Sex Differences in
Cardiovascular Disease

    Jennifer A. Tremmel, MD, SM
What heart disease looks like
Historical Perspective


      ! Surge of interest in the 1940s and 1950s with a focus on
        middle-aged men

      !...
Women in Cardiology Trials

                Trial        % Women
                BARI           26%
               CAVEAT ...
Enrollment of Women in NHLBI RCTs




                                                Mean percent of women
              ...
Mortality Trends

                                         Cardiovascular Disease Mortality Trends
                       ...
www.goredforwomen.org




www.nhlbi.nih.gov/health/hearttruth
AHA survey of women’s knowledge

  ALL WOMEN                                                   1997   2000      2003   200...
Cardiovascular Disease



  ! Leading cause of death among women in US
     – 1 in 4 deaths attributable to CAD
     – 1 i...
Sex Differences


   ! Women differ from men in terms of:
      ! Risk factor profiles
      ! Presentation
      ! Testin...
Heart Disease Risk Factors


    !   Age: women, " 55 yrs; men, " 45 yrs
    !   High LDL-cholesterol: " 160 mg/dl
    !  ...
Diabetes


  ! Having diabetes confers a greater relative risk of CVD events in
    women compared with men




Barrett-Co...
Diabetes Trends from 1971 to 2000


 ! Mean BMI increased (for
   all)                                                 Age...
Impaired Fasting Glucose


   ! Women with IFG have a significantly increased 4-year odds of
     developing CHD or CVD co...
Prehypertension (120-139/80-89)

                                            Cumulative hazard of cardiovascular
         ...
Lipids


    ! Low HDL and high triglycerides:

         ! Independent predictors of CVD mortality in women

         ! Mo...
Obesity and Physical Activity


     ! More adult women than men in the United States are obese
       and sedentary

    ...
?Other risk factors


      ! Maternal Placental Syndrome (gestational hypertension,
        pre-eclampsia, placental abru...
Class III Recommendations




                                                  }
   ! Menopausal Hormone Therapy
        ...
Menopausal Hormone Therapy


                Are Hormone Effects on Clinical CVD
                Different if Started Clos...
HT and CVD



  ! Combined WHI trials of CEE and CEE+MPA

  ! 27,347 postmenopausal women

  ! Main outcomes:
      ! CHD ...
Events by Age Group at Baseline in
Combined Trials



             50-59 years             60-69 years             70-79 y...
Events by Years Since Menopause
in Combined Trials


                <10 years            10-19 years              >20 yea...
Age and Years Since Menopause



 ! Short-term use of HT has no apparent benefit or
   harm in CHD risk in younger women c...
Conclusions on HT



 ! HT should not be initiated (or continued) for the
   express purpose of preventing cardiovascular
...
Symptoms


  ! Chest pain is most common symptom in men and women

  ! Men tend to report chest pain more often

  ! In wo...
Symptoms

                                     !   SOB
                                     !   Nausea/Vomiting
          ...
Prodromal Symptoms



   ! 95% of women report prodromal symptoms

   ! Average 5 symptoms

   ! Most common are fatigue (...
Non-invasive Testing


   ! Exercise treadmill testing

      ! Lower specificity in women compared with men (higher false...
Coronary Artery Disease



   ! Trends apparent across stable angina, unstable
     angina, NSTEMI, and STEMI
        •   ...
Coronary Artery Disease



    ! Trends apparent across stable angina, unstable
      angina, NSTEMI, and STEMI
         •...
Stages of CAD




                                    Acute Coronary Syndromes (ACS)



 Asymptomatic ! Stable angina ! US...
STEMI
PCI (Percutaneous Coronary Intervention)
Angina


! 74 population samples of
  13,331 angina cases in
  199,494 women and 11,511
  cases in 201,821 men from
  31 c...
Stable Angina




Daly et al. Circulation 2006;113:490-498
Stable Angina: after visit to cardiologist




  ! Of patients having an angiogram, 63% of women and 87% of men had
    si...
Stable Angina: one year follow-up

                                 Cumulative probability of death or MI


! Women with c...
USA & NSTEMI: Early Invasive vs. Conservative



  ! Three major
    randomized, controlled
    trials with sex data
     ...
USA & NSTEMI: Early Invasive vs. Conservative


     ! Higher risk women benefit similarly to men from an early
       inv...
STEMI

                                      Men     Women   p-
Variable
                                      n=740   n=3...
STEMI


     ! Later presentation, slower treatment

                   Characteristic                    Women (n = 68,10...
When Guidelines are Followed




Novack et al. Am J Med 2008;121:597-603
Symptoms and D2B-Case



   ! 62 yo Tongan woman arrives in ER at 0129

   ! PMHx: DM, htn, dyslipidemia, obesity, CRI

  ...
EKG
Sequence of Events


   ! ASA at 0205, serial SLNTG

   ! STEMI call at 0211

   ! Interventional Fellow consenting at 023...
Angiogram




  Peak TnI 0.9, peak CKMB 5.6, peak total CK 256
Predictors of D2B Delay


                                                       40K patients who underwent
              ...
Delay with EMS




       ! Women are 50% more
         likely to be delayed in
         the EMS setting




Concannon et ...
Relative impact of delayed D2B time in women



! Delays in D2B time
  have a greater impact
  on late mortality in
  wome...
STEMI: Younger Women


       ! Younger women present later, have more diabetes, and are
         sicker (higher Killip cl...
STEMI: Long-term Survival




Alter et al. J Am Coll Cardiol 2002;39:1909-16
Depression after an MI


! Following an MI, the prevalence of major depression is higher in
  women than men, with younger...
PCI: NHLBI Dynamic Registry


 ! Shows improving outcomes (in-hospital mortality)
     ! 1985-1986: Adjusted OR 4.53, 95% ...
PCI: NHLBI Dynamic Registry

 ! No sex difference in death or MI in-hospital or at one year
 ! No sex difference in IIb/II...
PCI Complications

 ! Bleeding complications more common in women (RPH, bleed
   requiring transfusion, hematoma requiring...
RPH — Independent Predictors




   ! Smaller body surface area (BSA <1.73m2)

   ! High puncture

   ! Being a woman (73%...
IIb/IIIa Inhibitors


  ! Women benefit from IIb/IIIa inhibitor use similar to men

  ! But women have higher rates of ble...
IIb/IIIa Inhibitors


    ! Women have more bleeding whether or not IIb/IIIa
      inhibitors are used, however, 25% of th...
Radial vs. Femoral Access


  ! 3261 consecutive
                                                                         ...
Effect Most Pronounced in Women


  ! The protective effects of transradial interventions are
    most pronounced in women...
CABG: In-hospital Mortality


   ! Women have higher in-hospital mortality than men, as
     well as higher rates of posto...
CABG: Outcomes


     ! The 30 day mortality after
     CABG decreased
     significantly from 1991-2004,
     particularl...
Pathophysiology: Non-obstructive CAD




                                           Up to 20% of
                         ...
Pathophysiology


   ! Women presenting with symptoms suggestive of angina
     are significantly less likely than men to ...
Sex Differences Research




  Is there truly a sex
      difference in
        coronary
    pathophysiology?
Plaque Distribution




 ! A long, diffuse
   lesion that is
   moderately
   narrowed can
   cause a similar
   reduction...
Case


   ! 60 yo woman
                                        ! Movie Removed
   ! Hypertension

   ! Recent presentatio...
IVUS


   ! MLA 2.7mm2
                    ! Movie Removed
   ! 24-26mm long
Post-stent


   ! 2.5 x 28mm Cypher stent
                                  ! Movie Removed
   ! Post-dilated with a 2.75m...
The Coronary Microcirculation



                          The resistance vessels are all lined
                          ...
Microcirculatory Dysfunction


                               ! Adenosine (endothelium-
                                 i...
Microcirculatory Dysfunction




                               IMR: 63 x 0.52 = 32.8
Endothelial Dysfunction




                                      All major cardiac risk factors
                         ...
Case


   ! 48 yo woman

   ! No significant risk factors except a 15-pack yr hx of tobacco
     use 18 years ago

   ! Lo...
Endothelial Dysfunction



   ! Movie Removed
Example Patient




   ! Started Imdur 30 mg daily

   ! Decreased max. exertional heart rate from 180s to 160s

   ! Incr...
Sex Differences in Atheroma Burden and
Vascular Function Abnormalities




 Han et al. Eur Heart J 2008;29:1359-1369
Summary


! Focus on exercise, weight reduction, avoidance of insulin
  resistance/diabetes, hypertension, and ! triglycer...
Summary


! Throughout care, treat a woman like a woman
 (except when we know there’s a benefit to treating her like a man...
Thank You
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Jennifer Tremmel - Sex Differences In Cardiovascular Disease

  1. 1. Sex Differences in Cardiovascular Disease Jennifer A. Tremmel, MD, SM
  2. 2. What heart disease looks like
  3. 3. Historical Perspective ! Surge of interest in the 1940s and 1950s with a focus on middle-aged men ! Studies enrolled primarily men Lee et al. JAMA. 2001;286:708-713
  4. 4. Women in Cardiology Trials Trial % Women BARI 26% CAVEAT 18% COMET 20% VANQUISH 3% BENESTENT 19% 4S 18% CABRI 22% HOPE 25% TNT 19% PAMI 25% SIRIUS 28% TAXUS 18% COURAGE 15%
  5. 5. Enrollment of Women in NHLBI RCTs Mean percent of women enrolled in all trials (27%) vs. mean percent of all patients with CVD Kim et al. J Am Coll Cardiol 2008;52:672-675 who were women (53%)
  6. 6. Mortality Trends Cardiovascular Disease Mortality Trends for Women and Men United States: 1979-2004 520 500 Deaths in Thousands 480 460 440 420 400 0 380 79 80 85 90 95 00 04 Years Males Females Rosamond et al. Circulation 2007;115;e69-e171, Source: NCHS and NHLBI
  7. 7. www.goredforwomen.org www.nhlbi.nih.gov/health/hearttruth
  8. 8. AHA survey of women’s knowledge ALL WOMEN 1997 2000 2003 2005 Identify heart disease as leading cause of death 30% 34% 46% 55% Perceive heart disease as their greatest health threat 7% 8% 13% 21% Perceive cancer as their greatest health threat 61% 62% 51% (38%) Report heart health discussions initiated by their doctor 30% 38% 38% 46% ! Minority women face the highest risk of dying from CVD, however they have a poor awareness that heart disease is the leading killer of women -European-American: 68% -African-American: 31% -Hispanic-American: 29% Mosca et al. J Women’s Health 2007;16:68-81
  9. 9. Cardiovascular Disease ! Leading cause of death among women in US – 1 in 4 deaths attributable to CAD – 1 in 2 deaths for all forms of CVD ! Heart disease: ! Second-leading cause of death for women 45 to 64 years ! Third-leading cause of death for women age 25 to 44 years ! Kills more than 500,000 women per year ! Kills 6 times as many women as breast cancer ! Kills almost twice as many women as all forms of cancer combined
  10. 10. Sex Differences ! Women differ from men in terms of: ! Risk factor profiles ! Presentation ! Testing ! Treatment ! Outcomes ! Pathophysiology (?)
  11. 11. Heart Disease Risk Factors ! Age: women, " 55 yrs; men, " 45 yrs ! High LDL-cholesterol: " 160 mg/dl ! Low HDL-cholesterol: < 40 mg/dl* – * < 50 mg/dl may be more appropriate cut-point for women – Optimal, " 60 mg/dl (considered a “Negative Risk Factor”) ! Diabetes (fasting glucose " 126 mg/dl) = CHD equivalent ! High Blood Pressure: " 140/90 mm Hg ! Obesity ! Sedentary Lifestyle ! Cigarette Smoking ! Family History of premature CHD: ! 1st degree male relative (father, brother) < 55 yrs ! 1st degree female relative (mother, sister) < 65 yrs
  12. 12. Diabetes ! Having diabetes confers a greater relative risk of CVD events in women compared with men Barrett-Connor et al. Arch Int Med. 2004;164:934-942
  13. 13. Diabetes Trends from 1971 to 2000 ! Mean BMI increased (for all) Age-adjusted cardiovascular ! Average age of diagnosis disease mortality rates among men decreased for women and women age 35 to 74 years (mean age 51.6 to 48.7, 16.8 *Annual deaths per 1000 persons p<0.05 ) ! Men with diabetes 5.8 experienced a 43% relative reduction in age-adjusted 8.1 all-cause mortality, but 7.1 women had no change ! The difference in all-cause mortality between women with and without diabetes more than doubled Gregg, E. W. et. al. Ann Intern Med 2007;147:149-155, NHANES data
  14. 14. Impaired Fasting Glucose ! Women with IFG have a significantly increased 4-year odds of developing CHD or CVD compared to men CHD CVD Women Men Women Men 2003 Definition* 1.7 (p=0.048) 0.9 (p=0.55) 1.4 (p=0.16) 1.1 (p=0.56) (FPG 100-125) 1997 Definition† 2.2 (p=0.02) 0.9 (p=0.67) 2.1 (p=0.01) 1.0 (p=0.98) (FPG 110-125) Diabetic* 2.5 (p=0.01) 2.6 (p<0.001) 2.3 (p=0.007) 2.8 (p<0.001) (FPG !126 or on med) * Referent group is FPG <100mg/dl CHD = MI, stable and unstable angina, a CHD death † Referent group is FPG <110mg/dl CVD = any CHD event, CVA, TIA, claudication, CHF, or CVD death Levitsky et al. J Am Coll Cardiol 2008;51:264-70
  15. 15. Prehypertension (120-139/80-89) Cumulative hazard of cardiovascular events by JNC7 blood pressure category ! Prehypertension is independently associated with an increased risk of MI, CVA, HF, and CV death in post- WHI data, n=60K menopausal women 39% had prehtn at baseline Prehtn: HR 1.66 (1.44 to 1.92) Htn: HR 2.89 (2.52 to 3.32) *Adj by BMI, DM, hyperchol, tob use Hsia et al. Circulation 2007;115:855-860
  16. 16. Lipids ! Low HDL and high triglycerides: ! Independent predictors of CVD mortality in women ! More powerful determinants of CAD risk in women than total cholesterol and LDL levels. Bass et al. Arch Int Med. 1993;153:2209-2216
  17. 17. Obesity and Physical Activity ! More adult women than men in the United States are obese and sedentary ! Obesity and physical inactivity independently contribute to the development of CHD in women Li et al. Circulation. 2006;113:499-506
  18. 18. ?Other risk factors ! Maternal Placental Syndrome (gestational hypertension, pre-eclampsia, placental abruption, placental infarction) ! Doubled risk of premature CVD, +/- simply reflection of pre- pregnancy risks Others: • Gestational Diabetes • Peripartum Vasc Dissection • Low birth-weight children • PCOS • Hypothalamic hypoestrogenemia • Weight gain during pregnancy Ray et al. Lancet 2005;3666:1797-1803 (CHAMPS)
  19. 19. Class III Recommendations } ! Menopausal Hormone Therapy Not recommended for ! Antioxidants (Vitamin E, C, beta-carotene) primary or secondary prevention ! Folic Acid ! Aspirin in women < 65 years for primary prevention of MI Mosca et al. Circulation 2007;115:1481-1501
  20. 20. Menopausal Hormone Therapy Are Hormone Effects on Clinical CVD Different if Started Closer to Menopause? ! Secondary analysis of WHI E+P trial (2003)1 ! Non-significant reduction of CHD risk in women less than 10 years since menopause ! Secondary analysis of WHI CEE trial (2006)2 ! Non-significant reduction of CHD risk in women age 50-59 ! Significant reduction in revascularizations in women age 50-59 ! Small numbers in subgroups may have obscured a real effect ! Both trials showed an increased risk of stroke not modified by age or years since menopause 1. Manson et al. N Engl J Med 2003;349:523-534 2. Hsia et al. Arch Intern Med 2006
  21. 21. HT and CVD ! Combined WHI trials of CEE and CEE+MPA ! 27,347 postmenopausal women ! Main outcomes: ! CHD (nonfatal MI, silent MI, or CHD death) ! Stroke ! Other outcomes: ! Mortality (all-cause) ! Global Index (first occurrence of CHD, CVA, PE, breast CA, colorectal CA, endometrial CA, hip fracture, or death from other causes) Rossouw et al. JAMA 2007;297:1465-1477
  22. 22. Events by Age Group at Baseline in Combined Trials 50-59 years 60-69 years 70-79 years P for Trend N= 8,832 N= 12,362 N= 6,153 No. of HR No. of HR No. of HR Cases Cases Cases (95% CI) (95% CI) (95% CI) CHD 120 0.93 352 0.98 294 1.26 0.16 (0.65-1.33) (0.79-1.21) (1.00-1.59) 81 1.13 258 1.50 237 1.21 0.97 Stroke (0.73-1.76) (1.17-1.92) (0.93-1.58) Death 164 0.70 465 1.05 445 1.14 0.06 (0.51-0.96) (0.87-1.26) (0.94-1.37) Global 556 0.96 1378 1.08 1134 1.14 0.09 Index (0.81-1.14) (0.97-1.20) (1.02-1.29) Rossouw et al. JAMA 2007;297:1465-1477
  23. 23. Events by Years Since Menopause in Combined Trials <10 years 10-19 years >20 years P for Trend N= 7,137 N= 8,977 N= 8,293 No. of HR No. of HR No. of HR Cases Cases Cases (95% CI) (95% CI) (95% CI) CHD 90 0.76 216 1.10 352 1.28 0.02 (0.50-1.16) (0.84-1.45) (1.03-1.58) 64 1.77 179 1.23 255 1.26 0.36 Stroke (1.05-2.98) (0.92-1.66) (0.98-1.62) Death 120 0.76 291 0.98 507 1.14 0.51 (0.53-1.09) (0.78-1.24) (0.96-1.36) Global 425 1.05 922 1.12 1307 1.09 0.82 Index (0.86-1.27) (0.98-1.27) (0.98-1.22) Rossouw et al. JAMA 2007;297:1465-1477
  24. 24. Age and Years Since Menopause ! Short-term use of HT has no apparent benefit or harm in CHD risk in younger women close to menopause ! Increased risk of stroke (and breast CA) in women closer to menopause ! Screen for and treat risk factors for CVA before starting HT ! Increased risk of CHD for older women "20 years from menopause, particularly those with vasomotor symptoms ! Vasomotor sxs in older women may be a marker of increased CHD risk
  25. 25. Conclusions on HT ! HT should not be initiated (or continued) for the express purpose of preventing cardiovascular disease in either younger or older postmenopausal women ! The current recommendations are that hormone therapy be limited to the treatment of moderate-to-severe menopausal symptoms, with the lowest effective dose used for the shortest duration necessary
  26. 26. Symptoms ! Chest pain is most common symptom in men and women ! Men tend to report chest pain more often ! In women, it’s not always the first or most significant symptom ! Women may experience more transient pain and may have more subtle differences in their description ! heaviness ! pressure ! tightness ! squeezing ! sharp ! stabbing
  27. 27. Symptoms ! SOB ! Nausea/Vomiting ! Transient non-specific chest discomfort ! Women report a greater number of less common ! Arm/shoulder pain, usually left-sided, symptoms but more often right sided than men ! Abdominal pain ! Indigestion ! Men report more chest pain, diaphoresis, belching, and ! Back pain or pain radiating to the back hiccups ! Neck pain ! Although equally likely to have ! Jaw pain exertional symptoms, more likely to report pain at rest, ! Headache during sleep, or with mental stress ! Fatigue ! Symptoms may be worse ! Dizziness during menstrual period ! Loss of appetite ! Palpitations ! Cough
  28. 28. Prodromal Symptoms ! 95% of women report prodromal symptoms ! Average 5 symptoms ! Most common are fatigue (71%), sleep disturbance (49%), SOB (42%), indigestion (40%), and anxiety (36%) ! Only 30% report chest discomfort ! General occur for at least a month prior to event
  29. 29. Non-invasive Testing ! Exercise treadmill testing ! Lower specificity in women compared with men (higher false positive rate), but slightly higher sensitivity ! Stress echocardiography and nuclear perfusion scan ! Sensitivity is similar to ETT (~80%), specificity better(~80%) ! CAC with EBCT or MDCT ! Sensitive, but not specific for significant CAD ! Radiation. Angio based on CAC alone not currently recommended ! Cardiac MRI ! Still not sufficient for coronaries, but may become more useful as a non-invasive study of the coronary microcirculation
  30. 30. Coronary Artery Disease ! Trends apparent across stable angina, unstable angina, NSTEMI, and STEMI • older at presentation (~5-10 years) • more comorbidities (hypertension, high cholesterol, diabetes) • more likely to have depression before and after their diagnosis • more likely to be in heart failure • more likely to have a history of angina (and more severe) • less likely to present with STEMI • more likely to have NO obstructive disease Daly et al. Circulation 2006;113:490-498 GUSTO IIb trial. Hochman et al. NEJM 1999;341:226-32 Gan et al. NEJM 2000;343:8-15 Fang et al. Am J Cardiol 2006;97:1722-1726 Anand et al. JACC. 2005;46:1845-51 (post-hoc analysis of the CURE trial)
  31. 31. Coronary Artery Disease ! Trends apparent across stable angina, unstable angina, NSTEMI, and STEMI • later to present, slower to receive treatment • less likely to receive guideline-based medical therapy including aspirin and statins • less likely to have an angiogram or undergo revascularization • significantly higher rates of moderate or severe bleeding • more likely to have continued/recurrent angina after treatment • less likely to be referred for cardiac rehab • more death and MI at short- and long-term follow-up Daly et al. Circulation 2006;113:490-498 GUSTO IIb trial. Hochman et al. NEJM 1999;341:226-32 Gan et al. NEJM 2000;343:8-15 Fang et al. Am J Cardiol 2006;97:1722-1726 Anand et al. JACC. 2005;46:1845-51 (post-hoc analysis of the CURE trial)
  32. 32. Stages of CAD Acute Coronary Syndromes (ACS) Asymptomatic ! Stable angina ! USA ! NSTEMI ! STEMI USA=unstable angina NSTEMI=non-ST elevation myocardial infarction STEMI=ST elevation myocardial infarction (big heart attack
  33. 33. STEMI
  34. 34. PCI (Percutaneous Coronary Intervention)
  35. 35. Angina ! 74 population samples of 13,331 angina cases in 199,494 women and 11,511 cases in 201,821 men from 31 countries, 5 countries being English speaking ! Angina is more prevalent among women than men (pooled random-effects sex ratio of 1.20 (95% CI 1.14 to 1.28, P<0.0001)). ! Ratio was 1.40 (95% CI 1.28 to 1.52) among Americans (non-whites>whites) Hemingway et al. Circulation 2008;117:1526-1536
  36. 36. Stable Angina Daly et al. Circulation 2006;113:490-498
  37. 37. Stable Angina: after visit to cardiologist ! Of patients having an angiogram, 63% of women and 87% of men had significant CAD (p<0.001) ! Women had more single vessel disease (46% vs. 30%) ! Men had more double/triple vessel disease (32%/38% vs. 22%/32%) ! Among patients with proven CAD, women were less likely to be revascularized (adjusted OR 0.70, 95% CI 0.52 to 0.94, p=0.019) or to receive statins and antianginal drugs
  38. 38. Stable Angina: one year follow-up Cumulative probability of death or MI ! Women with confirmed CAD were ! more likely to have continued angina (57% vs. 47%, p=0.007) ! Suffered more death and MI
  39. 39. USA & NSTEMI: Early Invasive vs. Conservative ! Three major randomized, controlled trials with sex data ! FRISC II ! RITA-3 ! TACTICS-TIMI 18 Lagerqvist et al. J Am Coll Cardiol 2001;38:41-8
  40. 40. USA & NSTEMI: Early Invasive vs. Conservative ! Higher risk women benefit similarly to men from an early invasive strategy, whereas lower risk women may have excess events MACE events at 180 days in higher risk patients Glaser et al. JAMA 2002;288:3124-3129 (TACTICS-TIMI 18)
  41. 41. STEMI Men Women p- Variable n=740 n=308 value Age (mean) 57.21 64.45 <0.01 Diabetes 18.78 25.65 0.01 History of Congestive Heart Failure 3.78 9.09 <0.01 Hypertension 53.78 68.83 <0.01 Cardiogenic Shock 8.11 18.83 <0.01 Outcomes Mortality 3.11 7.47 <0.01 Re-infarction 0.95 1.62 0.35 Median Time to Treatment Symptom Onset to Door (min) 84.0 97.0 0.02 Door to Balloon (min) 105.0 118.2 <0.01 PCI within 90 min 35% 26% 0.006 Moscucci et al. AHA abstract 2004
  42. 42. STEMI ! Later presentation, slower treatment Characteristic Women (n = 68,108) Men (n = 70,848) p Value Time to EKG – min 37.2 ± 50.0 33.5 ± 48.9 <0.001 Chest pain >6 hr before arrival 30.8% 27.6% <0.001 ! Less thrombolysis, aspirin, and cath ! Less likely to be admitted to a hospital capable of revascularization (45% vs. 52%, p<0.001) ! Less likely to undergo revascularization when admitted to a capable hospital (54% vs. 60%, p<0.001) ! Higher adjusted short-term mortality Gan et al. NEJM 2000;343:8-15 Fang et al. Am J Cardiol 2006;97:1722-1726
  43. 43. When Guidelines are Followed Novack et al. Am J Med 2008;121:597-603
  44. 44. Symptoms and D2B-Case ! 62 yo Tongan woman arrives in ER at 0129 ! PMHx: DM, htn, dyslipidemia, obesity, CRI ! Complains of 1-2 hours of constant, nonradiating chest/epigastric pain, weakness, diaphoresis, headache, SOB, N/V, palpitations, and light-headed. No cough, fevers, or chills. BP 220/110.
  45. 45. EKG
  46. 46. Sequence of Events ! ASA at 0205, serial SLNTG ! STEMI call at 0211 ! Interventional Fellow consenting at 0230 ! Heparin bolus at 0239, Aggrastat at 0253 ! Patient arrives cath lab at 0305 ! Sheath in at 0313, left coronary images 0324 ! Balloon inflated at 0336 ! D2B = 127 minutes
  47. 47. Angiogram Peak TnI 0.9, peak CKMB 5.6, peak total CK 256
  48. 48. Predictors of D2B Delay 40K patients who underwent primary angioplasty for MI Angeja et al. Am J Cardiol 2002;89:1156-1161, NRMI data
  49. 49. Delay with EMS ! Women are 50% more likely to be delayed in the EMS setting Concannon et al. Circ Cardiovasc Qual Outcomes. 2009;2:9-15
  50. 50. Relative impact of delayed D2B time in women ! Delays in D2B time have a greater impact on late mortality in women compared with men Brodie et al. JACC 2006;47:289-295
  51. 51. STEMI: Younger Women ! Younger women present later, have more diabetes, and are sicker (higher Killip class, lower SBP) ! They have more complications such as hypotension, heart failure, cardiogenic shock, and major bleeding, and are less likely to undergo angiography and revascularization OR for Death during Hospitalization for MI in Women vs. Men Vaccarino et al. NEJM 1999;341:217-25
  52. 52. STEMI: Long-term Survival Alter et al. J Am Coll Cardiol 2002;39:1909-16
  53. 53. Depression after an MI ! Following an MI, the prevalence of major depression is higher in women than men, with younger women have the highest prevalence of depression (40%) Prevalence of Depression by Age and Sex 50 45 Patients with Depression, % 40 men 35 women 30 25 20 15 10 5 0 !60 >60 Age Mallik, S. et al. Arch Intern Med 2006;166:876-883
  54. 54. PCI: NHLBI Dynamic Registry ! Shows improving outcomes (in-hospital mortality) ! 1985-1986: Adjusted OR 4.53, 95% CI 1.39-14.7 ! 1997-1998: Adjusted OR 1.60, 95% CI 0.76-3.35 ! Most recent analysis includes BMS and DES (2001-2004) ! Attempted lesions in women had a smaller reference vessel diameter than those in men in both BMS and DES ! Men had more vein graft PCIs ! Otherwise, similar angiographic characteristics Abbott et al. Am J Cardiol 2007;99:626-631
  55. 55. PCI: NHLBI Dynamic Registry ! No sex difference in death or MI in-hospital or at one year ! No sex difference in IIb/IIIa or antiplatelet therapy ! No sex difference in stent thrombosis rates One-year event rates for repeat PCI ! Women have more vascular access site complications (p<0.001)
  56. 56. PCI Complications ! Bleeding complications more common in women (RPH, bleed requiring transfusion, hematoma requiring repair or prolonged hospital stay) ! Coronary vascular injury seen in younger women (intimal tear, dissection, acute occlusion, or side branch closure) Argulian et al. Am J Cardiol 2006;98:48-53
  57. 57. RPH — Independent Predictors ! Smaller body surface area (BSA <1.73m2) ! High puncture ! Being a woman (73% were ") ! Use of a IIb/IIIa inhibitor* Farouque et al. JACC 2005;45:363-8 *Significant in Whitlow et al, CCI 2006 n=28,378
  58. 58. IIb/IIIa Inhibitors ! Women benefit from IIb/IIIa inhibitor use similar to men ! But women have higher rates of bleeding p < 0.001 for both " and # p = 0.004 for major bleeding event p < 0.001 for minor bleeding events Cho et al. J Am Coll Cardiol 2000;36:381-6 (Pooled analysis of EPIC, EPILOG, and EPISTENT)
  59. 59. IIb/IIIa Inhibitors ! Women have more bleeding whether or not IIb/IIIa inhibitors are used, however, 25% of the bleeding risk in women is attributable to excess dosing Alexander et al. Circulation 2006;114:1380-1387
  60. 60. Radial vs. Femoral Access ! 3261 consecutive Women=black interventional and/or Men=gray diagnostic procedures ! Major bleeding (A) ! RPH or death ! Required surgical intervention ! Required blood transfusions ! Hg <4g/dl ! Hematoma >50% of the limb, associated with pt. discomfort and prolonged hospital stay ! Minor bleeding (B) ! All other puncture-related hemorrhages Pristipino et al. Am J Cardiol 2007;99:1216-1221 *p=0.0008 vs. radial; **p=0.00001 vs. radial
  61. 61. Effect Most Pronounced in Women ! The protective effects of transradial interventions are most pronounced in women Rao et al. J Am Coll Cardiol Intv 2008;1:379-86
  62. 62. CABG: In-hospital Mortality ! Women have higher in-hospital mortality than men, as well as higher rates of postoperative MI, neurologic complications, and renal failure. This is particularly true for younger women Vaccarino et al. Circulation 2002;105:1176-1181
  63. 63. CABG: Outcomes ! The 30 day mortality after CABG decreased significantly from 1991-2004, particularly in women ! Increased use of arterial grafts ! After CABG, women are more likely to be readmitted than men, typically for unstable angina and CHF rather than MI ! Overall, women have similar or better long-term survival than men, but are more likely to have recurrent angina and lower QOL Humphries et al. J Am Coll Cardiol 2007;49:1552-8 Guru et al. Circulation 2006;113:507-16
  64. 64. Pathophysiology: Non-obstructive CAD Up to 20% of symptomatic patients presenting for coronary angiography will have no significant coronary artery disease on angiography While ~60% are women, nearly 40% are men
  65. 65. Pathophysiology ! Women presenting with symptoms suggestive of angina are significantly less likely than men to have angiographic evidence of obstructive CAD ! Women tend to get more diffuse atherosclerosis ! Women frequently have evidence of microvascular disease ! Women frequently have evidence of endothelial dysfunction !WISE Study (Women’s Ischemic Syndrome Evaluation) NOT A BENIGN PATHOLOGY Associated with long-term CV !Sponsored by AHA/NHLBI events and death !Four-center project, ~1000 women (mean age 59±12 years) enrolled. Women were presenting with suspected ischemia and were referred for elective coronary angiography.
  66. 66. Sex Differences Research Is there truly a sex difference in coronary pathophysiology?
  67. 67. Plaque Distribution ! A long, diffuse lesion that is moderately narrowed can cause a similar reduction in distal flow as a short, focal lesion that is severely narrowed
  68. 68. Case ! 60 yo woman ! Movie Removed ! Hypertension ! Recent presentation to ER with CP, ruled out ! Stress echo: mid-distal anterior and apical ischemia
  69. 69. IVUS ! MLA 2.7mm2 ! Movie Removed ! 24-26mm long
  70. 70. Post-stent ! 2.5 x 28mm Cypher stent ! Movie Removed ! Post-dilated with a 2.75mm balloon.
  71. 71. The Coronary Microcirculation The resistance vessels are all lined by a single layer of endothelial cells
  72. 72. Microcirculatory Dysfunction ! Adenosine (endothelium- independent vasodilator) induces hyperemia ! CFR: (normal " 2.5) hyperemic coronary flow resting coronary flow ! IMR: (normal < 20) distal coronary pressure hyperemic coronary flow ! FFR 0.86 ! CFR 1.6 ! IMR 35
  73. 73. Microcirculatory Dysfunction IMR: 63 x 0.52 = 32.8
  74. 74. Endothelial Dysfunction All major cardiac risk factors have been found to associated with endothelial dysfunction in a cumulative fashion. Endothelial dysfunction is at least partially reversible through risk factor modification.
  75. 75. Case ! 48 yo woman ! No significant risk factors except a 15-pack yr hx of tobacco use 18 years ago ! Low stamina and excessive tachycardia with exercise for the past year ! VO2 stress echo ! anterior ischemia ! Cath lab ! Normal appearing coronary arteries on angiography ! Only minimal plaque on IVUS ! Mild microvascular disease (IMR 23) ! Tested endothelial function
  76. 76. Endothelial Dysfunction ! Movie Removed
  77. 77. Example Patient ! Started Imdur 30 mg daily ! Decreased max. exertional heart rate from 180s to 160s ! Increased running distance from 0.5 to 2 miles ! Decreased running time from 14 min/ml to 11-12 min/ml ! More energy after work-outs
  78. 78. Sex Differences in Atheroma Burden and Vascular Function Abnormalities Han et al. Eur Heart J 2008;29:1359-1369
  79. 79. Summary ! Focus on exercise, weight reduction, avoidance of insulin resistance/diabetes, hypertension, and ! triglycerides and " HDL ! Hormone Therapy: Smallest dose, shortest duration ! Aspirin for 1° prevention of MI or CV death if " 65 ! Be attuned to “atypical” symptoms ! Women tend to be older, present later and sicker, have less extensive CAD, have more complications (particularly bleeding), and more recurrent/refractory symptoms ! Post-PCI/Post-MI/Post-CABG ! Standard medical care (ASA, b-blocker, statin, ACE inhibitor, Plavix) ! Continued aggressive risk factor modification ! Rehab (!) ! Depression/Stress
  80. 80. Summary ! Throughout care, treat a woman like a woman (except when we know there’s a benefit to treating her like a man) ! New paradigm ! Key to ultimately changing outcomes (and Monterey) www.womensheart.stanfordhospital.com
  81. 81. Thank You

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