Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population

Abstract

Aims: Using a large, contemporary primary care population we aimed to provide absolute long-term risks of cardiovascular death (CVD) based on the QTc interval and to test whether the QTc interval is of value in risk prediction of CVD on an individual level.

Methods and results: Digital electrocardiograms from 173 529 primary care patients aged 50-90 years were collected during 2001-11. The Framingham formula was used for heart rate-correction of the QT interval. Data on medication, comorbidity, and outcomes were retrieved from administrative registries. During a median follow-up period of 6.1 years, 6647 persons died from cardiovascular causes. Long-term risks of CVD were estimated for subgroups defined by age, gender, cardiovascular disease, and QTc interval categories. In general, we observed an increased risk of CVD for both very short and long QTc intervals. Prolongation of the QTc interval resulted in the worst prognosis for men whereas in women, a very short QTc interval was equivalent in risk to a borderline prolonged QTc interval. The effect of the QTc interval on the absolute risk of CVD was most pronounced in the elderly and in those with cardiovascular disease whereas the effect was negligible for middle-aged women without cardiovascular disease. The most important improvement in prediction accuracy was noted for women aged 70-90 years. In this subgroup, a total of 9.5% were reclassified (7.2% more accurately vs. 2.3% more inaccurately) within clinically relevant 5-year risk groups when the QTc interval was added to a conventional risk model for CVD.

Conclusion: Important differences were observed across subgroups when the absolute long-term risk of CVD was estimated based on QTc interval duration. The accuracy of the personalized CVD prognosis can be improved when the QTc interval is introduced to a conventional risk model for CVD.

Keywords: Cardiovascular death; Gender; Marquette 12SL validation; QTc interval; Risk prediction.

Figure 1

Multivariable-adjusted HRs for all-cause, cardiovascular, and non-CVD by categories of the QTc_Fram interval. All models were adjusted for heart failure, myocardial infarction, valvular heart disease, Charlson comorbidity index (0 points, 1 point, or ≥2 points), treatment with ACE-inhibitors or ARBs, beta-blockers, or calcium antagonists prior to inclusion, treatment with QTc-prolonging medications or digoxin on the day of ECG recording, left ventricular hypertrophy on the index ECG, and age was used as the timescale. The vertically dotted lines represent a HR of 1. The horizontal solid lines represent 95% CIs.

Figure 2

Predicted 5-year risk of CVD based on subgroups. Both models for CVD and the competing models of non-CVD were independently performed for women and men in age groups 50–70 and 70–90 years, and contained the following covariates: age as a linear parameter, myocardial infarction, heart failure, valvular heart disease, a modified Charlson comorbidity index (0 points, 1 point, or ≥2 points), treatment with ACE-inhibitors or ARBs, beta-blockers or calcium antagonists prior to inclusion, treatment with QTc-prolonging medications or digoxin on the day of ECG recording, and left ventricular hypertrophy on the index ECG. Boxes denote the median risks (horizontal line) and interquartile ranges (lower and upper border) whereas whiskers denote the 5th and 95th percentiles. Numbers above the whiskers denote the median risk for the respective subgroup. Heart rate-correction was based on the Framingham formula (QTc_Fram).

Figure 3

Cumulative incidence based on QTc_Fram interval subgroups. Predictions were based on Cox models fitted within the respective age- and gender-determined subgroups and were adjusted for covariates as described in Figure 2. Optimal QTc_Fram intervals were the QTc_Fram intervals that were associated with the lowest relative risk of CVD (Figure 1).

Figure 4

(A) Reclassification within various 5-year risk categories based on predictions with and without QTc_Fram interval. The predictive models are described in Figure 2. Very low risk was defined as ≤5% risk of dying within 5 years, low risk was >5 to ≤15%, intermediate risk was >15 to ≤25%, high risk was >25% to ≤35%, and very high risk was defined as >35% risk of dying within 5 years (indicated by grey lines). Red and orange dots (CVD and non-CVD, respectively) above and green dots (survivors) below the squares with the black borders denote appropriate reclassifications whereas red and orange dots below and green dots above denote inappropriate reclassifications. Dots within the black-bordered squares denote individuals who were not reclassified. (B) Summary of reclassifications by subgroups. Numbers above or below columns denote the absolute number of appropriate and inappropriate reclassifications, respectively.