Hemostasis in postmenopausal women on HRT

Transcription

1 10 Hemosasis in posmenopausal women on HRT Epidemiological observaional sudies have shown ha menopause is associaed wih cerain modificaions in he parameers ofhemosasis. I is hus reasonable a envisage wheher HRT could influence hese parameers (Oura, 1995). Differen approaches can be followed o obain an answer: he observaional approach which consiss of analysing he poenial links beween HRT and he variables of hemosasis, and he inervenional approach (conrolled randomized rial) which is he only way of assessing he disinc effec of HRT. In his chaper, sudies of hese wo ypes will be reviewed and heir resuls analysed and commened on. Observaional sudies The procedures and resuls of eigh repors are summarized in ables 10.1 and W.II. Since mos of hese sudies have been performed in he Unied Saes, HRT was adminisered orally and consised of conjugaed equine esrogen combined or no wih a progesogen. In France (Derby e al., 1995), naural esrogen (l7-esradiol) is preferred; i is adminisered ransdermally and combined wih a pregnane or a norpregnane, or wih naural progeserone. I has o be poined ou ha, in observaional sudies, he ype of HRT is very rarely described in deail. In he Healhy Women cohor sudy performed in he Unied Saes in he lare eighies, 207 women (49 o 56 years old) were recruied using car insurance company lisings (Meilhan e al., 1992). Thiry six per cen of he 163 posmenopausal women were on HRT. Afer age adjusmen, he resuls indicaed ha HRT was associaed wih significan decreases in fibrinogen and anihrombin III and an increase in plasminogen. In conras, facor VII was no modified. The Scoish Hear Healh sudy is a large cohor sudy. I considered women, 25 o 69 years old, recruied by general praciioners during 1988 (Lee e al., 1993). Only 2 % of he 2611 menopausal women were on HRT. A single hemosasis parameer, fibrinogen, was evaluaed and shown o 151

2 Auhors Sudy Counry Design Sample size Age Populaion Recruimen Period Meilhan e al. (1992) Healhy Women USA Cross-secional Car drivers Lee e al. (1993) Scoish Hear Healh Scoland Cross-secional General populaion 1988 Scarabin e al. (1993) Paris France Cross-secional healh check-up 1989 Nabulsi e al. (1993) ARIC USA Cross-secional Communiies Manolio e al. (1993) Cardiovascular Healh USA Cross-secional Random sample from Communiies Gebara e al. (1995) Framingham USA Cross-secional 749 Framingham Salomaa e al. (1995) Finrisk Haemosasis Finland Cross-secional Random sam pie 1992 Meilhan e al. (1996) Oseoporoic Fracures USA Cross-secional Communiies ::c o So :l '"El co g f}.. :l co o :l co a.. '"co :::!. '".. \.Tl N Table 10.1 : Hormone replacemen herapy and hemosasis : characerisics of he sudies. Shahar e al. (1996) Nesed case-conrol 288

3 PAI-1 Ohers facors ac Plasminogen '" -+ VIII c -+ PA ag D.dimers -+ Pro C'" ag PA ag ag Vllag '" Plasminogen '" ANAlYSIS 8 ocf> El" :!J. Cf> S '1j o Cf> icf> :fi 8(J) ::: o ::: Table : Hormone replacemen herapy and hemosasis : main resuls Auhors Sudy F Vile Fibrinogen Meilhan e al. (1992) Healhy Women -+ ATIII Lee e al. (1993) Scoish Hear Healh Scarabin e al. (1993) Paris Nabulsi e al. (1993) ARIC '" Shahar e al. (1996) '" -+ Manolio e al. (1993) Cardiovascular Healh Gebara e al. (1995) Framingham '" Salomaa e al. (1995) Finrisk Haemosasis -+ Meilhan e al. (1996) Oseoporoic Fracures. U1 (;.)

4 Hormone replacemen herapy. Influence on cardiovascular risk be significanly decreased in HRT-reaed women as compared wih heir unreaed, age-mached, counerpars. The Paris sudy, a ransversal sudy, was published in Two hundred and fify-nine women (45 o 54 years old), were recruied in a check-up cener (Scarabin e al, 1993). Ou of he 120 posmenopausal subjecs, 17 % were on HRT (in mos cases ransdermal esrogen combined wih a progesogen). Afer age adjusmen, HRT was relaed o a significan decrease in coagulaion facor VII and PAI-1 aciviy. Fibrinogen levels were no significanly modified. The Aric sudy (an American sudy) is he larges so far published : women, 45 o 64 years old, were recruied in differen communiies in he eighies (Conlan e al, 1994; Folsom e al, 1991; Nabulsi e al, 1993). An analysis of he firs daa colleced in his cohor sudy and in a case-conrol sudy concerning 288 women seleced ou of he overall cohor have been published. The case-conrol sudy concerned 142 women presening a hickening of heir caroid and 146 normal conrols (Shahar e al, 1996). Afer age-adjusmen, he daa showed ha anihrombin III and PA anigen were decreased in au reaed women, as compared wih unreaed women. In subjecs receiving only esrogens, coagulaion facor VII and C proein were significanly increased, while in subjecs receiving an esro-progesogen combinaion hey were no modified. Fibrinogen, PAI-1 anigen, D-Dimers and coagulaion facor VIII levels were no influenced by eiher reamen. In he Cardiovascular healh sudy (an American cohor sudy) 2955 women were enrolled. They were older han 65 and lived in differen communiies (Manolio e al, 1993). HRT was or had been uilized by 39 % of hem. Ongoing reamen was associaed wih a significan decrease in fibrinogen and a significan increase in coagulaion facor VII, as compared wih neveruser age-mached subjecs. Similar levels of coagulaion facor VII were measured in never-users and in women who had disconinued HRT. A ransversal analysis has been performed using he Framingham cohor daa (Gebara e al, 1995). PAI-1 and PA anigen were analyzed in 749 subjecs and a significan decrease in hese wo parameers was observed in reaed menopausal women as compared wih unreaed women. In he Finrisk hemosasis sudy, a randomized sample comprising Finnish women, (25 o 64 years old) was sudied in relaion o menopause and HRT, for coagulaion facor VII, facor VII anigen, fibrinogen and plasminogen (Salomaa e al, 1995). Fibrinogen only was shown o be decreased in HRT users as compared wih age-mached non-users. Facor VII was no significanly modified while facor VII anigen and plasminogen were significanly increased. The oseoporoic fracures sudy (a cohor sudy) performed in he Unied 154 Saes enrolled women 65 o 82 years old, living in communiies. I was

5 Hemosasis in posmenopausal women on HRT essenially aimed a evaluaing he fracure risk facors in aging women (Meilhan e al., 1996). Ou of a oal of subjecs, 273 were randomly chosen (139 HRT users and 138 age-mached non-users), and i was observed ha fibrinogen and PAI-1 were significanly lower in reaed subjecs han in unreaed subjecs. Inervenional sudies In his approach, conrolled and randomized rials are underaken o appreciae he disinc effecs ofhrt. Table 10.III describes he five sudies which are analyzed below. Among hese sudies, four considered fibrinogen, which is a poen predicor of coronary disease in men and women (PEPI, 1995 ; Conard e al., 1995 ; Scarabin e al., 1997 ; Wriing Group for he esradiol cloing facors sudy, 1996). The PEPI rial, which is he larges as i included 875 subjecs, indicaed ha fibrinogen was significanly decreased in HRT -reaed groups (combined or cyclic reamens) as compared wih placebo (PEPI, 1995). Neverheless he size of his fall was raher weak. These resuls have been confirmed by an lalian sudy (Esradiol cloing facors sudy group), showing ha fibrinogen is lowered in women receiving coninuous ransdermal esrogen reamen combined wih a sequenial progesogen (medroxyprogeserone aceae) reamen (Wriing Group for he esradiol cloing facors sudy, 1996). Two oher rials including smaller groups did no confirm hese daa (Conard e al., 1995 ; Scarabin e al., 1997). As far as facor VII is concerned, a significan decrease in HRT -reaed women was observed only in an Ialian rial. In his sudy a coninuous ransdermal esrogen combined wih a sequenial progesogen was compared wih a placebo (Wriing Group for he esradiol cloing facors sudy, 1996). This observaion was no confirmed by Scarabin e al. (1997). Anihrombin III and proein C are poen coagulaion inhibiors. Caine e al. (1992) used wo dosages of conjugaed equine esrogens (1.25 mg and mg) and found ha a significan dose-dependen decrease in anihrombin III couid be observed as weil as a significan increase in proein C only in women receiving he high dose. In he lalian sudy, anihrombin III was shown o be decreased and proein C unchanged in women reaed wih coninuous esrogen and sequenial progesogen (Wriing Group for he esradiol cloing facors sudy, 1996). Scarabin e al repor ha, following oral reamen, anihrombin III was decreased while ransdermal reamen did no modify his parameer (Scarabin e al., 1997). Finally no significan modificaions in anihrombin III or proein C levels were repored by Conard e al. (1995). 155

6 '1j U1 S 0 ::l :: 0\ 0 Si n Table : Characerisics and resuls of randomized conrolled rials S ::l Auhors Counry Sam pie Age Follow-up size (monhs) Treamen (dose per day) Resuls ::r Caine e al. (1992) USA CE mg F1 +2 dose dependen 2. CE 1.25 mg Fp A HRT /placebo ;1 3. placebo AT III, Pro S dose dependen. Pro C group 2/placebo ::l " PEPI (1995) USA placebo Only fibrinogen ::l 2. CE mg in placebo group / any acive reamen n 3. CE mg + MPA 10 mg cyclic 2 No differences among any reamen 0 4. CE mg + MPA 2.5 mg ::l 5. CE 0,625 mg + MP 200 mg cyclic 2 n il' Conard e al. (1995) France placebo Plasminogen in reamen group/placebo 9:' 0 2. E2 1mg (25 days) + NA 2,5 mg cyclic 2 No change AT III, Fibrinogen, F 1+2, Pro S, 3. E2 1.5mg (25 days) + NA 3.75 mg cyclic 2 ProC il' en n>:: Esradiol Cloing Facors Ialie TTS E2 50 mg (21 days)+ MPA 10 mg cyclic Fibrinogen, FVII, AT III, Pro S, : in group 2 / Si Sudy Group 2. TTS E2 50 mg + MPA 10 mg cyclic placebo :J. (1996) 3. placebo No change FVlllc, PAI-1 ac, pro C. en :>;" Same variaions in group 1/placebo bu no significan Scarabin e al. (1997) plasminogen : no differences beween he hree groups. France E2 valerae 2mg (25 days)+mp 200 mg cyclic F1 +2, GFC in group 1/3 2. Gel E2 2.5 mg (25 days) + MP 200 mg cyclic AT III, -PA ag, PAI-1 ac in group 1/3 3. no hormonal reamen F1 +2 in group 1/2 Fibrinogen, FVII, vwf, Pro C, O-Oimer and

7 Hemosasis in posmenopausal women on HRT Markers of coagulaion acivaion have been sudied in wo rials. Caine e al. (1992) observed ha hese markers (fragmens 1+2) were significanly increased, his modificaion being dose-dependen. Scarabin e al. (1997) repored a similar effec when he reamen was adminisered orally. Two rials have considered variables of he fibrinolyic sysem. No significan modificaions of PAI-1 aciviy were observed in he Ialian rial. In conras, in he sudy repored by Scarabin e al. significan decreases in PAI-1 aciviy and in PA anigen were found, bu, once again, only in he oral reaed group (Scarabin e al ; Wriing Group for he esradiol cloing facors sudy, 1996). Moreover, a significan increase in global fibrinolyic capaciy was observed in his same group, while ransdermal reamen did no modify hese parameers (Scarabin e al, 1997). Criical analysis Resuls of observaional sudies sugges ha an increase in fibrinolyic poenial and a decrease in fibrinogen could be associaed wih HRT. N everheless, i is difficul o know wha combinaion HRT was adminisered in erms of esrogens and progesogens. In addiion, observaional sudies are subjec o biases, meaning ha hey canno ascerain a cause-effec relaion. Only randomized conrolled rials can provide a scienific evaluaion of reamen. So far, such rials are rare because hey are difficul o underake. The sudies previously repored involved small samples and shor periods (6 monhs). The PEPI rial is he only one o include a reasonable number of subjecs (875) for hree years, bu fibrinogen was he sole coagulaion parameer sudied. In he five case-conrol rials published, various HRT were used. Globally, oral esrogen reamens, alone or combined wih progesogens, did no have a derimenal effec on fibrinogen and could even be beneficial. Two sudies considered markers of coagulaion acivaion. Esrogen reamens adminisered per os are relaed o a significan dose-dependen increase in hese markers. As far as naural esrogens are concerned, he influence of heir roue of adminisraion was sudied in only one publicaion. l was shown ha he oral roue was relaed o an acivaion of he coagulaion sysem and o a parallel increase in fibrinolyic poenial, while he ransdermal roue did no modify hemosasis in he shor erm. None of hese randomized sudies gives any informaion on he influence of he differen progesogens used in France. T 0 conclude, resuls of observaional sudies sugges ha an increase in fibrinolyic poenial and a decrease in fibrinogen could be associaed wih HRT 157

8 Hormone replacemen herapy. Influence on cardiovascular risk bu observaional sudies are subjec o biases, meaning ha hey canno ascerain a cause-effec relaion. In he case-conrol rials published, globally, oral esrogen reamens, alone or combined wih progesogens, did no have a derimenal effec on fibrinogen and could even be beneficial When he markers of coagulaion are esed, i appears ha oral reamen is relaed wih an acivaion of hese markers. Long erm randomized rials will be necessary for a beer knowledge of he influence of he various available HRTs on hemosasis. BIBLIOGRAPHY CAINE YG, BAUER KA, BARZEGAR S e al. Coagulaion acivaion following esrogen adminisraion o posmenopausal women. Thromb Haemos 1992, 68: CONARD J, DENIS C, BASDEVANT A e al. Cardiovascular risk facors and combined esrogenprogesin replacemen herapy: a placebo-conrolled sudy wih nomegesrol aceae and esradiol. Ferril Seri11995, 64 : CONLAN MG, FOLSOM AR, FINCH A, DAVIS CE e al. Anihrombin 1II : associaions wih age, race, sex and cardiovascular disease risk facors. The Aherosclerosis Risk in Communiies (ARIC) Sudy Invesigaors. Thromb Haemos 1994, 72 : DERBY CA, HUME AL, MCPHILUPS JB, BARBOUR MM, CARLETON RA. Prior and curren healh characerisics of posmenopausal esrogen replacemen herapy users compared wih nonusers. Am J Obse Gynecol 1995, 173 : FOLSOM AR, WU KK, DAVIS CE, CONLAN MG e al. Populaion correlaes of plasma fibrinogen and facor VII, puaive cardiovascular risk facors. Aherosclerosis 1991, 91 : GEBARA OCE, MITTLEMAN MA, SUTHERLAND P, UPINSKA 1 e al. Associaion beween increased esrogen saus and increased fibrinolyic poenial in he Framingham Offspring Sudy. Circulaion 1995, 91 : GURA T. Esrogen: key player in hear disease among women. Science 1995, 269: LEE AJ, LOWE GDO, SMITH WCS, TUNSTALL-PEDOE H. Plasma fibrinogen in women: relaionships wih oral conracepion, he menopause and hormone replacemen herapy. Br J Haem 1993, 83 : MANOUO TA, FURBERG CD, SHEMANSKI L e al. Associaions of posmenopausal esrogen use wih cardiovascular disease and is risk facors in older women. Circulaion 1993,88 : MEILHAN EN, KULLER LH, MATTHEWS KA, KISS JE. Hemosaic facors according o menopausai saus and use of hormone replacemen herapy. Ann Epidemiol 1992, 2 : MEILHAN EN, CAULEY JA, TRACY RP, MACY EO e al. Associaion of sex hormones and adiposiy wih plasma levels of fibrinogen and PAI-1 in posmenopausal women. Am J Epidemio11996, 143: NABULSI AA, FOLSOM AR, WHITE A, PATSCH W e al. Associaion of hormone-replacemen herapy wih various cardiovascular risk facors in posmenopausal women. The Aherosclerosis Risk in Communiies Sudy Invesigaors. N Engl] Med 1993, 15 : 328 PEPI. Effecs of esrogen or esrogenfprogesin regimens on hear disease risk facors in posmenopausal women. The Posmenopausal EsrogenfProgesin Inervenions (pepi) Trial. The Wriing Group for he PEPI Trial (see commens) (published erraum appears injama 1995, : 1676). JAMA 1995, 273 :

9 Hemosasis in posmenopausal women on HRT SALOMAA V, RASI V, PEKKANEN J, VAHTERA E e al. Associaion of hormone replacemen herapy wih hemosaic and oher cardiovascular risk facors. The Finrisk hemosais sudy. Arerioscler Thromb Vase Biol 1995, 15: SCARABIN PY, PLU-BUREAU G, BARA L, BONITHON-KOPP C e al. Haemosaic variables and menopausal saus: influence of hormone replacemen herapy. Thromb Haemos 1993, 70: SCARABIN PY, ALHENC-GELAS M, PLU-BUREAU G e al. Effecs of oral and ransdermal esrogenfprogeserone regimens on blood coagulaion and fibrinolysis in posmenopausal women: a randomised conrolled rial. Arerioscler Thromb Vase Biol 1997, 17: SHAHAR E, FOLSOM AR, SALOMAA VV, STINSON VL e al. Relaion of hormone replacemen herapy o measures of plasma fibrinolyic aciviy. Circulaion 1996, 93 : WRITING GROUP FOR THE ESTRADIOL CLOTTING FACTORS STUDY. Effecs on haemosasis of hormone replacemen herapy wih ransdermal esrdiol and oral sequenial medroxyprogeserone aceae: a 1-year, double-blind, placebo-conrolled sudy. Thromb Haemos 1996, 75 :