Mukul Chandra, MD, FACC

1
Women and Heart Disease

• Mukul Chandra, MD, FACC
• Miami Valley Cardiologists,
• Wright State University,
• Dayton, Ohio
• mchandra_at_mvcdayton.com

2

• A 68 year old female employee of the postal
  service comes with chest uneasiness that feels
  like heartburn. No past medical history. Resting
  EKG, labs are normal.

3
Expeditiously Identify, Treat and Discharge
4
Coronary Angiogram
5
Overview

• Where Things Stand Today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?

• Where We Need to Take Them for Tomorrow
• Public awareness/education
• Research

6
Overview

• Where Things Stand Today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where We Need to take them for tomorrow
• Public awareness/education
• Research

7
Impact of CV disease in women mortality
CV disease is the leading cause of death in US
women
CDC Vital Statistics Report 2001
8
Impact of CV disease Mortality compared with
Breast Cancer
LEADING CAUSES OF DEATH FOR AMERICAN WOMEN 2000
9
Mortality over time in women is not improving
like it is in men
Heart Disease and Stroke Statistics 2003
Update, American Heart Association
10
CV disease kills predominantly women over 65
3rd leading cause of death in women age 25-45
2000 Heart and Stroke Statistical Update
11
Death from CV disease in women by race

2nd Leading Cause
12
Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we Need to take them for Tomorrow
• Public awareness/education
• Research

13
It is more difficult to identify heart disease in
women

• Symptoms may differ
• Most women and men have chest pain
• However, more women present without chest pain
• 49 of women v. 38 of men

Canto JG et al, JAMA 20002833223-3229
14
Women more often have other presenting symptoms
of heart attack
Adapted from Milner, et al.AJC 1999
15
We miss the diagnosis more often in women

• We fail to hospitalize more women who present to
  the emergency room with acute cardiac ischemia
• Women younger than 55 were 7 times less likely to
  be hospitalized
• Women older than 55 were 2 times less likely to
  be hospitalized

• Pope, JH, et al. NEJM 20003421163-1170

16
Women who have heart attacks have important
differences from men in their underlying
characteristics

• They are generally sicker and older

WD Weaver, for GUSTO 1 Investigators, JAMA 1996
17
Women with heart attacks have poorer outcomes
than men

• Higher mortality
• 30 day mortality double in women
• (11.3 v. 5.5)
• 35 day mortality 60 greater in women
• 44 of women with heart attack died within 1 year
  compared with 27 of men

WD Weaver, for GUSTO 1 Investigators, JAMA
1996 FTT Collaborative Group, Lancet
1994343311-322 Kannel et al.,Arch Intern Med.
199515557-61

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Increased Morbidity from heart attacks
Adapted from Weaver et al. JAMA 1996
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Young women with heart attacks are more likely to
die in the hospital than young men
Adapted from Vaccarino, et al NEJM 1999
20
Why so much more mortality?

• Differences in baseline characteristics explain a
  portion of the differences in outcomes
• Public Health perspective the same
• Regardless of cause, women have higher mortality
  rates with heart attacks

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Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we need to take them for tomorrow
• Public awareness/education
• Research

22
Invasive therapies are given less often to women

• Medicare population study
• slightly less angioplasty and stent and coronary
  artery bypass grafting surgery in women with
  heart attack
• though no translation to difference in mortality
• More studies show underutilization rates of
  cardiovascular procedures are slowly improving

Gan et al., N Engl J Med 20003438-15
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Fibrinolysis (clot busters)Major therapy for
heart attack victims

• Benefit preserved in women (12 reduction in 35
  day mortality)
• Stroke (bleeding type) rate is double, but is not
  significantly increased when accounting for age
• Major bleeding is higher in women

• Less eligible women than men receive
  fibrinolytics

FTT Collaborative Group, Lancet
1994343311-322 WD Weaver, for GUSTO 1
Investigators, JAMA 1996
24
Even ideal women less often receive beneficial
therapies
Medicare CCP--Gan, et al., NEJM 20003438-15.
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Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we need to take them for tomorrow
• Public awareness/education
• Research

26
Women are doing better with Angioplasty and
Coronary Stenting, but still not as well as men

• NHLBI dynamic registry data 1997-8
• 2524 patients, 895 women (35)
• Higher unadjusted one year mortality than men
• 6.5 v 4.3
• Similar mortality when adjusting for differences
  in baseline characteristics

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Outcomes in Women v Men undergoing Angioplasty or
Stenting at One Year
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Detrimental effects of invasive therapies women
have higher mortality with coronary artery surgery
12 MONTHS
6 MONTHS
Lagerqvist et al. JACC 2001. 38418 Glaser et
al., JAMA 20022883124-3129
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We are not sure which therapeutic strategy works
best for women with certain heart attacks or
unstable coronary syndromes

• How should we treat these syndromes in men and
  women?
• 3 Landmark trials past 5 years in US and
  worldwide enrolling thousands of men and women
• All 3 reported that invasive care is superior to
  conservative care with medications
• However, closer analyses reveal.

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We are not sure which therapeutic strategy works
best for women with certain heart attacks or
unstable coronary syndromes
MEN
WOMEN
Better ALL 3 LANDMARK TRIALS
Invasive Management
(versus medications,conservative care)
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Efficacy of gender specific therapies for
cardiovascular disease prevention the hormone
replacement trials

• Background
• Biologic plausibility to hormones and protective
  effects
• Women present later in life with heart disease,
  usually some period of time after menopause
• Small, then larger, observational studies
• Not randomized to one therapy versus another
• Many inherent biases with this study design
• Many showed benefit of hormones in reducing CV
  disease events
• Hormones became an accepted treatment for women
  after menopause

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Efficacy of gender specific therapies for
cardiovascular disease prevention the hormone
replacement trials

• HERS trial
• 2763 postmenopausal women
• Less than age 80
• With history of coronary heart disease
• Randomize to
• PREMPRO (conjugated estrogen plus
  medroxyprogesterone) OR
• Placebo
• Primary Outcome
• Nonfatal Heart Attack
• Coronary heart disease death

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HERS conclusions

• 4.1 years therapy
• Did not reduce overall CV risk
• Trend to early increase in CV risk
• Increase risks of venous thromboembolism
• Increase risk gallbladder disease 40

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Hormone Replacement TrialsWomens Health
Initiative

• 160,000 postmenopausal women 50-79
• 27,000 randomized to Estrogen, Estrogen
  Progesterone, or placebo
• Increase in heart attack and stroke with hormone
  groups
• Increase in venous thromboembolism
• Estrogen/Progestin study (16,608 patients)
• 26 increase invasive breast cancer
• 29 increase in coronary heart disease events
• 41 increase in stroke

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Menopausal Hormone TherapyImplications of
recent findings for future research
36
Guide to Preventive Cardiology for Women

• Consensus Panel Statement Circulation 1999
• Coronary heart disease (CHD) is the leading cause
  of death and a significant cause of morbidity
  among American women
• CHD is largely preventable
• Findings from HERS challenged previous
  observational data and do not support initiation
  of CEE combined with MPA in older postmenopausal
  women with confirmed coronary disease

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Guide to Preventive Cardiology for Women - cont

• Consensus Panel Statement Circulation 1999
• For women with CHD already on estrogen
  replacement therapy for gt 1 year, it may be
  reasonable to continue therapy while awaiting the
  results of HERS follow-up study and other ongoing
  trials of ERT with clinical end points
• Aggressive risk factor management is indicated
  for secondary prevention
• Aggressive risk factor management should be based
  on the future probability of a cardiovascular
  event in women who have not yet had an event.

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AHA Media Advisory- July 9, 2002

• Results of the WHI trial show an increased
  overall health risk in women taking combined
  (estrogen plus progestin) hormone replacement
  therapy (HRT) as compared to placebo.
• In particular, the study demonstrated no benefit,
  and possibly an increased risk, regarding CHD and
  stroke in women taking combined HRT.
• This is an important study that demonstrates the
  value of large, randomized trials to guide
  clinical decisions and to advise the public.

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Implications for Clinical Practice

• AHA statement on Preventive Cardiology for Women
  is currently being updated
• Based on current evidence, the AHA advises that
  women do not start or continue combined HRT for
  the prevention of coronary heart disease

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Implications for Research

• Effects of estrogen and progesterone formulations
  and dosing other than daily combined CEE and MPA
  on the cardiovascular system are less studied
• Basic science and mechanistic studies help focus
  large clinical trials, but the latter are needed
  to direct clinical practice guidelines
• Studies on the mechanisms by which HRT results in
  early increase in CV risk could assist in
  determining who may be at lower risk if HRT is to
  be prescribed for non cardiac indications

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Cardiovascular Events In HERS and WHI
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Implications for Research

• No cardiovascular benefit is derived from
  combined CEE and medroxyprogesterone
• An early increase in cardiovascular risk is seen
  with start of this therapy although the absolute
  increase in risk is low
• Further research to determine the benefit of HRT
  on non cardiac outcomes that show promise should
  continue

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Implications for research

• For studies of HRT for non cardiac outcomes
• women without CHD should be informed about the
  results of WHI
• women with established CHD should be informed
  about the results of HERS

44
Hormones and CV disease conclusions

• No benefits and likely harm for CV diseaseshould
  not be continued nor initiated for primary
  prevention

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Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we need to go for tomorrow
• Public awareness/education
• Research

46
Public Awareness impacts directly upon womens
outcomes

• Increased awareness of risk factors of heart
  disease can reduce it through primary prevention
• Increased awareness of symptoms of heart disease
  matters
• Time is critical to limiting the damage of heart
  attacks
• Patients presenting in the first 60 minutes of
  heart attack have half the mortality of patients
  after 60 minutes

47
Women are not sufficiently aware and present late

• Women with heart attacks present for care and are
  treated later than men

48
We are improving in our awareness, but not enough

• AHA National Study of awareness of CV disease
  among women
• Increased awareness of heart disease as leading
  killer of women
• (46 2003 v. 30 1997)
• But only 13 of women view CVD as their major
  health threat
• Majority of women reported good relationships
  with their doctors
• But, only 38 reported doctors ever discussed
  heart disease with them

49
Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we need to go for tomorrow
• Public awareness/education
• Research

50
Public Education

• Get to emergency care faster when having a heart
  attack
• Discuss heart disease and their individual risk,
  and prevention measures, with their own doctors

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Public awareness campaigns

• Heart Truth campaign
• National Wear Red Dress Day

• American College of Cardiology, American Heart
  Association, and several others provide joint
  guidelines for primary prevention in women in
  2004
• Physicians need to educate women over 20 and
  focus on primary prevention

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Primary Prevention Guidelines for women over age
20

• Stratify women into optimal, lower, intermediate,
  or high risk for cardiovascular events
• All women should be counseled on lifestyle
  approaches tobacco cessation, regular exercise,
  weight management, heart healthy diet
• Other interventions, including blood pressure
  control, lipid control, and cardiovascular
  medicines are based on patient and risk

Although smoking has declined in the US, 2001
National Health Interview survey shows current
smoking 23 white women 18 black women 12
hispanic women 32 American Indian/Alaskan
women 6 Asian women
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Overview

• Where things stand today
• Impact CV disease
• Are Women different?
• What therapies do women get?
• Do these therapies work?
• What role does public awareness play?

• Where we need to go for tomorrow
• Public awareness
• Research

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Research
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Research

• Recall the importance of single sex trials like
  the hormone replacement trials in identifying
  definitively the value of therapies in women
• Recall the importance of mixed sex trials like
  the unstable coronary syndrome trials being
  designed to look for potential differences
  between women and men and ensure that women are
  getting the same benefits of the overall trial

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Our present level of research is not achieving
adequately our research goals

• An example
• Sudden cardiac death is a leading cause of death
  in men and women who have had prior heart attack
  or have heart failure
• A recent (2002) seminal study of the use of
  internal cardiac defibrillators for these
  patients showed that they reduce death
  significantly
• Leads to a major change in practice
• Only 12 of the patients in this trial were women

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Our present level of research is not achieving
adequately these goals

• Current recommendations for the treatment of
  heart disease are based upon studies primarily
  conducted on middle aged men
• Agency for Healthcare Research and Quality
  commissioned review
• UCSF investigators reviewed 15 years of research
• Only 162 of 810 eligible articles provided
  separate findings on women

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Research questions

• Why do women have poorer outcomes with heart
  attacks and their treatments?
• Why do young women who have heart attack do so
  poorly compared with young men?
• What new screening and diagnostic tests may help
  women identify cardiovascular disease?
• What treatments are most useful in women?
• How can we reduce the complications of our
  present treatments in women?

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Research goals

• 1. single sex trials
• HERS, WHI have highlighted the importance of
  careful randomized study for determining the
  efficacy or harm of therapies within women
• 2. mixed sex trials
• designed with women in mind (adequately
  powered) to show us potential differences in
  therapeutic responses between men and women
• 3. basic and translational research
• genetic polymorphisms, novel biomarkers, new
  diagnostic modalities

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Conclusions
61

• Where Things Stand Today
• Impact CV disease
• Number one killer of women
• More women die annually of CV disease than men
• Are Women different? Yes
• More likely to have unusual symptoms than men
• More likely to miss the diagnosis of heart attack
  in women
• More likely to die after heart attack than men
• More likely to suffer other complications of
  heart attacks
• What therapies do women get?
• More likely to get treatment late for heart
  attack
• Women do not get the treatments they need as
  often as men
• Do these therapies work?
• Invasive and medical therapies often have more
  adverse effects in women than men
• Hormone replacement does not prevent
  cardiovascular disease events in post menopausal
  women
• Antioxidant vitamins do not reduce cardiovascular
  events in postmenopausal women

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• What role does public awareness play?
• Women do not identify heart disease as their
  major health threat
• Women and their doctors rarely discuss heart
  disease
• Women come to attention later with heart attacks
  than men
• Where We Need to Take Them for Tomorrow
• Public awareness/education
• Educational campaigns
• Increase focus on primary prevention measures
  amongst physicians
• Research
• Single sex and mixed sex trials are important
• Yet women need much more representation and
  explicit study in these trials
• Basic and translational research needed to
  improve screening, testing, and outcomes for
  women from cardiovascular disease

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