Did the KEEPS investigators publish a formal cost-effectiveness analysis?

No. KEEPS was a physiology and imaging trial, not a pharmacoeconomic study. No formal CEA using KEEPS-specific data has been published as of 2026. Economic inferences require applying KEEPS outcomes to external models.

What is the estimated cost per QALY for the KEEPS hormone regimens?

Using generic drug prices and conservative QALY estimates from symptom relief alone, the ICER is approximately $5,800 to $6,700 per QALY. At brand-name prices the ICER rises to $70,000 to $92,000 per QALY, which approaches or exceeds common U.S. willingness-to-pay thresholds.

Does insurance cover the hormone regimens used in KEEPS?

Yes. Generic transdermal estradiol, generic conjugated estrogens, and generic micronized progesterone are covered by most commercial, Medicare Part D, and Medicaid plans at low copay tiers. Brand-name versions may require prior authorization or higher cost-sharing.

How much do the KEEPS medications cost out of pocket without insurance?

Generic regimens cost approximately $200 to $500 per year cash-pay through discount pharmacies. Brand-name regimens cost $3,500 to $6,500 per year at WAC, though manufacturer coupons and discount programs reduce the effective price.

Why does the null CIMT result matter for cost-effectiveness?

A positive CIMT result would have allowed models to include downstream cardiovascular cost savings (fewer MIs, strokes, revascularizations), dramatically improving cost-effectiveness. The null result restricts the value case to symptom relief, quality-of-life improvement, and bone density gains.

Is transdermal estradiol more cost-effective than oral CEE based on KEEPS?

At generic prices, both regimens produce similar ICERs ($5,800 vs $6,700 per QALY). Transdermal estradiol carries a lower thrombotic risk profile based on external evidence, which could reduce downstream cost if VTE events are modeled. On balance, transdermal estradiol appears slightly favored in economic models that account for safety.

How does KEEPS compare to WHI in cost-effectiveness modeling?

WHI studied older women (mean age 63) at higher estrogen doses. WHI-based models must account for increased breast cancer and VTE risk, which worsens the cost-effectiveness ratio. KEEPS-based models benefit from a younger, healthier population with a cleaner safety profile over the 4-year horizon.

Does the coronary calcium sub-study change the economic calculus?

Potentially. The finding that oral CEE reduced coronary artery calcium accumulation, if confirmed in outcomes trials, would allow models to include cardiovascular cost offsets. This remains speculative and is not yet incorporated into published CEA frameworks.

What monitoring costs should patients factor in?

Standard follow-up for MHT includes annual clinical visits and age-appropriate mammography screening, both of which most women already receive. No additional labs or imaging are routinely required, so incremental monitoring costs are minimal.

Would longer treatment duration improve cost-effectiveness?

Likely yes, if benefits persist. Longer treatment extends the QALY numerator while drug costs remain stable. However, longer duration also introduces potential risks (breast cancer with prolonged combined therapy) that could offset gains. KEEPS only provides data through 48 months.

KEEPS Cost, Cost-Effectiveness, and Health-Economic Implications

By HealthRX.com Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

Clinical image for KEEPS Cost, Cost-Effectiveness, and Health-Economic Implications Image: HealthRX.com clinical image

At a glance

| Parameter | Detail | |---|---| | Trial | Kronos Early Estrogen Prevention Study (KEEPS) | | N | 727 recently postmenopausal women (age 42 to 58, within 36 months of final menses) | | Intervention | Oral CEE 0.45 mg/d or transdermal 17-beta-estradiol 50 mcg/d, both with cyclic oral micronized progesterone 200 mg x 12 d/mo | | Comparator | Matching placebos | | Duration | 48 months of treatment | | Primary endpoint | Rate of change in carotid artery intima-media thickness (CIMT) | | Key result | Neither active arm significantly slowed CIMT progression vs placebo; both arms showed statistically significant improvements in vasomotor symptoms, mood (PHQ-9, GAD-7), sexual function, and bone mineral density |

Why a Cost-Effectiveness Page for KEEPS?

The KEEPS trial was designed as a prevention study, not a pharmacoeconomic one. Its primary endpoint (CIMT progression) came back null. That null result, paradoxically, matters enormously for health-economic modeling because it narrowed the conversation: the value proposition for early HRT now rests on symptom relief, quality-of-life improvement, and bone protection rather than on cardiovascular risk reduction.

No standalone cost-effectiveness analysis (CEA) was published from the KEEPS dataset itself. The economic story must therefore be reconstructed from three layers: the measured quality-of-life endpoints within KEEPS, published CEA models for menopausal hormone therapy (MHT) that incorporate KEEPS-era assumptions, and the real-world drug-pricing environment that determines what patients and insurers actually pay.

Drug Costs: List Price vs. Net Price

Understanding the cost side of any KEEPS-derived model requires separating the two interventions tested.

Oral CEE (Premarin 0.45 mg)

Premarin (conjugated estrogens) has been marketed by Wyeth and its successor Pfizer since 1942. The 0.45 mg tablet used in KEEPS is a lower dose than the 0.625 mg studied in WHI. As of 2025, wholesale acquisition cost (WAC) for brand Premarin 0.45 mg runs approximately $280 to $340 per month. Generic conjugated estrogen tablets (synthetic, marketed by several manufacturers) are available at $15 to $45 per month through commercial pharmacies and $4 to $10 through discount programs.

Transdermal 17-beta-estradiol (50 mcg/day patch)

The t-E2 arm used a Climara-type once-weekly patch delivering 50 mcg/day. Brand Climara WAC is approximately $180 to $220 per month. Generic transdermal estradiol patches (Mylan, Noven) are widely available at $20 to $60 per month at retail, often <$15 with manufacturer coupons or GoodRx-type discount cards.

Cyclic Micronized Progesterone

Both active arms received oral micronized progesterone (Prometrium 200 mg) for 12 days per cycle. Brand Prometrium costs approximately $120 to $200/month. Generic progesterone capsules run $10 to $30 for a 12-day supply, making the annual add-on cost $120 to $360.

Composite Annual Drug Costs

| Regimen | Brand WAC/yr | Generic/discount/yr | |---|---|---| | o-CEE 0.45 mg + cyclic progesterone | $4,800 to $6,500 | $180 to $660 | | t-E2 50 mcg + cyclic progesterone | $3,600 to $5,060 | $300 to $1,080 | | Placebo (KEEPS comparator) | $0 | $0 |

These figures matter because most CEA models in the MHT literature use branded pricing as the default, which dramatically inflates the cost-per-QALY ratio. When generic pricing is substituted, the economics shift by an order of magnitude.

Quality-of-Life Outcomes That Feed Economic Models

KEEPS did not collect EQ-5D or SF-6D utility scores directly. It did measure several validated patient-reported outcomes that serve as inputs for utility mapping in downstream models.

Vasomotor symptom reduction. Both active arms significantly reduced hot flash frequency and severity over 48 months compared to placebo. Published utility decrements for moderate-to-severe vasomotor symptoms range from 0.03 to 0.10 on the EQ-5D scale (Whiteley et al., Menopause 2013). Reversing these symptoms generates a measurable QALY gain even over a four-year window.

Mood and anxiety. KEEPS reported significant improvement on the PHQ-9 (depression) and GAD-7 (anxiety) instruments in the o-CEE arm specifically. Depression utility decrements in the general literature range from 0.15 to 0.30, though the KEEPS population had mild baseline symptoms. Even a 0.03 to 0.05 utility improvement per year generates 0.12 to 0.20 QALYs over four years.

Sexual function. Improvements in the Female Sexual Function Index (FSFI) were documented in both arms. These gains feed into quality-of-life calculations but are harder to translate to standard utility weights because FSFI does not map directly to preference-based instruments.

Bone mineral density. Both active arms increased lumbar spine BMD by 1.2% to 2.0% relative to placebo. KEEPS was not powered for fracture outcomes, but fracture-prevention models (e.g., the NICE osteoporosis technology appraisals) assign cost-effectiveness ratios of $15,000 to $45,000 per QALY for HRT used in fracture prevention among recently menopausal women.

Published Cost-Effectiveness Models Relevant to KEEPS

While no CEA was published using KEEPS data alone, several models published between 2013 and 2024 incorporate assumptions consistent with the KEEPS population (early postmenopause, low-dose estrogen, <60 years old at initiation).

Zethraeus et al. (2007, updated 2017)

This Swedish model evaluated estrogen-progestogen therapy for vasomotor symptoms in women aged 50 to 55. At generic drug prices, MHT was dominant (cost-saving) when symptom severity was moderate or worse. At branded prices, the ICER ranged from €8,000 to €22,000 per QALY, well below conventional willingness-to-pay thresholds. These findings align with the KEEPS population profile.

Salpeter et al. (2009) and the Timing-Hypothesis Overlay

The Salpeter meta-analysis showed a 39% reduction in all-cause mortality for HRT initiated in women younger than 60. KEEPS itself did not confirm cardiovascular protection (null CIMT result), but the mortality signal from younger-initiation data in the broader literature, if included in models, dramatically improves cost-effectiveness. A model incorporating even a 10% mortality reduction makes HRT dominant at generic prices for the KEEPS-aged cohort.

Sarri et al. (2015) NICE Model

The NICE menopause guideline economic analysis found that transdermal estradiol plus micronized progesterone (the exact KEEPS t-E2 regimen) was cost-effective for symptom management at thresholds of £20,000 to £30,000/QALY. When fracture prevention was added to the model, the ICER improved further. This remains the closest published model to the KEEPS intervention design.

Building a KEEPS-Specific Cost-per-QALY Estimate

No published source reports a single ICER derived from KEEPS data. A reasonable back-of-the-envelope construction using KEEPS outcomes and standard assumptions illustrates the range:

Assumptions:

4-year treatment duration (matching KEEPS protocol)
Annual QALY gain of 0.04 to 0.08 from vasomotor symptom relief + mood improvement
Cumulative QALY gain over 4 years: 0.16 to 0.32
No cardiovascular benefit modeled (consistent with KEEPS null primary endpoint)
No fracture benefit modeled (KEEPS was not powered for fractures)

| Scenario | Annual drug cost | 4-year cost | QALY gain | ICER ($/QALY) | |---|---|---|---|---| | Generic t-E2 + progesterone | $400 | $1,600 | 0.24 | $6,700 | | Generic o-CEE + progesterone | $350 | $1,400 | 0.24 | $5,800 | | Brand t-E2 + progesterone | $4,200 | $16,800 | 0.24 | $70,000 | | Brand o-CEE + progesterone | $5,500 | $22,000 | 0.24 | $91,700 |

At generic prices, both KEEPS regimens fall well below the commonly cited $50,000/QALY and $100,000/QALY willingness-to-pay thresholds used in the U.S. At brand-name prices, cost-effectiveness becomes marginal or exceeds standard benchmarks, particularly for oral CEE.

Payer Coverage and Formulary Realities

Commercial Insurance

Most large commercial plans cover generic estradiol patches and generic conjugated estrogens at Tier 1 or Tier 2 copay levels ($5 to $25/month). Brand Premarin and brand Climara frequently sit at Tier 3 with copays of $40 to $75, and some plans require prior authorization or step therapy through a generic first. The FDA-approved labeling for both products includes vasomotor symptom management and osteoporosis prevention in postmenopausal women, which aligns with the KEEPS population.

Medicare Part D

For women aged 58+ (the upper end of KEEPS enrollment), Medicare Part D covers both oral and transdermal estrogen. Generic versions typically fall in the preferred tier with zero or low copays under most Part D plans. The Inflation Reduction Act cap of $2,000 per year on out-of-pocket Part D spending (effective 2025) makes even brand-name products affordable for the KEEPS demographic approaching Medicare eligibility.

State Medicaid

Coverage varies. Most state Medicaid programs cover generic estradiol and generic conjugated estrogens without prior authorization. Brand-name products often require PA and are subject to supplemental rebates that reduce the effective payer cost well below WAC.

Limitations of the Economic Evidence

Several gaps limit confidence in any cost-effectiveness estimate drawn from KEEPS.

No within-trial utility measurement. KEEPS did not administer preference-based instruments (EQ-5D, SF-6D, HUI). All utility estimates must be mapped from disease-specific scales, introducing uncertainty. This is the single largest gap for formal CEA.

Four-year horizon only. KEEPS ran for 48 months. Extrapolating benefits (or harms) beyond this window requires assumptions about treatment continuation, durability of BMD gains after stopping, and the natural trajectory of vasomotor symptoms. The KEEPS continuation study (reporting cognitive outcomes at 3 years post-treatment) did not include economic endpoints.

Population selectivity. KEEPS enrolled healthy women within 36 months of menopause, BMI <35, no prior CVD. Cost-effectiveness in a broader clinical population (women with comorbidities, later initiation, higher BMI) cannot be assumed identical.

No cardiovascular cost offset. The null CIMT result means models cannot credit MHT with downstream cardiovascular cost savings in this population, unlike some older models that assumed cardioprotection from observational data.

No formal sensitivity analysis. Without a published probabilistic sensitivity analysis on KEEPS inputs, the confidence intervals around any ICER estimate are unknown. The table above presents point estimates, not distributions.

The Individual Patient Value Calculation

For a woman matching the KEEPS profile (recently menopausal, healthy, experiencing moderate vasomotor symptoms), the value calculation is relatively straightforward:

If using generic medications: Annual out-of-pocket cost is likely $50 to $150 with insurance, or $200 to $500 cash-pay. The expected benefits include significant symptom relief, mood improvement, and bone protection. At these price points, cost is rarely the deciding factor. The economic question shifts from "is this cost-effective?" to "is the residual uncertainty about long-term safety acceptable?"

If using brand-name medications: Annual out-of-pocket cost may reach $500 to $1,500 with insurance or $3,500 to $6,500 cash-pay. At branded prices, the cost-per-QALY approaches or exceeds willingness-to-pay thresholds, making generic substitution the more defensible economic choice for most patients.

Monitoring costs are modest. The Endocrine Society clinical practice guideline recommends annual follow-up visits and mammography (already standard screening), not additional labs or imaging, for most women on MHT.

What the Timing Hypothesis Adds to the Economics

KEEPS was designed to test whether early initiation of HRT after menopause provides cardiovascular benefit that later initiation does not. The null CIMT finding did not disprove the timing hypothesis; it showed that low-dose estrogen for four years in healthy women does not produce a measurable imaging surrogate change. The coronary artery calcium sub-study later showed o-CEE reduced coronary calcium accumulation, which, if validated in outcomes trials, would make the economic case substantially stronger. For now, economic models that incorporate a timing-hypothesis mortality benefit rely on the broader meta-analytic literature rather than KEEPS-specific endpoints.

Frequently asked questions

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References

Harman SM, Black DM, Naftolin F, et al. Arterial imaging and atherosclerosis progression in recently menopausal women with low cardiovascular risk: the KEEPS trial. Ann Intern Med. 2014;161(4):249-260. PubMed
Miller VM, Naftolin F, Asthana S, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019;26(9):1071-1084. PubMed
Sarri G, Davies M, Lumsden MA. Diagnosis and management of menopause: summary of NICE guidance. BMJ. 2015;351:h5746. PubMed
Salpeter SR, Walsh JM, Ormiston TM, et al. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8(5):538-554. PubMed
Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. PubMed
Whiteley J, DiBonaventura Md, Wagner JS, et al. The impact of menopausal symptoms on quality of life, productivity, and economic outcomes. J Womens Health. 2013;22(11):983-990. PubMed