Department of Epidemiology and Biostatistics Clinical and Translational Sciences Institute DESIGNING

1
Department of Epidemiology and BiostatisticsClini
cal and Translational Sciences Institute
DESIGNING CLINICAL RESEARCHSession 1Steve
Hulley MD, MPH

• Chapters 1 2
• The story of HERS, JAMA 20093012493

2
Evidence-based medicine (EBM)Hierarchy of type
of evidence

• Theory, doctrine, intuition
• Personal experience
• Pathophysiology
• Epidemiology
• Clinical trials of Surrogate outcomes
• Clinical trials of Disease outcomes
• Benefits vs harms

3
Anatomy of research What its made of

• Research question
• Significance
• Design
• Subjects
• Population
• Sample
• Variables
• Predictor
• Outcome

4
Physiology of research How it works

• Using measurements in a sample
• to draw inferences about
• phenomena in a population

5
(No Transcript)
6
Hulleys Research Question (1993)

• Should postmenopausal women receive hormones?
• Subjects postmenopausal women
• Predictor hormones
• Outcome ?

7
Premarin conjugated equine estrogens

• 1942 FDA approves Premarin for hot flashes
• 1966 book Feminine Forever by RA Wilson MD
• Menopause is a hormone deficiencytotally
  preventable
• 70s and 80s evidence supporting CHD prevention
• 1990s Premarin leading prescription drug in the
  US

8
Improved Research Question

• Does estrogen treatment prevent
• heart attacks in postmenopausal women?
• Subjects postmenopausal women
• Predictor estrogen Rx vs no estrogen
• Outcome heart attacks

9
Is RQ FINER?

• Need to specify the design
• of the study

10
Designs

• Observational study
• Cohort
• Cross-sectional
• Case control
• Randomized clinical trial
• Surrogate endpoints
• Endpoints of primary interest

11
Cohort design

• Subjects
• 5000 post-menopausal women living in the Bay Area
• Predictor
• Taking estrogen?
• Outcome
• Subsequent 3-year incidence of MI

12
Cross-sectional design

• Subjects
• 2000 PM women seen at SFGH
• Predictor
• Taking/took estrogen?
• Outcome
• History of MI?

13
Case-control design

• Subjects
• Cases 50 PM women with MI in the SFGH ED
• Controls 50 PM women with trauma in the SFGH ED
• Predictor
• Taking/took post-menopausal estrogen?
• Outcome
• Cases vs controls

14
Observational Studies of Estrogen and CHD

• Author (year) Relative risk
• Lafferty (1985) 0.2
• Sullivan (1990) 0.2
• Hammond (1979) 0.3
• Nachtigall (1979) 0.3
• Stampfer (1991) 0.3
• Bush (1987) 0.4
• Pettiti (1987) 0.5
• Grodstein (1996) 0.6
• Henderson (1991) 0.7
• Psaty (1994) 0.7
• Wolf (1991) 0.7
• Falkeborn (1992) 0.7
• Criqui (1988) 1.0
• Combined 0.65

p lt .05
15
NB, when choosing a research question and design

• Importance of thorough literature review and
  scholarship

16
Randomized blinded trial design Surrogate
outcomes

• Subjects
• 60 Post-menopausal women
• Predictor
• Randomized to estrogen vs placebo
• Outcome 4 weeks later
• LDL-C decreased by 10, plt.01
• HDL-C increased by 10, plt.01

17
Evidence that PM estrogen prevents CHD

• Epidemiology
• case-control and cohort studies of PM women
• 35 lower risk of CHD in estrogen users
• age-specific CHD rates in women lag behind men
• Trials of surrogate outcomes/pathophysiology
• estrogen improves LDL and HDL
• estrogen improves endothelial function
• estrogen prevents atherogenesis in animals

18
With all this evidence

• Did we really need a clinical trial with disease
  outcomes? Was it even ethical?
• Evidence-based medicine said yes
• To prove benefit for important outcomes
• To know all about harms as well as benefits

19
Is RQ FINER?

• Feasible
• Interesting
• Novel
• Ethical
• Relevant

20
Feasible?

• Clinical trial of estrogen vs placebo to prevent
  MI/CHD death in 10,000 women with prior
  hysterectomy

21
More feasible

• Secondary prevention trial of estrogen
  progestin vs placebo to prevent MI/CHD death in
  2500 women with a uterus and prior CHD
• Participants willing, available in 20 centers
• Wyeth-Ayerst willing to fund, with UCSF
  controlling the science

22
Please notice the changes in research question

• Observational RQ
• Is estrogen associated with heart attacks in
  postmenopausal women?
• Intended clinical trial RQ
• Does estrogen prevent CHD events in
  postmenopausal women?
• HERS RQ
• Does estrogen progestin prevent new CHD events
  in postmenopausal women with coronary disease?

23
Premarin conjugated equine estrogens

• 1942 FDA approves Premarin for hot flashes
• 1966 book Feminine Forever by RA Wilson MD
• Menopause is a hormone deficiencytotally
  preventable
• 70s and 80s evidence supporting CHD prevention
• 80s and 90s MPA added to prevent endometrial Ca
• 1990s Premarin leading prescription drug in the
  US

24
Interesting?
25
Novel?

• First disease endpoint trial of this RQ

26
Ethical?

• Equipoise (uncertain whether benefits or harms
  predominate)
• Benefits of hormone Rx
• Reduce menopausal symptoms
• ? Prevent CHD
• ? Prevent fractures
• ? Prevent Alzheimers Disease
• ? Improve quality of life
• Harms
• ?Venous thrombo-embolism
• ? Breast cancer

27
Relevant?

• Premarin 1 US prescription drug in the 90s
• Decision faced by half the population

28
HERS trial(Heart and Estrogen/progestin
Replacement Study)

• Subjects
• 2763 women age lt 80 (mean age 67)
• postmenopausal, with a uterus
• documented coronary disease
• Predictor
• .625 mg Premarin 2.5 mg MPA (EP)
• vs blinded placebo, randomly assigned
• Outcome
• 4-year rate of non-fatal MI and CHD death

29
Venous Thromboembolic Eventsin HERS
Treatment Group
P - value
RH
E P
Placebo

• DVT/PE 34 13 2.7 0.003 Deep vein
  thrombosis 25 9 2.8 0.008 Pulmonary embolism
  11 4 2.8 0.08
• Grady, Ann Int Med 2000132689

30
MI/CHD death in HERS Early harm and later
benefit?

• Year E P Placebo RH 95 CI
• 1 57 38 1.5 1.0-2.3
• 2 47 49 1.0 0.7-1.5
• 3 35 42 0.8 0.5-1.3
• 4 5 40 53 0.7 0.5-1.1
• Hulley et al JAMA 1998280605-13

P for trend 0.03
31
HERS overall CHD findings
Treatment Group

• All primary
• CHD events 290 293 .99 .99
• Hulley et al JAMA 1998280605-13

E P
Placebo
RH p
32
Why the null CHD result?Three possibilities

• 1. HERS got the wrong answer
• 2. The observational and other studies got the
  wrong answer
• 3. They answered different questions

33
1. HERS got the wrong answer

• Random error?
• Systematic error?

34
Random error?
Treatment Group
E P
Placebo
p
RH

• All primary
• CHD events 290 293 .99 .99
• Hulley et al JAMA 1998280605-13

35
Random error?
Treatment Group
E P
Placebo
95 CI
RH

• All primary
• CHD events 290 293 .99 .84-1.17
• Hulley et al JAMA 1998280605-13

36
Benefit with longer follow-up in HERS?
Primary CHD events
E P
Placebo
95 CI
RH

• 4.1 year trial 179 182 .99 .81-1.22
• 6.8 year trial 290 293 .99 .84-1.17
• follow-up
• Grady, Hulley et al JAMA 200228858-66

37
Benefit in other cardiovascular outcomes? 6.8
years in HERS
E P
Placebo
95 CI
RH

• Unstable angina 137 157 0.87 .69-1.09 Coronary
  surgery 144 155 0.93 .74-1.16
• Angioplasty 255 253 1.02 .85-1.21
• Peripheral arterial dis 154 177 0.87 .70-1.08
• Stroke / TIA 171 158 1.09 .88-1.35
• Grady, Hulley et al JAMA 200228858-66

38
HERS got the wrong answer Systematic error?

• Randomization
• Blinding
• Co-intervention
• Biased outcome ascertainment
• Adherence to treatment
• Loss to follow-up

39
Randomization problems?
Treatment Group
Baseline Characteristic
Placebo(n 1383)
E P(n 1380)
P-value
Age 67 67 0.3 Caucasian 88 90 0.1 Current
smoker 13 13 0.8 Diabetes 19 18 0.4 DBP (mm
Hg) 73 73 0.9 LDL-C (mg/dl) 145 145 0.8 HDL-C
(mg/dl) 50 50 0.4 Aspirin 78 78 0.7 Lipid
meds 45 47 0.3
40
Blinding problems?

• Problem EP often causes bleeding and breast
  tenderness
• Solutions
• Separate gynecology staff from CVD staff
• No CHD prevention advice
• Blinded adjudication of hard outcomes

41
Adherence problems?
Treatment Group
E P
Placebo

• Taking study drug
• at year 1 82 91
• at year 3 75 81
• Taking open label estrogen 3 8

42
Follow-up problems?
Treatment Group
E P
Placebo

• Randomized 1383 1380
• Lost to follow-up 0 0

43
2. The observational studies got the wrong answer

• Random error?
• Systematic error?
• Confounding?

44
Confounding

• Big problem in epidemiologic studies of drugs for
  prevention
• Hormones, vitamin E, beta carotene
• Women who take them are inherently healthier
• Statistical adjustment only a partial solution
• Randomized blinded trials needed to solve the
  problem

45
3. HERS answered a different question

• Other populations more responsive?
• Primary prevention earlier in menopause
  
• Other interventions better benefit/harm ratio?
• Estrogen only
• Different E, different P
• Lower doses

46
Three possibilities

• Physiology
• 1. HERS got the wrong answer
• 2. The observational studies got the wrong
  answer
• Anatomy
• 3. They answered different questions

47
Need additional disease outcome trials

• Replication to confirm HERS findings and extend
  to
• other populations
• other hormone preparations

48
ReplicationThe primary prevention Womens
Health Initiative

• WHI EP Trial
• Subjects16,608 women with a uterus, mean age 63
• Predictor EP vs placebo (as in HERS)
• Outcome MI CHD death (as in HERS)
• WHI Estrogen-only Trial
• Subjects10,739 women with no uterus, mean age 64
• Predictor E vs placebo
• Outcome MI CHD death

49
Disease outcomes in HERS and WHI
RH (95 CI)

• Outcome HERS EP WHI EP WHI E-alone
• MICHD death 1.0 (0.8-1.2) 1.3 (1.0-1.6) 0.9
  (0.8-1.1)
• Stroke 1.2 (0.9-1.7) 1.4 (1.1-1.8) 1.4 (1.1-1.8)
• Pulm Embolism 2.1 (1.3-3.4) 2.1 (1.6-2.8) 1.3
  (0.9-2.1)
• Breast cancer 1.3 (0.8-1.9) 1.3 (1.0-1.6) 0.8
  (0.6-1.0)
• Hip fracture 1.1 (0.5-2.5) 0.7 (0.5-1.0) 0.6
  (0.4-0.9)
• Dementia 2.0 (1.2-3.5) 1.5 (0.8-2.7)
• Hulley, JAMA 20042911769 (editorial)
• Schumaker, JAMA 20042912947

50
Breast cancer in WHI

• EP Placebo p
• Invasive breast cancer
• cases/10,000 women/yr 41 33 .003
• Mean diameter (cm) 1.7 1.5 .04
• Regional node metastases 25 16 .04
• Chlebowski, JAMA 2003 2893243

51
Million Women Case Control StudyHormones and
breast cancer

• OR (CI)
• Estrogen-alone 1.3 (1.2-1.4)
• Similar for premarin and estradiol oral and
  patch
• EP 1.7 (1.6-1.9)
• Similar for MPA, norethisterone and
  norgestrel
• Million Women Study, Lancet 2003362419

52
Quality of life

• EP Placebo p
• HERS1
• Physical function 21 22 .03
• Energy/fatigue 51 52 .05
• Mental health 75 76 .10
• (lower scores worse function)
• WHI2
• Little difference
• general health, mental health, depression,
  sexual satisfaction, sleep, physical function,
  pain
• 1. Hlatky, JAMA 2002287591
• 2. Hays, NEJM 2003 348

53
Menopausal symptoms by age and treatment,after 1
year in HERS
Age 50-59
Age 70-79

• EP plac p EP plac p
• Hot flushes 10 27 lt.01 5 8 .11
• Trouble sleeping 46 54 .08 42 48 .11
• Vaginal dryness 20 28 .06 18 21 .32

54
Loose end Findings in younger menopausal women

• RH (95 CI)
• CHD events in WHI EP
• years since menopause
• lt 10 0.9 (0.5 - 1.5)
• 10 - 19 1.2 (0.8 - 1.8)
• gt 20 1.7 (1.2 - 2.4)
• Manson, NEJM 2003349523

55
2009 Ethical!

• Equipoise removed
  
• Benefits of hormone Rx
• Reduce menopausal symptoms
• Prevent fractures
• Neutral
• Not prevent CHD
• Not improve quality of life
• Harms
• Cause venous thrombo-embolism
• Cause breast cancer
• Cause stroke
• Cause dementia

56
Bottom lines

• HERS did get the right answer
• If properly designed and carried out,
• experiments trump observational studies
• Observational studies of drugs are often
  confounded
• Practice guidelines on hormones after menopause
• Do not use for prevention of CHD, dementia
• This applies to any regimen, pending further
  trials
• Can use for treating menopausal symptoms
• Low dose, short duration

57
Annual Number of US Prescriptions for Hormone
Therapy
WHI
HERS
Hersh, JAMA 200429147
Source IMS Health NPA Plus
58
Meanwhile, how to prevent heart attacks

• Patients at high risk of CHD
• Aspirin
• Beta blockers
• Cholesterol lowering (statins)
• ACE inhibitors
• All patients
• Treat high BP
• Dont smoke
• Stay fit, eat well, avoid overweight

59
The research cycle
Develop research question
Infer conclusions
Design study
Implement study
Analyze results
60
Next