Lipids and Cardiovascular Effects of Aromatase Inhibitors and SERMs

1
Lipids and Cardiovascular Effects of Aromatase
Inhibitors and SERMs

• Brussels, October 13, 2007
• Per.lonning_at_helse-bergen.no

2
Cardiovascular Disease

• Cardiovascular diseases (mainly MI and cerebral
  stroke) are the main cause of death for both
  sexes in Western Societies
• Women a lower risk compared to men before
  menopause has been interpreted as a preventive
  effect of estrogens (Am J Epidemiol 136 408-16,
  1992)
• Method problems in epidemiology interacting
  factors example smoking, diabetes
• Cause of death not allways correctly certified

3
The Estrogen Paradox I

• HRT known to increase risk of thromboembolic
  disease (Thromb Haemost. 84961-7, 2000) the
  reason however is not clear
• Total cholesterol levels and LDL-cholesterol
  increase risk of MI and HDL-cholesterol lowers it
  (Arterioscler Thromb Vasc Biol. 202408-13, 2000
  Circulation 821916-24, 1990)
• Estrogens increase HDL-cholesterol, reduce
  LDL-cholesterol but also increase triglyceride
  levels (J Lipid Res.301137-45, 1989 JAMA 291
  1701-12, 2004)

4
WHI CEE Trial Lipid Levels
Percent Change, 1 Year
LDL-C
HDL-C
TG
TC
The Womens Health Initiative Steering Committee.
JAMA 20042911701-1712.
5
The Estrogen Paradox II

• Traditionally, estrogens considered preventive
  supported by observational studies (Ann Intern
  Med 117 1016-37, 1992 N Engl J Med 335 453-61,
  1996)
• Recently, large randomized studies have found HRT
  (E / - P) not to prevent MI or other CV
  incidents neither among women with a known
  diagnosis of CV disease (Am Coll Cardiol 38 1-7,
  2001 Lancet 360 2001- 2008, 2002 JAMA
  280605-613, 1998 N Engl J Med 349 535-45,
  2003) or healthy women (N Engl J Med 349 523-34,
  2003 JAMA 291 1701-12, 2004)

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The Estrogen Paradox III

• Effects of estrogens on CV diseases can not be
  evaluated by studying single components most
  likely, complex interactions with multiple
  factors
• The observation time in most studies on HRT lt 5
  years (many studies interrupted early due to
  safety recommendations
• Estrogens may have beneficial long-term effects
  by positive interaction with HDL / LDL, but
  negative short-term-interactions (coagulation,
  thromboembolic risk)??????????? Tamoxifen

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The Tamoxifen Paradox I

• Partial estrogen agonist / antagonist
• Influence plasma lipids in an estrogen-like
  manner (?)
• Conflicting evidence suggest a cardiopreventive
  effect (?)

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The Tamoxifen Paradox II

• Tamoxifen reduce LDL-cholesterol levels
  conflicting evidence suggest an increase in
  HDL-levels (Br J Cancer 58 497-99, 1988 Ann
  Intern Med 115 860-64, 1991 Am J Cardiol 76
  1072-3, 1995 J Clin Oncol 13 2900-05, 1995)
• In summary, an estrogen agonistic effecthead to
  head comparison suggest similar effects of
  tamoxifen and estrogen HRT on LDL-levels,
  probably less effect of tamoxifen on HDL-levels
  ??? (Am J Cardiol 76 1072-3, 1995)
• Conclusions moderate changes (10-30) number of
  individuals enrolled small by todays standards
  potential differences between HRT and tamoxifen
  dose-response (we have no way of equilibrating
  tamoxifen dose to estrogen standards

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The Tamoxifen Paradox III

• Surprisingly? tamoxifen seems to cause similar
  effects in pre- as in postmenopausal women, at
  least with respect to lowering plasma LDL (Br J
  Cancer 58 497-99, 1988 J Endocrinol 119 335-9,
  1988)
• tamoxifen increase blood levels of estrogens in
  premenopausal women due to disturbing follicle
  maturation

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Effect of Tamoxifen on BMD
Powles et al J Clin Oncol 14 78-84, 1996
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Tamoxifen and Cardiac Risk Individual Large
Trials

• Scottish study 1070 patients cardiac death 10
  tam, 25 controls hazard 0.37
• (CI 0.18 0.77) (BMJ 311 977-80, 1995
• Stockholm risk of hospital admission for for
  cardiac disease 0.68 (CI 0.48-0.97) (J Natl
  Cancer Inst 85 1398-1406, 1993) interestingly,
  from the study comparing 5 versus 2 years tam a
  sign favour for long-term 0.37 (CI 0.15 0.92)
• NSABP B-14 hazard ratio of tam versus contr of
  dying from MI 0.66 (CI 0.27 1.61) (J Natl
  Cancer Inst 89 776-782, 1997)

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Tamoxifen Oxford Meta-Analysis
Tamoxifen

• Trend for reduced heart mortality (p 0.06)

EBCTCG. Lancet 2005 365 16871717
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A second Meta-analysis (Braithwaite et al J Gen
Intern Med 18 937-47, 2003)

• Myocardial infarction incidense
• 6 trials, 29.542 individuals
• median follow-up of 5.5 years
• total no of events 74 (tamoxifen) versus 82
  (control)
• Hazard ratio 0.90 (CI 0.66 1.23)

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A second Meta-analysis (Braithwaite et al J Gen
Intern Med 18 937-47, 2003)

• Myocardial infarction death rate
• 12 trials, 27.790 individuals
• median follow-up of 5.6 years
• total no of events 37 (tamoxifen) versus 61
  (control)
• Hazard ratio 0.62 (CI 0.41 0.93)

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A second Meta-analysis (Braithwaite et al J Gen
Intern Med 18 937-47, 2003)

• Tamoxfen thromboembolic disease risk 1.88 (CI
  1.17 3.01)

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The Estrogen Paradox III

• Effects of estrogens on CV diseases can not be
  evaluated by studying single components most
  likely, complex interactions with multiple
  factors
• The observation time in most studies on HRT lt 5
  years (many studies interrupted early due to
  safety recommendations
• Estrogens may have beneficial long-term effects
  by positive interaction with HDL / LDL, but
  negative short-term-interactions (coagulation,
  thromboembolic risk)??????????? Tamoxifen

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Does Duration of Tamoxifen Affect CHD Outcome?

• Methods and patients
• 4,610 patients entered randomized trial
• Tamoxifen 2 years vs 5 years of adjuvant therapy

Cumulative Mortality from Coronary Heart Disease
Wald Test 2-Sided p.22
Cumulative Mortality ()
Tamoxifen 2 Years
Tamoxifen 5 Years
Years Since Start of Treatment
Nordenskjöld et al. J Natl Cancer Inst.
2005971609-1610
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Aromatase Inhibitor Adjuvant Trials
ATAC
BIG
Comparison
MA.17
Extension lack of cross-resistance
NSABP 033
Tamoxifen
Anastrozole
IES
Letrozole
ABCSG / ARNO
Lack of cross-resistance
Exemestane
Placebo
ITA
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Warning!

• Cardiovascular incidents and deaths not primary
  endpoints of any of the large AI trials
• not only trial design, but the way the parameters
  were registered differ substantially
• there are reasons for not substituting one
  regimen for another going through the evidence

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Inhibition of Aromatization by Anastrozole and
Letrozole
Crossover 1
Crossover 2
92
92
94
94
Inhibition ()
96
96
98
98
100
100
Anastrozole
Letrozole
Anastrozole
Letrozole
Anastrozole vs Letrozole, P0.003
Geisler et al. J Clin Oncol 20 751-757, 2002
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Plasma SHBG Levels During Treatment With
Exemestane Androgenic Effect of
17-Hydroxyexemestane
150
OH
100
of Pretreatment
O
50
CH2
17-Hydroexemestane
0
0
5
200
10
25
50
100
Exemestane (mg/d)
Data points geometric mean Bars 95 CI of
mean. SHBG sex hormonebinding
globulin Johannessen et al. Clin Cancer Res.
199731101-8
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027 Study Assessments and Follow-up
BMD Bone markers Hormones Lipids Coagulation
BMD Bone markers Hormones Lipids Coagulation
BMD Bone markers Hormones Lipids Coagulation
BMD Bone markers Hormones Lipids Coagulation
BMD Bone markers Hormones Lipids Coagulation
BMD Bone markers Hormones Lipids Coagulation
Exemestane 25 mg po daily
Random
Double-blind
Placebo po daily
24
18
0
12
6
36
Months
Treatment Period
Follow-up
Lonning, et al. J Clin Oncol. 2005235126-5137
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Lipid Profile
Effect of exemestane and placebo on lipids
P lt 0.001
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LIPID PROFILE
Effect of exemestane and placebo on lipids
P lt 0.004
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Lipid Changes MA17 (Ann Oncol 16707-15, 2005)
Statistical comparison Var (AB) Var A Var
B SD X (SD X12 SD X22)1/2
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HOMOCYSTEINE
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COAGULATION
Effect of exemestane and placebo on fibrinogen,
PT and APTT
APTT
Fibrinogen
PT
The analysis of variance did not indicate any
significant effect of exemestane on the
coagulation parameters.
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(No Transcript)
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BIG 1-98
R A N D O M I Z E
A
Tamoxifen
B
Letrozole
C
Letrozole
Tamoxifen
D
Letrozole
Tamoxifen
0
2
5
YEARS

• N Engl J med 353 2747-57, 2005
• J Clin Oncol 25 486-492, 2007

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BIG I-98

• Thromboembolic events 1.5 (2.0) Letro versus
  3.5 (3.8) Tam p lt 0.001
• Cardiac events 4.1 (5.5) Letro versus 3.8 (5.0)
  Tam p gt 0.4
• Ischemic heart disease 1.4 (2.2) Letro versus
  1.2 (1.7) Tam p gt 0.2

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BIG I-98

• Cardiac death 13 events in the Letrozole arm, 6
  events in the Tam arm p not stated (N Engl J med
  353 2747-57, 2005)
• Other causes of death CVA 7 versus 1,
  thromboembolic events 2 versus 2, sudden detah
  unknown causes 10 versus 10
• All CV sudden deaths Letro 32, tam 19
• Deaths from any cause Letro 166, tam 192
• Non vascular or sud detah L 134, Tam 173
• N 4000 each arm, med follow-up 26 months
• Increase CV death all causes 13/4000 gt2y, prox
  0.15 year

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ATAC Pre-specified Adverse Events ()
p-valuelt0.0001 lt0.0001 lt0.0001 0.02 0.03
0.0004 lt0.0001 lt0.0001 lt0.0001
T 40.9 10.2 13.2 0.8 2.8 4.5
29.4 7.7 5.1
A 35.7 5.4 3.5 0.2 2.0 2.8
35.6 11.0 1.3
Hot flashes Vaginal bleeding Vaginal
discharge Endometrial cancer Ischemic
cerebrovascular Venous thromboembolic Joint
symptoms Fractures Hysterectomy
ICD 4.1 3.4
0.1
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IES Sequential Study

• Venous thromboembolic events Exemestane n 28
  (1.2), tamoxifen n 54 (2.3) p 0.004
• CV events (ex thromboembolic events) letrozole n
  382 (16.5), tamoxifen n 350 (15.0) p
  0.16

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IES Deaths
Tamoxifen(n 2372)
Exemestane(n 2352)
222
261
Total number of deaths
166
149
Breast cancer deaths
95
Intercurrent deaths
73
35
20
Other cancers
11
17
Vascular
13
14
Cardiac
21
14
Other
8
15
Unknown
Coombes, ASCO 2006.
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Sequential Tamoxifen - Arimidex

• CV events not reported in the metanalysis (Lancet
  Oncol 7 991-6, 2006)
• German Austrian incidense of thrombosis and
  MI less than 1 each in both arms (Lancet 366
  455-62, 2005)

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Extended Therapy versus Placebo

• MA.17 Cardiavascular events total n 149
  (5.8) letrozole arm, 144 (5.6) in the placebo
  arm

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Summary

• HRT and tamoxifen seems both to enhance
  thromboembolic risk
• HRT and tamoxifen may both cause a sligth
  reduction in MI and MI death rates in the long
  term, but data conflicting
• Uncertain whether Ais may cause any increase in
  MI or CV risk as well as death. Any potential
  small difference in the clinical studies may be
  related to beneficial effects of tamoxifen?
• There is a need for long-term follow-up in all
  the clinical studies