Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects

Abstract

Background: Childhood cancer survivors treated with cardiotoxic therapies are recommended to have routine cardiac assessment every 1 to 5 years, but the long-term benefits are uncertain.

Objective: To estimate the cost-effectiveness of routine cardiac assessment to detect asymptomatic left ventricular dysfunction and of angiotensin-converting enzyme inhibitor and β-blocker treatment to reduce congestive heart failure (CHF) incidence in childhood cancer survivors.

Design: Simulation model.

Data sources: Literature, including data from the Childhood Cancer Survivor Study.

Target population: Childhood cancer survivors.

Time horizon: Lifetime.

Perspective: Societal.

Intervention: Interval-based echocardiography assessment every 1, 2, 5, or 10 years, with subsequent angiotensin-converting enzyme inhibitor or β-blocker treatment for patients with positive test results.

Outcome measures: Lifetime risk for systolic CHF, lifetime costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs).

Results of base-case analysis: The lifetime risk for systolic CHF among 5-year childhood cancer survivors aged 15 years was 18.8% without routine cardiac assessment (average age at onset, 58.8 years). Routine echocardiography reduced lifetime risk for CHF by 2.3% (with assessment every 10 years) to 8.7% (annual assessment). The ICER for assessment every 10 years was $111 600 per quality-adjusted life-year (QALY) compared with no assessment. Assessment every 5 years had an ICER of $117 900 per QALY, and ICERs for more frequent assessment exceeded $165 000 per QALY.

Results of sensitivity analysis: Results were sensitive to treatment effectiveness, absolute excess risk for CHF, and asymptomatic left ventricular dysfunction asymptomatic period. The probability that assessment every 10 or 5 years was preferred at a $100 000-per-QALY threshold was 0.33 for the overall cohort.

Limitation: Treatment effectiveness was based on adult data.

Conclusion: Current recommendations for cardiac assessment may reduce CHF incidence, but less frequent assessment may be preferable.

Figure 1. CHF model diagram

Health states for the CHF model are depicted in this figure. Individuals enter the model with no ALVD and face monthly rates of developing ALVD based on age-specific CHF rates. Individuals with ALVD face a risk of developing symptomatic CHF. Once CHF develops, individuals face disease-specific mortality risks. All individuals face mortality risks from background mortality rates, late-recurrence and non-cardiac late-effects (including second cancers, pulmonary, external and other causes). Individuals are followed throughout their lifetime. ALVD = asymptomatic left ventricular dysfunction; CHF = congestive heart failure.

Figure 2. Cumulative CHF incidence

Panel A depicts cumulative CHF incidence by years since diagnosis for the cohort of childhood cancer survivors (overall and anthracycline subgroups) and general population. Compared to the general population, the lifetime relative risk of CHF was 1.3 (range 1.1 to 1.7) for no anthracycline, 2.1 (range 1.2 to 3.1) for <250 mg/m² anthracycline, and 3.4 (range 2.2 to 4.4) for ≥250 mg/m² anthracycline. Dark blue line indicates the overall cohort. Black line indicates the general population. Light blue lines depict anthracycline subgroups (none, <250 mg/m², ≥250 mg/m²). Panel B shows the reduction in lifetime CHF risk for the assessment strategies (vs. no assessment) for the overall cohort. The solid line represents the reduction using base case estimates, while the bars depict the 95% credible interval from probabilistic sensitivity analysis based on 1000 second-order Monte Carlo simulations. CHF = congestive heart failure.

Figure 3. Tornado diagram on sensitivity analysis for select model parameters

Based on one-way sensitivity analyses, this figure depicts the relative influence of select model parameters on results for the overall cohort. The x-axis shows the effect of changes in selected variables on the ICER the assessment every 10 years (compared to no assessment). The y-axis shows the selected model parameters, with upper and lower bounds used in the sensitivity analysis in parentheses. The shaded bars indicate the variation in the ICER caused by changes in the value of the indicated variable while all other variables were held constant. Solid black line indicates the ICER for the base case. Dotted red line represents the commonly used $100,000 per QALY cost-effectiveness threshold. QALY = quality-adjusted life year.

Figure 4. Threshold analysis on ACEI and BB treatment effectiveness for overall cohort and anthracycline subgroups at a $100,000 per QALY cost-effectiveness threshold

This figure depicts how effective treatment would have to be for a specific assessment strategy to be optimal from a cost-effectiveness framework for two scenarios: when only 2D echocardiography is available (Panel A) and when 2D echocardiography and cMRI are available (Panel B). On the x-axis, the relative risk of developing CHF associated with treatment is depicted, with 0 indicating complete reduction of risk, and 1 indicating no treatment effect. The colored regions indicate the range of values over which the specific strategy would be considered the optimal strategy given a willingness to pay of $100,000 per QALY gained. Black solid and dotted lines indicated the base case estimate (RR = 0.63) and 95% CI (RR = 0.49 to 0.83) from the post hoc analysis of the SOLVD Prevention trial (27). As an example, if only 2D echocardiography is available, for the ≥250 mg/m² anthracycline high-risk subgroup, annual assessment was the preferred strategy only if treatment reduced the risk of developing CHF by 45% (RR = 0.55); no screening or less frequent screening was preferred at all other values. In contrast, if cMRI was available, even if treatment completed reduced CHF risk, annual assessment was still not the preferred strategy. Note: the 95%CI from the SOLVD Prevention Trial is shown to depict the uncertainty in treatment effectiveness among adults. The uncertainty range among childhood cancer survivors is likely wider, including lower and negligible benefit (–40, 43). CHF = congestive heart failure; ACEI = angiotensin converting enzyme; BB = beta-adrenergic blocking agents; SOLVD = Studies of Left Ventricular Dysfunction; 2D echo = two-dimensional echocardiography; cMRI = cardiac magnetic resonance imaging.

Appendix Figure 1. Threshold analysis on ACEI and BB treatment effectiveness for overall cohort and anthracycline subgroups at a $50,000 per QALY cost-effectiveness threshold

This figure depicts how effective treatment would have to be for a specific assessment strategy to be optimal from a cost-effectiveness framework for two scenarios: when only 2D echocardiography is available (Panel A) and when 2D echocardiography and cMRI are available (Panel B). On the x-axis, the relative risk of developing CHF associated with treatment is depicted, with 0 indicating complete reduction of risk, and 1 indicating no treatment effect. The colored regions indicate the range of values over which the specific strategy would be considered the optimal strategy given a willingness to pay of $50,000 per QALY gained. Black solid and dotted lines indicated the base case estimate (RR = 0.63) and 95% CI (RR = 0.49 to 0.83) from the post hoc analysis of the SOLVD Prevention trial (27). Note: the 95%CI from the SOLVD Prevention Trial is shown to depict the uncertainty in treatment effectiveness among adults. The uncertainty range among childhood cancer survivors is likely wider, including lower and negligible benefit (–40, 43). CHF = congestive heart failure; ACEI = angiotensin converting enzyme; BB = beta-adrenergic blocking agents; SOLVD = Studies of Left Ventricular Dysfunction; 2D echo = two-dimensional echocardiography; cMRI = cardiac magnetic resonance imaging.

Appendix Figure 2. Cost-effectiveness acceptability curves for the overall cohort and anthracycline subgroups

Depicted in this figure are cost-effectiveness acceptability curves, which illustrate the uncertainty surrounding the estimate of ICERs, for the overall cohort (Panel A), <250 mg/m² anthracycline (Panel B), and ≥250 mg/m² anthracycline (Panel C). In each figure, the probability that a given strategy is the preferred strategy is depicted across a range of willingness-to-pay thresholds. For example, at a threshold of $100,000 per QALY, the probability that assessment every 5 years is the preferred strategy is 0.26 for the overall cohort. In contrast, for the ≥250 mg/m² anthracycline subgroup, the probability that assessment every 2 years was preferred was 0.57. Results are based on 1000 second-order Monte Carlo simulations in which model variables were simultaneously varied. The red line indicates the $100,000 per QALY threshold commonly used as a benchmark in the US. QALY = quality-adjusted life year.