ALLHAT

1. ALLHAT Cost-effectiveness in the ALLHAT Antihypertensive Trial Heidenreich P A, et al. J Gen Intern Med 23(5):509–16

2. ALLHAT Objectives • Estimate the relative effectiveness of the antihypertensive agents on survival, quality of life (QOL), and quality-adjusted life-years (QALY) • Estimate the resource usage associated with these agents • Use this information for a cost-effectiveness analysis with cost per quality-adjusted life-year as the unit of analysis

3. ALLHAT Randomized Design of ALLHAT BP Trial 42,418 High-risk hypertensive patients Consent / Randomize Amlodipine Chlorthalidone Doxazosin Lisinopril Follow until death or end of study (4-8 years, mean 4.9 years)

4. ALLHAT 0.50 1 2 0.50 1 2 Lisinopril Chlorthalidone Better Better Amlodipine Chlorthalidone Better Better Summary of Outcomes Relative Risks and 95% CI

5. ALLHAT Total and Cause-Specific Mortality Are the differences between chlorthalidone & amlodipine real? Are they plausible?

6. ALLHAT Overall Conclusions Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.

7. Cost Effectiveness • Although overall outcomes are best and drug acquisition costs are least for chlorthalidone, is it the most “cost-effective”? Traditionally, CE outcomes are restricted to survival and quality of life, and costs include ALL major treatment costs. • Specifically: Cost-effectiveness = difference in total treatment costs divided by the difference in life-years (LYs) CE = [Cost Drug A – Cost Drug B] / [LY Drug A – LY Drug B] OR Difference in cost divided by the difference in quality-adjusted life-years (QALYs). CE = [Cost Drug A – Cost Drug B] / [QALY Drug A – QALY Drug B]

8. Health Outcomes • Survival time (life-years) during the trial = the area under Kaplan-Meier survival curve • Survival time after the trial • Relative risk of death for chlorthalidone treated patients compared with the U.S. population (matched to gender and mean age) during the course of the trial. • Assumed relative risk (0.65) remained constant over patient’s lifetime. • Proportional hazards model to determine the risk ratio for death during the trial for lisinopril vs. chlorthalidone and for amlodipine vs. chlorthalidone. • Assumed that the differences in mortality would approach 0 at a relative rate of 10% per year. • Sensitivity analyses - varied persistence of drug effects after trial from 0 years to patient’s entire lifetime.

9. Quality-Adjusted Survival • ALLHAT collected annual estimate of quality of life (0-100 scale). • Using a Torrance transformation1 these estimates are transformed into QOL utilities whose distribution better matches standard utility values (e.g., time-tradeoff or standard gamble). • Unlike an analog scale, these standard utilities are elicited by having patients tradeoff quality of life for length of life. • Mean utility over time in ALLHAT is determined for each patient. An overall mean is determined for each trial arm. • Quality-adjusted survival = mean utility x survival during the trial. • Following the trial period, we assumed that quality of life remained constant for each patient until death. 1 Torrance G. Socio-Economic Planning Sci. 1976;10:129-36.

10. Major Direct Medical Costs Medical costs = hospital costs + drug costs + office visits • Societal perspective, even though indirect costs not incorporated • Hospital costs • Medicare (MEDPAR) and VA (Patient Treatment File) for trial participants. • Cost of hospitalization = DRG-specific Medicare case weight x conversion factor for 2004. • Professional fees - increase hospital costs by 25%. • Patients not in Medicare and not in the VA system (17%) - multi-step estimation procedure. • ALLHAT recorded use of medication and number of office visits. • Drug costs =Median wholesale price (2004, common dosage) + $7 per 100 dispensing fee • Office visit cost = Medicare intermediate follow-up office visit ($50)

11. Medical Costs: Analyses • Cumulative medical costs during the trial - actuarial method of Etzioni • Lifetime cost of care • Assumed that inpatient costs, outpatient costs, and drug costs remained constant following year six of the trial. • Additional cost of care per patient per year to account for the cost of non-hypertension related care - increased with age - based on U.S. national health care expenditure data • Adjusted all costs to 2004 dollars using the medical component of the Consumer Price Index (Bureau of Labor Statistics). All cost and survival outcomes were discounted at 3% per year.

12. Main Model Inputs –Relative Risk and Quality of Life

13. Main Model Inputs – Drug Costs, Office Visit Costs, and Discount Rate

14. Sensitivity Analysis • Varied all parameters through the specific ranges. • Parameter is sensitive if cost-effectiveness ratio doubled above baseline. • Separate analysis - assumed that patients with new-onset diabetes had increased risk of death (RR 2.0) and increased annual costs ($2000 per year) following conclusion of the trial. • Although there is no universally accepted threshold for cost-effectiveness, $50,000 per QALY gained is commonly used.

15. Results – Survival

16. In-Trial Costs - Hospitalization

17. In-Trial & Lifetime Costs –Drug, Outpatient, & Total

18. In-Trial Cost-Effectiveness for Different First-Step Antihypertensive Treatments

19. Results – Lifetime Cost-Effectiveness • $53,500 for the chlorthalidone treated patients • $4,800 higher for patients treated with amlodipine and • $3,700 higher for patients treated with lisinopril • Bootstrap resampling - chlorthalidone treated patients had the lowest in trial and lifetime costs in all (500/500) samples.

20. Sensitivity to Daily Cost of Drug Therapy • Amlodipine compared with chlorthalidone - $37,000 per life year gained. • If amlodipine costs were reduced by 50% with chlorthalidone drug costs unchanged, then the incremental cost-effectiveness of initial treatment with amlodipine compared with chlorthalidone dropped to $58,100 during the first six years and to $22,500 over the patient’s lifetime.

21. Sensitivity to society’s threshold for cost-effectiveness on the optimal first-step treatment for hypertension – 100 bootstrap samples • $20,000 threshold - chlorthalidone preferred in 74% of samples • $100,000 threshold - amlodipine preferred in 63% of samples There is substantial uncertainty in the appropriate first-step therapy, with no treatment being preferred in over 90% of bootstrap samples.

22. Impact of Incident Diabetes • New-onset diabetes at 4 years is more frequent in chlorthalidone group (11%) than in the amlodipine group (9.3%) • Assume patients who developed diabetes incurred additional cost of $2000 per year • Increased risk of death (relative risk 2.0) after the conclusion of the trial • Adjusted cost-effectiveness (amlodipine vs chlorthalidone): • $40,200 per year of life gained • $35,600 per quality-adjusted life year gained

23. Impact of Race • Non-Black participants -- Lisinopril dominated amlodipine in base case • Life-years slightly greater for lisinopril compared with chlorthalidone (0.09 years) - $34,600 per life-year gained • Preferences in bootstrap resampling: Lisinopril 44% Chlorthalidone 30% Amlodipine 25% • Black participants • Amlodipine dominated lisinopril • Life-years slightly greater for amlodipine compared with chlorthalidone (0.14) - $38,000 per life-year gained • Preferences in bootstrap resampling: Amlodipine 59% Chlorthalidone 45% Lisinopril 1%

24. Conclusions • Substantial savings can be achieved by using chlorthalidone instead of amlodipine or lisinopril as the first drug for the treatment of hypertension. • Non-significant mortality benefit with amlodipine, if real, could make it economically attractive compared with chlorthalidone. • Small survival differences may have an important influence on the cost-effectiveness of pharmaceuticals • Even a large trial such as ALLHAT may be underpowered to determine the most cost-effective treatment.

25. Lessons Learned – About Power • A randomized trial with power to exclude “clinically important differences” in survival will often have inadequate power to determine the most cost-effective treatment. • 99,000+ patients required for 80% power to demonstrate that amlodipine was not a cost-effective alternative to chlorthalidone at the $50,000 per life-year gained threshold.

26. Lessons Learned

27. The Paradox How can the results imply that amlodipine is more cost-effective than chlorthalidone ? • The drug is more expensive than chlorthalidone • The aggregate of pre-specified disease-specific outcomes point to amlodipine being less effective • Total mortality and QOL differences are small and insignificant • Favorable differences in some non-CVD causes of death are not biologically plausible

28. Extra slides

29. Major Direct Medical Costs Medical costs = hospital costs + drug costs + office visits • Societal perspective, even though indirect costs not incorporated • Hospital costs • Medicare (MEDPAR) and VA (Patient Treatment File) hospitalization data obtained for trial participants. • Cost of hospitalization = DRG-specific Medicare case weight x conversion factor for 2004. • Account for professional fees by increasing hospital costs by 25%. • Patients not in Medicare and not in the VA system (17%) - multi-step estimation procedure. • Probability of having inpatient costs was determined for the Medicare and VA patients adjusting for age, gender, race, diabetes, and use of the VA system. • Logistic model  probability of inpatient costs for those not in the VA or Medicare. • For Medicare and VA patients with hospitalizations - estimated log-linear regression model of annual hospital costs that included age, race, gender, diabetes, and use of the VA health system. • Log costs were transformed back to costs using a smearing algorithm. • Estimated costs from this model x probability of having hospital costs = estimated hospital costs for those not in Medicare or the VA system.

30. Major Direct Medical Costs • ALLHAT recorded use of medication and number of office visits. • Drug costs • Median wholesale price - 2004 Drug Topics Red Book - most common dosage • Dispensing fee of $7.00 for each 100 doses. • The cost of an office visit • Medicare reimbursement - intermediate intensity follow-up office visit ($50) • Cumulative medical costs during the trial - actuarial method of Etzioni • Product of the yearly cost of care for survivors and the Kaplan-Meier estimate of survival to adjust for censoring. • Lifetime cost of care • Assumed that inpatient costs, outpatient costs, and drug costs remained constant following year six of the trial. • Additional cost of care per patient per year to account for the cost of non-hypertension related care - increased with age - based on U.S. national health care expenditure data • Adjusted all costs to 2004 dollars using the medical component of the Consumer Price Index (Bureau of Labor Statistics). All cost and survival outcomes were discounted at 3% per year.

31. Incremental costs and outcomes of amlodipine vs. chlorthalidone arms for 500 bootstrap samples. Amlodipine was more expensive in all (100%) samples, amlodipine had a better outcome in 84%, and the cost per life-year (LY) gained was less than $50,000 in 49%. Points to the right of the diagonal line indicate samples where amlodipine was cost-effective at a threshold of $50,000 per LY gained.

32. Incremental costs and outcomes of lisinopril vs. chlorthalidone arms for 500 bootstrap samples. Lisinopril was more expensive in all (100%) samples, lisinopril had a better outcome in 45%, and the cost per life year (LY) gained was less than $50,000 in 18%. Points to the right of the diagonal line indicate samples where lisinopril was cost-effective at a threshold of $50,000 per LY gained.

33. Sensitivity Analyses • Sensitivity to the daily cost of drug therapy. • Amlodipine compared with chlorthalidone - $37,000 per life year gained. • If amlodipine costs were reduced by 50% with chlorthalidone drug costs unchanged, then the incremental cost-effectiveness of initial treatment with amlodipine compared with chlorthalidone dropped to $58,100 during the first six years and to $22,500 over the patient’s lifetime. • Sensitivity to society’s threshold for cost-effectiveness. • $20,000 threshold - chlorthalidone preferred in 74% of samples • $100,000 threshold - amlodipine preferred in 63% of samples • Additional cost associated with diabetes • Additional costs $2000 per year • Increased risk of death (relative risk 2.0) after the conclusion of the trial • Cost-effectiveness of amlodipine compared with chlorthalidone = $40,200 per year of life gained and $35,600 per quality-adjusted year of life gained.