objectives primary prevention of heart disease · 9/29/2015 2 impact of ascvd in women • single...

9/29/2015

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Samia Mora, MD, MHSAssociate Professor, Harvard Medical School

Associate Physician, Brigham and Women’s Hospital

October 2, 2015

Financial disclosures: Dr Mora has received

research grant support from Atherotech Diagnostics,

served as consultant to Pfizer, Lilly, Cerenis Therapeutics

Primary Prevention of Heart Disease:

What works? What doesn’’’’t?1. To review current challenges for atherosclerotic

cardiovascular disease (ASCVD) prevention, with a focus on the impact in women

2. Aspirin for the prevention of ASCVD

Secondary prevention

Primary prevention

Sex differences

Guideline recommendations

3. Statins for the prevention of ASCVD

Objectives

1. To review current challenges for atherosclerotic cardiovascular disease (ASCVD) prevention, with a focus on the impact in women



Primary prevention

Sex differences



ObjectivesCardiovascular disease is the leading cause of

death in women and men (US: 1979–2009)

Mozaffarian et al. Circulation 2015;131:e29-e322Copyright © American Heart Association

Women

Men

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Impact of ASCVD in Women

• Single largest killer of women in US

• One in 30 women will die of breast cancer, vs. one in 3 will die from CVD

• One woman dies from CVD every minute

• CVD deaths in women = all deaths from cancer, lung disease, and Alzheimer disease combined

Impact of ASCVD in Women

•Black women ~ 40% more likely to die from CVD compared with White women

•Death rate in US women ages 35-54 is increasing, possibly due to obesity

•Two thirds of women who die suddenly had no prior symptoms (vs. ~ half of men)

•More women than men will have a second heart attack after their first heart attack

Impact of ASCVD in Women• More strokes than coronary heart disease (CHD) in women (opposite in men)

• Gestational diabetes (2-10% of pregnancies): increases risk of future diabetes by 30 to 60%

•Unique risk factors for stroke in women:

• pregnancy

• hormone therapy

• more hypertension at >age 65

Lifetime Risk of ASCVD Death for Women by Risk Factors at Age 45

Berry et al. NEJM 2012;366:321-9

4 Major Risk Factors:

Smk, DM, TC>240, BP>160/100 or HTN

Optimal Risk Factors:

Non-smk, non-DM, TC<180, BP <120/80

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Awareness lagging among women that heart disease is their leading cause of death

Mosca L et al. Circulation 2013; 127:1254-63

Copyright © American Heart Association




Primary prevention

Sex differences



Objectives

Aspirin: Mechanism of ActionAspirin: Mechanism of ActionAspirin: Mechanism of ActionAspirin: Mechanism of Action

Membrane PhospholipidsMembrane PhospholipidsMembrane PhospholipidsMembrane Phospholipids

Arachadonic AcidArachadonic AcidArachadonic AcidArachadonic Acid

Prostaglandin HProstaglandin HProstaglandin HProstaglandin H2222

COXCOXCOXCOX----1111

Thromboxane AThromboxane AThromboxane AThromboxane A2222

↑↑↑↑ Platelet AggregationPlatelet AggregationPlatelet AggregationPlatelet Aggregation

VasoconstrictionVasoconstrictionVasoconstrictionVasoconstriction

ProstacyclinProstacyclinProstacyclinProstacyclin↓↓↓↓ Platelet AggregationPlatelet AggregationPlatelet AggregationPlatelet Aggregation

VasodilationVasodilationVasodilationVasodilation

AspirinAspirinAspirinAspirin

Adhesion1

Platelets

Lipidcore

CollagenGP la/lla bind

von WillebrandFactor/GP lb bind

Activation2

Thrombin

ADP

5 HT

TXA2 Aggregation3

FibrinogenActivatedGP llb/llla

Handin RI. Harrison’s Principles of Internal Medici ne. Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339.

Schafer AI. Am J Med. 1996;101:199-209.

Platelets are central to coronary thrombosis

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Meta-analysis of 16 randomized trials of aspirin(N=17,000 participants, 3306 serious vascular events)

• �� 31%, nonfatal MI

• �� 20%, major CHD events

• �� 19%, total stroke

• �� 19%, any serious vascular event

(Results similar in men and women)

Aspirin Evidence: Secondary Prevention of ASCVDAspirin Evidence: Secondary Prevention of ASCVDAspirin Evidence: Secondary Prevention of ASCVDAspirin Evidence: Secondary Prevention of ASCVD

Antithrombotic Trialist Collaboration. Antithrombotic Trialist Collaboration. Antithrombotic Trialist Collaboration. Antithrombotic Trialist Collaboration. LancetLancetLancetLancet 2009;373:18492009;373:18492009;373:18492009;373:1849

Antithrombotic Trialists’ (ATT) Collaboration 1. To review current challenges for atherosclerotic cardiovascular disease (ASCVD) prevention, with a focus on the impact in women



Primary prevention

Sex differences



Objectives

• The role of aspirin in primary prevention has not been as clear, particularly among women.

• The assessment of the benefits of aspirin in primary prevention is more complicated, since the absolute risks of vascular events are lower than in secondary prevention while complication rates (eg., bleeding) are comparable.

Aspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionAspirin Evidence: Primary Prevention

Number of Events (Aspirin vs. Control)

Rate ratio (95% CI) (Aspirin vs. Control)

Major coronary event 934 vs. 1115 0.82 (0.75-0.90)

Non-fatal MI 596 vs. 756 0.77 (0.69-0.86)

CHD mortality 372 vs. 393 0.95 (0.82-1.10)

Stroke 655 vs 682 0.95 (0.85-1.06)

Hemorrhagic 116 vs. 89 1.32 (1.00-1.75)

Ischemic 317 vs. 367 0.86 (0.74-1.00)

Unknown cause 222 vs. 226 0.97 (0.80-1.18)

Vascular death 619 vs. 637 0.97 (0.87-1.09)

Any serious vascular event 1671 vs. 1883 0.88 (0.82 vs 0.94)

Major extracranial bleed 335 vs. 219 1.54 (1.30-1.82)

Antithrombotic Trialists’ (ATT) Collaboration

Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849-60


Meta-analysis of 95,456 low risk patients randomized to aspirin

(100 mg every other day to 500 mg daily) vs. placebo for 4 to 10 years

Aspirin reduces the risk of ischemic events, but with a higher rate of bleedingAspirin reduces the risk of ischemic events, but with a higher rate of bleedingAspirin reduces the risk of ischemic events, but with a higher rate of bleedingAspirin reduces the risk of ischemic events, but with a higher rate of bleeding

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0.5 1.0 1.5 2.0

Non-fatal MI

Vascular Mortality

Major GI and extracranial bleeds

Serious Vascular Events

Antiplatelet Better Antiplatelet Worse

Rate Ratios for

Vascular Events

0

P=0.0001

Effect of antiplatelet treatment on vascular events

Antithrombotic Trialist Collaboration. Lancet 2009;373:1849

Stroke

Aspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionAspirin Evidence: Primary Prevention Aspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and Efficacy

0.50.50.50.5 1.01.01.01.0 1.51.51.51.5 2.02.02.02.0

500500500500----1500 mg1500 mg1500 mg1500 mg 34343434 19191919

160160160160----325 mg325 mg325 mg325 mg 19191919 26262626

75757575----150 mg150 mg150 mg150 mg 12121212 32323232

<75 mg<75 mg<75 mg<75 mg 3333 13131313

Any aspirinAny aspirinAny aspirinAny aspirin 65656565 23232323

Antiplatelet BetterAntiplatelet BetterAntiplatelet BetterAntiplatelet Better Antiplatelet WorseAntiplatelet WorseAntiplatelet WorseAntiplatelet Worse

Aspirin DoseAspirin DoseAspirin DoseAspirin Dose No. of Trials (%)No. of Trials (%)No. of Trials (%)No. of Trials (%)Odds Ratio for Odds Ratio for Odds Ratio for Odds Ratio for

Vascular EventsVascular EventsVascular EventsVascular Events

0000

Indirect comparisons of aspirin doses on vascular events in Indirect comparisons of aspirin doses on vascular events in Indirect comparisons of aspirin doses on vascular events in Indirect comparisons of aspirin doses on vascular events in

highhighhighhigh----risk patientsrisk patientsrisk patientsrisk patients

Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86


2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta----analysisanalysisanalysisanalysis

Outcome No. trials No. individuals Summary Relative Risk

Nonfatal MI 10 114,734 0.78 (0.71-0.87)

Nonfatal stroke 10 99,655 0.95 (0.85-1.06)

CVD mortality 11 118,445 0.94 (0.86-1.03)

Total mortality 11 118,445 0.94(0.89-0.99)

Guiruis-Blake JM et al. 2015 www.uspreventiveserv icestaskforce.org


2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta2015 U.S. Preventive Task Force Services updated meta----analysisanalysisanalysisanalysis

Outcome No. trials No. individuals Summary Relative Risk

Nonfatal MI 10 114,734 0.78 (0.71-0.87)

8 (≤100 mg) 87,524 0.83 (0.74-0.94)

Nonfatal stroke 10 99,655 0.95 (0.85-1.06)

7 (≤100 mg) 68,734 0.86 (0.76-0.98)

CVD mortality 11 118,445 0.94 (0.86-1.03)

8 (≤100 mg) 87,524 0.97 (0.85-1.10)

Total mortality 11 118,445 0.94(0.89-0.99)

8 (≤100 mg) 87,524 0.95 (0.89-1.01)

Guiruis-Blake JM et al. 2015 www.uspreventiveservi cestaskforce.org

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Bleeding risks with aspirin

Risk factors for bleeding

Age

Male sex

GI hospitalization

Excess alcohol use

Current smoking

Hypertension

Diabetes

Liver / renal disease

Concomitant meds(NSAIDs, anticoagulants)

Whitlock E et al. 2015 www.uspreventiveservicesta skforce.org

Proton Pump Inhibitors (PPIs) may decrease risk of GI bleeding on aspirin

Tran-Duy A. et al. 2015 Int J Clin Pract doi:10. 1111/ijcp.12634

GI: Gastrointestinal




Primary prevention

Sex differences



Objectives

Aspirin in Primary Prevention: Sex differences?

Ridker, P. et al., N Engl J Med 2005; 352:1293-204 .

1.0 5.00.50.2 0.2

BDT, 1988

Combined

PPP, 2001

HOT, 1998

TPT, 1998

PHS, 1989

RR of MI Among Men

2.0

RR = 0.68 (0.54–0.86)P = .001

RR of Stroke Among Men

RR = 1.13 (0.96–1.33)P = .15

1.00.2 2.0 5.00.5

HOT, 1998

Combined

WHS, 2005

PPP, 2001

RR of MI Among Women

Aspirin Better Placebo Better

RR = 0.99 (0.83–1.19)P = .95

2.0

Aspirin Better Placebo Better

1.0

RR of Stroke Among Women

5.00.50.2

RR = 0.81 (0.69–0.96)P = .01

0.5 1.0 2.0 5.0

Berger JS et al. JAMA. 2006;295:306-313

Physicians’ Health Study (PHS)Physicians’ Health Study (PHS)Physicians’ Health Study (PHS)Physicians’ Health Study (PHS)

22,071 men randomized to aspirin (325 mg every other day) followed 22,071 men randomized to aspirin (325 mg every other day) followed 22,071 men randomized to aspirin (325 mg every other day) followed 22,071 men randomized to aspirin (325 mg every other day) followed

for an average of 5 yearsfor an average of 5 yearsfor an average of 5 yearsfor an average of 5 years

Aspirin reduces the risk of MI among men in the PHSAspirin reduces the risk of MI among men in the PHSAspirin reduces the risk of MI among men in the PHSAspirin reduces the risk of MI among men in the PHS

End pointEnd pointEnd pointEnd point Relative Risk (95% CI)Relative Risk (95% CI)Relative Risk (95% CI)Relative Risk (95% CI) P valueP valueP valueP value

CV Mortality 0.96 (0.60-1.54) NS Myocardial infarction Fatal 0.34 (0.15-0.75) 0.007 Nonfatal 0.59 (0.47-0.74) <0.00001 Total 0.56 (0.45-0.70) <0.00001 Stroke Fatal 1.51 (0.54-4.28) 0.43 Nonfatal 1.20 (0.91-1.59) 0.20 Total 1.22 (0.93-1.60) 0.15

Physicians’ Health Study Research Group. Physicians’ Health Study Research Group. Physicians’ Health Study Research Group. Physicians’ Health Study Research Group. NEJMNEJMNEJMNEJM 1989;321:1291989;321:1291989;321:1291989;321:129----35353535

CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, NS=NonsignificantCI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, NS=NonsignificantCI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, NS=NonsignificantCI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, NS=Nonsignificant

Aspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in Men

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Mean Follow-Up Period of 10 years

First Major Cardiovascular Event:

Nonfatal Myocardial Infarction, Nonfatal Stroke, Ca rdiovascular Death

Aspirin(100 mg po onalternate days)

39,876 Initially healthy womenAge 45 years and older (mean age 54.6)

19,934 on Aspirin 19,942 on Placebo

Placebo

The Women’s Health Study

Aspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in Women

Ridker P et al. N Engl J Med. 2005;352:1293-1304.

Women’’’’s Health Study: Major Cardiovascular Events(Nonfatal Myocardial Infarction, Nonfatal Stroke, C ardiovascular Death)

0 2 4 6 8 10

Years of Follow -Up

0.00

0.01

0.02

0.03

Cum

ulat

ive

Eve

nt R

ate

0 2 4 6 8 10

Placebo

Aspirin

RR = 0.91 95% CI 0.80 – 1.03

P = 0.13

9 percent

Aspirin for Primary Prevention in Women?

39,876 women randomized to aspirin (100 mg every other day) or placebo

for 10 years

Ridker P et al. N Engl J Med. 2005;352:1293-1304.

0 2 4 6 8 10Years of Follow-Up

0.00

0.01

0.02

Cum

ulat

ive

Eve

nt R

ate

0 2 4 6 8 10

0.00

0.01

0.02

Placebo

Aspirin


0.00

0.01

0.02

Cum

ulat

ive

Eve

nt R

ate

0 2 4 6 8 10

0.00

0.01

0.02

AspirinPlacebo

Years of Follow-Up

0.00

0.01

0.02

Cum

ulat

ive

Eve

nt R

ate

Aspirin

Placebo


0.00

0.01

0.02

Cum

ulat

ive

Eve

nt R

ate

0 2 4 6 8 10

AspirinPlacebo

Total StrokeRR = 0.83 (0.69-0.99)

P = 0.04

Myocardial InfarctionRR = 1.02 (0.84-1.25)

P = 0.83

Ischemic StrokeRR = 0.76 (0.63-0.93)

P = 0.009

Hemorrhagic StrokeRR = 1.24 (0.82-1.87)

P = 0.31

0 2 4 6 8 100 2 4 6 8 10

Women’’’’s Health Study – Stroke and Myocardial Infarction

Aspirin Placebo RR 95%CI P(N=19,934) (N=19,942)

Age (years)

45–54 (24,025) 163 161 1.01 0.81-1.26 0.92

55–64 (11,754) 183 186 0.98 0.80-1.20 0.84

>65 (4,097) 131 175 0.74 0.59-0.92 0.008

Major CV Event* = Nonfatal MI, nonfatal stroke, car diovascular death

The Women’s Health Study: Subgroup Analyses, Primary Endpoint of Major CV Eve nt*

*P for interaction by age = 0.05 for total CVD and 0.03 for MI

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† Major CV Event = nonfatal MI, nonfatal stroke, ca rdiovascular death

Endpoint Aspirin Placebo RR (95%CI) P

Major CV Event† 131 175 0.74 (0.59–0.92) 0.008

Total MI 41 62 0.66 (0.44–0.97) 0.04

Total Stroke 68 86 0.78 (0.57–1.08) 0.13

44 Fewer Major CV Events16 Additional GI Hemorrhages Requiring Transfusion

Women’’’’s Health Study: Subgroup Analyses, Age > 65 years




Primary prevention

Sex differences



Objectives

2010 Aspirin Recommendations for Patients with Diabetes Mellitus (ADA/AHA/ACC)

• Use aspirin 75 to 162 mg/day for secondary ASCVD prevention

• Consider aspirin 75 to 162 mg/day for primary ASCVD prevention in diabetic patients at increased risk

– Those at risk for ASCVD (10-year risk >10%)—men >50 yrs, women >60 yrs, with > 1 additional risk factor (family history of premature ASCVD, HTN, smoking, dyslipidemia, albumi nuria)

• Not sufficient evidence for aspirin for primary pre vention in low risk groups

Pignone M et al JACC 2010;55:2878

2011 AHA guidelines: CVD Prevention in women

• Aspirin (75 to 325 mg/d) in high-risk womenIf aspirin-intolerant: substitute clopidogrel

• Aspirin (81 mg/d or 100 mg every other day) in at risk women ≥65 years is reasonable if BP is controlled and benefit outweighs risk

• Aspirin in at risk women <65 years for preventing

ischemic stroke may be reasonable if benefit

outweighs risk

• Not Recommended: for preventing myocardial infarction in optimal risk women <65 years

Mosca et al. Circulation 2011;123:1243-1262

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2015 U.S. Preventive Services Task ForceDraft Recommendations for low dose aspirin

Guiruis-Blake JM et al. 2015 www.uspreventiveservi cestaskforce.org

Population Recommendation Grade

Adults age 50-59 yrs For primary prevention of ASCVD and colorectal cancer if:- ≥ 10% ASCVD risk *- Not at increased risk of bleeding- Life expectancy of at least 10 yrs- Willing to take aspirin for at least 10 yrs

B (Moderate)

Adults age 60-69 yrs Individualize the decision if:- ≥ 10% ASCVD risk, - Not at increased risk of bleeding- Life expectancy of at least 10 yrs- Willing to take aspirin for at least 10 yrs

C

Adults < 50 yrs Insufficient evidence I

Adults ≥ 70 yrs Insufficient evidence I

*Pooled Cohort Equations available at http://my.americanheart.org/cvriskcalculator




Primary prevention

Sex differences



Objectives

The information to estimate ASCVD risk (2013):age, sex, race, TC, HDL-C, SBP, BP Rx, diabetes ,

smoking �� 10-yr risk of MI, fatal or nonfatal stroke, CHD dea th

�� lifetime risk

Prior (ATP III, 2001): Age, sex, TC, HDL-C, SBP, BP Rx, smoking

�� 10-yr risk of MI, CHD death

Goff et al JACC 2014;63:2935-59

*Pooled Cohort Equation available at http://my.americanheart.org/cvriskcalculator

2013 Cholesterol Guidelines

• New Equations* for ASCVD risk assessment

- Stroke included, in addition to MI

- Separate equations for blacks

• 4 Statin benefit groups

- Adults with clinical ASCVD

- Adults with LDL-C ≥190 mg/dL

- Adults 40 to 75 yrs of age with diabetes

- Adults ≥7.5% estimated 10-yr risk of ASCVD

•No LDL-C or non-HDL-C treatment targets

*Pooled Cohort Equation available at http://my.americanheart.org/cvriskcalculator

Stone et al JACC 2014;63:2889-934

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• High Risk– Clinical ASCVD* – LDL >190 mg/dL, age >21 years– Primary prevention – Diabetes: age 40-75 y,

LDL 70-189 mg/dL• Primary prevention

No diabetes, ≥7.5% 10-year ASCVD risk, age 40-75 years, LDL 70-189 mg/dL

*Acute coronary syndrome, MI, angina, coronary or o ther arterial revascularization, stroke, TIA, atherosclerotic per ipheral arterial disease (PAD)

4 Groups of High Risk Individuals

Stone et al JACC 2014;63:2889-934

Individuals Not in a Statin Benefit Group

Additional factors may inform clinical decision making

• Family history of premature ASCVD*• High lifetime risk • LDL–c ≥160 mg/dL• hs-CRP ≥ 2 mg/L• CAC score ≥ 300 or ≥75th percentile• Ankle brachial index (ABI) < 0.9

* onset <55 y first degree male or <65 first degree female

Stone et al JACC 2014;63:2889-934

Statin Evidence: Primary Prevention in WomenStatin Evidence: Primary Prevention in WomenStatin Evidence: Primary Prevention in WomenStatin Evidence: Primary Prevention in Women

.1 .5 1 5 10

AFCAPS/TexCAPS 1998

MEGA 2006

JUPITER 2008

0.63 (0.49-0.82) P<0.001P for heterogeneity 0.56ALL

Favors Statin Favors Placebo

(0.34-1.31)

(0.49-1.10)

(0.37-0.80)

21/498

56/2718

70/3375

14/499

40/2638

39/3426

RR 95% CI Placebo Statin

0.67

0.73

0.54

Year

13,154 Women; 240 CVD events

Mora S et al., Circulation 2010;121:1069

1. Reviewed current challenges for atherosclerotic cardiovascular disease (ASCVD) prevention, with a focus on the impact in women

2. Reviewed evidence on aspirin for the prevention of ASCVD


Primary prevention

Sex differences


3. Reviewed evidence on statins for the prevention of ASCVD

Topics discussed

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Thank you!

Ongoing aspirin trials

Depta JP and Bhatt DL CCJM 2015;82:91-96

objectives primary prevention of heart disease · 9/29/2015 2 impact of ascvd in women • single...

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