Abstract

ALLHATCost-effectiveness in the ALLHAT Antihypertensive TrialHeidenreich P A, et al. J Gen Intern Med 23(5):50916

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ObjectivesEstimate 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 agentsUse this information for a cost-effectiveness analysis with cost per quality-adjusted life-year as the unit of analysis

ALLHAT

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Randomized Design of ALLHAT BP Trial42,418High-risk hypertensive patientsConsent / RandomizeAmlodipineChlorthalidoneDoxazosinLisinoprilFollow until death or end of study (4-8 years, mean 4.9 years)

ALLHAT

3The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large, simple, double-blind, randomized, active-controlled trial evaluating the effects of drug treatment based on amlodipine, lisinopril, and doxazosin, each compared with chlorthalidone, on coronary heart disease in patients with hypertension and an additional risk factor for cardiovascular disease. The doxazosin arm was stopped about 2 years early due to an excess of cardiovascular events and futility of finding a difference for the primary CHD outcome. The data are not included in this presentation.

Amlodipine / ChlorthalidoneLisinopril / ChlorthalidoneCHD0.98 (0.91, 1.08)0.99 (0.91, 1.08)Death0.96 (0.89, 1.02)1.00 (0.94, 1.08)CombinedCHD1.00 (0.94, 1.07)1.05 (0.98, 1.11)Stroke0.93 (0.82, 1.06)1.15 (1.02, 1.30)CombinedCVD1.04 (0.99, 1.09)1.10 (1.05, 1.16)HF1.38 (1.25, 1.52)1.19 (1.07, 1.31)

Amlodipine Chlorthalidone Better Better

0.5012

Lisinopril Chlorthalidone Better Better

0.5012

Summary of OutcomesRelative Risks and 95% CI

ALLHAT

4As you can see here for the primary endpoint of fatal CHD and nonfatal MI, these drugs did not differ from one another. Thus the older drug, diuretic, was unsurpassed by the newer classes. Similarly, in all secondary endpoints, chlorthalidone was unsurpassed, and, in fact when one looks at heart failure, chlorthalidone clearly bests the newer classes. Cost-effectiveness analysis focuses on survival or total mortality, which was not different in either comparison. In particular, amlodipine was slightly favored (relative risk 0.96) but the confidence limits overlapped 1.0.

Total and Cause-Specific Mortality

ALLHATChlorAmlodp*Lisinp*Total17.3%16.8%0.2017.2%0.90CVD8.0%8.5%0.768.5%0.39Non-CVD8.9%8.0%0.058.6%0.57Cancer4.3%3.8%0.314.1%0.86Accident / suicide /homicide0.6%0.4%0.0050.4%0.14* Compared with chlorthalidone

Are the differences between chlorthalidone & amlodipine real?Are they plausible?

5With regard to the non-significant difference between chlorthalidone and amlodipine for total mortality, note that amlodipine is favored not for CVD mortality but for non-CVD mortality, especially deaths from violence and from cancer. So there are both biological and statistical grounds for questioning any survival advantage for amlodipine.

Overall Conclusions

ALLHATBecause 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.

6This was the conclusion of the ALLHAT trial. 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.

Cost EffectivenessAlthough 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]

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Health OutcomesSurvival time (life-years) during the trial = the area under Kaplan-Meier survival curve Survival time after the trialRelative 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 patients 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 patients entire lifetime.

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Quality-Adjusted SurvivalALLHAT 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.

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Major Direct Medical CostsSocietal perspective, even though indirect costs not incorporatedHospital costsMedicare (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 feeOffice visit cost = Medicare intermediate follow-up office visit ($50)

Medical costs = hospital costs + drug costs + office visits

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Medical Costs: Analyses

Cumulative medical costs during the trial - actuarial method of Etzioni Lifetime cost of careAssumed 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 dataAdjusted 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.

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Main Model Inputs Relative Risk and Quality of LifeBaseline ValueRange TestedRelative risk of death Chlor vs US population0.650.5 1.0 Amlod vs chlorthalidone0.972* Lisin vs chlorthalidone1.001* Duration of differences following the trialDecreases 10% per year0 years tolifetimeQuality of life (ALLHAT average over 6 years) Chlorthalidone0.8484* Amlodipine0.8517* Lisinopril0.8480** Uncertainty evaluated with bootstrap sampling using trial data

Main Model Inputs Drug Costs, Office Visit Costs, and Discount RateBaseline ValueRange TestedDrug 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$1.50 - 1.65Cost of office visits ($%) Level 3 CPT for established patient Medicare allowed charge (CPT 99213)$50$25 100Annual discount rate for costs and utilities3%0-5%CPT = Current Procedural Terminology

Sensitivity AnalysisVaried 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.

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Results SurvivalChlorAmlodLisinUnadjusted 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 trial4.48 years 0.624.51 years 0.624.47 years 0.63 Estimated lifetime survival11.9 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.

In-Trial Costs - HospitalizationMean Cost ChlorDifference in Cost vs. ChlorAmlodLisinHospitalization ($) 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)+572NS = 95% CI includes 0

Although hospitalizations accounted for 80% of follow-up costs, differences between trial arms were small compared to the differences in costs of antihypertensive treatment (on next slide). Total hospitalization costs weresimilar for amlodipine and chlorthalidone with amlodipine having higher heart failure costs, but less noncardiovascular hospitalization costs. Total hospital costs were higher for lisinopril than for chlorthalidone-treated patients with significantly higher costs for stroke- and cancer-related hospitalizations.16

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

The cost of drug therapy was lowest for chlorthalidone. Differences in the cost of study drug treatment accounted for 80% of the differences in total costs. Additional antihypertensive treatment was greatest for patients treated with lisinopril.

Outpatient visits and their associated costs were nearly identical among arms.

The lifetime discounted cost of care was approximately $53,500 for the patients initially treated with chlorthalidone.Costs were $4,800 higher for patients initially treated with amlodipine and $3,700 higher for patients treated with lisinopril.

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In-Trial Cost-Effectiveness for Different First-Step Antihypertensive TreatmentsTreatmentCostIncremental CostYears of LifeIncremental Life-YearsIncremental Cost-Effectiveness $ / Life-YearChlor$11,4475.200Lisin$13,671+$2,2245.195-0.005DominatedAmlod*$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.

Using the point estimates for differences in cost and survival, lisinopril was less effective and more expensive compared with chlorthalidone during the trial. Amlodipine increased longevity at a cost of $160,000 per LY gained during the trial. 18

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 lisinoprilBootstrap resampling - chlorthalidone treated patients had the lowest in trial and lifetime costs in all (500/500) samples. TreatmentCostIncremental CostYears of LifeIncremental Life-YearsIncremental Cost-Effectiveness $ / Life-YearChlor$53,53613.224Lisin$57,236+$3,70013.218-0.006DominatedAmlod*$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.

19Looking at lifetime cost-effectiveness, lisinopril was again less effective and more expensive compared withchlorthalidone. Amlodipine increased longevity at a cost of $48,400 during the patients lifetime.

Sensitivity to Daily Cost of Drug TherapyAmlodipine 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 patients lifetime.

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Sensitivity to societys 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

With bootstrap resampling, the preferred initial treatment was amlodipine in 50% of lifetime samples, chlorthalidone in 40%, and lisinopril in 10%, assuming that a universal payer is willing to pay $50,000 per LY gained (the middle column). The choice of initial treatment was sensitive to a universal payers threshold for cost-effectiveness: at the $20,000 threshold, chlorthalidone was preferred in 74% of the samples; at $100,000, amlodipine was preferred in 63% of the samples.21

Impact of Incident DiabetesNew-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 yearIncreased risk of death (relative risk 2.0) after the conclusion of the trialAdjusted cost-effectiveness (amlodipine vs chlorthalidone):$40,200 per year of life gained$35,600 per quality-adjusted life year gained

Impact of RaceNon-Black participants--Lisinopril dominated amlodipine in base caseLife-years slightly greater for lisinopril compared with chlorthalidone (0.09 years) - $34,600 per life-year gainedPreferences in bootstrap resampling:Lisinopril 44% Chlorthalidone 30% Amlodipine 25%Black participantsAmlodipine dominated lisinoprilLife-years slightly greater for amlodipine compared with chlorthalidone (0.14) - $38,000 per life-year gainedPreferences in bootstrap resampling:Amlodipine 59% Chlorthalidone 45% Lisinopril 1%

ConclusionsSubstantial 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 pharmaceuticalsEven a large trial such as ALLHAT may be underpowered to determine the most cost-effective treatment.

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Lessons Learned About PowerA 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.

Lessons LearnedProblemsPossible solutionsDeveloping the base caseUse many sources and expertsCollecting QOL dataIn a large, simple trial, one may consider better methods for QOLSources & ranges of values for various costsLong-term trial cost may change; direct medical costs only vs additional costsImputing dataConsider several methods to check for consistencySensitivity analysesShould look at various scenariosProjections of costs and effects beyond the data collection periodCould consider using further follow-up data, e.g., passive surveillance

The ParadoxHow can the results imply that amlodipine is more cost-effective than chlorthalidone ?The drug is more expensive than chlorthalidoneThe aggregate of pre-specified disease-specific outcomes point to amlodipine being less effectiveTotal mortality and QOL differences are small and insignificantFavorable differences in some non-CVD causes of death are not biologically plausible

Extra slides

Major Direct Medical CostsSocietal perspective, even though indirect costs not incorporatedHospital costsMedicare (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

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Major Direct Medical CostsALLHAT recorded use of medication and number of office visits. Drug costsMedian 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 careAssumed 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 dataAdjusted 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.

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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.

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.

Sensitivity AnalysesSensitivity 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 patients lifetime.Sensitivity to societys 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 trialCost-effectiveness of amlodipine compared with chlorthalidone = $40,200 per year of life gained and $35,600 per quality-adjusted year of life gained.

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