Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management

Abstract

Background: Beta-blockers are the mainstay therapy in patients with the congenital long-QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high-risk subsets of these populations.

Methods and results: Multivariate analysis was carried out to identify age-related gender- and genotype-specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0-14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15-40 years age group. Gender-genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta-blocker therapy was associated with a significant risk-reduction in high-risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life-threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta-blocker-treated patients. However, high-risk patients who experienced syncope during beta-blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient-years).

Conclusions: The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.

Figure 1. Probability of cardiac events by genotype

Kaplan-Meier estimates of the probability of (A) a first cardiac event of any-type; and (B) aborted cardiac arrest or sudden cardiac death, by genotype from birth through age 40 years.

Figure 1. Probability of cardiac events by genotype

Kaplan-Meier estimates of the probability of (A) a first cardiac event of any-type; and (B) aborted cardiac arrest or sudden cardiac death, by genotype from birth through age 40 years.

Figure 2. Probability of cardiac events by gender

Kaplan-Meier estimates of the probability of (A) a first cardiac event of any-type; and (B) aborted cardiac arrest or sudden cardiac death, by gender from birth through age 40 years.

Figure 2. Probability of cardiac events by gender

Kaplan-Meier estimates of the probability of (A) a first cardiac event of any-type; and (B) aborted cardiac arrest or sudden cardiac death, by gender from birth through age 40 years.

Figure 3. Residual event rates during β-blocker therapy

Residual rate of (A) cardiac events (comprising syncope, appropriate ICD shocks, aborted cardiac arrest, or sudden cardiac death); and (B) life-threatening events (comprising aborted cardiac arrest or sudden cardiac death) during β-blocker therapy in high-risk subsets of LQT1 and LQT2 patients. Data regarding the rate of residual life-threatening events in each subset are shown separately for events that were preceded by syncope during β-blocker therapy and for events that occurred without prior syncope during therapy. Event rates were analyzed in LQT1 and LQT2 patients who were on β-blocker therapy at any time during follow-up. In each age-related subgroup event rates per 100 person-years were calculated by dividing the number of events during β-blocker therapy by the total follow-up time in years on β-blocker therapy, and multiplying the result by 100; event rates per 100 person-years are converted at the bottom of each figure to event rates per treated patient during the 14 years- (age-group: 0-14 years) and 25 years- (age-group: 15-40 years) follow-up time in each age-range. ACS = aborted cardiac arrest; SCD = sudden cardiac death.

Figure 3. Residual event rates during β-blocker therapy

Residual rate of (A) cardiac events (comprising syncope, appropriate ICD shocks, aborted cardiac arrest, or sudden cardiac death); and (B) life-threatening events (comprising aborted cardiac arrest or sudden cardiac death) during β-blocker therapy in high-risk subsets of LQT1 and LQT2 patients. Data regarding the rate of residual life-threatening events in each subset are shown separately for events that were preceded by syncope during β-blocker therapy and for events that occurred without prior syncope during therapy. Event rates were analyzed in LQT1 and LQT2 patients who were on β-blocker therapy at any time during follow-up. In each age-related subgroup event rates per 100 person-years were calculated by dividing the number of events during β-blocker therapy by the total follow-up time in years on β-blocker therapy, and multiplying the result by 100; event rates per 100 person-years are converted at the bottom of each figure to event rates per treated patient during the 14 years- (age-group: 0-14 years) and 25 years- (age-group: 15-40 years) follow-up time in each age-range. ACS = aborted cardiac arrest; SCD = sudden cardiac death.

Figure 4. A proposed strategy for the management of LQT1 and LQT2 patients

Patients are categorized as low-risk and high-risk based on the findings of the present study. BB = β-blockers; ICD = implantable cardioverter defibrillator; LCSD = left cardiac sympathetic denervation; Rx = treatment. *Lifestyle modifications include restriction from competitive sports and swimming in patients with both genotypes; and avoidance of unexpected auditory stimuli in the bedroom (especially during rest or sleep) and potassium supplements (to levels > 4 mEq/L) in LQT2 patients. ^†Some authorities recommend different therapeutic approaches, including routine administration of β-blocker therapy to low-risk patients and primary ICD therapy to high-risk patients with ≥ 2 risk factors.