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MEOICAL PHOGR6SS
R e v i c w A r i i c l c
Mcdical Progress
ORAL CONTRACEPTIVES AND THE
RISK OF VENOUS THROMBOSIS
JAN P. VANDENBROUCKE. M.D., PH.D., JAN ROSING, PH.D.KITTY W.M. BLOEMENICAMP, M.D., PHJ3., SASKIA MIDDELDORP, M.D., PH.D-, FRANS M. HELMERHORST, M.D., PH.D..
BONNO N. BOUMA, PH.D.,
AND FRITS R. ROSENOAAL, M.D., PH.D.
I
N thc early 1960s, shordy aftcr ehe introduction of ora! contraceptives, thc first casc rcports ap-pearcd dcscribing vcnous dvombosis and pulmo-naxy cmboli in womcn using this meihod of birch control. Latcr, myocardial infarction and strokc wcrc also found to bc associaccd with the usc of oral con-traceptives. These observadons Icd to numerous cp-idcmiologic and clinicaJ studies of oral-contraccpcivc pills and thrombosis and subscqucntly to thc dcvel· opmcnt of ncw oral contraccpcivcs with a lowcr es· trogen contcnt. These lowcr-cstrogcn contraccptives wcre considcrcd safcr: changes in hcmostatic factors rcmained smaJI, inconsistcnt in dirccuon, and mostly within thc normal ränge.1 <Reccn: studies have challcnged thc concept that rcdacing thc dose of estrogcn in oral contraccpcivcs diminatcs the risk ofvcnous thrombosis. These stud-ics havc includcd cpidcmiologk data suggesung that ccrtain progcstins may increase die risk of thrombosis associaicd with low-cstrogen preparaüons, new find-ings rcgarding individual gcnctic susccpdbiliücs to thc ihrombogenic cfFcct of oral contraccpdves, and new insights into thc hcmostatic changes that prcdisposc womcn to thrombosis. These advances havc consc-qucnccs with rcspcct to die dcvclopment of ncw corv rraccpdves and tailoring of thc prescripdon of cur-rcndy availablc prcparadons.
hron> tlic Dcparlmc;iu iif'Oini"! Epidcmiologv ( I P,V.. I-'R.K.), <hc D": pjrtmcni olOhkiijcnn. G>i\ccology. and Rjcpnxluctivr: McdiCirvc (K.W M H . H M H l . Jnd ilic Tfit<»\>bo>is ind Hicmoituii Rx«ifch Center (HK. R. ). L.cidcn Uni^crsuy Modical Ccnccr, Leiden; Thc DcpirtmcnC of BiiXhcmi^· trv, CjrJiovjiiuljr Ksscjrch Inscicute. Mmtriclit (J.R.J. ehe Dcpirtmcni of V«cular Mcdicinc, Aodcmic Mcdlcal Center. Amstcrdim (S M ), *nd (hc I hronibosiS jnd l lcmo««ii Labontofy. Dcpirtmcnt of Hcmjtology. UnivcrSity Hospital Utrecht, Utrecht (B.N.B.) — »II in ihc Ncthcflmdi AJUre«« rcpnni rcqucit» (o Dr. Vindenbroucke « thc Dcpjruncnf df Clin ical hpidcmiology, Leiden Uru'veruty Mcdiol Center, Γ.Ο BOT 9600, 2300 KC Leiden, the Nerhcrlindi, or « «JbroudccemiU.mcdCie.Iciilcnuni»' nl
Artcrial thrombosis is also a complication of OraJ-contraccptivc thcrapy, but thc risk factors for this condition diffcr from diosc for venous thrombosis, For examplc, smoking incrcascs die risk of myocar-dial infarction associatcd widi thc usc of oral contra-ceptivcs,1·* but it has no rnatcrial cffcct on die risk of
venous thrombosis in uscrs of oraJ contraceptives.7·11
In contrast, several prothrombotic gcncuc dcfccts arc strong risk factors for venous thrombosis and increase thc risk associatcd wid\ die usc of oral contraceptives, but most arc Ukely to bc only wcak risk factors for my-ocardial infarction or strokc. This rcview will focus on rcccnt dcvclopmcnts in our understanding of venous thrombosis äs a sidc cffcct of oral-contraccptivc use.
RISKS ASSOCIATED WITH LOW-DOSE ORAL CONTRACEPTIVES
In 1981, Stadel estimatcd that thc risk of vcnous thrombosis was increased by a factor of four in uscrs of oral contraceptives.* This csdmatc rcflcctcd die usc ofthc oral concraccptiv« availablc in thc 1970s, which wcrc prcdominantly "high-dosc" (cstrogcn Content, 50 ^g or more of ethinylcstradiol). At diar timc( litdc
was known about the cffcct of lowering die dose of cihinylcstradiol bclow 50 /xg.
Primarily on thc basis of srudics involving die usc of "low-dosc" oral contraceptives (30 to 40 μξ of
cthinylescradiol), an expert committcc of die World Health Organization concludcd in 1998 diät currcnt
uscrs of oral conaaceptivcs havc a risk of vcnous thrombosis that is three to six timcs that of non-users.10 Thc higlicst risk occurred during thc first ycar
of usc, and an increased risk persistcd until, but not bcyond, thc discontinuaüon of thc contraceptives, A rccent rcview of studies involving healthy young womcn without risk factors11 also rcported that die
risk of vcnous d\rombosis increased by a factor of 3 to 6; onc study estimatcd an increasc in risk by a factor of 11 (Tablc l).12'16 Thc absolute risk, howevcr,
rc-mains low. A basc-linc risk of Icss dian l per 10,000 pcrson-ycars is increased to 3 to 4 per 10,000 pcr-son-years during thc timc whcn oral contraceptives arc being uscdA*·11
Onc issuc of conccrn rcgarding thc merhods uscd in scudics of die risk of vcnous thrombosis wich or.il contracepcivcs is thc possibility of diagnostic-suspi-cion and rcfcrral bias. In othcr words, die awarcncss by thc physician that a paticnt wich calf pain or swcüing is taking oral contraceptives might increase thc likc-lihood that thc paticnt will bc cvaluated for dccp-vcin thrombosis17 and might lead to an ovcrcstimation of
the risk poscd by oral contraceptives. Thc finding in early studies that thc risks associatcd with oral
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TABUE i. CURRJENT BEST EVIDENCE OF THE RJSK OF VENOUS THROMBOSIS AMONG AITAIIENTLY HEALTHY Usens OF AVMLABLE LOW-DOSE COMWNED URAL CONTRACEPTWES."
STUOY IMXUDEO
Aae STUDV DESIGN
No. IN WHOM VENOU
DEYSlOitO 135% Cl|
Hclmricli er jl." 1976-1983 18-49 O«- NonfetaJ dccp «cnous ihrombocmboUsm 5 11,0(3.7-32.01 control and pulmoniry cmbolum
Vcncy et »I.» 1968-I98S 2S-S6 Cohort Fatal nid nonfccil superficii! vcnous 3 3.3(0.9-111) chrombophkbiris, dccp vcnous tHrom·
bocmboliim, »nd pulmonary craboliun
World Hc»J<ri 1989-1993 15-49 CMC- NonJatal dccp vcnous chtombocmbolism 132 ftorn Eufopc, <3S yr old 4.3 (2.9-6 5) Organizition" controt md pulmoniry cmboüim 42 from Europc, >35 yr old 3.9 (2.3-6.6) 93 from dcvcloping councry, <3S yrold 3.2 (2.3-4.5) 28 irom dcvclopuig couiury, ^ 35 yr old 2.5 (1.5-43) (ick er il." 1991-1994 <40 Cohort Nonfitil dccp vcnous thromboemboüsm 75 6.1 (Z.5-15.1)
ind pulmOQwy cmboliim
Lc»is et J."> 1993-1995 16-44 Cxx- BtJ aiid nonfatal dccp vcnous thrombo- 334 4.4(3.4-58) control cmbolum and pulmoiur)» embolism
•Adapccd from Haruufatd snd Owcn-Smiih." CI dcnot« confidcncc intcrvaj,
traceptives wcre similar rcgardlcss of whccher thc di-agnosis of vcnous chrombosis was ccrrain or uncercain suggesccd nhac such a bias was not the ocplanation for thc obscrved risks.18·1*
Morc rcccndy, two scudics addrcsscd this issue by focusing on women who wcre rcfcrred to tcscing fä-cilidcs for clinically suspccted dccp-vcin thrombo-sis.10·71 A casc was dcfincd äs an objcctivcly confirmed diagnosis of vcnous thrombosis, and controls wcre womcn with similai causc for clinical suspicion who proved not to havc venous thrombosis. Information about thc usc of oral contraceptives was obtaincd be-fbrc diagnostic tcsting was conductcd. The relative risk of confirmed vcnous thrombosis associatcd with oral concraccpüvcs was 6.4 (95 perccnt confidcrice in-tcrval, 1.2 to 34.3) in the smaller srudyMand 3.9 (95 pcrcent confidcncc intcrval, 2.6 to S.7) in thc largcr study.11 These rcsults confirm thc cxistcncc of an in-creascd risk associatcd wjth thc use of modern oral contraceptives that cannot be cxplained by surveil-lance bias.
THE EFFECT OF PROGESTINS IN COMBINED PRETARATIONS Betöre 1995, ehe progcstin componcnt of oral contraccpcives was not gcncrally thought to concrib-ute to thc risk of thrombosis. Howcvcr, morc rcccnt data. showing a higher risk of vcnous thrombosis with third-gcneration progcstins (dcsogcstrcl and gcsto-dcne) than with sccond-gcncration progestins (e.g., levonorgcstrel and norgcstrel) havc challcngcd this view.'s-22-;M Whcreas thc bencficial cffects of third-gcneration progcstins on thc Icvels of high-dcnsity lipoprotcin cholcsterol had suggcstcd that thcy might
lowcr thc risk of artcrial thrombosis, srudies dcmon-strated a relative risk of vcnous thrombosis in uscrs of thesc oral contraceptives thai was six to nine times that in nonusers.22·24
Of 16 original studics addressing thc risk of third-gcneration äs compared with sccond-gcneraüon oral concracepdves, 3 found no diffcrcncc betwccn thc rwo typcs of contraceptives25·27 and all the others found higher risks associatcd with the use of third-gencra-tion preparathird-gencra-tions, with estimatcs of risk ranging from 1.4 to 4 times äs high äs that associatcd with sccond-gcncration preparations.15·21'24·28 3S In a prospective srudy Lnvolving a pharmacy data base in the Nethcr-lands, the absolute risk associatcd with third-gcner-ation contraceptives approachcd l per 1000 ncw users per ycar during the ftrst ycar of usc.32 This Unding is consisrcnt with thosc of earlier studies that also found higher risks among first-time uscrs.15·22·"·36
Findings of an incrcascd risk with thkd-gcncra-tion contraccptives led to a protractcd dcbatc about possiblc bias and confounding.6·16·37^' Some suggcst-cd that oral contraceptives werc being differentially prescribed on thc basis of thc paticm's undcrlylng risk fäctors,*1· but thc appropriate stratification for risk fac-tors such äs obcsity and age did nor climin^cc the dif-fcrcncc in risk betwccn third-gencracion and second-gencration contraccpcivcs.'^Thc possibility that thc findings werc due to sclcctivc "attrition of suscepti-blcs"16·'11 was addrcsscd by the confirmation of thc findings in a separate analysis of thc first ycar of use.6·36·*6 Rcanalyscs according to thc duration of usc wcre suggcsted,41·*3 but thcy failed to revcrse thc find-ings convincingly.*·40·415 Takuig into account thcsc and othcr methodologic considcrations, indcpendcnt
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MED1CAL PHOGRESS
pcrcs who wcrc not Tnvolvcd in the original studies concludcd that bias and confounding could not ex-plain thc consistcnt cpidcmiologic findings of an
in-crcascd risk.'0·"·48 Rcccnt package inscrts for
third-gcncration oral contraccptivcs uscd in the United States and thc United Kingdom cxplain chat thcy are associatcd wich a higher risk of venous thrombosis than are othcr oral contraceptivcs.
The epidcmiologic evidcncc that some oral contra-ceptivcs arc morc thrombogcnic than othcrs Icd to thc ducidation of thc hcmostatic mechanisms that may undcrlie thc association betwccn oral contraccptivcs and venous thrombosis.
SUSCEPTIBILITY TO PROTHROMBOTIC STATES
Heredrtary Resistance to Activated Protein C and the Fnctor V Leiden Mutation
In 1993, DahJbäck et al. dcscribed a ncwly
recog-nized hcrcditary prothrombotic condition49: thc di-minishcd anticoaguiant responsc, or rcsistancc, to ac-tivated protcin C. The activatcd protein C systcm is one of thc hemostatic chccks and balanccs that in-hibit coagulation. Dahlbäck et al. dcscribed pcrsons from families wich multiple episodcs of venous throm-bosis who had normal levels of protcin C, but in whom activated protein C did not have its cxpccted anticoagulant cfifcct. One year latcr, the molccular basis was identificd äs a mutation in coagulation fac-tor V (the Substitution of adcninc for gxuninc at nu-clcotide 1691) at one of thc sitcs whcre activated pro-tcin C cxcrts its inactivating cfFect by clcaving factor V.so Thc mutant factor is commonly rcfcrred to äs factor V Leiden. Its prevaJence is about 5 pcrccnt in whitc persons, with some gcographic Variation, but it is virtuajly absent in Asian and African popula-dons.51·" Thc presencc of factor V Leiden increascs the risk of venous thrombosis by a factor of 4 to 10 in hetcrozygotes and by a factor of 50 to 100 in ho-mozygotcs."
It is now recognizcd that factor V Leiden grcatly increascs die risk of venous thrombosis associatcd with oral-contraceptivc usc (Fig. 1).* As comparcd with thc basc-linc risk for women who do not use oral con-traccptives and do not carry factor V Leiden, the risk is increascd by a factor of 4 in thosc who use oral contraccptives but do not carry factor V Leiden, by a factor of 7 in carricrs of thc factor V mutation who do not usc oral contracepuvcs, and by a faccor of 35 in womcn who carry ehe mutation and also usc oral conuraccptivcs. This susccpdbility has bccn confirmcd in othcr studies 2*·5< and is even higher in the few \vom-cn who are homozygous for this mutation.53 Other Hereditary Prothrombotic Defects
The prevaJence of previously rccognized prothrom-bodc dcfccts — deficiencics of protein C, protein' S, and antithrombin — is rnuch lowcr than that of
fac-tor V Leiden; thcir combincd prevaJence is Icss dian 1 to 2 pcrccnt.ss·56 Thcir rarity maJccs it difficult to conduct extensive studies of thc intcraction bctwccn thcsc dcfects and the usc of oral contraccptivcs. Nev-crtheless, multiple casc rcports and studies in large families indicate that thc risk is particuiarly high in young womcn with these dcfccts who bcgin to usc oral contraccptives.57·59 Another reccntly idcntified gcnctic dcfcct, a mutation in the prothrombin genc (the Substitution of adcnine for guaninc at nuclco-tidc 20210), is a moderate risk factor for thrombosis; its prevalencc among whitc persons is approximately 2 to 4 pcrccnt,60·61 and it has also bccn shown to in-crease thc risk of venous thrombosis associatcd with the usc of oral contraceptives.27
Womcn who havc a prothrombotic dcfcct have oraj-contraceptivc-associated venous thrombosis no: only morc oftcn, but also sooncr: thcir risk of venous thrombosis in thc first ycar of usc is morc than 10 cimcs that in later ycars.6* Thus, thc dcvelopmcnt of venous thrombosis in the first ycar of usc may bc a warning that a woman has a hcrcditary risk factor for venous thrombosis.62
Prothrombotic Condltlons of Uncertaln Heradity
High levcls of factor VIII arc linked to blood groups other than Ο,*3·Μ which accoums in part for
the obscrvation that having a blood group other than O increases thc risk of venous thrombosis by a factor of about 1.6 in general, and by a factor of 3.3
among users of oral contraccptives.65 Howcver, some
data have suggcsted that thc effects of high levcls of factor VTII and thc usc of oral contraceptivcs are
merely additive.66
A rccent study of carricrs of factor V Leiden dcm-onstratcd that women with blood groups other than O wcre four times äs likcly to have venous
thrombo-sis than thosc with blood group O. This incrcased risk was grcatcr than prcvious gcncral estimatcs de-rivcd from studies in unselected paticnts and points to a possiblc interaction,*7
MECHANISMS OF VENOUS THROMBOSIS INDUCED BY ORAL CONTRACEPTIVES Until reccntly, it was unccrtain whcthcr thc usc of low-dose oral contraceptivcs disturbcd the hemostatic balancc.1 * Potential prothrombotic cfFects includcd increascs in thc Icvcls of coagulant factors and dc-creascs in thc levcls of thc anticoagulant protcins an-tithrombin and protcin S. Howevcr, thcse changes wcre bclicvcd to bc at Icast partially countcrbalanced by such antithrombotic cffccts äs increascs in thc Icv-els of other anticoagulant protcins and increased fibri-nolysis. Furthcrmorc, thc kvels of coagulation fäctors typically rcmained within the normal ränge during oral-concraceptivc usc.14
New studies of the cflccts of second-gencration and chird-gcncration oral contraccptivcs on thc
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28.5
Figur» 1. Cases of Deep-Vein Thrombosis per T0.000 Person-Years, According to the Use of Oral Contraceptives and the Presence of Fector V Leiden.
coagulant, anticoagulant, and fibrinolydc pathways, in contrast, indicacc that oral contraceptivcs have a nct prothrombotic effect. Quandtadvcly, ehe effcct is grcater with preparations that confcr a higher risk of thrombosis. The hemostatic fäctors involved in this
process arc shown in Figure 2.6i
Procoogulant Effects
A recenc randomized, crossover study69 confirmcd chat therc arc increascs in ehe Icvels of prothrombin, faccor VII, factor VIII, factor X, fibrinogcn, and prothrombin fragment 1+2 and decrcascs in the Icv-els of factor V during the use of oral contraccpdves, The incrcase in prothrombin and factor VII and the dccrcase in factor V wcrc significajntly more pro-nounced with the use of third-generation oral con-traceptivcs (those containing desogcstrcl) than with the use of second-gcncration oral contracepüvcs con-taining kvonorgcstrcl. It is now rccognized that mod-cratcly incrcascd levels of prothrombin60 and factor VIII«.** jj-c associaced with an increascd rLsk of vcnous chrombosis. Since faccor V may exhibit andcoagu-lant activity because of its ability co act äs a cofactor in ehe inactivation of activatcd factor VIII that is mc-diated by activatcd protcin. C,70·7' a dcaeasc in the Icvcl of factor V may conthbutc to ehe thrombotic side cfFccts of oral contraceptivcs.
Anticoagulant Effects
Oral contraccptives havc profound effccts ori the andcoagulant system. Bctween 1994 and 1997 thcre
wcrc sevcral rcports that acquired rcsistancc to acti-vated protcin C devclops in womcn who use oral con-traceptivcs. Likc carricrs of factor V Leiden (who have hcrcditary rcsistancc co activated protcin C), thcsc womcn bccomc less sensitive co the andcoagulant ac-tion of activated protcin C.72'74 Furchermorc, third-generarion oral contraceptivcs cause morc pronounccd resistance than do second-gcneration oral contra-ccptives.'6'78 The clinical rclcvancc of acquired resist-ance to activatcd protcin C during the use of oral contraceptivcs is evidcnced by the observation that the levcls of resistance reportcd among uscrs of oral contracepüvcs, carricrs of fector V Leiden, and heter-ozygous carriers of factor V Leiden who use oral con-traccptives corrclatc with the relative risks of venous thrombosis thac havc bccn found in cpidemiologic studies to be associatcd with diese condinons.76·7' Sincc rcsistancc to activated protcin C, cvcn in the ab-scncc of factor V Leiden, is an indcpcndent risk fac-tor for venous thrombosis,80·" thesc observations sup-port ehe theory that acquired resistance to activated protein C contribur.es to the incrcased risk of throm-bosis in uscrs of oral concraccptivcs. The molccular basis of acquired resistance to activated protcin C dur-ing the use of oral contraceptivcs is unknown. De-creascd Icvels of plasma protein S, the cofactor of acü-vated protein C (the Icvels of which werc significantly lowcr in uscrs of desogcstrcl82), onJy partially cxplain the resistance to activatcd protcin C found in users of oral contraceptivcs.
Fibrinolytic Effects
Changcs in fibrinolytic variables (plasminogcn, tis-suc plasminogen activator, plasminogcn-accivator in-hibitor type l, and plasmin-antiplasmin complexes) with the use of oral contraceptivcs suggcst that fibri-nolytic activity is incrcased.'•*·83 It is not known wheth-er enhanccd fibrinolytic activity during oral-contra-ceprjvc use has clinical implications, sincc changcs in die fibrinolytic System havc not bcen dcmonsuatcd to affcct the risk of vcnous thrombosis. One antifi-brinolytic mcchanism involves thrombin-activatablc fibrinolysis inhibitor (TAFI), which, whcn activated, inhibits fibrinolysis by rcmoving from fibrin the lysinc residucs that arc csscntial for the binding and activa-don of plasminogen.84·85 Elcvated Icvels of TAFI arc a risk factor for vcnous thrombosis.84 An assay for clot lysis chat probes ehe activity of boch ehe fibrinolytic system and ehe TAFI-dcpendenc andfibrinolytic path-way dcmonstraccd that the ovcrall clot-lysis omc rc-rnaincd unchangcd during oral-concraccptivc use.83 This finding suggcsts chat in ehe uscrs of oral con-traccpcivcs an enhanccd down-regulation of fibrinol-ysis by the TAFI system compcnsatcs for the incrcased fibrinolytic potcnrial. Lcvcls of TAFI arc higher in women taking concraccpdves containing desogcstrcl than in thosc taking contraccptivcs concaining levo-norgestrcl, indicadng a. strongcr down-regulation of
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'IXa + Villa-«· APC + protein S
/ \
.· Thrombomodulin
Antithrombin
TFPI -TAFI
Figur« 2. Regulären of Blood Coagulatlon and Fibrinolysis.
Coagulation Is mitiated by a tissue factor (TF)-factor Vlla complex that can activate factor IX or factor X. At high tissue factor con-centrations. factor X is aciivated primarily by the TF-Vlla complox, whersas at Iow tissuo factor concentrations the contrlbmion of the factor iXa-'actor Villa complex to ihe activation of factor X becomes more pronouncod. Tissue factor-dependent coaguletion is rapidly inhibited by tissue factor-pathway inhibitor (TFPI). Coagulation is maintamed ihrough tha activation by thrombin of factor XI. Through the intrinsic tenase complex (factors IXa and Villa) and the prothrombinase complex (factors Xa and Va), tha additlonal (hrombin required to down-regulate fibrinolysis is generaied by tha activation of thrombin-activalable fibrinolysis inhibitor (TAFI). Activated TAFI down-regulates fibrinolysis by removing fram partially degraded fibrin C-terminal lysine residues that ara involvod in the bindmg and activation of plasmlnogen. The coagulation System is regulated by the protein C pathway. Thrombin activates protein C in the presence erf thrombomodulin. Together with protein S, activated protein C (APC) is capable of inactivating factors Va and Villa, which rosults in a down-regulation of ihrombin gsneration and consequently in an up-ragulation of the fibrinolyric System. The activiiy of thrombin is comrolled by the inhibhor antithrombin. The solid arrows indicate activation and the broken arrows Inhibition, To improvg the clariTv of the figure, most zymogens and procoagulsnt surfacas are not depicted. Modified from Bouma er al."°wrth the permission of the publisher.
fibnnolysis w/ith ehe Former type of contraceptivc.83 The incrcased TAPI-dcpendent Inhibition of fibri-nolysis most likcly results from both clevaccd Icvels of TA H and cnhanced formadon of chrombin (thc
of TAPI), Overall Hemostatic Effect
Thc intrcdsc in procoagulant effeccs, ehe decrcasc in miricoagulam cffccrs, and thc cquivocal effecrs on fibnnolysis (wjth incrcascs in thc acdvity of the an-tifibrinolvxic sysccm) indicate that oral cociiraccptivcs havc a ner prothrombotic cfTcct. Significant diffcr-cnces betören users of oral contraccptivcs that coo-um Icvonorgcstrcl and users of thosc that contain dcsogestrcl in the plasma Icvels of prothrombin,
fac-r.or V, factor VII, and protein S and in susccptibiliry to thc anticoagulant action of activated protein C may cxplain ehe higher rtsk of venous thrombosis obscrved in users of thtrd-gcncration oral contraccptivcs. Thc morc pronounccd hcmostatic changcs associatcd wich chird-gcncradon oral concraceptivcs mighc bc rclat-cd to chcir incrcased estrogcnic profile, which might also cause thc moderarc incrcasc in thc Icvcl of high-dcnsity lipoproccm cholcstcrol that has bccn obscrved in womcn using thc;.c concraceptivcs.a7
CONCLUSIONS
Hormonal contraception is used by more than 100 mülion womcn worldwidc.10 Thc numbcr of ex-cess dcaths from cardiovascular discase (venous and
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artcrial combincd) among young, low-risk uscrs — nonsmokmg womcn betwccn 20 and 24 ycars of agc — rangcs from 2 to 6 per milhon per ycar world-widc,68 depcnding on the region of thc worid, the undcrlying cardiovascular risk, and ehe extcnt of thc scrcening for risk factors that is pcrformcd beforc ehe contraccptwes arc prcscribcd Whcrcas thc risk ofvenous thrombosis is more important foryounger uscrs, the risk of artcrial thrombosis bccomcs morc important at older agcs. Among oldcr smokcrs who usc oral contraccptivcb, thc number of cxcess dcaths is cstimatcd to vary from 100 to slightly morc than 200 per million per year88
Thc rcduction of thc dose of cstrogcn has had a limitcd effcct on reducmg thc nsk of venous throm-bosis. Third-gencracion progcstms in combination prcparaüons incrcase thc extcnt of adversc hcmostatic changes and thc associatcd risk of thrombosis and thus should not bc thc first choicc for ncw uscrs.34·39·40··*7 Thc ability to prescnbe prudcntly by withholding oraj contraceptivcs from womcn wuh known risk factors is hrnited by thc absencc, m the majorky of cases, of chnically rccogmzablc risk factors for venous throm-bosis. An mvcstigation m New Zcaland of a series of dcaths duc to pulmonary cmboh suggestcd that m most cases physicians could not havc foresecn the nsk *»
In contrast, prüdem prcscnbing can help prevent artenal thrombosis, almoM: all women who havc a myocardial tnfarction dunng thc usc of oral contracep-tivcs are oldcr and cithtr smokc or have othcr risk factors for artenal discase — in particular, hypcrten-sion.5 Thc avoidancc of thc use of oral contracep-tivcs by such womcn may underhc the rcduction in thc ratcs of artcrial thrombosis rcported m recent studies in industrializcd countrics.5·6·88 Thc beneficial cffcct that third-gcneration contraceptivcs theorcti-cally have on thc lipid profilc has not translated into a lowcr incidcnce of stroke or myocardial infarcdon in large casc-control studies.90·'1
To prcvcnt venous thrombosis whcn prcscribing oral contraceptivcs, physicians generaUy considcr a per-sonal history of venous thrombosis to bc an absolute contramdication, although littlc is known about the risk of recurrcncc dunng thc use of oral contracep-tivcs. Thc only cxisting cvidcnce is mdircct; venous thrombotic d\scasc that occurred during thc use of oral concraccptivcs was Icsb iikcly to rccur whcn the contraccpmes wcrc scoppcd 9! Contraccptives con-taming low dosci of progcbtm alonc (first-gcneration or sccond-gcncranon) arc associatcd vvith a lowcr nsk of venous chrombosis than arc combincd prcpara-nonsu'3; howcvcr, thc nsk among womcn with a rus-tory of thrombosis is unknown
Gross obesity is a recognizcd nsk factor tbr venous thrombosis, but it is unknown wheihcr it incrcases thc riik associated with thc usc of oral contraccptives, and thrombosis is rare evcn among obese uscrs.
Obe-sity is thercfore not considcrcd a contraindkation to thc use of oral comxaccpnvcs. Supcrficial varicosc vans that arc not thc conscquencc of a prcvious venous thrombosis arc not, by thcmselves, risk factors for dccp venous thrombosisw A family history of venous thrombosis may cause concern, although the scnsi-tivlry of a family history äs a markcr for idcntifying persons at high risk rcmains unclcar. A personal his-tory of supcrficial thrombophlebitis might also sug-gest a hercditary risk factor, espccially if it is couplcd with a family history of thc disordcr.
The susceptibility to venous thrombosis conferrcd by factor V Leiden and other prothrombotic muta-tions has led to quesmuta-tions about the valuc of screcning for thcse mutations beforc oral contraceptivcs are prcscnbed. In thc absencc of a clcar family history of venous thrombosis, there is Httlc jusüfkation to screen for prothrombotic mutations. More than half a million women would nccd to bc scrcencd for fäc-tor V Leiden to avoid a single dcath from pulmonary cmbolus, smce only 5 pcrccnt of women arc carricrs and thc mortality associatcd with venous thrombosis in young women is low95 [fall the costs associated with thc treatmcnt of all occurrcnccs of venous throm-bosis — induding the post-thrombonc syndromc that occurs in up to one third of pacients96 — wcrc con-sidcrcd, and if the cost of scrccmng becamc vcry low (Icss than about $9), scrccmng rmght be rationalizcd on economic grounds.97 Such cost-bcncfit calcula-tions, however, might bc too general to be of usc, sincc the nsk of carrying thc factor V Leiden muta-tion varies according to ehe prescncc or abscnce of a family history of thrombosis — prcsumably because of concomitant gcnctic or cnvironmental risk factors.98 Also, denymg oral contraccptives to womcn who test positive for factor V Leiden would leavc at least 5 per-ccnt of young women without acccss to ehe most cfBcacious form of contraception Morcover, thc im-plications of a prothrombotic gcnetic dcfect in a wom-an without a history of thrombosis are uncleaor, wom-and awarcness of the prcsencc of thc dcfect has daunt-ing psychosocial, mcdical, and legal conscqucnces (in tcrms of insurancc, in particular) Finally, thc absencc of a rccognizcd biochcmical or gencdc dcfect does not climinatc the possibility of thrombosis. Evcn in thc absencc of onc of thc defects thac are currcntly known to bc relevant, a svong family history of venous thrombos,is warranti caunon about the usc of oral concraccptivcs, purcly on climcal grounds In thc ab-scnce of decisivc dac.i rcgarding thc risks and benefits of gcnctic scrccmng bcfore prcscnbing oral contra-ccpnves, eithcr in thc general population or in high-risk familics, dccisions rcgarding screcning and pre-scribing should bc based on clmicaJ judgment that takcs into account cach woman's family history and risk factors.*5
Thc past fivc ycars have yiclded key advanccs in understanding thc cpidcmiology and thc hemostatic
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MEOICAL PROGRESS
mecharusms ofthc risk of vcnous chrombosis associ-atcd with thc usc of oral contracepdvcs. An Lncrcascd undcrstandmg of mdividual susccpubility to thc hc-mostatic changcs induccd by oral contracepdvcs and of markcrs of ehe nsk of thrombosis shodd Icad co ehe dcvclopmcnt of prcparations that arc cvcn safcr.
\Vc arc tndebted to thc foliovtnj fersansfor thcir fnviaui callab-oration and thetr extensive fcrnnal centributions to stvcral of fbc itudtes descnbcd in shis rcview: Dr J. Cttmtrs, Dr G Nuolacs, Dr. G. Tanj, und Mrt. M-C.L.G.D. Thomasxn of ibe Dcfurtmcnt ff Biocftemistry, CarAiwnscuIar Research Institute, Maastricht; Pro-fcaar H R Bullcr, Dr JCM Meijers, and Dr M M. Prinj ofthc Department of Vajcular Medictne, Acadcmic Medical Center, Am-sterdam; and Professor Κ.ΛΓ. Bertina oftitc Thromben; and Hcma-trajis Raearch Center, Leiden Universtty Meduat Center, Leiden— all in tke tJcthcrlandi
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Copyright O 2001 Massachuiciu Mcdical SuOiccy.
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