# Presentation: 045156

## Postmenopausal Hormone Replacement Therapy for Prevention of Chronic ConditionsReview of Evidence for the USPSTF

- Heidi D. Nelson MD, MPH
- Oregon Evidence-based Practice Center
- Oregon Health & Science University

***Oregon***
***EPC***

## Evidence Considered by the USPSTF

**Systematic review of published literature (1966-2001) conducted by EPC (*****JAMA***** 2002;                       288:872-881).**
**Women’s Health Initiative RCT results on combined CEE/MPA arm (*****JAMA***** 2002;288:321-333).**
**Heart and Estrogen/progestin Replacement Study RCT (HERS) and observational follow-up (HERS II) results after 6.8 years (*****JAMA***** 2002;288:58-66).**

## Methodology

**Explicit, “evidence-based.”**
**Systematic search/review of studies of HRT and primary prevention of specific clinical conditions.**
**Evaluate quality of individual studies based on established criteria.**

## USPSTF Levels of Evidence

**I****	****	****At least one well-conducted RCT**
**II-1****	****	****Controlled trials without randomization**
**II-2****	****	****Well-designed cohort or case-control ****	****	****	****studies, preferably from multiple sites**
**II-3****	****	****Multiple time-series with or without ****	****	****	****intervention. Dramatic before-after ****	****	****	****results (e.g. penicillin)**
**III****	****	****Expert opinion**

***Oregon***
***EPC***

## USPSTF - Strength of Evidence

**Good ****: Well-designed studies in representative populations with important health outcomes**
**Fair****: Sufficient evidence, but limited by number quality or consistency of studies; generalizability to practice; or intermediate health outcomes**
**Poor****: Insufficient due to limited number or power, flaws in design or conduct, gaps in evidence, or lack of evidence on most important outcomes.  **

***Oregon***
***EPC***

## Systematic Evidence Reviews

**Osteoporosis: bone density and fractures**
**Breast cancer incidence and mortality**
**Venous thromboembolism:  deep vein thrombosis and/or pulmonary embolism**
**Cognitive function and dementia**
**Cardiovascular disease: **
**- Coronary heart disease incidence and mortality**
**- Stroke incidence and mortality**
**- Combined cardiovascular disease incidence and mortality**

## Brief Reviews

**Colorectal cancer**
**Endometrial cancer**
**Ovarian cancer**
**Cholecystitis**

## Limitations of Systematic Review 

**Few RCTs of estrogen.**
**HRT use often based on self-report.**
**HRT use defined differently across studies.**
**Type of estrogen, use of progestin, dose, and regimen are not well defined or analyzed separately.**
**Users differ from nonusers in important ways that are not well measured or controlled for.**
**Not studied in nonwhite, non middle-class populations.**

***Oregon***
***EPC***

## Fractures(RR or HR with 95% CI)

| Outcome | USPSTF | WHI* | HERS** |
| --- | --- | --- | --- |
| Hip  | 0.76 (0.56-1.01) | 0.66 (0.33-1.33) | 1.61 (0.97-2.66) |
| Wrist  | 0.44 (0.23-0.84) | NA | 1.00 (0.65-1.53) |
| Vertebral | 0.60 (0.36-0.99) | 0.66 (0.32-1.34) | 0.89 (0.53-1.50) |
| Total | 0.73 (0.56-0.94)
(nonvertebral) | 0.76 (0.63-0.92) | 1.07 (0.89-1.29) |

***Nominal CI used for main outcomes (CAD, breast cancer), adjusted CI used for secondary outcomes.**
****Adjusted results (age and predictors of specific outcomes).**

## Colorectal Cancer(RR or HR with 95% CI)

| Outcome | USPSTF | WHI | HERS |
| --- | --- | --- | --- |
| Cases of colon cancer  | 
0.80 (0.74-0.86) | 
0.63 (0.32-1.24) | 
0.82 (0.46-1.47) |

## Colorectal Cancer

**	****Ever use - colon cancer****	****	****0.80 (0.74 - 0.86)**
**	****Ever use - rectal cancer****	****	****0.81 (0.72 - 0.92)**
**	****Current use - colorectal****	****	****0.66 (0.59 - 0.74)**

**18 observational studies, users tended to be healthier, less obese, more physically active, have healthier diets **
***Am Jour Med***** 1999;106(5):574-82.**

**Colorectal Cancer**

## 	Uncertain Benefit

**0.1   ****	****         1.0****	****               10.0**

**Relative Risk**

**Fixed effects**
**Random effects**

**	****Uncertain Benefit**
**	****Dementia Risk**
**	****Meta-analysis of 12 studies with**
**	****important methodologic limitations**
**	****	****	****Cohort**
**	****	****	****Case-control**
**	****	****	****Pooled estimates **
**	**** **

**Ever use of HRT**
**RR = 0.66 (0.53 - 0.82)**

## Cardiovascular Events(RR or HR with 95% CI)

| Outcome | USPSTF | WHI | HERS
2 ̊ prevention |
| --- | --- | --- | --- |
| CHD events | 0.91 (0.67-1.33) | 1.29 (1.02-1.63) | 0.97 (0.82-1.14)
 |
| CHD first year | NA | 1.78 (no CI) | 1.51 (1.00-2.27) |

## Stroke(RR or HR with 95% CI)

| Outcome | USPSTF | WHI | HERS |
| --- | --- | --- | --- |
| 
Stroke | 
1.12 (1.01-1.23)
 | 
1.41 (0.86-2.31) | 
1.09 (0.88-1.35) |

## Venous Thromboembolism(RR or HR with 95% CI)

| Outcome | USPSTF | WHI | HERS |
| --- | --- | --- | --- |
| VTE overall | 2.14 (1.64-2.81) | 2.11 (1.26-3.55) | 2.06 (1.26-3.36) |
| VTE first year | 3.49 (2.33-5.59) | 3.60 (no CI)
 | 3.28 (1.07-10.1) |

## Breast Cancer(RR or HR with 95% CI)

| Outcome
cases | USPSTF | WHI | HERS |
| --- | --- | --- | --- |
| Br cancer (<5 yrs) | 1.0 to 1.14 | NA | 1.38 (0.82-2.31)
 |
| Br cancer (5 or more yrs) | 1.23 to 1.35 | 1.26 (1.00-1.59) | 1.27 (0.84-1.94)
(total study) |

## Breast Cancer Incidence	  

**51 case-control studies**
**	****Current use****	****	****	****1.21 (p<0.001)**
**	****Ever use****	****	****	****1.14 (p<0.001)**
**	****Long-term (>5 years)****	****1.35 (1.21 - 1.49)**
**9 RCTs**
**	****Ever use****	****	****	****0.85 (0.38 - 1.89)**
**	**

***Lancet***** 1997;350:1047-1059.**
***BMJ *****1997;315:149-53****.**

## Cholecystitis(RR or HR with 95% CI)

| Outcome
cases | USPSTF | WHI | HERS
(biliary tract surgery) |
| --- | --- | --- | --- |
| Cholecy
(<5 yrs) | 1.8 (1.6-2.0) | NA | 1.39 (1.00-1.93)
 |
| Cholecy
(5 or more yrs) | 2.5 (2.0-2.9) | NA | 1.44 (1.10-1.90)
(total study) |

## Endometrial Cancer

**Unopposed estrogen use is associated with endometrial hyperplasia and endometrial cancer.**
**Risk for endometrial cancer does not appear to be increased when combining estrogen and progestin.**
**Current practice is to use combined HRT for women without prior hysterectomies.**

## Ovarian Cancer

**5 meta-analyses and 15 case-control studies: no consistent effect or dose-response effects.**
**2 large prospective cohorts suggest modest increased risk with estrogen (RR 1.2-1.6), higher with longer use (RR 2 to 3); third study found no increase.**
**One study suggests risk higher with E than EP.**
**Data suggestive but inconsistent.**

## Effects of Progestin & DoseFindings from USPSTF Review

| Outcome | Progestin | Dose |
| --- | --- | --- |
| Fractures;
Bone density | NA;
Similar response | NA;
Dose-response effect |
| Colon cancer | NA | NA |
| Dementia | NA | NA |

## Effects of Progestin & DoseFindings from USPSTF Review

| Outcome | Progestin | Dose |
| --- | --- | --- |
| CHD | NA | NA |
| Stroke | NA | NA |
| VTE | NA | Possible dose-response effect |
| Breast cancer | Suggestion of  increase risk | NA |
| Cholecystitis | NA | NA |

## Events Prevented with HRT 

**Hip**
**Fractures**

**Vertebral**
**Fractures**

**Colon **
**Cancer**
**Cases**

**Events Prevented with HRT **
**(Per Year in 10,000 Women 65-74 Years)**

**9**

**57**

**4**

**34**

**6**

**USPSTF**
**WHI**

**5**

**6**

## Events Caused with HRT 

**CHD **
**Events**

**Breast**
**Cancer**
**Cases**

**VTE **
**Events**

**Strokes**

**Cholecystitis**
**Cases**

**Events Caused with HRT **
**(Per Year in 10,000 Women 65-74 Years)**

**7**

**1.5**

**12**

**53.5**

**3**

**0**

**8**

**USPSTF**
**WHI**

**18**

**8**

## Summary of Evidence

| Potential Benefits | Evidence | Quality |
| --- | --- | --- |
| Osteoporosis
 | I, II-2 | Good for bone density; fair-good for fractures |
| Colorectal cancer | I, II-2 | Fair |
| Dementia | II-2 | Poor |

## Summary of Evidence

| Potential
Harms | Evidence | Quality |
| --- | --- | --- |
| CHD events | I, II-2 | Fair-good |
| Stroke | I, II-2 | Fair  |
| VTE | I, II-2 | Good |
| Breast cancer | I, II-2 | Good |
| Cholecystitis | I, II-2 | Fair |