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Sex-‐specific research and clinical care; Why women's cardiovascular
health can't wait.
Cardiology Rounds February 2015
(gender)
Every cell is sexed Every person is gendered
Sex
(gender)
• Biological construct (often understood as a binary man/woman)
• Encompasses hormones, genes, anatomy, physiology etc.
• Affects propensity for trajectories, prevalence and treatment of health conditions and diseases • Differences in drug absorption, body composition, metabolism, diseases and conditions according to sex
Gender
(gender)
• A social construct; developed by social scientists (Female/Male)
• Gender while rooted in biology is shaped by the environment and experiences
• Linked to power and to economic and social status • Is culturally specific, and temporal • Distinct from sex • Has a number of dimensions
– gender roles, – gender identity, – gender relations, – institutionalized gender
Binary vs Spectrum
What we know
• At this point all differences idenJfied are based on SEX-‐
Significant differences in health outcomes for men and women
• Men die younger than women. In Canada the mortality rate for men is 78 years compared to 82.7 years for women.
• Women experience a heavier burden of chronic illness.
• Men’s and women’s use of the health system differs.
• Men and women respond differently to therapies.
Understanding Sex and Gender Differences in Health Outcomes
• Neither biological (sex) nor gender (more on this measurement later!) explanaJons fully account for the differences in men’s and women’s health
• An understanding of how these factors combine to affect the health of men and women is not fully developed
Road to Health Inequity • Animals and human studies typically use males or do not idenJfy sex when females are included
• Women are unrepresented in clinical trials. Even when included, researchers fail to analyze and report by sex
Road to Health Inequity • Females of reproducJve age unsuitable due to risk of pregnancy: female reproducJve cycle and hormonal fluctuaJons increases variaJon
• Thalidomide and diethylsJlbestrol led to policies that excluded women from phase 1 and 2 RCT= majority of research from la\er half of 20th century biased towards men PARTICULARLY in CVD
Pilote and Humphries 2014 CCS
Road to Health Inequity • 1993 NIH –guidelines inclusion of women in all phases of RCTs ALSO phase III RCT assess sex-‐based differences
• Between 2000 and 2007 FDA approved 78 high risk CV devices based on paJent populaJon 67% men with sex specific analyses in only 41% of studies.
Pilote and Humphries 2014 CCS
Road to Health Inequity • EXAMPLE = Implantable cardioverter-‐defibrillator with approval granted despite low enrollment of women
• IMPLICATIONS = meta-‐analyses demonstrated lack of efficacy of implantable cardioverter-‐defibrillators in primary prevenJon trial in women with heart failure.
• VAD approved for paJents with advanced heart failure with 23% (44 women) in study populaJon – Device is marketed as suitable for women given small size, BUT risk of stroke reported to be 2 Jmes higher than in men (Heart mate II)
Pilote and Humphries 2014 CCS
Road to Health Inequity • Findings (based on men) are translated into clinical pracJce
• Outcome measures are not analyzed or reported by sex
Difference Specific to CV Disease • Cardiovascular disease affects women and men differently including – Prevalence – Underlying physiology – PresenJng symptoms – Risk factors – Outcomes
The Scope of the Problem
Heart Disease and Stroke StaJsJcs -‐ 2013 Update, AHA Barry Norris et al unpubished data 2014
• Cardiovascular disease is BY FAR the biggest killer of women
– Roughly 401,000 deaths/year from CVD (vs. 386,000 men) (US) – 176,255 deaths/year from CAD Vs 39,520 deaths from breast cancer
Women still report Breast Ca more likely to kill them compared to heart disease
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. CirculaJon 2005;111:499; Wenger NK. CirculaJon 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
Physiology • The role of
– Estrogen – Oral contracepJves – Pregnancy – Menopause and hormone therapy – Cholesterol/Triglycerides
The role of Estrogen • protecJve effect on women's cardiovascular health can change depending on a variety of factors and condiJons.
• Aper menopause, as natural estrogen levels drop, women reported to develop high cholesterol.
Oral ContracepIves
• Oral contracepJves (in small proporJon of women) increases the risk of high blood pressure and blood clots.
• The risk is greater if – Smoker – Hypertensive – Over the age of 40, – or already have a blood cloqng problem.
Pregnancy • Pre-‐eclampsia • GestaIonal diabetes
– increase the risk of the mother and baby developing diabetes later in life.
– The risk of a pregnancy-‐related stroke is greatest during childbirth and few weeks thereaper
Menopause • An increase in total blood cholesterol, low LDL or/and triglyceride levels
• A decrease in HDL • A tendency toward higher blood pressure
• An increase in central body fat = increased risk of thromboembolism and diabetes
Social and Environmental Influences
• Stress and poverty differ for women compared to men and accentuate differences in the – Expression – Diagnosis – Treatment – Outcomes
Lee et al 2003; Schulman et all 1999; Slopen et al 2012
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 MI
– Chest pain absent in 43% – Most common symptom:
• Dyspnea in 58% • Weakness in 55% • FaJgue in 43%
– Prodrome: • FaJgue in 71% • Sleep disturbance (48%), dyspnea (42%)
McSweeney JC, et al. CirculaJon 2003;108:2619
• 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
Symptoms in women with MI
• These women who presented without CP were sicker and fared worse: – More had DM – Later presentaJon – More Killip III/IV – More NSTEMI – Less Jmely therapies – Less anJplatelet meds, heparin, BB
Canto JG et al. JAMA 2012;307:813
Symptoms in women with MI
• Sudden cardiac death – Higher rates in men
– However, a significantly higher percentage of women who have SCD had no prior symptoms! (63% vs. 44%)
Canto JG et al. JAMA 2012;307:813
Symptoms in women with MI
Risk Factors for Women • Age over 55 • Dyslipidemia: high LDL and/or low HDL • Family hx of premature CAD
– First degree male < 55, female <65 • Diabetes • Smoking • Hypertension • Peripheral arterial disease
Risk factors for Women • Menopause • Obesity • High triglycerides • Metabolic syndrome • Sedentary lifestyle • Collagen vascular disease/autoimmune disease
• CKD
Risk factors for Women • Pregnancy-‐related
– Pre-‐eclampsia, eclampsia – GestaJonal diabetes – SJllbirth – Miscarriages, esp. mulJple
• Hx of cancer treatments (XRT)
• Depression and stress • Hx of trauma or abuse
Which risk factors are more predicIve in women?
• Low HDL is more predicJve than high LDL
• Lp (a) can be more predicJve in younger women
• TG can be more predicJve in older women, especially if >400 mg/dL (4.5 mmol/L) Rich-‐Edwards, JW et al. NEJM 1995; 332:1758; Miller VT.
Atherosclerosis 1994; 108 Suppl:S73; Orth-‐Gomer K. CirculaJon 1997;95:329
• Diabetes: almost double the risk of fatal CAD
• Smoking: – associated with 50% of all coronary events in women
– Risk elevated even with minimal use
Zuaneq G et al. JACC 1993;22:1788; Wille\ WC etal.NEJM 1987;317:1303
Which risk factors are more predicIve in women?
Effect of smoking
Njolstad I et al. CirculaJon 1996;93(3):450; Presco\ E et al. BMJ 1998;316(7137):1043
• 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
ReproducIve • Pregnancy is stress test to understand CVD
– Pre-‐eclampsia – • 3.8 x more likely to develop DM, • 11.6 x more likely to develop HTN requiring rx
– GestaJonal DM: up to 70% develop DM within 5 years – Recurrent pregnancy disorders strongly associated with cardiovascular risk factors
• Menopause – ONLY total cholesterol, LDL and ApoB demonstrated substanJal increase within 1 year before and a0er FMP –other CVD risk factors were indicaJve of model of chronological age
Magnussen 2009, Kim 2002, Ma\hews et all JACC 2009
Diagnosis • Treadmill stress tesJng • Nuclear stress tesJng • Stress echo • CT calcium score • Coronary CTA • Cardiac catheterizaJon with coronary angiography
Stress TesIng • ETT
– Lower accuracy for women – Studies with prevalence of CAD similar in men and women sJll show lower
accuracy – Other mechanisms suggested
• Digoxin-‐like effect of estrogen • Inappropriate catecholamine response to exercise • Different chest wall anatomy • Higher incidence of mitral valve prolapse • Developed using men, thresholds for abnormal established almost exclusively with men
• Stress Nuclear – Higher sensiJvity but lower specificity than ETT for diagnosis in women – Breast Jssue in women can cause arJfact (new isotope may decrease this
issue) • Stress Echo
– SensiJvity and specificity higher in stress echo than ETT and Thallium Scan
Kwok Y, et a;. Am J Cardiol 1999; 83:660.
Coronary Computed Tomographic Angiography (CTA)
• ROMICAT-‐II* trial-‐ evaluated sex-‐based differences in effecJveness of early cardiac CTA – Women had greater reducJon in LOS, lower admission rates, lesser increased cumulaJve radiaJon doses than men in a comparison of ED strategies
– Early CCTA strategy ‘a\racJve opJon’ in women presenJng to ER
Truong Q et al. CirculaJon 2013; 127;2494 * Rule out MI with CAT
Diagnosis
Shaw LJ et al. Ann Intern Med 1994;120:559; Hachamovitch R et al. JACC 1995; 26: 1457
• Women less likely to be referred for further evaluaJon if they have a posiJve stress test – Higher incidence of MI or death in these paJents
Treatment/PrevenIon
Mosca L et al; CirculaJon 2011;123:1243
• All women – Physical acJvity – Quit smoking – Dietary Intake – Weight Managemant
• BMI <25, waist circumference <35 in. – Treat risk factors: HTN, DM, dyslipidemia
– ASA – look at risk/benefit raJo – Treat depression
• Increasing awareness • Screening
Treatment in ACS or acute MI • Medical therapy Issues with dosages not simply due to women being smaller than men;women metabolize drugs differently because they have a higher percentage of body fat and are exposed to different levels of hormones
– Aspirin, beta blockers, ACE-‐inhibitors – StaJns
Treatment/PrevenIon PreventaJve drug intervenJons – ASA
• high risk women (class I level A), women with diabetes (Class IIA ; Level B) • At risk or healthy women >=65 yrs if BP controlled and risk for ischemic stroke
and MI prevenJon outweighs risk of GI bleed and Hemorrhagic stroke (Iia;B) • Atrial FibrillaJon for women with contraindicaJon to warfarin or at low risk of
stroke CHADS2 score <2 (Class I level A) – Warfarin-‐ Atrial fibrillaJon, low risk of stroke (Class I ; Level A) – Dabigatran -‐alternaJve to warfarin for AF (I;B) – Beta Blockers
• Up to 12 months (class I level A) or up to 3 years (Class I level B) all women post MI or ACS
• Long term for women with LV failure unless contraindicated (Class I ; Level A) • Long-‐term may be considered in women with CAD and Normal LVF (class IIb
level C)
Mosca et al 2011-‐ CirculaJon 123
Treatment/PrevenIon
Ace inhibitors/ARBs • Used in women aper MI and/or clinical evidences of HF LVEF
<=40% or DM (Class I ; Level A) • Women aper MI and/or clinical evidences of HF LVEF <=40% or
DM but INTOLERANT of ACE inhibitors ARBs used instead (Class I ; Level B)
Aldosterone Blockade • Use is indicated aper MI in women who do not have
hypotension, renal dysfuncJon, or hyperkalemia who are on doses of ACE inhibitors and B-‐blocker and have LVEF,≤40% with symptomaJc heart failure (Class I ; Level B)
IntervenIonal treatment in women • Less likely to be referred • Higher complicaJon rate than in men
– Smaller arteries, more bleeding
• But these pts do be\er than if no intervenJon • Higher peri-‐procedural rate of complicaJon but be\er 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. CirculaJon 2012; 126:2190
Treatment of ACS, NSTEMI, STEMI
• Early invasive strategy for high-‐risk paJents • PCI for STEMI
– Be\er than fibrinolysis or POBA
Glaser R et al. JAMA 2002;288:3124; Mueller C et al. JACC 2002;40:245; Lansky AJ et al. CirculaJon 2005;111:1611
Bleeding • Women have 2 xs more bleeding than men following PCI – Technical factors, medicaJon issues – RISK-‐PCI
• Same efficacy as in men • Higher bleeding • Higher mortality
Mrdovic Can J Cardiol 2013; 29:1097
Bleeding • Bleeding avoidance strategies
– Transradial approach, – Closure devices, – Bivalrudin
• Lower bleeding rates in both sexes
Radial and Bivalrudin ( OR 0.31 women vs 0.46 men)
JACC 2013; 61:2070; Circ 2013; 127:2295
Other cardiac causes of chest pain
• Women’s ischemic heart disease (syndrome X, microvascular disease)
• MyocardiJs
– Stress-‐induced cardiomyopathy
• Coronary dissecJon
Cancer and CV disease • Chemotherapy toxicity: anthracyclines and HercepJn – CommunicaJon and monitoring – Treatment of baseline risk factors: HTN, DM, CAD and LV dysfxn pts at higher risk
– Older paJents – CombinaJon chemo and higher dose chemo – CombinaJon with XRT
Cancer and CV disease • RadiaJon toxicity
– Effects on all parts of the heart – Most common sign: pericardial effusion – Starts within first 5 yrs aper rx, conJnues for at least 20 years
– Women with baseline cardiac risk factors who undergo chemotherapy at higher risk of cardiac events-‐ Dr. Edie Pituskin/ Dr Ian Pa\erson “Cardiac rehabilita7on in pa7ents undergoing high-‐dose chemotherapy and hematopoie7c stem cell /bone marrow transplanta7on – a prospec7ve descrip7ve study”
Darby et al. NEJM, 2013;368:987
State of the Union • Underlying causes for sex/gender differences sJll relaJvely unknown
Progress • Sex differences in the underlying biology
– Plaque is more diffusely deposited in women’s coronary arteries than men
– Women more open have disease in their smaller blood vessels which makes disease harder to diagnose with commonly used diagnosJc tests
– Autopsies show that younger women who suffer from sudden death are more likely to have died as a result of plaque eroding versus rupturing in men
Merz et all JACC 2006; Quyyumi AA JACC 2006;Burke et al CirculaJon, 2003
Progress • Explored relaJonship between estrogen and vascular disease -‐Premenopausal women less likely to develop CVD – Know that estrogen receptors exist throughout the vascular system but sJll don’t understand how this is related to differences observed in CVD.
– Some studies on estrogen receptors in smaller blood vessels where disease producing symptoms are more frequently found in women
Miller V, Women’s Health, 2010
Progress • Cardiometabolic disorders of pregnancy such as preeclampsia, put women & children at a higher risk for CVD
• Researchers have idenJfied deficiencies of vascular endothelial growth factor that builds new blood vessels and another one that shuts vessel building process down.
• Doctors now encouraged to ask about history of preeclampsia when assessing risk for CVD
Wilson et al BMJ 2003 326 (7394)
Progress • Women’s health iniJaJve and women’s health study have focuses on the prevenJon of CVD – Hormonal therapy in menopausal and post-‐menopausal women increases the risk for stroke and pulmonary embolisms
– Aspirin prevents strokes in women over the age of 65 but not in men.
Bailey et al, Curr Cardio Risk Rep 2010; Ridker et al, NEJM 2005
Awareness is lacking!
Awareness is lacking! • ~2500 women > 25 y.o. surveyed • Between 1997-‐2012, awareness among whole study populaJon nearly doubled: 30%à56%
• SJll low in minoriJes: – Blacks: 36% – Hispanics: 34%
Mosca L, et al. Fipeen-‐year trends in awareness of heart disease in women. CirculaJon 2013; 127.
Awareness
Mosca L, et al. Fipeen-‐year trends in awareness of heart disease in women. CirculaJon 2013; 127.
Awareness
Mosca L, et al. Fipeen-‐year trends in awareness of heart disease in women. CirculaJon 2013; 127.
GENESIS • Team of basic science, clinical epidemiological and health services researchers,
• GENESIS is invesJgaJng the sex and gender determinants for the development, presentaJon, process of care and outcome of cardiovascular disease (CVD) in pts under 55 years.
Outcomes Research • StraJfied by sex • Sex Differences in Premature Acute Coronary Syndrome Symptom • Sex and Gender-‐related Risk Factor Burden in PaJents with
Premature Acute Coronary Syndrome. • Depression and Disease Severity in PaJents with Premature Acute
Coronary Syndrome. • Chest Pain in Acute Myocardial InfarcJon: Are Men From Mars and
Women From Venus? • Sex-‐related differences in access to care among paJents with
premature acute coronary syndrome., • Health-‐Related Quality of Life in Premature Acute Coronary
Syndrome: • Sex or Gender Really MaXer? An Index for Measuring Gender in
PaIents with Acute Coronary Syndrome.
Gender Index • Create a ‘gender profile’ collected psychosocial variables related to – Gender role – Gender idenJty – Gender relaJons – InsJtuJonalized gender (distribuJon of power between men and women)
– CALCULATED a GENDER score
Gender distribuJon in men and women with premature ACS
Take-‐home points • CAD and CVD are by far the biggest health risks for women
• Awareness is sJll less than it needs to be
• PrevenJon CAN reduce risk
• Screening programs are available
Take-‐home points • Women can present differently, and do worse when they do
• Women are referred less open for appropriate tesJng and treatment
• Women can have more complicaJons from treatment, but sJll fare be\er than without rx
• Special consideraJons: pregnancy, menopause, comorbidiJes
Thank-‐you
Major Risk Factor IntervenJons • BP
– lifestyle intervenJons – Pharmacotherapy . Indicated when BP >-‐140/90
• Thiazide diureJcs • High risk women with ACS or MI = beta blockers and/or ace inhibitors /ARBs with
addiJon of thiazides as needed (Class 1 Level A) • Lipids and lipoprotein Levels
– Lifestyle intervenJons – Pharmacotherapy, LDL lowering drug therapy – In women > 60 years with esJmated CHD risk >10% staJns aper lifestyle
modificaJon and no acute inflammatory process is present – Low HDL –C niacin of fibrate therapy can be useful in high risk women aper
LDL-‐C goal is reached (Class IIb Level B) • Diabetes mellitus
– Lifestyle and pharmacotherapy useful in women to achieve HbA1c <7% (Class IIb Level B)
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