1. We’ve Come A Long Way-Prevention of Cardiovascular Disease in Women
Ned Ferguson, M.D.
University of Wisconsin Hospital and Clinics
Section of Cardiovascular Medicine
Preventive Cardiology
January 2005
Faculty, National WATCH Program-Women’s Agenda
Targeting Cholesterol in Heart Disease
Speaker, WATCH Program
Speaker, AHA Go Red for Women campaign

2. Welcome to this CME audioconference highlighting a new initiative called WATCH, The Women’s Agenda Targeting Cholesterol in Heart Disease.
I’m _____, academic and clinical title, institution .
Columbia University College of Physicians and Surgeons is delighted to sponsor this 1-hour continuing medical education program to help healthcare providers improve the practice of cardiovascular disease prevention, particularly related to women.
Please follow along as I describe these slides. I’ll assist by often mentioning the slide number being reviewed that is in the upper right corner. Also, you may want to write down your questions during this presentation. We’ll have time to discuss them toward the conclusion.
The WATCH Steering Committee, a national faculty of leaders in preventive cardiology and women’s health, has developed this program to disseminate information about new evidence-based CVD prevention guidelines for women, with a specific focus on optimal cholesterol management.

3. Cardiovascular Disease Prevention in Women
Scope of the problem
Lipids and CVD
Clinical trial evidence
The new evidence-based AHA guidelines
During this conference, we are going to focus on the evidence that supports cardiovascular prevention in women after discussing the magnitude of the problem and the relation between lipids and CVD. Finally, we will review the recent American Heart Association guidelines that are evidence-based to allow us to tailor lipid therapy to an individual women’s risk.

4. Deaths Due to Cardiovascular Diseases United States 1979–2001
520
Women
500
480
Men
Deaths (in Thousands)
460
440
420
Let’s start of by reviewing the magnitude of the problem of cardiovascular disease in women. Each year, nearly 500,000 women die of cardiovascular diseases, which is more than the next several causes of death combined, and accounts for nearly half of all women’s deaths.
And as you can also see on this slide, the number of women dying of cardiovascular diseases each year has exceeded the number in men for nearly 20 years. This trend likely reflects the aging of the women population, and underscores the public health impact of CVD among women.
400
380 79 81 83 85 87 89 91 93 95 97 99 01
Years
American Heart Association. Heart Disease and Stroke Statistics Update. Dallas, Texas: American Heart Association; 2003.

5. Cardiovascular Disease in Women: The Stats
1 in 5 women has some form of CVD
1 in 2.5 women will die of heart disease or stroke, compared with 1 in 30 from breast cancer
Heart disease and stroke are the No. 1 and 3 causes of death in women
In 2001, CVD
caused the deaths of 498,863 women
was the first listed diagnosis of 3,168,000 women discharged from hospitals
American Heart Association Heart and Stroke Statistical Update.
Dallas, Texas: AHA, 2003.

6. Leading Causes of Death for Women United States: 2001
Percent of Total Deaths
Black or African-American
White
Hispanic or Latino
36.5
37.6
32.6
20.5
21.7
21.1
6.1
5.1
5.5
4.2
2.9
2.8
2.3
2.8
2.9 A B F C G A B D F G A B E C F
A - Diseases of the Heart, and Stroke
B - Cancer
F - Diabetes Mellitus
C - Accidents
G - Nephritis, Nephrotic Syndrome
A - Diseases of the Heart, and Stroke
B - Cancer
D - Chronic Lower Respiratory Diseases
F - Alzheimer’s Disease
G - Influenza and Pneumonia
A - Diseases of the Heart, and Stroke
B - Cancer
E - Diabetes Mellitus
C - Accidents
F -Influenza and Pneumonia
Source: CDC/NCHS.
American Heart Association Heart and Stroke Statistical Update.
Dallas, Texas: AHA, 2003.

7. Prevalence of Cardiovascular Diseases in Americans Age 20 and Older by Age and Sex NHANES III:
79.0 80
70.7 70
65.2
Men
65.2 60
Women
51.0
48.1 50
Percent of Population 40
34.2
28.9 30 20
17.4
13.6
10.4
5.5 10
4.6
4.2
20-24
25-34
35-44
45-54
55-64
65-74
75+
Ages
Source: CDC/NCHS. These data include CHD, CHF, stroke and hypertension.
American Heart Association Heart and Stroke Statistical Update.
Dallas, Texas: AHA, 2003.

8. Age-Adjusted Death Rates for Coronary Heart Disease, Stroke, Lung and Breast Cancer for White and Black Females - United States: 2000
This slide highlights that minority women, in particular black women, have a higher rate of death due to both coronary heart disease and stroke compared with white women. This important sub-population should be a primary focus for prevention in our practice. This slide also shows that for both black and white women, coronary heart disease and stroke mortality are greater than death rates due to lung cancer and breast cancer in women.
American Heart Association. Heart Disease and Stroke Statistics Update. Dallas, Texas: American Heart Association; 2003.

9. New and Recurrent Attacks
Annual Number of American Women Having Diagnosed Heart Attack by Age: ARIC:
500
400
372,000
300
New and Recurrent Attacks
In Thousands
200
100
88,000
10,000
29-44
45-64
65+
Ages
Source: Extrapolated from rates in the NHLBI’s ARIC surveillance study, These data don’t include silent MIs.
American Heart Association Heart and Stroke Statistical Update.
Dallas, Texas: AHA, 2003.

10. Coronary Disease More Often Presents Atypically in Women
Chest pain/pressure/tightness is still common-but many may present with:
Back, jaw, neck, or shoulder discomfort
Vague, flu-like symptoms
Dizziness
Fatigue, exhaustion
Dyspnea
GI Symptoms-Nausea, Indigestion
Syncope

11. Women Often Have a Worse Prognosis Than Men
38% of women will die within 1 year after having a first MI, compared with 25% for men
64% of women who died suddenly of CHD had no previous symptoms of this disease, compared with 50% for men
Source: Framingham Heart Study, National Heart Lung Blood Institute.
American Heart Association Heart and Stroke Statistical Update. Dallas, Texas: AHA, 2003.

12. Women with coronary syndrome (ACS) are less
Women with coronary syndrome (ACS) are less commonly diagnosed with ACS: more women have unstable angina (UA) and less ST elevation with acute MI (STEMI) than men.
If recognized early, women with UA have a better prognosis than men, though a worse outcome with acute STEMI.
Women with non-STEMI have greater hospital mortality than men, but receive fewer diagnostic tests, fewer cardiology consultations, less percutaneous interventions and fewer beneficial discharge medications.

13. Women younger than 50 years of age have twice
Women younger than 50 years of age have twice the MI hospital mortality than comparably aged men. Women are more likely to have MI complications of shock, heart failure, recurrent chest pain, cardiac rupture, and stroke.
Antiplatlet therapy, thrombolysis, acute angioplasty, and CABG. All entail greater bleeding risk for women than men.

14. Post-CABG mortality rates in women are twice those in men.
Post-MI survival is influenced to a large extent by age and diabetes in women.

15. Anginal chest pain in women is less likely to be associated with flow-limiting obstructive coronary lesions than anginal chest pain in men.
Anginal chest pain in women without flow-limiting coronary lesions may be associated with endothelial dysfunction and impaired coronary flow reserve.
Such coronary microvascular dysfunction is associated with an increased rate of hospitalization for chest pain, a poor quality of life, and increased ongoing health care costs.
Women’s Ischemic Syndrome Evaluation, Executive Summary.
Circulation 2004;109:
e44-e63.

16. Women have been underrepresented in many
Women have been underrepresented in many major clinical hypertension and dyslipidemia trials.
In ALLHAT, there were 15,000 women and 17,000 men in this major hypertension trial.
However, men had better BP control and more men received two drugs to reach goal than women.
Women and men who achieved the same degree of BP control had the same clinical outcome.

17. Personal observation: The metabolic syndrome
Personal observation: The metabolic syndrome with its attendant greatly increased cardiovascular risk is taken less seriously in women than men.
Established clinical evidence: Framingham scoring tables seriously underestimate cardiovascular risk with women with the metabolic syndrome.

18. Mosca L et al. Circulation 2004; 109:573-579.
From 1997 to 2003, women have become more aware of CVD as leading cause of death
<50% of women continue to list CVD as leading cause of death in 2003
Young women feel least informed
Women at highest risk of CVD are the least likely to be aware they are at risk
Mosca L et al. Circulation 2004; 109:

19. Mosca L et al. Circulation 2004; 109:573-579.
Women’s Awareness1997, 2000, 2003: Women’s Perception of Leading Cause of Death 50 45 40 35 30 % 25
1997 20
2000 15
2003 10 5
Breast
Cancer
Heart
Unsure
Cancer
(general)
Disease
Mosca L et al. Circulation 2004; 109:

20. Mosca L et al. Circulation 2004; 109:573-9.
Women’s Awareness 2003: Perceived Leading Cause of Death by Ethnic Group 60 50 40 % 30
White
Black 20
Hispanic 10
Surprisingly, a recent national survey conducted by the AHA found that even though minority women have one of the highest rates of cardiovascular disease, they are paradoxically least aware. In this study that included a random and nationally representative sample of 1,024 women ≥25 years old, with an oversampling of black and Hispanic women, we can see that only a minority of women recognize that cardiovascular disease is their leading killer. This is an important observation because awareness of risk is the first step toward prevention. These data highlight the need for health care providers to help raise awareness of the real vs. perceived threat of CVD in women.
Breast Cancer
Cancer (general)
Heart
Unsure
Disease
African-American and Latino/Hispanic women, who are at higher risk for heart disease, were least likely to be aware.
Mosca L et al. Circulation 2004; 109:573-9.

21. Obesity Trends* Among U.S. Adults
BRFSS,
(*BMI ≥
30, or ~ 30 lbs overweight for 5’ 4” woman)
1991
1995
2002
This slide shows the growing epidemic of obesity in the US that will have important implications for rates of dyslipidemia, hypertension, diabetes and CVD in the near future. The states colored red have more than 25% of the population with a BMI or Body Mass Index greater than 30. The Behavioral Risk Factor Surveillance System Nationwide Trends Data show that the median percentage of people with BMI of 30 or greater was 12.6% in 1991, and grew to 22.1% in Each year, an estimated 300,000 US adults die of causes related to obesity. Increases occurred for both men and women in all age groups and for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans.
No Data <10% %–14%
15%–19% %–24%
>25%
Behavioral Risk Factor Surveillance System, Centers for Disease Control and Prevention.

22. NCEP ATP III: Clinical Identification of the Metabolic Syndrome*
*Diagnosis is established when 3 of these risk factors are present.
Risk Factor
Waist circumference
Men
Women
Triglycerides
HDL-C
Blood Pressure
Fasting glucose
Defining Level
> 102 cm (> 40 inches)
> 88 cm (> 35 inches)
≥ 150mg/dL
< 40 mg/dL
< 50 mg/dL
≥ 130 / ≥ 85 mm Hg
≥ 110 mg/dL
Obesity is associated with a constellation of metabolic risk factors and recently the National Cholesterol Education Program, The Adult Treatment Panel III has developed criteria to establish the diagnosis of the metabolic syndrome.
The diagnosis is established when 3 or more of the defining criteria on this slide are met (for women, waist circumference >35 inches) triglycerides equal or greater than 150 mg/dL, HDL-C less than 50 mg/dL, blood pressure greater than or equal to 130/85 mmHg, and a fasting glucose greater than or equal to 110 mg/dL). In order to not miss the diagnosis, it is important that we routinely measure the waist circumference in practice. Place a non-stretchable tape measure around the bare abdomen just above the hip bone. Be sure that the tape is snug, but does not squeeze or compress the skin, and is parallel to the floor. Have the patient relax and exhale as you measure their waist.
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:

23. NHANES III: Age-Adjusted Prevalence of ≥3 Risk Factors for the Metabolic Syndrome*40
Men
35.6 35
Women
28.3 30
25.7
24.8 25
22.8 % 20
16.4 15 10
The metabolic syndrome is quite prevalent among women, especially among sub-groups such as African-Americans and Mexican-American women.
And since 1 out of 5 Americans will have the metabolic syndrome, we need to identify this more rigorously in our practice so that we can institute appropriate treatment. There is also an ICD 9 code for metabolic syndrome to use for testing and treatment. 5
White
African-American
Mexican-American
*Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%.
Ford ES et al. JAMA. 2002;287:

24. WISE (Women’s Ischemia Syndrome Evaluation) Study: Obesity vs
WISE (Women’s Ischemia Syndrome Evaluation) Study: Obesity vs. Metabolic Syndrome in CV Risk
780 women referred for angiography for suspected myocardial ischemia
596 women (76%) overweight or obese by BMI
451 women (58%) with metabolic syndrome
Prevalence of significant angiographic CAD (>50% stenosis)
Metabolic syndrome but not BMI associated with:
Significant CAD
3-yr risk of MACE
Metabolic syndrome conferred 2-fold adjusted risk of death and MACE
Metabolic syndrome associated with elevated levels of hs-CRP
Reference
Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study. Circulation. 2004;109:
Kip KE, et al. Circulation. 2004;109:

25. WISE (cont’d): Relationship Between BMI, Metabolic Status, and Prevalence of Significant Angiographic CAD
P=0.002
P=0.0004
P=0.01
Prevalence of CAD, %
Reference
Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus the metabolic syndrome in cardiovascular risk in women: a report from the Women's Ischemia Syndrome Evaluation (WISE) study. Circulation. 2004;109:
Kip KE, et al. Circulation. 2004;109:

26. Increasing US Prevalence of Diabetes
1991
2001
Diabetes is a major risk factor for CVD, is associated with obesity, hypertension, and dyslipidemia. has been increasing to epidemic proportions. This slide shows a 60% increase in the prevalence of diabetes over a 10-year period. In 2001, the prevalence of physician-diagnosed diabetes was the same for men and women- 5.5%, about 6 million females.
This data is alarming because the age-adjusted prevalence of major CVD for women with diabetes is substantially higher for women without diabetes, and the age-adjusted major CVD hospital discharge rate for women with diabetes is almost four times the rate for women without diabetes.
No data
<4%
4%–6%
7%–8%
9%–10%
>10%
National Prevalence 7.9%
Mokdad AH et al. JAMA. 2003;28:76–79.

27. Mortality Due to Heart Disease in Men and Women With or Without Diabetes (US)35
29.9
Diabetes
No Diabetes 30 25
23.0
19.2 20
Mortality per Person-Years* 15
11.5
11.0 10
6.3
7.1
3.6 5
Men
Women
Men
Women
All heart disease
Ischemic heart disease
*Age-adjusted
Adapted from Gu K et al. Diabetes Care 1998;21:

28. Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64)10 10 9
Men
Women 8 11 6
Risk Ratio Vs. Nondiabetic 30 19 4 38 9 6 20 3* 2
BEN: This was in original set. I think you could delete this. I think the numbers on top of the bars represent the age-adjusted annual rate/1000 while the heights of the bars represents the risk ratio. It’s a bit confusion.
Total CVD
CHD
Cardiac Failure
Intermittent Claudication
Stroke
Age-Adjusted Annual Rate/1000
P<.001 for all values except *P<.05.
Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.
Ruderman N et al, eds. Oxford; 1992.

29. Cardiovascular Disease Prevention in Women
Scope of the problem
Lipids and CVD
Clinical trial evidence
The new evidence-based AHA guidelines
Let’s now discuss the relation between lipids and CVD in Women.

30. CVD Prevention in Women: Why a Focus on Lipid Management?
LDL predicts CVD in women similar to men
HDL and triglycerides are stronger predictors in women
Women are less likely than men to receive optimal lipid management
Minority women are less likely to receive optimal preventive care compared to white women
Evidence supports that women receive equal benefit from lipid management although less likely to receive than men
Why would we like to focus on lipid management? There are several reasons for this.
LDL cholesterol has been definitively related to the development of cardiovascular disease in both men and women.
We also need to recognize that there are other important risk factors. We also know that HDL and triglyceride levels are stronger predictors in women than in men. So, we need to pay particular attention to those parameters.
We also know that women are less likely than men to receive optimal lipid management.
And importantly, minority women, which was already demonstrated to be at highest risk for CV disease, are also the least likely to receive optimal preventive care compared to white women.
And lastly, evidence supports the statement that women receive equal benefit from lipid management despite they’re being less likely to receive it.

31. Cardiovascular Disease Mortality
Age-adjusted Cardiovascular Disease Mortality in Women by LDL-C and HDL-C (LRC Study) 25 20 15 10 5
HDL-C <50 mg/dL
HDL-C >50 mg/dL
Cardiovascular Disease Mortality
per 1000 Person-Years
< 130 mg/dL mg/dL ≥160 mg/dL
LDL-Cholesterol
At all levels of LDL-C, CVD mortality rates in women with low HDL-C levels were 3 to 4 times greater compared with women with high HDL-C levels
Bass KM et al. Arch Intern Med 1993;153:

32.       HYPERTRIGLYCERIDEMIA Low HDL Cholesterol Postprandial
Hyperlipidemia
Small, Dense LDL   
HYPERTRIGLYCERIDEMIA   
Triglyceride-Rich
Lipoprotein
Remnants
Procoagulant State
Insulin Resistance
Figure 2. Association of elevated serum triglyceride levels and atherogenic risk factors. Modified from Brewer HB Jr. Hypertriglyceridemia: changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. Am J Cardiol 1999;83:3F-12F, with permission from Excerpta Medica Inc.

33. Coronary Heart Disease in Relation to HDL-C and Triglyceride Levels in Women
Framingham Heart Study — National Heart, Lung, and Blood Institute
Women
163
150
143 60
CHD/1000/10 yr
The relationship between HDL cholesterol and triglycerides is depicted on this slide. Since the Framingham Heart Study began in 1948, 5127 people aged 30 to 62 years have been examined every 2 years to assess their CV disease status. These data are from participants aged 49 to 82 years who were followed for 12 years, and shows the relationship between the fasting HDL-C, triglyceride level, and subsequent incidence of CHD.
This slide depicts the synergy between abnormal levels of HDL and abnormal levels of triglyceride, further increasing cardiovascular risk in women.
Triglycerides (mg/dL)
HDL Cholesterol (mg/dL)
Castelli WP. Can J Cardiol. 1988;4:5A-10A.

34. Triglycerides (mg/dL)
Impact of Triglyceride Levels on Relative Risk of CHD: Framingham Heart Study
3.0
Men
2.5
Women
2.0
Relative Risk
1.5
1.0
0.5
0.0 50
100
150
200
250
300
350
400
Triglycerides (mg/dL)
Castelli WP. Can J Cardiol. 1988;4:5A-10A.

35. Estimated 10-Year Rate (%)
Estimated 10-Year CHD Risk in 55-Year-Old Adult Women According to Levels of Various Risk Factors Framingham Heart Study 30 27 25 20 20 15
Estimated 10-Year Rate (%) 8 10 5 5 A B C D
Blood Pressure (mm Hg) 120/ / / /90
Total Cholesterol (mg/dL)
HDL Cholesterol (mg/dL)
Diabetes No No Yes Yes
Cigarettes No No No Yes
Wilson PWF, et al. Circulation. 1998;97:

36. Multiple Risk Factors Tend to Occur Together
Framingham Heart Study — National Heart, Lung, and Blood Institute
57.5
Men and Women, 55 yr 60 38 50
28.8
23.4 40
16.5
Percent/10 yr
13.7 30
8.7
56.4 20
36.8
27.7
Men 10 17
9.2
11.3
5.5
Women
BP systolic
120
160
180
Cholesterol
220
260
HDL-C 50 35
Diabetes +
Cigarettes
LVH-ECG
Karen: PLEASE check all values especially in 2nd to last column, and provide back-up (per client)
Wilson PWF. Am J Hypertens. 1994;7(7 pt 2): 7S-12S.

37. Does a Low HDL Matter as a Risk Factor?-
C is an Independent
Predictor of CHD Risk Even When LDL – C is Low
0.0
1.0
2.0
3.0
Risk of CHD
Beyond LDL cholesterol, it’s still important for us to look at other lipid markers of risk. One might ask if a low HDL level is important. In this Framingham study, lipid and lipoprotein values, including fasting triglycerides, HDL, LDL and total cholesterol levels, were obtained on 2,815 men and women aged 49 to 82 years chiefly between 1969 and In the approximately four years following the characterization of lipids, coronary heart disease developed in 79 of the 1,025 men and 63 of the 1,445 women who at baseline were free of coronary heart diseases.
On this slide, we can see that regardless of what the level of LDL cholesterol, lower levels of HDL cholesterol are associated with increasing risk of cardiovascular disease in women. 25 45
HDL - C 65 85
(mg/dL)
100
160
220
LDL -
C (mg/dL)
Gordon T et al. Am J Med.1977;62:

38. Lipid Profiles in Diabetic and Nondiabetic Women
Framingham Offspring Study 50
Nondiabetic (n = 1879)) * *
Diabetic (n = 120) 40 * 30 *
Women (%) 20 10
One of the interesting points of this data is that >70% have LDL>100.
HDL-C <35 TG >250 HDL-C <35 LDL-C 160 LDL-C <100 LDL
TG >250 Pattern B
mg/dL
*P0.001
Siegel RD et al. Metabolism. 1996;45:

39. Change in Lipids After Menopause
Total Cholesterol
HDL-C
110
110
% of level at -6 months
before menopause
100
100 90 90
-24
-18
-12 -6 6
-24
-18
-12 -6 6
LDL-C
Triglycerides
110
110
There are unique challenges that we face in the management of lipids in women. And one of them is the menopause transition. It’s been documented that as women go through the menopause, there’s a worsening of CVD risk factors. In this study, the influence of the menopause on serum lipids and lipoproteins was examined longitudinally at 6-week intervals for 2-3 years in women undergoing the menopause. Serum lipid and lipoprotein profiles were also examined cross-sectionally in 4 groups of pre-menopausal, peri-menopausal and post-menopausal women, who were followed up longitudinally at 3-monthly examinations for 1-2 years. These results are based on 1360 examinations and 270 woman-years. And in this slide, we can see that the menopause significantly affects cholesterol and triglyceride levels. Other studies have shown that women who have less HDL-C
Menopause is associated with a more atherogenic lipid profile, which provides a challenge, but also an opportunity for physicians to evaluate what a woman’s needs are at the time of the menopause with respect to lipid management.
100
100
% of level at -6 months
before menopause 90 90
-24
-18
-12 -6 6
-24
-18
-12 -6 6
Months
Months
Jensen J et al. Maturitas 1990;12:

40. WHI Estrogen+Progesterone Study Absolute and Relative Risk or Benefit of Combo HRT
Increased
Absolute Risk
per 10,000
Women/Yr
Increased
Absolute Benefit
per 10,000
Women/Yr
Relative Risk
vs. Placebo
at 5.2 Years
Confidence Interval
Nominal
95%
Adjusted
95%
Health Event
Coronary Heart Disease (CHD)1
Strokes
Breast cancer
VTEs
Colorectal cancer
Hip fractures
Total fractures
1.24
1.41
1.26
2.11
0.63
0.66
0.76 6 8 18 6 5 44
Appropriate lipid management in the post-menopausal years is particularly relevant given the fact that the Women’s Health Initiative (WHI) has recently demonstrated that hormone replacement therapy has not been demonstrated to prevent cardiovascular events in women despite some beneficial lipid effects. The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at baseline. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD). After a mean follow-up of 5.2 years, the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (first row). And as you see on this slide, combination hormone therapy has been shown to increase the risk of coronary heart disease, stroke, breast cancer and thrombo-embolic events.
Despite the fact that there may be some benefit for colorectal cancer, hip fractures and total fractures, it is not recommended that it be used for cardiovascular prevention in women, despite some potential benefit with respect to lipoproteins.
Nominal = variability based on simple trial for single outcome; Adjusted = corrects
variability for multiple analyses over time.
1Manson JE et al. N Engl J Med. 2004;349:
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

41. WHI Estrogen Alone Trial:
Primary CHD Outcomes
Conjugated % CI Equine Estrogen Placebo Hazard Ratio Nominal Adjusted*
CHD † 177 (0.49%) 199 (0.54%) 0.91 (0.75,1.12) (0.72,1.15)
CHD Death 54 (0.15%) 59 (0.16%) 0.94 (0.65,1.36) (0.54,1.63)
Non-fatal MI 132 (0.37%) 153 (0.41%) 0.89 (0.70,1.12) (0.63,1.26)
Stroke 158 (0.44%) 118 (0.32%) ( )( )
Average follow-up was 6.8 years.
* Adjusted for multiple comparisons across time (OBF procedures). A Bonferroni adjustment for 6 outcomes was applied to all outcomes other than CHD, Breast Cancer and the global Index.
† CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths. There were 14 silent MIs.
More recently, estrogen, alone, has also not been shown to prevent coronary events.
The Estrogen Alone Trial was a component of the Women’s Health Initiative conducted in 40 US clinical centers beginning in This randomized, double-blind, placebo-controlled disease prevention study enrolled 10,739 postmenopausal women, aged years, with prior hysterectomy, including 23% of minority race/ethnicity. Women were randomly assigned to receive either mg/d of conjugated equine estrogen (CEE) or placebo. The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. As seen above, the use of CEE did not affect CHD incidence; also, it was associated with an increase in stroke, and a decrease in the risk of hip fracture. The authors recommended that CEE not be used for chronic disease prevention in postmenopausal women.
This has created a situation where we really need to reassess what should be done to prevent cardiovascular disease in women.
The Women’s Health Initiative Steering Committee. JAMA 2004;291: 5

42. Cardiovascular Disease Prevention in Women
Scope of the problem
Lipids and CVD
Clinical trial evidence
The new evidence-based AHA guidelines
Let’s now turn to the clinical trial evidence to support the management
of lipids in women

43. Meta-Analysis of Effects of Statins from Major Clinical Trials10
HDL-C
Coronary Events
Fatal CHD
Total Mortality 5 TC
LDL-C TG 5 -5
-10
Change %
-15
-13
-20
Several lipid-lowering trials have now shown an unequivocal benefit of statin therapy in both men and women. Data from the 5 trials in which 30, 817 participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was defined as the primary outcome between were used in this meta-analysis. Total cholesterol was reduced 20%, LDL-C by 28%, HDL-C increased 5%, and 13% reduction in triglycerides. Overall, statin treatment reduced risk 31% in major coronary events, fatal coronary heart disease was reduced 29%, and all-cause mortality was reduced 21%.
-20
-21
-25
-30
-28
-29
-31
-35
LaRosa JC et al. JAMA. 1999;282:

44. Risk Reduction for Major Coronary Events by Gender in Statin Trials5 10 15 15 20 22 27 37
Proportional Risk Reduction (%) 25 30 38 35 37 40 43 46 45 50 4S
CARE
LIPID
AFCAPS
Women
Men
LaRosa JC et al. JAMA.1999;282:

45. Major Vascular Event Rates by Gender and LDL Cholesterol: Heart Protection Study
Event Rate ratio & 95% CI
Sex
Male (n=15,454)
1666
(21.6%)
2135
(27.6%)
Female (n=5,082)
367
(14.4%)
450
(17.7%)
Baseline LDL cholesterol (mg/dL)
< 100
282
(16.4%)
358
(21.0%)
668
(18.9%)
871
(24.7%)
130
1083
(21.6%)
1356
(26.9%)
ALL PATIENTS
2033
(19.8%)
2585
(25.2%)
24% SE 3
This slide shows that even among the 3,421 patients with entry LDL cholesterol levels below 100mg/dL, a similar proportional reduction in risk of major events is seen to that among participants presenting with higher LDL levels. 5,082 women (25%) and 15,454 men (75%) with known coronary artery disease or at high risk between 40 and 80 years were enrolled in the Heart Protection Study and treated with simvastatin 40 mg or placebo in a 2 X 2 factorial design and followed for 5 years. Vitamin treatment had no effect in preventing vascular events. Again, this study shows that even among patients with LDL cholesterol of less than 100, there still was benefit.
Numbers in parentheses represent event rates for the subset of 3,421 patients with entry LDL-C levels <100 mg/dL.
reduction
(2P<.00001)
0.4
0.6
0.8
1.0
1.2
1.4
STATIN better
PLACEBO better
Available at: Accessed June 15,
Ballantyne CM. Am J Cardiol.2003;92(suppl):3K-9K.

46. Gender-Specific Effects of Statins on Lipids
CARE 4S 10 10 5 -5
-10
-10
-15
-20
-20
-25
-30
-30
-35
-40
-40
Total
LDL
HDL TG
Total
LDL
HDL TG
Women
Men
Lewis SJ et al, J Am Coll Cardiol 1998; 32:140.
Miettinin TA et al, Circulation 1997; 96:4211.

47. VA-HIT: Benefit of Gemfibrozil in Male Patients With Coronary Heart Disease* * ** *
We know we need to move beyond LDL cholesterol because many of our patients -- high-risk patients with coronary heart disease have multiple lipid abnormalities and despite substantial benefits of statin therapy, up to 2/3 of events in these trials occurred despite statin therapy. Data supporting intervention in high-risk patients with the metabolic syndrome come from the VA-HIT study. It demonstrates that among patients who have abnormal LDL cholesterol (mean 11122 mg/dL, treatment with a fibrate was associated with a substantial reduction in both non-fatal MI and CHD death (primary endpoint) and also the individual endpoint on stroke.
One year after randomization, the mean HDL-C level was 6% higher in the gemfibrozil group than in the placebo group.
Despite normal baseline levels, triglycerides were 31% lower.
There was no change in LDL-C.
These changes in lipids was associated with a significant reduction of 22% in the primary endpoint.
Treatment also resulted in a significant reduction of 29% in strokes.
Although this study was limited to men it is likely that the trial results generalize to women because other trials of lipid therapy have shown equal benefits for men and women. *
LDL-C HDL-C TG Nonfatal CHD Stroke†
MI or CHD Death Death
* P0.05; ** P=0.07; † Investigator designated
2,531 men with coronary heart disease, HDL ≤ 40 mg/dL,
and LDL ≤ 140 mg/dL were randomized to gemfibrozil (1200 mg/day) or or placebo, and
followed for a mean of 5.1 years.
Rubins HR et al. N Engl J Med. 1999;341:

48. Coronary Drug Project: 5-Year Events35 30
- 14%*
Placebo (n=1119)
Niacin (n=2789) 25 20
- 27%*
- 26%*
Event Rate % 15
- 47%*† 10
These data, from the Coronary Drug Project, which recruited 8,341 patients in , demonstrate the benefit of niacin therapy to reduce CVD events. Again, this trial was conducted in men, but clearly showed that, after 5 years of follow-up, treatment with niacin was associated with significant reduction of non-fatal MI (27%), CHD death or nonfatal MI (14%), and several other endpoints shown on this slide. These results are similar to those of the modern-day statin trials. And importantly, even after 15 years, there was a reduction of total mortality associated with the use of niacin compared to placebo. 5
Nonfatal MI/CHD
Nonfatal MI
Stroke/TIA
CV Surgery
*P<0.05
death
†5-year rate
Coronary Drug Project Research Group. JAMA. 1975;231:

49. HDL-Atherosclerosis Treatment Study (HATS) Niacin and Statin Regression Trial
89% Reduction
Composite Event Rate, %
23.7 25
21.4 20
14.3 15 10 5
2.6*
Because many of our high risk patients are going to have multiple lipid abnormalities, we often need to use a combination of lipid-improving therapies. The HATS trial was designed to look at the impact of the combination of simvastatin and niacin with or without anti-oxidant vitamins under progression of coronary heart disease. The trial provided an opportunity to look at clinical endpoints, although the primary endpoint was the mean change in the percent stenosis caused by the most severe lesion from the initial arteriogram to the final arteriogram.
This slide shows the significant reduction in events that was associated with the use of simvastatin and niacin in combination. Anti-oxidant vitamins were not demonstrated to have a benefit. Moreover, antioxidant vitamins appear to block the beneficial effects of simvastatin and niacin on cardiovascular outcome. This may possibly be related to the fact that anti-oxidant vitamins may interfere with the HDL raising impact of niacin therapy (Cheung M et al. Arterioscler Thromb Vasc Biol. 2001;21: ).
In this placebo-controlled secondary prevention study, 160 patients with CHD, low HDL-C (average, 31 mg/dl), and “mildly” elevated serum LDL-C levels (average, 125 mg/dl) were administered either niacin (N; slow-release or immediate-release, mean dose 2.4 g/d) plus simvastatin (S; mean dose 13 mg/d) or placebo with or without antioxidant vitamins (AV) for 3 years. In the group receiving niacin plus simvastatin without antioxidants, LDL-C levels were lowered by 42%; the LDL-C levels in the placebo groups were unaltered. HDL-C was increased by 26% in the niacin plus simvastatin group.
In addition, a meta-analysis conducted by Golderg et al. (Am J Cardiol. 2004;94: ) confirmed that women respond as well as men, and possibly slightly better, to treatment with extended-release niacin and that it is a safe and effective treatment option for women with dyslipidemia.
Placebo
S + N AV
S + N + AV
Coronary Death, MI, Stroke, or Revascularization
*P<.05 vs Placebo
Brown BG et al. N Engl J Med 2001;345:

50. Dose-Related Lipid Level Changes in Women by Monotherapy Niacin
Mean Change From Baseline (%) 30 26 24 20 20 10
1000 mg qhs (n=52)
1500 mg qhs (n=59)
-10
2000 mg qhs (n=53)
-11
-20
-16
-18
-20
-30
-28
-40
-36
LDL-C
HDL-C TG
LDL-C, low density lipoprotein-cholesterol; HDL-C, high density lipoprotein-cholesterol; TG,
Triglycerides. NIASPAN® [package insert]. Miami, Fla: Kos Pharmaceuticals, Inc.; 2003.

51. The CVD Prevention Paradox
Risk factors for CVD, including lifestyle, hypertension, dyslipidemia, and diabetes, have been established for decades.
Substantial data supports the statement that appropriate management of CVD risk factors saves lives, yet substantial numbers of patients don’t get lifesaving interventions.
Why?
Now that we’ve discussed the scope and the prevalence of some of these important risk factors, and have described the benefits of lipid-improving therapy on outcomes, it leads to an important paradox in preventive cardiology. And that is that we have known for decades what important risk factors are, such as lifestyle, hypertension, dyslipidemia, diabetes. We have also, in recent years, developed substantial data to support that appropriate treatment of these risk factors saves lives.
Yet, we have also documented that substantial numbers of patients and women in particular are not getting these life-saving interventions. And that is really the rationale for the WATCH program.

52. Cardiovascular Disease Prevention in Women
Scope of the problem
Lipids and CVD
Clinical trial evidence
The new evidence-based AHA guidelines
Let’s now turn our attention to the state of the art guidelines for the management of lipids in women.

53. Evidence-Based Guidelines for CVD Prevention in Women
The previous slides describe some of the rationale for establishing the American Heart Association evidence-based guidelines for cardiovascular prevention in women.
These guidelines were written in collaboration with several national agencies and professional organizations and represent the current state of the art. Some of the main points are:
Collaborative multi-disciplinary effort
27-member interdisciplinary Expert Panel
Addressed broad range of cardiovascular risk
Systematic search and summary of data
>7000 titles and abstract identified; >1200 full-text articles screened
Evidence Rating System utilized
Clinical recommendations published in Circulation, Feb 2004 and J Am Coll Cardiol, March 2004.
Mosca L et al. Circulation. 2004;109:

54. Evidenced-Based Guidelines or CVD Prevention in Women: Rationale
Significant advances in science base needed to be translated into clinical recommendations
Women were excluded from many early CVD trials and lack of data may be an obstacle to prevention in women
In the wake of HERS and WHI there was a heightened need to clarify what prevention strategies are based on the highest quality evidence
Recent survey showed women confused about prevention strategies
Further rationale for developing the American Heart Association guidelines was significant advances in science that we need to translate into clinical recommendations so that we can use them for our patients.
We also know that women were excluded from many early cardiovascular trials and that the lack of data on women may have been an obstacle to implement prevention strategies and practices. We’re really hopeful that by presenting these guidelines and the supporting data along with them, physicians will be more comfortable in treating their female patients to prevent CV disease.
We also demonstrated in a recent survey by the American Heart Association that many women are quite confused about prevention strategies.
In fact, a recent AHA national survey showed that the percent of women that believe antioxidant supplements protect the heart has increased since 1997.
Soon we will discuss that the Expert Panel has recommended that antioxidant supplements not be used for prevention. In fact, it may interfere with some of our lipid management strategies.
Mosca L, et al. Circulation. 2004; 109:
Mosca L et al. Circulation 2004; 109:573-9.

55. Classification and Levels of Evidence
Strength of Recommendation
Classification
Class I Intervention is useful and effective
Class IIa Weight of evidence/opinion is in favor of
usefulness/efficacy
Class IIb Usefulness/efficacy is less well established by
evidence/opinion
Class III Intervention is not useful/effective and may be harmful
Level of Evidence
A Sufficient evidence from multiple randomized trials
B Limited evidence from single randomized trial or other nonrandomized studies
C Based on expert opinion, case studies, standard of care
Generalizability Index
1 Very likely that results generalize to women
2 Somewhat likely that results generalize to women
3 Unlikely that results generalize to women
0 Unable to project if results generalize to women
There are some unique aspects of the classification scheme used to determine the guidelines. First, the recommendations are classified according to the strength of recommendation and the quality of the evidence to support it.
A Class I recommendation means that the intervention that we are discussing is useful and effective. And essentially, unless there’s a contraindication that we can document, we should be doing this in practice.
A Class IIa recommendation means that the weight of the evidence is in favor of usefulness or efficacy. Class IIb means that this intervention is less well established by evidence or opinion.
And as previously mentioned, a Class III recommendation is something that we want to avoid using in practice.
In addition to the strength of the recommendation, there are levels of evidence provided to support the recommendations. Level A means that there is sufficient evidence from multiple, randomized trials. Level B means the evidence is more limited, such as a single randomized trial or a non-randomized study. And Level C would be based on expert opinion, case studies or standard of care.
A unique aspect of the evidence-based prevention guidelines for women are the use of a generalizability index. This was provided because there are some situations, for example in lipid management, where women have not been included in some clinical trials, yet it’s important that we make an assessment as to whether or not data generated in men can be applied to women. So, a generalizability index of 1, for example, means that the expert panel rated this as very likely that the results were generalized for women.
Mosca L et al. Circulation 2004; 109:

56. ALOHA to Heart Disease Lay Guidelines
A-Assess your risk and rank yourself
L-Lifestyle interventions are top priority
O-Other interventions prioritized by expert rating
H-Highest priority for women at highest risk
A-Avoid Class III interventions (HRT, antioxidant supplements, and aspirin in low-risk women)
It is important that we tell our patients that there are resources available to assist them in understanding more about disease prevention. For example, a lay version of guidelines are now published on the Web at the website.
ALOHA is an acronym to help women remember what the guidelines are about. And we’d like physicians, too, to think about this strategy to help them in their efforts to prevent heart disease in women.
A stands for assessing risk and ranking patients with respect to the risk of cardiovascular disease. L stands for lifestyle interventions, which were given a top priority by our Expert Panel as a mechanism to prevent cardiovascular disease. O stands for other interventions that were prioritized by our expert-panel rating scheme. We’d like to give the highest priority in practice to recommendations that were rated as Class I, which will shortly be reviewed. H stands for highest priority, which is given to women who are at highest risk of future events. And lastly A, short for avoid, refers to which interventions to avoid, and have a Class III rating. Class III interventions are hormone therapy, antioxidant supplements, and aspirin therapy in low-risk women. These are strategies that are not proven to prevent heart disease and may potentially have adverse side effects. They are not recommended for use in your practice.
Mosca, L Circulation Patient Page (2004;109;e ).

57. Framingham Risk Assessment
A Cholesterol Management Implementation Tool for the Palm Operating System
Based on ATP III
The first step in guideline preventive therapy is to determine what the level of risk is for our patients. There are tools that can assist us in determining what this risk is. One of them is the Framingham risk assessment tool shown here, which can be obtained online at the NIH web site
And you can see that with just a handful of risk factors including age, gender, total cholesterol, HDL cholesterol, smoking status and systolic blood pressure, and whether or not your patient is being treated with high blood pressure medications, can help to determine what their absolute risk of developing or dying of CHD is in the next 10 years. Althouygh there are several other risk factors that may be important to determining your patient’s diagnosis, such as c-reactive protein, plasma glucose, and brain natriuretic peptide levels, and BMI, this risk score has remained a proven tool to aid in assessing cardiovascular risk.

58. Spectrum of CVD Risk in Women
Framingham Global Risk
Risk Group (10-y Absolute CHD Risk)
High ≥ 20%
Intermediate 10% to 20%
Lower ≤10%
Optimal ≤10%
The Guidelines describe the risk groups based on the Framingham global risk and other clinical characteristics. These are important because we use these to help determine the aggressiveness of our preventive strategy.
For example, a high risk group, based on the Framingham global risk score, corresponds to an absolute risk of coronary heart disease in the next 10 years of greater than or equal to 20%.
Intermediate risk would be classified as 10% to 20% absolute risk.
Lower risk is less than or equal to 10%.
And we also define the category which is our ultimate goal for everyone, which is to be at optimal risk, which includes a Framingham risk less than or equal to 10%, and that our patients are adhering to a very healthy lifestyle and that they have optimal levels of all risk factors.
Mosca L, et al. Circulation 2004; 109:

59. High CVD Risk in Women: Clinical Examples
Established CHD
Cerebrovascular disease*
Peripheral arterial disease
Abdominal aortic aneurysm
Diabetes mellitus
Chronic kidney disease†
*Cerebrovascular disease may not confer high risk for CHD if the affected vasculature is above the carotids.
Carotid artery disease (symptomatic or asymptomatic with >50% stenosis) confers high risk.
†As chronic kidney disease deteriorates and progresses to end-stage kidney disease, the risk of CVD increases substantially
This slide depicts typical clinical examples of a high-risk woman. The women who are at highest risk of a future cardiovascular event are those that have had a previous one. Examples include prior coronary heart disease, cerebral vascular disease, peripheral arterial disease, or an abdominal aortic aneurysm. We’ve already strongly emphasized the importance of diabetes as a cardiovascular risk equivalent. And something that you may not be as familiar with is that chronic kidney disease is now considered a cardiovascular risk equivalent and that we should be treating these patients as aggressively as we do our other patients that have established coronary heart disease.
Mosca L, et al. Circulation 2004; 109:

60. Intermediate CVD Risk in Women: Clinical Examples
Subclinical CVD‡
Metabolic syndrome
Multiple risk factors§
Markedly elevated levels of a single risk factor**
1st degree relative(s) with onset of atherosclerotic CVD at ≤ 55 y in men and ≤ 65 y in women
‡Patients with subclinical CVD and >20% 10-year CHD should be elevated to the high-risk category.
§Patients with multiple risk factors can fall into any of the 3 categories by Framingham scoring.
**Most women with a single, severe risk factor will have a 10-year risk >10%.
Typical clinical examples of women with intermediate risk women are shown here.
First of all, subclinical cardiovascular disease is being identified more frequently with the availability of tools such as the ultrafast CT scan. Women who are identified as having atherosclerosis, but have not yet had a clinical event fall into this category.
The metabolic syndrome is also a typical example. But, be aware that the metabolic syndrome patients may fall into a high-risk category or low risk category as well.
Multiple risk factors is a classic example of the intermediate risk woman. It’s also important to know that markedly abnormal levels of a single risk factor, such as the genetic abnormalities of a lipoprotein, that, despite a Framingham risk score of low or intermediate risk, may move women into the high risk category.
Also, those patients who have a first degree relative with premature heart disease would be considered an example of an intermediate risk. The last bullet also shows the importance of determining familial history in determining a women’s risk.
Mosca L, et al. Circulation 2004; 109:

61. Lower/Optimal CVD Risk in Women: Clinical Examples
May include women with multiple risk factors, metabolic syndrome, or ≤ 1 risk factors
Optimal
Optimal levels of risk factors and heart-healthy lifestyle
Lower risk patients may include women with multiple risk factors, the metabolic syndrome or typically women who have 1 or fewer risk factors for heart disease. And again, our optimal category, what we’re striving for, which means that women are living a heart-healthy lifestyle and have good optimal levels of all the risk factors.
Mosca L, et al. Circulation 2004; 109:

62. Clinical Recommendations
Lifestyle interventions
Major risk factor interventions
Preventive drug interventions
Atrial fibrillation/stroke prevention
Class III interventions
In the guidelines, the organization of the clinical recommendations is described here. It starts with lifestyle interventions which are a top priority in practice. Then, major risk factor interventions are reviewed. What follows is a discussion on preventive drug interventions. There is also have a section on the management of atrial fibrillation and stroke prevention, and, finally, the Class III interventions, which are not recommended in practice.
Mosca L et al. Circulation 2004; 109:

63. Class I Lifestyle Interventions
Cigarette smoking cessation
Physical activity
Cardiac rehabilitation (in women with recent MI)
Heart-healthy diet/therapeutic diet
Weight maintenance/reduction
Beginning with Class I lifestyle interventions, smoking cessation is a goal that we want to achieve in all of our patients. Note that we also want to avoid environmental smoke. Physical activity is also critical for women. Cardiac rehabilitation among women who have had a recent myocardial infarction or revascularization procedure is extremely important. Heart-healthy diet or a therapeutic diet should be incorporated, depending on their lipid level. And of course, weight maintenance and reduction, when indicated, is recommended for all women.
Mosca L, et al. Circulation 2004; 109:

64. What’s New in the Guidelines Concerning Lipid Management
Initiate statin treatment for high-risk women regardless of their LDL levels
Optimal level HDL-C > 50 mg/dl
Initiating niacin or fibrate therapy for low HDL or elevated non-HDL in high-risk women is a Class I recommendation
With respect to the lipid management guidelines, let’s highlight what is new and different from previous guidelines. First of all, there is a recommendation that we should be on a regimen of lifestyle therapy and concominant statin treatment for high-risk women regardless of their LDL cholesterol level.
An optimal level of HDL cholesterol is defined as greater than 50 milligram per deciliter for women.
We also have a Class I recommendation recommending initiating niacin or fibrate therapy for women who are classified as high risk and have a low HDL or an elevated non-HDL. In intermediate risk women, niacin or fibrate therapy is recommended when HDL-C is low or non—HDL-C elevated after LDL-C goal is reached. And as previously stated, Class I recommendations are what we are supposed to be doing in practice unless there is a contraindication.
Mosca L, et al. Circulation 2004; 109:

65. Major Risk Factor Interventions: Lipid, Lipoproteins
Optimal levels of lipids and lipoproteins in women:
LDL-C <100 mg/dL
HDL-C >50 mg/dL
Triglycerides <150 mg/dL
Non–HDL-C (total cholesterol minus HDL-C) <130 mg/dL
Encourage lifestyle approaches (Class I, Level B)GI=1
Before reviewing the major risk factor interventions in the lipids and lipoproteins category, let’s first review what the optimal levels are for these important risk factors in women.
Optimally, we’d like all women to have LDL cholesterol of less than 100 milligrams per deciliter. For HDL cholesterol, the cutoff is greater than 50 milligrams per deciliter. For triglyceride it is less than 150 milligrams per deciliter. And for non-HDL cholesterol (the total cholesterol minus the HDL cholesterol) less than 130 is the optimal level. And of course, the first step is to encourage lifestyle approaches to achieve these optimal levels.
Mosca L, et al. Circulation 2004; 109:

66. Major Risk Factor Interventions: Lipids and Lipoproteins
Heart-healthy diet
Consistently encourage overall healthy eating pattern
Fruits, vegetables, grains, low-fat or nonfat dairy products, fish, legumes, and sources of protein low in saturated fat.
Limit saturated fat intake to <10% of calories, limit cholesterol to <300 mg/d, and limit intake of trans fatty acids (Class I, Level B)GI=1
Diet therapy
In high-risk women or when LDL-C is elevated, reduce saturated fat intake to <7% of calories, cholesterol to <200 mg/d, and trans fatty acid intake (Class I, Level B)GI=1
One important distinction is the difference between a heart-healthy diet and diet therapy. A heart-healthy diet is primarily focusing on eating a plant-based diet and limiting saturated fat to less than 10% calories, cholesterol to less than 300 milligrams per day and to also limit the intake of trans-fatty acids.
When we need to manage an LDL cholesterol, we should encourage women to adopt a more aggressive diet. While quite similar to the heart-healthy diet, it’s more stringent (saturated fat <7% vs. <10% of calories, and cholesterol intake <200 mg/day vs. <300 mg/day).
Mosca L, et al. Circulation 2004;109:

67. Lipids and Lipoproteins: Pharmacotherapy
High risk women (10-year absolute CHD risk > 20%)
Initiate LDL-C–lowering (preferably statin) therapy with lifestyle therapy when LDL-C >100 mg/dL (Class I, Level A)GI=1, and initiate statin therapy when LDL-C <100 mg/dL unless contraindicated (Class 1, Level B)GI=1
Initiate niacin or fibrate therapy when HDL-C is low, or elevated non–HDL-C (Class I, Level B)GI=1
Let’s focus on the management of lipids based on a woman’s risk category, beginning with the high-risk women. Recall that these are women who have an absolute 10-year risk for a coronary event of equal to or greater than 20%. For these women, the guidelines recommend LDL cholesterol lowering, preferably statin therapy. This should be combined with lifestyle therapy being initiated in those with an LDL cholesterol level of greater than 100 milligrams per deciliter. This is a Class I Level A, or the strongest recommendation. In high-risk women who have an LDL cholesterol level of less than 100 milligrams per deciliter, the expert panel also recommended initiating statin therapy as a Class I recommendation, unless there’s a contraindication. However, because the abundance of evidence is less to support this statement compared with an LDL-C >100 mg/dL at baseline, this is given a level B rating.
Another Class I recommendation for high-risk women is that we should be initiating niacin therapy or fibrate therapy when the HDL cholesterol is low or the non-HDL cholesterol is elevated. It’s important to point out that dietary supplemental niacin should not be used as a substitute for prescription niacin, which many of your patients may ask about. And that means over-the-counter niacin should really only be used if they are approved and monitored by a physician.
Class I Intervention is useful and effective
Level A Sufficient evidence from multiple randomized trials
B Limited evidence from single randomized trial or other nonrandomized studies
Mosca L, et al. Circulation 2004;109:

68. “Dietary supplement niacin must not be used as a substitute for prescription niacin…”
No-flush (inositol hexaniacinate)
Contains no free nicotinic acid
Should not be used to treat dyslipidemia
Sustained-release
Hepatotoxicity associated with several formulations
Immediate-release
Shown to prevent cardiovascular disease and death
TID dosing:
increases flush
difficult to titrate
lessens compliance
Extended-release
Approved by the FDA available only by prescription
Once before bedtime dosing
In discussing with your patients the importance of using prescription niacin, I’d like to clarify for you that your patients might go to the drug store and ask you about some of these formulations that are available. The no-flush preparation has no free nicotinic acid – the active ingredient for treating dyslipidemia – and should not be used for this purpose.
The over-the-counter sustained release niacin that is available has a very slow-release niacin, and some preparations have been associated with hepatotoxicity. Since niacin is classified as a dietary supplement, the production and marketing are not strictly regulated by the FDA, and the free nicotinic acid content is not guaranteed. So, we are not recommending that these be used either. And immediate release or crystalline niacin, which was used in some clinical trials, that was shown to prevent cardiovascular disease, the problem has been that they have been associated with several side effects, including flushing, and they’ve been difficult to titrate. So, there have been some difficulties in terms of compliance with patients. And some of this can then be addressed with an extended-release formulation such as Niaspan®, which is now available, that treats HDL cholesterol, LDL cholesterol, triglyceride. As you’ll see, it is not associated with many of the difficulties that have been demonstrated with these more immediate release preparations.
Meyers CD et al. Ann Intern Med 2003;139: HPS Collaborative Group. Lancet. 2002;360;7-22.

69. Lipids and Lipoproteins: Pharmacotherapy
Intermediate Risk Women (10-yr absolute CHD risk 10%-20%)
Initiate LDL-C–lowering therapy (preferably statin) if LDL-C level is > 130 mg/dL on lifestyle therapy (Class I, Level A), or niacin or fibrate therapy when HDL-C is low or non–HDL-C is elevated after LDL-C goal is reached (Class I, Level B)GI=1
Now, let’s move on to intermediate risk women, those who have 10% to 20% absolute risk over the next 10 years. The recommendations include initiating LDL-lowering therapy, preferably with a statin if the LDL cholesterol is greater than or equal to 130 milligrams per deciliter on lifestyle therapy. And again, use niacin and fibrate therapy when HDL cholesterol is low or non-HDL cholesterol is elevated after the LDL goal has been reached.
Class I Intervention is useful and effective
Level A Sufficient evidence from multiple randomized trials
B Limited evidence from single randomized trial or other nonrandomized studies
Mosca L, et al. Circulation 2004;109:

70. Lipids and Lipoproteins: Pharmacotherapy
Lower Risk Women (10-yr absolute CHD risk <10%)
Consider LDL-C–lowering therapy:
0 or 1 risk factor when LDL-C level is > 190 mg/dL
If multiple risk factors are present when LDL-C is >160 mg/dL (Class IIa, Level B)
Niacin or fibrate therapy when HDL-C is low or non–HDL-C elevated after LDL-C goal is reached (Class IIa, Level B)GI=1
Among the lower risk women, those who now fall into a coronary heart disease risk of less than 10% over the next 10 years, LDL-lowering therapy can be considered among women who have 0 or 1 risk factor when the LDL cholesterol is greater than or equal to 190, or if there are multiple risk factors present when the LDL is equal to or exceeds 160 milligrams per deciliter or niacin or fibrate therapy when HDL-C is low or non—HDL-C elevated after LDL-C goal is reached.
Class I Intervention is useful and effective
Level A Sufficient evidence from multiple randomized trials
B Limited evidence from single randomized trial or other nonrandomized studies
Mosca L, et al. Circulation 2004;109:

71. ACC/AHA/NHLBI Clinical Advisory on Statins
Combination therapy is generally safe
1% incidence of CK (>3x) elevation with statin and fibrates
Incidence CK (>3x) elevation is even less with statin and niacin
CK and statins
Obtain baseline CK
Obtain CKs if patient reports suggestive muscle symptoms
Discontinue statin if CK > 10x in patients with muscle symptoms
If muscle symptoms without CK or with moderate CK elevation, follow clinically
Asymptomatic patients with moderate baseline CK elevation may still be safely treated with statins
Some of your patients will have questions about the safety of statins even though it is a class I recommendation for high and intermediate risk women and this may be one barrier to adherence to the guidelines. This may partly be due to the voluntary withdrawal of cerivastatin (Baycol) from the U.S. market on August 8, 2001, by the manufacturer, in agreement with the FDA, had prompted concern on the part of physicians and patients regarding the safety of statins. In response the American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute issued a Clinical Advisory, intended to summarize for professionals the current understanding of statin use, focused on myopathy, and to provide updated recommendations for the appropriate use of statins, including cautions, contraindications, and safety monitoring for statin therapy. They stated that “statins have proven to be extremely safe in the vast majority of patients receiving them. Few significant side effects were observed in clinical trials, and post-marketing reports of adverse events have been very limited when considered in comparison to the very large number of persons safely receiving these drugs. Even so, these drugs are not entirely free of side effects, and as for all drugs, they should be used appropriately and judiciously. This advisory encourages the appropriate use of statins while pointing out the possibility of side effects in certain patients. If statins are used with appropriate caution in these selected patients, the likelihood of developing clinically important myopathy should be substantially reduced.”
Pasternak RC et al. J Am Coll Cardiol. 2002;40:

72. Bottom Line Can we identify women at risk? (yes)
Do we have therapy to reduce risk? (yes)
Do we uniformly apply this knowledge? (no)
Patient related
Physician barriers
Health system barriers
Societal issues
Compliance
Let’s review the bottom line about lipid management in women. First of all, we know we can identify women at risk. We also have shown that we have therapy to reduce risk, yet, unfortunately, we’re not yet uniformly applying this knowledge in our practice. So, how can we better improve the practice of prevention among women and optimize their lipid therapy?
As a beginning, we should be aware that there are barriers at many levels, including those associated with patients, the physician, the health system, and society. We also need to pay attention to compliance. We need to discuss with patients what their concerns are and what their side effects might be. We need to educate them about ways to reduce side effects, for example, by using aspirin therapy prior to the use of extended-release niacin to limit flushing. We can also consider single-pill combination therapy to improve compliance. We can help by putting into proper perspective for our patients what the potential side effects are along with the benefits that have been documented with substantial clinical evidence.

73. Conclusions CVD is leading killer of women yet awareness is suboptimal
Lipids are common and important risk factors in women
Substantial data exists on reducing CV events by treating dyslipidemia in women
If new guidelines are more uniformly implemented, the burden of CVD in women will be reduced
In conclusion, cardiovascular disease remains the leading killer of women and we need to continue our efforts to raise awareness. We’ve shown that lipids are common and important risk factors in women and that we have substantial data to support the statement that appropriate management of lipids will result in a reduction of cardiovascular disease. And finally, the hope is that by sharing the new guidelines with you that this allows you to put prevention more confidently and consistently into your own practice.