Women and Coronary/Ischemic Heart Disease

PCOMS Winter ConferenceRonald L Walsh, D.O.

The Heart Institute at LargoJanuary 29, 2015

DISCLOSURES:

I HAVE NO FINANCIAL/ETHICAL CONFLICTS FOR THIS PRESENTATION

WHY???Women traditionally did not take

heart disease seriously and until recently, neither did many physicians; yet CVD in women is a major problem.

Recent studies have brought attention to the need to recognize, prevent and secondarily treat heart disease in women.

Improvement in this area has potential for major benefits in both US women and women in many industrialized countries.

Case ReportDJ is a 36 y/o female mother of 2 who suddenly experienced severe burning in her

upper chest and neck while

Case Study

DJ is a 36 y/o female mother of 2 who suddenly experienced severe burning in her upper chest and neck while driving to pick up her children. She went to the nearest ER and was diagnosed with a NSTEMI and following w/u including angiography was treated medically including aspirin, statin, beta-blocker and ARB. 4 years later she developed anginal symptoms and received 2 coronary stents and has been stable since then. She had a very strong family hx/o premature CAD and dyslipidemia. Her younger sister was screened for CAD and is on aggressive preventive therapy.

Myths vs Facts

Myths Facts

Men are more likely to have heart disease

Heart disease is the #1 killer of men and women; 50,000 more women than men die of heart disease every year

Cancer is a bigger threat than heart disease

Nearly twice as many US women die from heart disease and stroke than from all cancers combined

Doctors are aware of women’s risk for heart disease and act accordingly

Undertreatment and underdiagnosis of heart disease in women contributes to excess mortality in women

Magnitude of the Problem2.5 million women per year in the

US are hospitalized with cardiovascular disease (CVD)

Deaths from CVD = 500,000/yr

Leading cause of death in US women: CAD

>230,000 women die from CAD each year

The Problem

Although death rates from Cardiovascular Disease have declined overall, there is less improvement in survival among women compared to men, according to the American Heart Association’s 2010 Statistical Update Report.

The reasons for this include:

The Problem (Cont.)

LACK OF PROFESSIONAL AWARENESS AND PREVENTIVE FOCUS.

LESSER VALIDATION OF DIAGNOSTIC TESTS IN WOMEN.

LACK OF RECOGNITION OF GENDER DIFFERENCES.

LACK OF EDUCATION AND AWARENESS AMONG WOMEN.

Women and Heart Disease: AHA Stats (Roger et al)More common than you may think 42.7 million women are currently living with

some form of cardiovascular disease (CVD).1 7.5 million women are currently living with

coronary heart disease (CHD).1 More than 3 million women have a history of

heart attack.1 1Roger V L, Go A S, Lloyd-Jones D, Adams R J,. et al. Heart Disease

and Stroke Statistics 2011 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2011; 121:e1-e192.

The Scope of the Problem

One woman dies every minute from cardiovascular disease in

the U.S.!

Heart Disease and Stroke Statistics - 2013 Update, AHA

The Scope of the Problem

CVD accounts for a third of all female deaths

CVD and CAD disproportionately affect African-American and Latina women

CDC data and Heart Disease and Stroke Statistics - 2012 Update, AHA

The Scope of the Problem

Women are roughly 10 yrs older than men when they present, and have more co-morbidities

Young women also develop CAD and have a worse prognosis than men

Women are more likely to wait before presenting to medical attention

Stangl V, et al. Eur Heart J 2008;29:707; Mosca L et al. Circulation 2005;111:499; Wenger NK. Circulation 2004;109:558; Alter DA et al. JACC 2002;39:1909

The Scope of the Problem

Women are referred less often for appropriate testing or treatment

Women with MI are more likely to have complications and increased mortality

Fewer women have been included in studies, so there’s less data

Prevalence of stroke by age and sex (NHANES: 2005–2008).

20-39 40-59 60-79 80+0

2

4

6

8

10

12

14

16

18

0.3

1.6

7.2

14.5

0.5

2.4

8.2

14.8

Men Women

Age

Per

cen

t o

f P

op

ula

tio

n

Source: NCHS and NHLBI.

©2010 American Heart Association, Inc. All rights reserved. Roger VL et al. Published online in Circulation Dec. 15, 2010

Awareness is lacking!

Awareness is lacking!~2500 women > 25 y.o. surveyedBetween 1997-2012, awareness among whole study population nearly doubled: 30%56%(Still 44% Unaware!!!)

Still low in minorities:Blacks: 36%Hispanics: 34%

Mosca L, et al. Fifteen-year trends in awareness of heart disease in women. Circulation 2013; 127.

Awareness

Mosca L, et al. Fifteen-year trends in awareness of heart disease in women. Circulation 2013; 127.

Risk FactorsAge over 55Dyslipidemia: high LDL and/or low

HDLFamily hx of premature CAD

First degree male < 55, female <65

DiabetesSmokingHypertensionPeripheral arterial disease

Risk factorsMenopauseObesityHigh triglyceridesMetabolic syndromeSedentary lifestyleCollagen vascular

disease/autoimmune diseaseCKD

Risk factorsPregnancy-related

Pre-eclampsia, eclampsiaGestational diabetesStillbirthMiscarriages, esp. multiple

Hx of cancer treatments (XRT)Depression and stressHx of trauma or abuse

Effect of smoking

Women who smoke have a six-fold increased risk of MI (vs. 3x in men)

Risk was higher for women smokers than men regardless of age

Njolstad I et al. Circulation 1996;93(3):450; Prescott E et al. BMJ 1998;316(7137):1043

ReproductivePregnancy-related

“failed stress test:Pre-eclampsia – 3.8x more likely to develop DM, 11.6x more likely to develop HTN requiring rx

Gestational DM: up to 70% develop DM within 5 years

MenopauseMagnussen 2009, Kim 2002

Development of Atherosclerotic Plaques

NormalFatty streak

Foam cells

Lipid-rich plaque

Lipid core

Fibrous cap

Thrombus

Ross R. Nature. 1993;362:801-809.

Most Myocardial Infarctions Are Causedby Low-Grade Stenoses

Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.(Adapted from Falk et al.)

Falk E et al, Circulation, 1995.

(Adapted from Glagov et al.)

Coronary RemodelingCoronary Remodeling

Normalvessel

MinimalCAD

Progression

Compensatory expansionmaintains constant lumen

Expansion overcome:

lumen narrows

SevereCAD

ModerateCAD

Glagov et al, N Engl J Med, 1987.

• Eccentric, lipid-rich• Fragile fibrous cap• Prior luminal obstruction <

50%• Visible rupture

and thrombus

Constantinides P. Am J Cardiol. 1990;66:37G-40G.

Features of a Ruptured Atherosclerotic Plaque

Libby P. Circulation. 1995;91:2844-2850.

Vulnerable Plaque

•Thin fibrous cap•Inflammatory cell infiltrates: proteolytic activity•Lipid-rich plaque

Lumen LipidCore

Fibrous Cap

•Thick fibrous cap•Smooth muscle cells:

more extracellular matrix•Lipid-poor plaque

Stable Plaque

LumenLipidCore

Fibrous Cap

Vulnerable Versus Stable Atherosclerotic Plaques

Correlation of CT angiography of the coronary arteries with intravascular ultrasound illustrates the ability of MDCT to demonstrate calcified and non-calcified coronary plaques (Becker et al., Eur J Radiol 2000) Non-calcified, soft, lipid-rich plaque in

left anterior descending artery (arrow) (Somatom Sensation 4, 120 ml Imeron 400). The plaque was confirmed by intravascular ultrasound (Kopp et al., Radiology 2004)

Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)

RevascularizationAnti-anginal Rx

Exertional angina• (+) ETT

Severe fibrotic plaque• Severe obstruction• No lipid• Fibrosis, Ca2+

Pharmacologic stabilizationEarly identification of high-risk?

Plaque rupture• Acute MI• Unstable angina• Sudden death

Vulnerable plaque•Minor obstruction•Large lipid pool•Thin fibrous cap

Courtesy of PH Stone, MD.

From: Microemboli and Microvascular Obstruction in Acute Coronary Thrombosis and Sudden Coronary Death: Relation to Epicardial Plaque Histopathology

J Am Coll Cardiol. 2009;54(23):2167-2173. doi:10.1016/j.jacc.2009.07.042

Coronary Artery Occlusion From Eroded PlaqueEpicardial coronary arteries with occlusive macroscopic thrombus (A to C) due to plaque erosion. Longitudinal sections (A, B, and C) and transaxial sections from a different vessel (D, E, and F) show the deep lipid core is not exposed. Immunostains of the thrombus for platelet (CD61, B and E) and fibrin (C and F) components reveal that the typical thrombus frequently is a mixed platelet-fibrin mixture. Images are from patients not included in the study, but illustrate typical coronary thrombus in sudden death due to plaque erosion. CD61 immunostain shows platelets within the thrombus are diffusely scattered throughout (slender arrow in B); junction between thrombus and the arterial plaque (thick arrow in B). The ‘cap’ of this thrombus is very fibrin-rich (arrow in C).

Figure Legend:

What are the symptoms?

Chest pain or discomfort

Unusual upper body discomfort

Shortness of breath

Breaking out in a cold sweat

Unusual or unexplained

fatigue (tiredness)

Light-headedness or sudden dizziness

Nausea (feeling sick to the stomach)

Symptoms in women with MI

Study of 515 women with MIChest pain absent in 43%Most common symptom:

Dyspnea in 58%Weakness in 55%Fatigue in 43%

Prodrome:Fatigue in 71%Sleep disturbance (48%), dyspnea (42%)McSweeney JC, et al. Circulation

2003;108:2619

Symptoms in women with MI

Over 1,000,000 men and women in NRMI registry, 1994-2006 (481,581 women)42% of women presented without CP (vs. 31% of men)

Higher in-hospital mortality in women (14.6%) than in men (10.3%)

Younger women without chest pain were at the highest risk

Canto JG et al. JAMA 2012;307:813

Women with MIThese women who presented

without CP were sicker and fared worse:More had DMLater presentationMore CHFMore NSTEMILess timely therapiesLess antiplatelet meds, heparin, BB Canto JG et al. JAMA 2012;307:813

Risk of Sudden Cardiac Arrest

Sudden cardiac deathHigher rates in menHowever, a significantly higher percentage of women who have SCD had no prior symptoms! (63% vs. 44%)

Canto JG et al. JAMA 2012;307:813

Aspirin : Primary Prevention in WomenWomens’ Health Study (WHS)

0.00

0.01

0.02

0 2 4 6 8 10

Cum

ulat

ive

Inci

denc

e of

MI

Placebo

Aspirin

P=0.83

Ridker P et al. NEJM 2005;352:1293-304

Years

39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years

Aspirin does not reduce the risk of MI in low risk women

But…

Stroke Statistics U.S. StatisticsThe risk stroke doubles each decade after

the age of 55. ~25% of strokes occur in people < 65 years of

age. Stroke death rates are higher for African

Americans than for whites, even at younger ages.

Each year, about 55,000 more women than men have a stroke.

The risk of ischemic stroke in current smokers is about double that of nonsmokers

High blood pressure is the most important risk factor for stroke. 

U.S. Centers for Disease Control and Prevention and the Heart Disease and Stroke Statistics - 2010 Update

New Anticoagulants for AFDabigatran (Pradaxa): RELY Trial;

Available Now, GI side effects major problem but very effective and accepted by pts.

Rivaroxaban ROCKET AF Trial: FDA just approved it and should be available soon.

Apixaban ARISTOTLE and AVERROS Trials reported and expected FDA approval soon.

NOTE: New Guidelines use CHADS2VA2Sc scoring and extra point just for being female is due to the known higher risk of stroke in women!

Risk Assessment

Risk Stratification by Framingham Risk Equation (FRE)(Older Recommendation since 2003)

Calculates Cornary Heart Disease Risk (MI, Angina, SCA) and NOT overall Cardiovascular Risk (CAD, Stroke, CHF, PVD)

Calculates a 10 year risk of CHD for all patients with two or more risk factors that do not already meet criteria for CHD equivalent

Source: Mosca 2004

Problems with using only the Framingham Risk Equation (FRE)in WomenWomen have higher risk of STROKE and

CHF in middle age and beyond than men do and this is not accounted for in FRE of only CHD risk. Therefore other factors need to be taken into account to predict true risk for total CVD events.

It is difficult for a woman <75 y/o even with several abnormal risk factors to exceed a FRE of even 10% 10-year risk let alone a 20% risk.

Therefore, other risk factors need to be considered to more accurately predict a true CVD event risk for older women.

Recommendation to begin with a Global Risk Assessment using the Pooled Cohort Equations to estimate 10-year ASCVD RiskTakes into account multiple factors that correlate to TOTAL CV Risk.

Pooled Cohort Equations 10-year ASCVD Risk Calculator (Framingham, ARIC, CARDIA, and CHS)

Key differences between old and new guidelines

Factor Old Guideline New Guideline

Goal Lower LDL Lower CVD risk

Determination of treatment

Based on risk factors (+/-risk of hard CHD events) and LDL

Based on risk of hard ASCVD events and LDL

Lifestyle versus meds in high risk

Lifestyle first, then meds (unless CHD equivalent)

Meds on foundation of lifestyle

Choice of meds Any Focus on statins

Dosing of statins ---- Based on risk

Monitoring of effect

To various LDL goals To expected effect—30% or 50% reduction in LDL from baseline

Know these lower risk numbersBlood pressure 120/80LDL cholesterol <100HDL cholesterol > 50 Triglycerides < 150Non HDL cholesterol <130BMI 18.5-24.9 (kg/m2)Waist < 35 inches female or 40 maleDiabetes: hemoglobin A1C <6.5%

Major Risk Factor InterventionsBlood Pressure

Target BP<120/80 mmHgPharmacotherapy if BP> 140/90, or > 130/80

in diabetics or patients with renal diseaseLipids

Follow newer guidelines by new Pooled Risk Equation

Diabetes Target HbA1C<6.5%Smoking Cessation

Source: Mosca 2004

Lifestyle Interventions

Smoking Physical Activity Heart healthy dietWeight reduction/maintenancePsychosocial factorsOmega 3 fatty acidsCardiac rehabilitation

Source: Mosca 2004

Relative Risk of Coronary Events for Smokers Compared to Non-Smokers

3.12

5.48

1

0

1

2

3

4

5

6

Never Smoked 1-14 Cigarettes perday

15 Cigarettes perday

Relative Risk

Source: Adapted from Stampfer 2000

Guideline on Treatment of Cholesterol

Total Cholesterol Distribution: CHD vs Non-CHD Population

Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.

35% of CHD Occurs in People with TC<200 mg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal

Risk of CHD by HDL-C and Total-C levels; aged 48–83 yCastelli WP et al. JAMA 1986;256:2835–2838

02468

101214

< 40 40–49 50–59 60< 200

230–259200–229

260

HDL-C (mg/dL) Tota

l-C (m

g/dL

)

14

-y in

cid

en

ce

rate

s (%

) fo

r C

HD

11.24

11.91

12.50

11.91

6.56

4.67

9.05

5.53

4.85

4.153.77

2.782.06

3.83

10.7

6.6

High- and Moderate-Intensity Daily Statin Therapy

High Intensity (Lowers LDL-C ≥ 50%)Atorvastatin 40-80

mgRosuvastatin 20-40

mg

Moderate Intensity (Lowers LDL-C 30-50%)Atorvastatin 10 (20)

mgRosuvastatin (5) 10

mgSimvastatin 20–40 mgPravastatin 40 (80)

mgLovastatin 40 mgFluvastatin XL 80 mgFluvastatin 40 mg

2x/dayPitavastatin 2–4 mg

Bold = Tested in RCT andreviewed by Expert PanelBlue= Not tested in RCT reviewed by Expert Panel

Efficacy of Intensive Lowering of LDL-C in Subjects with Low Baseline LDL-C

Meta-analysis of RCT’s of >1000 participants and ≥2 years treatment duration of more versus less intense statin trials involving 169,138 subjects

The major vascular event reduction, among in those with baseline LDL-C <77mg/dL per further 39 mg/dL reduction was 29% (99% CI 2-48, p=0.007); in those with baseline LDL-C <70 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction (RR 0.63, 99% CI 0.41-0.95, p=0.004).

Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:1670-81

Overall ApproachA (strong)E (expert opinion)

A (strong)

A (strong)E (expert opinion)

B (moderate)

Tailoring Primary Prevention to Risk

Thresholds for Prescribing Statins

0.0% 5.0% 10.0% 15.0% 20.0% 25.0%0

10

20

30

40

50

60

70

80

90

100

110

120

Series1

10-yearASCVD risk

NN

T t

o p

reve

nt

1 A

SC

VD

eve

nt

ove

r 10 y

ears

NNH=33

BENEFITS AND HARMS WITH HIGH INTENSITY STATIN TREATMENTAssumes a 45% relative risk reduction in ASCVD from high intensity statin

treatment

Circulation Nov 11, 2013: epub

NEJM, epub March 2014

Too Many People Treated?

SummaryNew cholesterol guidelines offer

improvements in evidence-based recommendations, but have been controversial

To realize the potential of the guideline, we need agreement and strategies to aid implementation

Dietary Interventions

Depression and CHD: Results from the Women’s Health Initiative Study

Depression is an independent predictor of CHD death among women with no history of CHD

Source: Wassertheil-Smoller 2004

Psychosocial Stressors in Women with CHD: The Stockholm Female Coronary Risk Study

Among women who were married or cohabitating with a male partner, marital stress was associated with nearly 3-fold increased risk of recurrent CHD events

Living alone and work stress did not significantly increase recurrent CHD events

Source: Orth-Gomer 2000

Coronary Disease Mortality and Diabetes in Women

0

10

20

30

40

50

60

0 - 3 4 - 7 8 -11

12 -15

16 -19

20 -23

Duration of follow-up (yrs)

Mo

rtal

ity

Rat

e (p

er 1

000

wo

men

)

Diabetic WomenNondiabetic Women

Source: Adapted from Krolewski 1991

Benefits of ASA in Women with Established CAD

2.7

5.15.1

9.1

0123456789

10

Aspirin No Aspirin

Mortality at 3 Years

Follow-Up (%)

CVDMortality

All CauseMortality

* P = 0.002 **P = 0.0001

*

**

Source: Adapted from Harpaz 1996

Preventive Drug InterventionsAspirin – Lower risk women

Many women, especially those age 65 and older, may benefit from taking low-dose aspirin every other day to prevent stroke

Women over age 65 may benefit from taking low-dose aspirin to reduce major cardiovascular events

The use of low dose aspirin in lower risk women should be balanced against the risk of increased risk of GI bleeding.

Source: NHLBI

Menopausal Hormone Therapy and CVD: Summary of Major Randomized Trials

Use of estrogen plus progestin associated with a small but significant risk of CHD and stroke (Much worse in smokers!)

Use of estrogen without progestin associated with a small but significant risk of stroke

Use of all hormone preparations should be limited to short term menopausal symptom relief

Source: Hulley 1998, Rossouw 2002, Anderson 2004

DiagnosisTreadmill stress testingNuclear stress testing Stress echoCT calcium scoreCoronary CTACardiac catheterization with

coronary angiography

Stress Testing (sensitivity/specificity)

ETT only (lower than in men)61% and 70%

Stress Nuclear (similar in men)78% and 64%

Stress Echo (similar in men)86% and 79%

Kwok Y, et a;. Am J Cardiol 1999; 83:660.

Interventional treatment in womenLess likely to be referredHigher complication rate than in

menSmaller arteries, more bleeding

But these pts do better than if no intervention

Higher peri-procedural rate of complication but better long-term survival than men

Anand SS et al. JACC 2005;46:1845; King KM et al. JAMA 2004;291:1220; Anderson ML et al. Circulation 2012; 126:2190

Bleeding

Women have more bleeding than menTechnical factors, medication issues

RISK-PCISame efficacy as in menHigher bleedingHigher mortality

Can J Cardiol 2013; 29:1097

Bleeding

Bleeding avoidance strategiesTransradial approach, closure devices, bivalrudin

Lower bleeding rates in both sexes

Higher absolute bleeding rate

JACC 2013; 61:2070; Circ 2013; 127:2295

Other cardiac causes of chest painWomen’s ischemic heart disease

(syndrome X, microvascular disease)Myocarditis

Stress-induced cardiomyopathyCoronary dissection

Plaque erosion with distal embolization

Take-home points

CAD and CVD are by far the biggest health risks for women

Awareness is still less than it needs to be

Prevention CAN reduce riskDiagnostic testing accuracy can be

different between men and women.Clinical presentations and awareness

are different in women and men.

SUMMARYCVD is overall more common and severe in

women than men taking into account all age groups.

Women do not get the same evaluation and guideline treatment that comparable men receive.

Awareness of CVD in women in greatly improving as well as increased adherence to guidelines due to increased initiatives over the last decade.

Expect to see more studies include larger numbers of women to better evaluate diagnostic and theraputic options for women with CVD.

Questions / Comments

THE END, THANK YOU