Differences In Efficacy Of Antiplatelet Therapy-Is That Gender Specific?

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1 Differences In Efficacy Of Antiplatelet Therapy-Is That Gender Specific? DR.O.SAI SATISH PROFESSOR DEPARTMENT OF CARDIOLOGY NIMS

2 Death is inevitable but Premature death is not Sir Richard Doll

3 Topic outline Epidemiology of thrombotic disorders in women Sex differences in platelet biology Platelet reactivity Inflammation Role of hormones in platelet biology and inflammation Clinical evidence of sex difference in response to antiplatelet therapy Aspirin Thienopyridines GPIIb/IIIa inhibitors Sex differences in bleeding associated with antiplatelet therapy.

4 Introduction Many RCT have shown the benefit of antiplatelets therapy in CVD,their findings cannot be generalised to subgroups,if not sufficiently represented in the study population. Women are under represented in CV trials. Sex differences in response to anti thrombotic therapies, in response to bleeding vs thrombotic risk remain unclear. A better understanding of these differences will lead to development of optimised therapies for the treatment and prevention of ischemic events in women,while minimising bleeding risk.

5 Epidemiology of thrombotic disorders in women IHD and stroke accounts for -25% of deaths among women world wide. In US- in 2007, CAD accounted for 15.6% of deaths while strokes accounted for 6.7% Prevalence of various thrombotic disorders varies greatly with age Incidence of CAD triples around menopause. Women with AMI high mortality than men regardless of reperfusion technique.

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7 Sex differences in platelet biology WCC&IVUS2015

8 Platelet reactivity Platelets from women without CAD are more reactive than those of men in response to standard concentrations of agonists like ADP and thrombin receptor agonist protein.(trap). Among asymptomatic patients, platelets from women bound more fibrinogen in response to low and high concentrations of ADP, showed more spontaneous aggregation compared with men after adjustment for risk factors like diabetes, hypertension,aspirin usage. Aspirin absorbtion slows during menstrual mid-cycle.

9 genestar study(genetic study of aspirin responsiveness)-among healthy men and women, demonstrated higher platelet reactivity among women compared with men in response to varying concentrations of ADP, arachidonic acid, or epinephrine. becker DM, segal J, vaidya D et al; sex differences in platelet reactivity and response to low dose aspirin therapy.jama 2006;295; After aspirin therapy, For arachidonic acid-males and females showed similar response. For ADP and collagen, women showed more reactivity WCC&IVUS2015

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11 Inflammation Activated platelets through the release of cytokines, mediate an inflammatory response that further amplifies platelet response during plaque rupture. In womens health study, among post menopausal womenhscrp,pselectin,leucocyte count-higher and were more predictive of future CV events. Antiplatelets therapies-pleiotrophic anti inflammatory effects beyond their antiplatelet action. Both aspirin and clopidogrel showed similar response in men and women.

12 Role of Hormones Mega karyocytes and platelets express estrogen receptor β and androgen receptor(ar). Platelet NOS release and TXA2 generation can be modulated by estrogens and androgens. Conflicting evidence of the role of menstrual hormones on aggregation-some supporting and others negating. Platelets bind more fibrinogen during the LUTEAL phase than the follicular phase suggesting that hormones regulates platelet activation.

13 Clinical evidence of sex difference in response to antiplatelet therapy

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16 Aspirin Meta analysis of 6 randomised trials MI risk was significantly reduced in men No MI risk reduction in females. Secondary analyses from these trials showed no clear benefit with aspirin doses >100 mg compared with lower doses. Even though females showed higher platelet reactivity, higher aspirin dose was not beneficial.

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18 Thienopyridines Meta analysis of 5 large RCT (JACC 2009;54; ) Clopidogrel treatment was associated with significant reduction in all 3 CV end points-cv death,mi or stroke. In males- all 3 end points were achieved. In females- only MI reduction was observed. Prasugrel and ticagrelor did not show any difference between males vs females.

19 Cytochrome P 450 2C19 allele independently associated with variable response to clopidogrelprodrug metabolism to active metabolite. These polymorphisms are similarly distributed among males and females- no difference in clopidogrel resistance between males and females are observed.

20 CILASTAZOL Cilostazol as an add on drug to aspirin and clopidogrel in pts with PCI has shown substantial benefit among women than men. Am Heart J 2009;157;733-9

21 GP IIb/IIIa Inhibitors-Gender differences

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23 significant reduction in MI was seen at day 30 in pts with ACS -Seen in males- Worse in females-women were older, more co morbid conditions, and larger infarcts. Concamitant use of clopidogrel-did not show any gender differences. (NEJM 2009;360; )

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25 Sex differences in bleeding with antiplatelet therapies Womens health study- serious GI bleed requiring transfusion was more common in women receiving aspirin. In ACS patients, sex related differences in bleeding risk are consistently demonstrated. In CRUSADE registry, women who underwent PCI had higher in hospital major bleeding. Women had more access related bleeding like-access site bleeding, retroperitoneal bleeding etc. Smaller blood vessels, vascular reactivity etc contributed to more bleeding in women. WCC&IVUS2015

26 TAKE HOME MESSAGE Women are under represented in most of the clinical trails conducted. Women have more platelet reactivity when compared to men even without associated CAD. Even after aspirin therapy, women showed more reactivity towards ADP, collagen. Conflicting evidence on the role of menstrual hormones on aggregation-some supporting while others negating.

27 Regarding prevention trials, aspirin showed no MI risk reduction, while clopidogrel showed MI risk reduction in females. No difference in clopidogrel resistance in males vs females. More bleeding side-effects was noticed in females with use of GPIIb/IIIa inhibitors. More studies with women are needed focussing on CVD as the primary end point on gender differences and efficacy of antiplatelet drugs WCC&IVUS2015

28 Thank u WCC&IVUS2015