip class, higher systolic and diastolic blood pressures, and higher heart rates at the start of the study, and they were markedly older. They also had lower LVEF, were more likely to have a history of diabetes or hypertension, and were less likely to have been treated with reperfusion therapy, amiodarone (Cordarone), or beta blocking agents (Table 2).
There were 126 deaths within the first 30 days after MI and 72 cardiac arrests with resuscitation (comprising 19% of all patients with such events throughout the study). This resulted in an event rate of 1.4% per month (95% confidence interval [CI], 1.2%-1.6%). The rate of cardiac arrest with resuscitation and the rate of sudden death diminished dramatically during the first year after MI, further decreasing to 0.14% per month (95% CI, 0.11-0.18) after 2 years. Table 1 shows event rates and the cumulative incidence of events during follow-up. Of the patients who died within the first 30 days (19% of the total), 83% did so after hospital discharge.
The Figure shows the cardiac arrest with resuscitation and sudden death rates during the period of the study. Patients with an LVEF of 30% or below (n = 3852) more commonly had an increased incidence of early events. Of the 156 sudden deaths occurring in the first 30 days after MI, 85 (54%) occurred in patients with an LVEF of 30% or below. Among those who had an LVEF from 31% to 41% (n = 4998), 6% (n = 295) died suddenly or had cardiac arrest during the study. The rate of cardiac arrest with resuscitation or sudden death was increased 6-fold in the first month versus after 12 months, even for patients with an LVEF above 40%. During the first 30 days after MI, a 21% increase in the risk of cardiac arrest with resuscitation or sudden death occurred for each reduction of 5% in LVEF.
The most commonly used measure of ventricular function is LVEF. As a predictor of risk after MI, LVEF has become the gold standard for deciding whether to initiate implantable cardioverter defibrillator (ICD) therapy. The VALIANT data suggest that the early period after MI represents an especially vulnerable time for sudden death. Although absolute risk peaks immediately after an MI and for patients with the lowest LVEF, even patients with a higher LVEF (> 40%) are also at substantially greater risk in the early stage after MI. Risk, as well as the predictive value of LVEF, declines rapidly in the first month after MI and reaches a steady-state value after approximately 1 year. The in­creased risk in this initial 4-week period after MI despite modern-day treatments, including inhibitors of the renin-angiotensin system, beta blocking agents, and aspirin, highlights the need for additional measures to protect patients during this early vulnerable period.
Two pieces of evidence from this analysis suggest that the increased risk of sudden death after MI may be preventable. First, of the 164 resuscitated patients in this cohort, the majority were alive at the end of the trial. Second, the majority of patients who had sudden cardiac death in the first 30 days after MI did so after hospital discharge, when they were considered stable.
The biggest question posed by this analysis is whether the cardiovascular community should consider implementing early intervention strategies for patients who are at increased risk. The data for early ICD implantation are not currently compelling.5-7 The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which evaluated the use of early ICD therapy after MI, failed to show a benefit for early ICD implantation. The DINAMIT patients, however, were enrolled an average of almost 2 weeks later than those in the VALIANT study, and this may have selected for patients who had already survived the early vulnerable period. It is also possible that the DINAMIT study was underpowered to show a benefit in high-risk patients. Whether early intervention strategies targeting the highest risk patients will be of benefit in a vulnerable population remains to be seen.
The results of the VALIANT analysis present a number of challenges. First, future studies aimed at further stratifying risk for sudden versus nonsudden death after MI are necessary. Second, having identified patients at high risk for sudden death, it remains to be seen if early, short-term interventions (eg, automatic external defibrillators or noninvasive vest defibrillators) may prove to be a practical and cost-effective approach to preventing sudden death.
Results from VALIANT broaden our understanding of the temporal nature of sudden death, but by no means complete it. Future research aimed at stratifying risk for sudden death versus nonsudden death is necessary to best target those patients at highest risk for dying suddenly after MI. Identifying the cohort of high-risk patients who would benefit most from early, and even potentially short-term, intervention might help reduce the risk of sudden death in this vulnerable period after MI.