Anticoagulation of Pregnant Women With Mechanical Heart Valves


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Anticoagulation of Pregnant Women With Mechanical Heart Valves

  1. 1. ORIGINAL INVESTIGATIONAnticoagulation of Pregnant WomenWith Mechanical Heart ValvesJeffrey S. Ginsberg, MD, FRCPC; Wee Shian Chan, MD; Shannon M. Bates, MDCM; Scott Kaatz, DOT he management of pregnant women with mechanical heart valves is challenging. Re- cently, based on small numbers of patients and poor-quality data, correspondence from Aventis Pharmaceuticals Inc has described treatment “failures” and concerns about tera- togenicity with the use of the low-molecular-weight heparin (LMWH) enoxaparin. Thecompany issued a “Warning” that enoxaparin should not be used in patients with prosthetic heartvalves and a “Precaution” about potential teratogenicity. This has created a huge problem for phy-sicians managing pregnant women with prosthetic heart valves because the alternatives, unfrac-tionated heparin and warfarin, are problematic. There have been case reports of failures (includ-ing death from thrombosed valves) with unfractionated heparin, whereas the package insert forwarfarin states that the drug is contraindicated during pregnancy because of potential teratogenic-ity. Initially, LMWHs appeared suitable for pregnant patients with prosthetic heart valves. Unfor-tunately, the company correspondence, presumably supported by the Food and Drug Administra-tion (FDA), raises medicolegal concerns with use of any LMWH. We believe that pharmaceuticalcompanies and the FDA should not endorse scientifically unsupported claims that eliminate ac-ceptable therapeutic options. This correspondence has created considerable confusion among pa-tients and treating physicians and is likely to lead to frivolous lawsuits and preclude the perfor-mance of properly designed trials in pregnant women. We believe a consensus conference amongexperts in the field to identify key unresolved issues and a commitment by the FDA and industryto perform appropriate studies are now critical. Arch Intern Med. 2003;163:694-698 North American women, including those (enoxaparin sodium) Injection, a low- with mechanical heart valves, expect an un- molecular-weight heparin (LMWH).1 eventful pregnancy and a healthy baby. Un- The warning referred to the manage- fortunately, women with mechanical heart ment of pregnant and nonpregnant patients valves have a high risk of both adverse with mechanical heart valves and stated: fetal and maternal experiences, primarily due to thromboembolic complications The use of Lovenox is not recommended for and the antithrombotic therapy given to thromboprophylaxis in patients with pros- thetic heart valves. Cases of prosthetic heart prevent these complications. As a result, the valve thrombosis have been reported in pa- management of pregnant women with me- tients with prosthetic valves who have re- chanical heart valves is difficult. This was ceived enoxaparin for thromboprophylaxis. exacerbated by a recent “Warning” and Some of these cases were pregnant women in “Precaution” issued by Aventis Pharmaceu- whom thrombosis led to maternal deaths and ticals Inc, the manufacturers of Lovenox fetal deaths. Pregnant women with prosthetic heart valves may be at higher risk for throm-From the Departments of Medicine, McMaster University, Hamilton, Ontario boembolism.(Drs Ginsberg and Bates), University of Toronto, Toronto, Ontario (Dr Chan), andHenry Ford Hospital, Detroit, Mich (Dr Kaatz). Dr Kaatz has received research The precaution was specific for thefunding from Aventis Pharmaceuticals Inc, Roche Diagnostics, DuPont Pharma use of enoxaparin during pregnancy andPharmaceuticals, Astra-Zeneca, Merck, Sandoz, and NPS, and serves as a consultant under the headings “Pregnancy” andfor Astra Zeneca and Aventis Pharmaceuticals Inc. “Teratogenic Effects” stated: (REPRINTED) ARCH INTERN MED/ VOL 163, MAR 24, 2003 WWW.ARCHINTERNMED.COM 694 Downloaded from on December 6, 2010 ©2003 American Medical Association. All rights reserved.
  2. 2. There have been reports of congenital anomalies in infants born So, how should pregnant women with mechanicalto women who received enoxaparin during pregnancy includ- prosthetic heart valves be managed?ing cerebral anomalies, limb anomalies, hypospadias, periph- Antithrombotic therapy is essential, because the riskeral vascular malformation, fibrotic dysplasia, and cardiac de- of valve thrombosis and death or systemic embolism isfects. A cause and effect relationship has not been established high if it is not given. With currently used regimens (in-nor has the incidence been shown to be higher than in the gen-eral population. cluding warfarin, UFH, and LMWH, either alone or in sequence), pregnancy in a woman with a mechanical heart The warning was based on the results of a very small valve carries a risk of maternal mortality from valve throm-trial and an undisclosed number of postmarketing reports bosis estimated at 1% to 4%.2 Many factors determine theof thrombosed valves in patients receiving enoxaparin. The risk of valve thrombosis, including valve type and posi-randomized controlled trial, conducted in South Africa and tion, presence of atrial fibrillation, left atrial size, his-not sponsored by Aventis Pharmaceuticals, of pregnant tory of previous thrombosis, number of mechanical valves,women with prosthetic heart valves was stopped after 12 and adequacy of anticoagulation. Valve designs havepatients were enrolled. In this study, women were ran- changed significantly over the last few years and there isdomly allocated to receive enoxaparin (1 mg/kg twice daily) less thrombogenic potential associated with newer bileaf-or a regimen consisting of unfractionated heparin (UFH) let valves. Management is problematic because theseand warfarin given sequentially. Few details are available; women require anticoagulant therapy and there are nohowever, according to Aventis Pharmaceuticals, 2 of 7 controlled clinical trials to provide guidelines with re-enoxaparin-treated women developed thrombosis and out- spect to the optimal antithrombotic agent or the inten-flow obstruction of their prosthetic valves, causing mater- sity of anticoagulant therapy. Unfortunately, pregnantnal (and fetal) death. The postmarketing reports con- women (and often women of childbearing potential) aresisted of an undisclosed number of valve thromboses in usually excluded from trials that involve evaluation ofenoxaparin-treated patients (including pregnant women) drugs. Performing studies involving only pregnant womenwith prosthetic heart valves. Based on the small numbers is extraordinarily difficult, because of “ethical” con-in the trial, and the inability to determine accurate inci- cerns, often resulting in the refusal of institutional ethi-dence rates from postmarketing data, the true incidence cal review boards to approve such studies. Conse-of valve thrombosis in enoxaparin-treated pregnant women quently, the best available evidence for the managementwith mechanical heart valves, and whether thrombosis rates of most diseases in pregnant women is very poor, usu-are higher in such women than warfarin-treated nonpreg- ally consisting of case reports, small series, and “expertnant patients, are unknown. opinion.” A further problem is the philosophy of most Teratogenicity can result from numerous causes, in- pharmaceutical companies of avoidance of the develop-cluding use of drugs, or simply by chance. The com- ment of drugs for use in pregnancy because of medico-pany claims a “cause and effect relationship has not been legal concerns and the perception that the potential prof-established nor has the incidence been shown to be higher its are not worth the liability.than in the general population,” thereby avoiding direct Prior to the development of LMWHs, 2 regimensindictment of physicians who prescribe enoxaparin dur- were commonly recommended in pregnant women withing pregnancy. However, the “Precaution” was presum- mechanical heart valves: (1) warfarin, for most of the preg-ably issued to minimize potential liability against Aventis nancy, usually with substitution of UFH between 6 andPharmaceuticals and has the potential to inhibit physi- 12 weeks of gestation (to avoid warfarin embryopathy;cians from prescribing enoxaparin and other LMWHs in see below) and near term (to avoid neonatal hemor-pregnant women. In view of the evidence that neither UFH rhage), and (2) UFH throughout pregnancy.3 Evidencenor LMWH crosses the placenta, an increase in terato- supporting the use of these regimens is poor and is de-genicity seems biologically implausible. rived from case reports, case series, small cohort stud- Subsequently, a “Dear Health Care Professional” let- ies, and questionnaires. Further, the use of both warfa-ter from Aventis summarizing the additions to the Warn- rin and UFH is problematic during pregnancy. Warfarining and Precaution sections of the Lovenox prescribing crosses the placenta and can cause fetal abnormalities asinformation was disseminated, presumably supported by well as hemorrhage, particularly during and immedi-the Food and Drug Administration (FDA).1 Both the warn- ately after delivery. Although UFH does not cross theing and the precaution are based on poor evidence and placenta and does not harm the fetus, it must be givenare likely to affect physicians’ practices, as well as the fea- parenterally (usually by subcutaneous injection twicesibility of further research into the management of preg- daily) and like warfarin can cause maternal hemor-nant women with mechanical heart valves. When an ad- rhage, and also can cause maternal osteoporosis andverse pregnancy outcome occurs, the likelihood of thrombocytopenia.3medicolegal action against the attending physician is high, Many experts have suggested that LMWHs may beeven if the care given was reasonable. Undoubtedly, many a suitable option for prophylaxis of systemic embolismphysicians will avoid enoxaparin (and other LMWHs) in in pregnant women with mechanical heart valves.3 Likepregnant women with mechanical heart valves and, per- UFH, they do not cross the placenta and, therefore, ithaps, particularly unnecessarily, for other indications in seems biologically implausible that they could be tera-pregnancy. Physicians who use an LMWH in pregnant togenic. In support of this, a recent overview found nowomen with mechanical heart valves face a high prob- increase in teratogenicity with LMWH use during preg-ability of being sued if an adverse experience occurs in nancy.4 Further, when compared with UFH, LMWHs havethe mother or the neonate. distinct advantages, including the potential for subcuta- (REPRINTED) ARCH INTERN MED/ VOL 163, MAR 24, 2003 WWW.ARCHINTERNMED.COM 695 Downloaded from on December 6, 2010 ©2003 American Medical Association. All rights reserved.
  3. 3. neous administration once, rather than twice, daily pos- avoided by using a heparin (instead of warfarin) for thesibly less bleeding for an equivalent antithrombotic last part (2-4 weeks) of pregnancy.effect, less osteoporosis, and less heparin-inducedthrombocytopenia.5 In addition, because they produce Unfractionated Heparina predictable antithrombotic effect when given to pa-tients subcutaneously on a weight-adjusted basis, no Since it does not cross the placenta, UFH is not terato-laboratory monitoring is required in this patient popu- genic. However, multiple reports of thrombosed valves withlation.5 However, the pharmacokinetics of LMWHs are the use of UFH, causing maternal morbidity and mortal-different in pregnant than in nonpregnant subjects be- ity, have raised serious concerns about its effective-cause of changes in volume of distribution resulting ness.2,13-16 One plausible explanation for the failure of UFHfrom an increase in plasma volume and changes in renal is inadequate dosage. It is known that low-dose heparinclearance of LMWH. Consequently, although empiric, (5000 IU every 8-12 hours subcutaneously) is inadequatewe recommend periodic anti-factor Xa level monitor- for prevention of thrombosis of mechanical prosthetic hearting, with dose adjustments to ensure a consistent anti- valves during pregnancy16; it is unclear whether 12-coagulant effect.3 Nevertheless, many experts were hourly subcutaneous UFH adjusted to prolong a mid-hopeful that LMWHs would improve the management interval activated partial thromboplastin time (aPTT) re-of pregnant women with mechanical heart valves. sult to 1.5 to 2.5 times control is adequate. After initial Until properly designed, adequately powered trials heparin therapy, this regimen has been shown to be as ef-of currently available agents are performed or new anti- fective as warfarin (with a target international normalizedthrombotics suitable for use in pregnant women are de- ratio [INR] of 2.0-3.0) for the prevention of recurrence inveloped, recommendations for the management of preg- nonpregnant patients with acute venous thromboembo-nant women with mechanical heart valves must be based lism.17 However, based on several considerations, this regi-on case reports, case series, and expert consensus. men of UFH might be less effective in pregnant women with mechanical heart valves. First, 1.5 times control, the usual BASIS FOR RECOMMENDATIONS lower limit of the therapeutic range, corresponds to sub- therapeutic heparin levels (anti-factor Xa levels 0.3 U/mL)To make sensible recommendations, the following ques- using most currently available aPTT reagents.18 Second, ex-tions should be addressed. For warfarin: (1) What are cept for patients who have bileaflet mechanical aortic valvesthe true incidence and the clinical impact of warfarin em- and do not have atrial fibrillation, the recommended tar-bryopathy? (2) Does warfarin truly cause other fetal prob- get INR range for patients with mechanical heart valves (2.5-lems when given to pregnant women? For UFH and 3.5) is higher than the corresponding target INR range forLMWH: (1) What is the true incidence of failure (valve the treatment of acute venous thromboembolism (2.0-thrombosis)? (2) What is the incidence of other adverse 3.0), suggesting that more intense antithrombotic therapyexperiences (bleeding, osteoporosis, thrombocytope- is appropriate.19 Further, although warfarin, with a targetnia)? For LMWH: Does LMWH truly cause fetal prob- INR of 2.0 to 3.0, is highly effective in the long-term treat-lems when given to pregnant women? ment of acute venous thromboembolism, even with the use of a more intense warfarin regimen (INR of 2.5-3.5), the Warfarin addition of aspirin to the warfarin regimen improves effi- cacy for patients with mechanical heart valves (albeit at theWarfarin is the drug of choice in nonpregnant patients cost of an increase in the rate of minor bleeding).20 Givenwith mechanical heart valves and is highly effective in this information, we recommend that if subcutaneous UFHpreventing thromboembolic complications. In preg- is used to prevent thrombosis in pregnant women with me-nant women, it can cause a specific embryopathy, con- chanical heart valves, the starting dose should be highsisting of nasal hypoplasia and epiphyseal stippling, al- (17500-20000 U every 12 hours) and adjusted aggres-beit only when administered between 6 and 12 weeks of sively to achieve a mid-interval aPTT of at least 2.0 timesgestation.6 In a recent critical review of the available pub- control or a result that corresponds to an anti-factor Xa hep-lished literature, the authors estimated that the true in- arin level of at least 0.3 to 0.5 U/mL. Finally, adjunctivecidence of warfarin embryopathy with exposure be- aspirin therapy should be considered in high-risk women,tween 6 and 12 weeks of gestation was low ( 5%)2; this such as those with previous systemic embolism and thosecontrasted with estimates of 30% or higher.7 Further, in with atrial fibrillation.recent follow-up studies of children born with warfarin The rate of major bleeding in pregnant patientsembryopathy, major morbidity was uncommon, and many treated with UFH has been reported to be approxi-of these infants developed normally.8-11 mately 2%, which is consistent with the reported rates Other problems, such as fetal central nervous sys- of bleeding associated with heparin therapy in nonpreg-tem abnormalities, have been reported in association with nant patients and with warfarin therapy when used forwarfarin use at any stage of pregnancy.12 However, these the treatment of deep vein thrombosis.21 Unfortunately,events are rare and it is unclear whether the incidence adjusted-dose subcutaneous UFH can cause a persistentof any of these complications is higher than in pregnan- anticoagulant effect at the time of delivery, which can com-cies not associated with warfarin use. Finally, since war- plicate its use prior to labor.22 Approximately 3% of non-farin crosses the placenta, maternal use can cause fetal pregnant patients receiving UFH develop immune, IgG-hemorrhage, particularly during and immediately after mediated thrombocytopenia, which is frequentlydelivery.12 However, this is likely to be rare and can be complicated by extension of preexisting venous throm- (REPRINTED) ARCH INTERN MED/ VOL 163, MAR 24, 2003 WWW.ARCHINTERNMED.COM 696 Downloaded from on December 6, 2010 ©2003 American Medical Association. All rights reserved.
  4. 4. boembolism or new arterial thrombosis.23 In pregnant higher than that associated with warfarin adjusted to tar-women, the true incidence of IgG-mediated thrombocy- get an INR of 2.5 to 3.5. If UFH or LMWH is used, suf-topenia is unknown. Long-term heparin therapy has been ficient doses must be initiated and the doses adjusted ac-reported to cause osteoporosis in both laboratory ani- cording to the results of appropriate laboratory tests,mals and humans.3,24 Further, symptomatic vertebral frac- preferably anti-factor Xa levels or, with UFH, the aPTT.tures have been reported to occur in about 2% to 3% of To summarize, there are still insufficient groundspatients receiving UFH for periods of 1 month or more to make definitive recommendations about optimal an-and significant reductions in bone density have been re- tithrombotic therapy in pregnant patients with mechani-ported in up to 30% of patients receiving long-term UFH.24 cal heart valves because properly designed studies have not been performed. Based on the above considerations, Low-Molecular-Weight Heparin UFH and LMWH are unlikely to be teratogenic. Al- though warfarin almost certainly can cause an embry-The true incidence of valve thrombosis in enoxaparin- (or opathy if given between 6 and 12 weeks of gestation, itother LMWH-) treated pregnant women with mechanical has probably been overestimated in frequency and clini-heart valves and the optimal LMWH treatment regimen for cal impact. If UFH is used, it should be initiated in hightheir patients are unknown. Based on published data, there doses (17500-20000 U every 12 hours) and adjusted ac-have been a small number of patients treated with LMWH, cording to a 6-hour postinjection aPTT (minimum tar-most successfully.25,26 The small numbers of patients with get of twice control) or anti-factor Xa heparin level (mini-valve thrombosis in the randomized trial of enoxaparin (2 of mum target of 0.3 U/mL).3 If an LMWH is used, it should7, 29%) have very wide confidence intervals (4%-71%) and, also be initiated in high doses and adjusted according towhen combined with the limitations of the postmarketing a 4- to 6-hour postinjection anti-Xa heparin level (mini-data, preclude an accurate estimate of the true rate of fatal mum target of 0.5 U/mL).3 In addition, for some high-and nonfatal valve thrombosis despite the information con- risk patients (eg, those with a history of systemic embo-tained in the recent “Precaution” and “Dear Health Care lism), aspirin, 80 to 325 mg/d, should be administeredProfessional” letter.1 in an attempt to reduce the risk of thrombosis, recog- The potential for teratogenicity of LMWHs lacks bio- nizing that it increases the risk of bleeding.20logic plausibility because it has been demonstrated thatthese agents do not cross the placenta. In support of this, TREATMENT RECOMMENDATIONSa recent comprehensive overview concluded that therewas no teratogenicity associated with LMWHs.4 Women with mechanical heart valves should be care- fully counseled about the risks associated with available OTHER ISSUES anticoagulant options prior to, or shortly after, becom- ing pregnant. The practice of substituting warfarin withWarfarin, with a target INR of 2.5 to 3.5 (except in pa- UFH or an LMWH between 6 and 12 weeks of gestationtients with uncomplicated bileaflet mechanical aortic probably eliminates the risk of warfarin embryopathy (orvalves), is standard antithrombotic therapy for nonpreg- other teratogenic effects) but might subject women to annant patients with mechanical prosthetic heart valves.19 increased risk of thromboembolism if inadequate dosesIt is highly likely that warfarin therapy is safe during preg- are used.nancy when used up to 6 weeks of gestation and from One of the following approaches is recommended:12 weeks of gestation until just prior to ( 2 weeks) de- 1. “Aggressive” adjusted-dose UFH throughout preg-livery.4 It is also likely that both the incidence and the nancy; ie, administered subcutaneously every 12 hoursmorbidity of warfarin embryopathy have been overesti- in doses adjusted to maintain the mid-interval aPTT at amated with warfarin use between 6 and 12 weeks of ges- minimum of twice control or an anti-factor Xa heparintation; the true incidence is probably less than 5% and level of at least 0.3 U/mL.the morbidity is low.2,8-11 2. Adjusted-dose LMWH throughout pregnancy; ie, However, the use of warfarin during pregnancy has administered subcutaneously every 12 hours in doses ad-important medicolegal implications (especially in North justed to maintain a 4- to 6-hour postinjection anti-America) as the package insert for the most commonly factor Xa heparin level at a minimum of 0.5 U/mL.prescribed brand (Coumadin; DuPont Pharma, Wilm- 3. UFH or LMWH (as above) until the 13th weekington, Del) states that warfarin is contraindicated dur- of pregnancy, then warfarin with a target INR of 2.5 toing pregnancy. 3.5 until the middle of the third trimester, followed by Neither UFH nor LMWH crosses the placenta and reinitiation of UFH or LMWH until delivery.both are highly unlikely to be teratogenic. Reports of treat-ment failures with UFH and LMWH, resulting in throm- With any of the 3 above regimens, adjunctive aspi-bosed valves and sometimes death, have been pub- rin therapy should be considered. Long-term anticoagu-lished, leading many to conclude that these agents should lants should be resumed post partum with all regimens.not be used in pregnant patients with mechanical pros-thetic heart valves.16 Many of these failures were associ- CONCLUSIONSated with inadequate dosing (eg, UFH, 5000 U every 12hours or “prophylactic” doses of LMWH). The true in- The management of pregnant women with mechanicalcidence of failure with either drug, given in adequate valves is a particularly difficult challenge. The paucity ofdoses, is unknown and it is unclear whether the risk is methodologically sound studies has hampered the devel- (REPRINTED) ARCH INTERN MED/ VOL 163, MAR 24, 2003 WWW.ARCHINTERNMED.COM 697 Downloaded from on December 6, 2010 ©2003 American Medical Association. All rights reserved.
  5. 5. opment of definitive treatment recommendations. With the chanical heart valves: a systematic review of the literature. Arch Intern Med. 2000; 160:191-196.information contained in the package insert for warfarin, 3. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy.the concern about treatment failures with UFH, and the Chest. 2001;119:122s-131s.recent “Warning,” “Precaution,” and “Dear Health Care Pro- 4. Sanson BJ, Lensing AWA, Prins MH, et al. The use of low-molecular-weight hep-fessional” letter from Aventis Pharmaceuticals, physi- arin in pregnancy. Thromb Haemost. 1999;81:668-672.cians treating these patients have been left without a widely 5. Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-698. 6. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulationaccepted treatment option and their medicolegal expo- during pregnancy. Am J Med. 1980;68:122-140.sure is very high. The precaution about teratogenic effects 7. Iturbe-Alessio I, Del Carmen Fonseca M, Mutchinik O, et al. Risks of anticoagu-also unnecessarily complicates the treatment and prophy- lant therapy in pregnant women with artificial heart valves. N Engl J Med. 1986;laxis of venous thromboembolism during pregnancy. In ad- 315:1390-1393. 8. Harrod MJE, Sherrod PS. Warfarin embryopathy in siblings. Obstet Gynecol. 1981;dition, this new “information” will undoubtedly hamper 57:673-676.the feasibility of conducting clinical trials designed to im- 9. Van Driel D, Wesseling J, Rosendaal FR, et al. Growth until puberty after in uteroprove the management of pregnant women with mechani- exposure to coumarins. Am J Med Genet. 2000; valves. Pharmaceutical companies and the FDA have a 10. Takano H, Smith WL, Sato Y, Kao SCS. Cervical spine abnormalities and insta-responsibility to disseminate information about drugs that bility with myelopathy in warfarin-related chondrodysplasia: 17-year follow-up. Pediatr Radiol. 1998;28:497-499.affect patient safety. However, the FDA and other regula- 11. Howe AM, Lipson AH, de Silva M, et al. Severe cervical dysplasia and nasal car-tory agencies must not endorse scientifically unsupported tilage calcification following prenatal warfarin exposure. Am J Med Genet. 1997;claims that have the potential to “close the door” on ac- 71:391-396.ceptable therapeutic options. In this instance the result has 12. Ginsberg JS, Hirsh J, Turner CD, et al. Risks to the fetus of anticoagulant therapybeen confusion and worry among patients and treating phy- during pregnancy. Thromb Haemost. 1989;61:197-203. 13. Golby AJ, Bush EC, DeRook FA, et al. Failure of high dose heparin to preventsicians, and will likely lead to frivolous lawsuits and the recurrent cardioembolic strokes in a pregnant patient with a mechanical heartabandonment of research designed to improve the man- valve. Neurology. 1992;42:2204-2206.agement of pregnant women with mechanical heart valves. 14. Watson WJ, Freeman J, O’Brien C, et al. Embolic stroke in a pregnant patient In our opinion, the next steps should include (1) a with a mechanical heart valve on optimal heparin therapy. Am J Perinatol. 1996; 13:371-372.consensus among experts in the field to systematically 15. Hurwitz A, Milwidsky A, Medina A, et al. Failure of continuous intravenous hepa-gather the best available evidence and generate recom- rinization to prevent stroke in a pregnant woman with a prosthetic valve and atrialmendations for the management of pregnant women with fibrillation. J Reprod Med. 1985;30:618-620.mechanical heart valves; (2) identification of key unre- 16. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prosthe-solved issues that will lead to the performance of appro- ses. Br Heart J. 1994;71:196-201. 17. Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus war-priate studies to address these issues; and (3) a commit- farin sodium in the long-term treatment of venous thrombosis. N Engl J Med.ment by the FDA (and industry) to support appropriately 1982;306:189-194.designed trials to solve, rather than create problems. The 18. Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeuticstatus quo is unacceptable. range for heparin therapy. Ann Intern Med. 1993;119:104-109. 19. Stein PD, Alpert JS, Bussey HI, et al. Antithrombotic therapy in patients with me- chanical and biological prosthetic heart valves. Chest. 2001;119:220s-227s.Accepted for publication December 3, 2002. 20. Turpie AGG, Gent M, Laupacis A, et al. A comparison of aspirin and placebo in Dr Ginsberg is a Career Investigator of the Heart and patients treated with warfarin after heart-valve replacement. N Engl J Med. 1993;Stroke Foundation of Ontario and the recipient of a Re- Chair from the Canadian Institutes of Health Research/ 21. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R. Heparin therapyAstra Zeneca. Dr Bates is the recipient of a New Investiga- during pregnancy: risks to the fetus and mother. Arch Intern Med. 1989;149: 2233-2236.tor Award from the Canadian Institutes of Health Research/ 22. Anderson DR, Ginsberg JS, Burrows R, Brill-Edwards P. Subcutaneous heparinbioMerieux, Inc. ´ therapy during pregnancy: a need for concern at the time of delivery. Thromb Corresponding author and reprints: Jeffrey S. Gins- Haemost. 1991;65:248-250.berg, MD, FRCPC, McMaster University Medical Center, 23. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.1200 Main St W, Room 3X28, Hamilton, Ontario, Canada N Engl J Med. 1995;332:1330-1335.L8N 3Z5 (e-mail: 24. 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