QTc Prolongation and Risk of Sudden Cardiac Death: Is the Debate Over?

February 03, 2006

February 3, 2006 -- A recent analysis of the prospective, population-based Rotterdam Study found that prolongation of the heart-rate corrected QT (QTc) interval increased the risk of sudden cardiac death (SCD) in adult patients by 60%, independent of other known risk factors. [1] These findings, the authors conclude, suggest that QTc prolongation should be considered an independent predictor of SCD in adult patients. Arthur J. Moss, MD (University of Rochester Medical Center, Rochester, New York), who wrote an accompanying editorial, agrees, but he questions whether the results will influence risk management strategies in a clinical setting.

Terms such as "controversy" and "debate" are frequently used when describing QTc prolongation as a risk factor for death. The QT interval is the measure of time between the onset of ventricular depolarization and completion of ventricular repolarization. A prolonged QT interval is thus considered an attractive noninvasive risk factor for SCD since a delay in ventricular repolarization can provoke arrhythmias, such as ventricular fibrillation and torsade de pointes. Unfortunately, available data have yielded conflicting results, thus fueling the ongoing debate on the clinical significance of abnormal QTc prolongation. According to the study authors, the majority of QTc studies have evaluated total or cardiovascular death, but few have specifically addressed SCD.

European Guidelines Used To Classify QTc Prolongation in 3 Gender-Specific Categories

Sabine M.J.M. Straus, MD, PhD (Erasmus Medical Center, Rotterdam, The Netherlands), and colleagues studied the relationship between QTc duration and the probability of SCD in a population of 6134 adults (aged 55 and older; median, 69.2 years) who were followed between 1990 and 1999. The authors used the most recent European regulatory guidelines to stratify baseline QTc prolongation into 3 gender-specific groups: "normal," "borderline," and "abnormal" (Table 1).

Table 1. Cut-off Points of QTc Prolongation Classification by Gender
QTc prolongation (ms) Men Women Total No. of Patients
Normal ≤ 430 ≤ 450 4344
Borderline 431-450 451-470 1109
Abnormal > 450 > 470 681

A dose-response relationship between degree of QTc prolongation and degree of cardiovascular comorbidities at baseline was clearly evident; as the degree of QTc prolongation worsened, so too did the incidence of cardiovascular comorbidities.

Over a median follow-up period of 6.7 years, 1407 (22.8%) participants died. Using "the most recent definition of SCD," (see footnote) 125 of these deaths were identified as SCD (incidence approximately 3 per 1000 person-years). The authors noted that participants who died from SCD had a significantly longer mean QTc interval compared with participants who died from other causes (441.9 ms vs 431.3 ms, respectively; P < .000).

Risk of SCD Increased 8-fold in Patients Aged 55-68 Years

After adjusting for other risk factors, the risk of SCD was more than 2-fold higher in participants with abnormal QTc compared with those in the normal group. The risk was greater in men than in women and was most pronounced among participants younger than 68 years. Most notably, patients 55-68 years in the abnormal QTc group faced an 8-fold increase in the risk of SCD (Table 2).

Table 2.Risk of SCD: Borderline and Abnormal QTc Intervals*
  Borderline † Abnormal †
HR 95% CI HR 95% CI
All 1.6 0.9-3.1 2.5 1.3-4.7
Age
  58-68 yrs 3.7 1.1-14.0 8.0 2.1-31.3
  > 68 yrs 1.3 0.6-2.7 2.1 1.0-4.4
Gender
  Male 1.8 0.8-2.6 2.6 1.1-5.8
  Female 1.3 0.5-3.7 2.5 1.0-7.1
*Adjusted for age, gender, smoking, cholesterol/HDL ratio, body mass index, hypertension, diabetes, myocardial infarction, heart failure, and heart rate. Normal QTc used as reference value.
Borderline QTc: male 431-450 ms; female 451-470 ms; abnormal QTc: male ≥ 451 ms; female ≥ 471 ms
CI = confidence interval; HR = hazard ratio

Straus and colleagues report that "the increase in risk of sudden cardiac death corresponded with an attributable risk proportion of 0.6, meaning that in our study 60% of all cases of sudden cardiac death were associated with an abnormally prolonged QTc interval."

The increased risk of SCD noted in younger patients "may be partly explained by depletion of susceptible patients at an older age," the authors write. They note that although the number of SCDs attributable to abnormal QTc prolongation is larger in the younger patients in their study, "the absolute risk of sudden cardiac death, however, increases with age." The present study was limited to patients aged ≥ 55 years, and the authors caution that further study is needed before their findings can be applied to other age groups.

Is the Debate Over?

Acknowledging the conflicting findings from other published studies, Straus and colleagues contend that their study is strengthened by its size, long-term follow-up period, and the use of European guidelines to categorize QTc prolongation into 3 gender-specific categories. In addition, they note that 70% of their study population underwent 2 ECGs, whereas "in all studies QTc prolongation was based on one baseline ECG and related to outcomes that usually occurred many years later" -- such as the Framingham study. Conducted over a 30-year period, the Framingham study suggested that QTc prolongation was not a predictor of total mortality or sudden death.

In his editorial, Dr. Moss focused on the "details" and suggested that "important design difference[s]" between the Rotterdam and Framingham studies "may explain a good portion of the discrepant results." Dr. Moss pointed to the fact that Framingham participants were younger at time of enrollment (ages 30-65 years) and, thus, the majority of baseline ECGs were recorded in patients "probably before the development of subclinical cardiac disease." By contrast, "the Rotterdam study recorded the first of two baseline ECGs when the subjects were enrolled in the study at age 55 years, anage when subclinical cardiac disease is likely to be present in many of the subjects." He contends that "it is possible that the length of the QTc interval is just a marker for the severity of underlying subclinical cardiac disease... and that the risk is related to the latent underlying cardiac problem." But the "simplest explanation" as to the mechanisms associated with the observed risk association, he stated, is that "QTc prolongation, whatever the cause, is proarrhythmic, and this alone contributes to an increased probability of arrhythmic SCD."

According to Dr. Moss, Straus and colleagues "have clarified a somewhat controversial area." He believes that the "dose-response effect" observed by using the 3 gender-specific categories to classify degree of QTc prolongation in the Rotterdam study "adds considerable strength and significance to the association of QTc prolongation and the risk of SCD in older adults." A remaining question, he stated, "is whether this well-crafted risk-stratification study can be translated into effective management strategies to reduce SCD and improve survival in subjects with prolonged ventricular repolarization."

References
  1. Straus SM, Kors JA, De Bruin ML, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362-367.

  2. Moss AJ. QTc prolongation and sudden cardiac death. The association is in the detail. J Am Coll Cardiol. 2006;47:368-369.

SCD was defined as "natural death attributable to cardiac causes, heralded by abrupt loss of consciousness, within one hour after onset of acute symptoms, or an unwitnessed, unexpected death of someone seen in a stable medical condition < 24 h previously with no evidence of a non-cardiac cause. If death was witnessed and occurred within one hour after the start of symptoms, we assumed it to be a sudden cardiac death, without additional review of medical records."

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