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

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

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

4. Amlodipine / ChlorthalidoneLisinopril / Chlorthalidone CHD0.98 (0.91, 1.08)0.99 (0.91, 1.08) Death0.96 (0.89, 1.02)1.00 (0.94, 1.08) Combined CHD 1.00 (0.94, 1.07)1.05 (0.98, 1.11) Stroke0.93 (0.82, 1.06)1.15 (1.02, 1.30) Combined CVD 1.04 (0.99, 1.09)1.10 (1.05, 1.16) HF1.38 (1.25, 1.52)1.19 (1.07, 1.31) Summary of Outcomes Relative Risks and 95% CI ALLHAT

5. Total and Cause-Specific Mortality ALLHAT ChlorAmlodp*Lisinp* Total17.3%16.8%0.2017.2%0.90 CVD8.0%8.5%0.768.5%0.39 Non-CVD8.9%8.0%0.058.6%0.57 Cancer4.3%3.8%0.314.1%0.86 Accident / suicide / homicide 0.6%0.4%0.0050.4%0.14 * Compared with chlorthalidone Are the differences between chlorthalidone & amlodipine real? Are they plausible?

6. Overall Conclusions ALLHAT 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 transformation 1 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 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) Medical costs = hospital costs + drug costs + office visits

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 Baseline ValueRange Tested Relative risk of death Chlor vs US population0.650.5 – 1.0 Amlod vs chlorthalidone0.972* Lisin vs chlorthalidone1.001* Duration of differences following the trial Decreases 10% per year 0 years to lifetime Quality of life (ALLHAT average over 6 years) Chlorthalidone0.8484* Amlodipine0.8517* Lisinopril0.8480* * Uncertainty evaluated with bootstrap sampling using trial data

13. Main Model Inputs – Drug Costs, Office Visit Costs, and Discount Rate Baseline ValueRange Tested Drug cost per day ($) – average wholesale price (Redbook 2004) Chlorthalidone (25 mg)$0.19$0.05 – 0.19 Amlodipine (10 mg)$2.47$1.50 – 2.47 Lisinopril (40 mg)$1.65$1.50 - 1.65 Cost of office visits ($%) Level 3 CPT for established patient Medicare allowed charge (CPT 99213) $50$25 – 100 Annual discount rate for costs and utilities 3%0-5% CPT = Current Procedural Terminology

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 ChlorAmlodLisin Unadjusted Survival during trial A/C: HR 0.96 (0.89 – 1.03) L/C: HR 1.01 (0.94 – 1.08) 5.20 years+6 days (-2 to +14) -2 days (-10 to +6) Estimated lifetime survival* 13.2 years+37 days (-29 to +95) -2 days (-67 to +62) Quality-adjusted † Survival during trial 4.48 years  0.62 4.51 years  0.62 4.47 years  0.63 Estimated lifetime survival 11.9 years+37 days (-10 to +95) +7 days (-47 to +58) * In 500 bootstrap samples, survival was longest for the amlodipine group in 73% of samples, for the chlorthalidone group in 14%, and for the lisinopril group in 13%. † The mean quality of life value (0-100) over the six years of the trial was not significantly different among trial arms.

16. In-Trial Costs - Hospitalization Mean Cost – Chlor Difference in Cost vs. Chlor AmlodLisin Hospitalization ($) Heart failure368+68+18 (NS) Ischemic HD1,876+58 (NS)+87 (NS) Stroke240-3 (NS)+54 Other CVD988+1 (NS)+50 (NS) Cancer1,069+26 (NS)+225) Other non-CVD4,063-320+138 (NS) Total8,604-170 (NS)+572 NS = 95% CI includes 0

17. In-Trial & Lifetime Costs – Drug, Outpatient, & Total Mean Cost – Chlor Difference in Cost vs. Chlor AmlodLisin Drug cost ($) Study drug618+2,681+1,383 Other drug1,168+17 (NS)+241 Total1,786+2,698+1,624 Outpatient visit costs ($) 1,057-9 (NS)+28 (NS) Total in-trial cost ($)11,447+2,519+2,224 Lifetime cost ($)53,536+4,802+3,700 NS = 95% CI includes 0

18. In-Trial Cost-Effectiveness for Different First-Step Antihypertensive Treatments TreatmentCost Incremental Cost Years of Life Incremental Life-Years Incremental Cost- Effectiveness – $ / Life-Year Chlor$11,4475.200 Lisin$13,671+$2,2245.195-0.005Dominated † Amlod*$13,966+$2,5195.216+0.016+$160,000 * Amlodipine compared with chlorthalidone – lisinopril eliminated by dominance (chlorthalidone more effective and less expensive). † Costs are greater and effectiveness is less than chlorthalidone.

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. TreatmentCost Incremental Cost Years of Life Incremental Life-Years Incremental Cost- Effectiveness – $ / Life-Year Chlor$53,53613.224 Lisin$57,236+$3,70013.218-0.006Dominated † Amlod*$58,338+4,80213.323+0.099+$48,400 * Amlodipine compared with chlorthalidone – lisinopril eliminated by dominance (chlorthalidone more effective and less expensive). † Costs are greater and effectiveness is less than chlorthalidone.

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 There is substantial uncertainty in the appropriate first-step therapy, with no treatment being preferred in over 90% of bootstrap samples. $20,000 threshold - chlorthalidone preferred in 74% of samples $100,000 threshold - amlodipine preferred in 63% of 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 ProblemsPossible solutions Developing the base caseUse many sources and experts Collecting QOL dataIn a large, simple trial, one may consider better methods for QOL Sources & ranges of values for various costs Long-term trial cost may change; direct medical costs only vs additional costs Imputing dataConsider several methods to check for consistency Sensitivity analysesShould look at various scenarios Projections of costs and effects beyond the data collection period Could consider using further follow-up data, e.g., passive surveillance

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

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29. Major Direct Medical Costs 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. Medical costs = hospital costs + drug costs + office visits

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.