Download PDF
Thromb Haemost 2020; 120(06): 924-936
DOI: 10.1055/s-0040-1710326
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients: A U.S. Perspective

Alex C. Spyropoulos
1   Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Zucker School of Medicine at Hofstra/Northwell, The Feinstein Institute for Medical Research, Northwell Health at Lenox Hill Hospital, New York, New York, United States
,
Walter Ageno
2   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Alexander T. Cohen
3   Department of Haematological Medicine, Guy's and St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
,
C. Michael Gibson
4   Baim Institute, Boston, Massachusetts, United States
,
Samuel Z. Goldhaber
5   Division of Cardiovascular Medicine, Brigham and Woman's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Gary Raskob
6   University of Oklahoma Health Sciences Center, Hudson College of Public Health, Oklahoma City, Oklahoma, United States
› Author Affiliations
Further Information

Publication History

19 December 2019

03 April 2020

Publication Date:
03 June 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Venous thromboembolism (VTE) remains a major cause of morbidity and mortality in hospitalized medically ill patients. These patients constitute a heterogeneous population, whose VTE risk is dependent upon the acute medical illness, immobility status, and patient-specific risk factors that have been incorporated into individualized VTE risk assessment models. Randomized placebo-controlled trials (RCTs) have shown both efficacy and net clinical benefit of in-hospital thromboprophylaxis, which is supported by guideline recommendations. The data for extended posthospital discharge thromboprophylaxis are more nuanced. RCTs comparing standardized duration low-molecular weight heparin versus extended duration direct oral anticoagulants, such as betrixaban and rivaroxaban, have shown efficacy and net clinical benefit in select groups of high VTE and low-bleed risk populations of hospitalized medically ill patients. These oral agents are now approved for both in-hospital and extended thromboprophylaxis. However, the most recent guidelines do not recommend routine use of these agents for extended thromboprophylaxis. Longitudinal studies in medically ill patients have shown that the majority of VTE events occur in the posthospital discharge setting within 6 weeks of hospitalization. This, coupled with the short hospital length-of-stay and lack of routine postdischarge thromboprophylaxis in U.S. health care settings, has dampened quality improvement efforts aimed at reducing hospital-acquired VTE. The aim of this multidisciplinary document is to provide an evidence-based framework to guide clinicians in assessing VTE and bleeding risk in hospitalized medically ill patients using an individualized, risk-adapted, and patient-centered approach, with the aim of providing clinical pathways toward the use of appropriate type and duration of available thromboprophylactic agents.

Keywords

venous thromboembolism - medically ill - extended thromboprophylaxis - heparin - direct oral anticoagulants
 

  • References

  • 1 Anderson Jr FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol 2007; 82 (09) 777-782
    CrossrefPubMedGoogle Scholar
  • 2 Miao B, Chalupadi B, Clark B. , et al. Proportion of US hospitalized medically ill patients who may qualify for extended thromboprophylaxis. Clin Appl Thromb Hemost 2019; 25: 1076029619850897
    CrossrefPubMedGoogle Scholar
  • 3 Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008; 28 (03) 370-372
    CrossrefPubMedGoogle Scholar
  • 4 Grosse SD, Nelson RE, Nyarko KA, Richardson LC, Raskob GE. The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs. Thromb Res 2016; 137: 3-10
    CrossrefPubMedGoogle Scholar
  • 5 Mahan CE, Borrego ME, Woersching AL. , et al. Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost 2012; 108 (02) 291-302
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Piazza G, Seddighzadeh A, Goldhaber SZ. Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent. Chest 2007; 132 (02) 554-561
    CrossrefPubMedGoogle Scholar
  • 7 Monreal M, Kakkar AK, Caprini JA. , et al; RIETE Investigators. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry. J Thromb Haemost 2004; 2 (11) 1892-1898
    CrossrefPubMedGoogle Scholar
  • 8 Goldhaber SZ, Dunn K, MacDougall RC. New onset of venous thromboembolism among hospitalized patients at Brigham and Women's Hospital is caused more often by prophylaxis failure than by withholding treatment. Chest 2000; 118 (06) 1680-1684
    CrossrefPubMedGoogle Scholar
  • 9 Spyropoulos AC, Anderson Jr FA, FitzGerald G. , et al; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
    CrossrefPubMedGoogle Scholar
  • 10 Baglin TP, White K, Charles A. Fatal pulmonary embolism in hospitalised medical patients. J Clin Pathol 1997; 50 (07) 609-610
    CrossrefPubMedGoogle Scholar
  • 11 Samama MM, Cohen AT, Darmon JY. , et al; Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341 (11) 793-800
    CrossrefPubMedGoogle Scholar
  • 12 Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110 (07) 874-879
    CrossrefPubMedGoogle Scholar
  • 13 Cohen AT, Davidson BL, Gallus AS. , et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332 (7537): 325-329
    CrossrefPubMedGoogle Scholar
  • 14 Kahn SR, Lim W, Dunn AS. , et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e195S-e226S
    CrossrefPubMedGoogle Scholar
  • 15 Flanders SA, Greene MT, Grant P. , et al. Hospital performance for pharmacologic venous thromboembolism prophylaxis and rate of venous thromboembolism: a cohort study. JAMA Intern Med 2014; 174 (10) 1577-1584
    CrossrefPubMedGoogle Scholar
  • 16 Mahan CE, Fisher MD, Mills RM. , et al. Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population. Thromb Res 2013; 132 (05) 520-526
    CrossrefPubMedGoogle Scholar
  • 17 Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med 2012; 7 (03) 231-238
    CrossrefPubMedGoogle Scholar
  • 18 Martin AC, Huang W, Goldhaber SZ. , et al. Estimation of acutely ill medical patients at venous thromboembolism risk eligible for extended thromboprophylaxis using APEX criteria in US hospitals. Clin Appl Thromb Hemost 2019; 25: 1076029619880008
    CrossrefPubMedGoogle Scholar
  • 19 Cohen AT, Harrington RA, Goldhaber SZ. , et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
    CrossrefPubMedGoogle Scholar
  • 20 Spyropoulos AC, Ageno W, Albers GW. , et al; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med 2018; 379 (12) 1118-1127
    CrossrefPubMedGoogle Scholar
  • 21 Spyropoulos AC, Lipardi C, Xu J. , et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022
    CrossrefPubMedGoogle Scholar
  • 22 Nicolaides AN, Fareed J, Kakkar AK. , et al. Prevention and treatment of venous thromboembolism--International Consensus Statement. Int Angiol 2013; 32 (02) 111-260
    PubMedGoogle Scholar
  • 23 Schünemann HJ, Cushman M, Burnett AE. , et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
    CrossrefPubMedGoogle Scholar
  • 24 Cohen AT, Tapson VF, Bergmann JF. , et al; ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371 (9610): 387-394
    CrossrefPubMedGoogle Scholar
  • 25 Geerts WH, Heit JA, Clagett GP. , et al. Prevention of venous thromboembolism. Chest 2001; 119 (1, Suppl): 132S-175S
    CrossrefPubMedGoogle Scholar
  • 26 Alikhan R, Cohen AT, Combe S. , et al; MEDENOX Study. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164 (09) 963-968
    CrossrefPubMedGoogle Scholar
  • 27 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160 (22) 3415-3420
    CrossrefPubMedGoogle Scholar
  • 28 Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375 (9715): 657-663
    CrossrefPubMedGoogle Scholar
  • 29 Green KB, Silverstein RL. Hypercoagulability in cancer. Hematol Oncol Clin North Am 1996; 10 (02) 499-530
    CrossrefPubMedGoogle Scholar
  • 30 Pottier P, Hardouin JB, Lejeune S, Jolliet P, Gillet B, Planchon B. Immobilization and the risk of venous thromboembolism. A meta-analysis on epidemiological studies. Thromb Res 2009; 124 (04) 468-476
    CrossrefPubMedGoogle Scholar
  • 31 Hull RD. Relevance of immobility and importance of risk assessment management for medically ill patients. Clin Appl Thromb Hemost 2013; 19 (03) 268-276
    CrossrefPubMedGoogle Scholar
  • 32 Raskob GE, Spyropoulos AC, Zrubek J. , et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 2016; 115 (06) 1240-1248
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Spyropoulos AC. Emerging strategies in the prevention of venous thromboembolism in hospitalized medical patients. Chest 2005; 128 (02) 958-969
    CrossrefPubMedGoogle Scholar
  • 34 Cohen AT, Spiro TE, Spyropoulos AC. , et al; MAGELLAN Study Group. D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial. J Thromb Haemost 2014; 12 (04) 479-487
    CrossrefPubMedGoogle Scholar
  • 35 Huang W, Anderson FA, Spencer FA, Gallus A, Goldberg RJ. Risk-assessment models for predicting venous thromboembolism among hospitalized non-surgical patients: a systematic review. J Thromb Thrombolysis 2013; 35 (01) 67-80
    CrossrefPubMedGoogle Scholar
  • 36 Spyropoulos AC, Raskob GE. New paradigms in venous thromboprophylaxis of medically ill patients. Thromb Haemost 2017; 117 (09) 1662-1670
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Greene MT, Spyropoulos AC, Chopra V. , et al. Validation of risk assessment models of venous thromboembolism in hospitalized medical patients. Am J Med 2016; 129 (09) 1001.e9-1001.e18
    CrossrefPubMedGoogle Scholar
  • 38 Mahan CE, Liu Y, Turpie AG. , et al. External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR). Thromb Haemost 2014; 112 (04) 692-699
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Gibson CM, Spyropoulos AC, Cohen AT. , et al. The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open 2017; 1 (01) e56-e65
    Google Scholar
  • 40 Spyropoulos AC, Lipardi C, Xu J. , et al. Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH Open 2020; 4 (01) e59-e65
    Google Scholar
  • 41 Mahan CE, Hussein MA, Amin AN, Spyropoulos AC. Venous thromboembolism pharmacy intervention management program with an active, multifaceted approach reduces preventable venous thromboembolism and increases appropriate prophylaxis. Clin Appl Thromb Hemost 2012; 18 (01) 45-58
    CrossrefPubMedGoogle Scholar
  • 42 Decousus H, Tapson VF, Bergmann JF. , et al; IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139 (01) 69-79
    CrossrefPubMedGoogle Scholar
  • 43 Rosenberg D, Eichorn A, Alarcon M, McCullagh L, McGinn T, Spyropoulos AC. External validation of the risk assessment model of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) for medical patients in a tertiary health system. J Am Heart Assoc 2014; 3 (06) e001152
    PubMedGoogle Scholar
  • 44 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10 (07) 448-450
    CrossrefPubMedGoogle Scholar
  • 45 Belch JJ, Lowe GD, Ward AG, Forbes CD, Prentice CR. Prevention of deep vein thrombosis in medical patients by low-dose heparin. Scott Med J 1981; 26 (02) 115-117
    CrossrefPubMedGoogle Scholar
  • 46 Tapson VF, Decousus H, Pini M. , et al; IMPROVE Investigators. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132 (03) 936-945
    CrossrefPubMedGoogle Scholar
  • 47 Sandler DA, Martin JF. Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis?. J R Soc Med 1989; 82 (04) 203-205
    CrossrefPubMedGoogle Scholar
  • 48 Halkin H, Goldberg J, Modan M, Modan B. Reduction of mortality in general medical in-patients by low-dose heparin prophylaxis. Ann Intern Med 1982; 96 (05) 561-565
    PubMedGoogle Scholar
  • 49 Gärdlund B. ; The Heparin Prophylaxis Study Group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. Lancet 1996; 347 (9012): 1357-1361
    CrossrefPubMedGoogle Scholar
  • 50 Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146 (04) 278-288
    Google Scholar
  • 51 Administration USFD. FDA approved betrixaban (BEVYXXA, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients. 2017; 2019
    PubMed
  • 52 Administration USFD. Lovenox (enoxaparin) Information. 2015; 2019
    PubMed
  • 53 Johnson JPCoJ. U.S. FDA Approves XARELTO® (rivaroxaban) to Help Prevent Blood Clots in Acutely Ill Medical Patients. 2019
    PubMed
  • 54 Owodunni OP, Lau BD, Streiff MB. , et al. What the 2018 ASH venous thromboembolism guidelines omitted: nonadministration of pharmacologic prophylaxis in hospitalized patients. Blood Adv 2019; 3 (04) 596-598
    CrossrefPubMedGoogle Scholar
  • 55 Hull RD, Schellong SM, Tapson VF. , et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153 (01) 8-18
    PubMedGoogle Scholar
  • 56 Goldhaber SZ, Leizorovicz A, Kakkar AK. , et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
    CrossrefPubMedGoogle Scholar
  • 57 Cohen AT, Spiro TE, Büller HR. , et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
    CrossrefPubMedGoogle Scholar
  • 58 Chi G, Yee MK, Amin AN. , et al. Extended-duration betrixaban reduces the risk of rehospitalization associated with venous thromboembolism among acutely ill hospitalized medical patients: findings from the APEX trial (acute medically ill venous thromboembolism prevention with extended duration betrixaban trial). Circulation 2018; 137 (01) 91-94
    CrossrefPubMedGoogle Scholar
  • 59 Bajaj NS, Vaduganathan M, Qamar A. , et al. Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: a trial sequential and cumulative meta-analysis. PLoS Med 2019; 16 (04) e1002797
    CrossrefPubMedGoogle Scholar
  • 60 Chiasakul T, Evans CR, Spyropoulos AC, Raskob G, Crowther M, Cuker A. Extended vs. standard-duration thromboprophylaxis in acutely ill medical patients: a systematic review and meta-analysis. Thromb Res 2019; 184: 58-61
    CrossrefPubMedGoogle Scholar
  • 61 Chi G, Goldhaber SZ, Kittelson JM. , et al. Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost 2017; 15 (10) 1913-1922
    CrossrefPubMedGoogle Scholar
  • 62 Vaitkus PT, Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Goldhaber SZ. ; PREVENT Medical Thromboprophylaxis Study Group. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost 2005; 93 (01) 76-79
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Kalayci A, Gibson CM, Chi G. , et al. Asymptomatic deep vein thrombosis is associated with an increased risk of death: insights from the APEX trial. Thromb Haemost 2018; 118 (12) 2046-2052
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Raskob G, Spyropoulos A, Cohen A. , et al. Increased risk of death in acutely ill medical patients with asymptomatic proximal deep vein thrombosis or symptomatic venous thromboembolism: insights from the Magellan study. Blood 2019; 134
    PubMedGoogle Scholar
  • 65 Prandoni P, Bilora F, Marchiori A. , et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348 (15) 1435-1441
    CrossrefPubMedGoogle Scholar
  • 66 Gibson CM, Chi G, Halaby R. , et al; APEX Investigators. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX trial substudy (acute medically ill venous thromboembolism prevention with extended duration betrixaban). Circulation 2017; 135 (07) 648-655
    CrossrefPubMedGoogle Scholar
  • 67 Gibson CM, Korjian S, Chi G. , et al; APEX Investigators. Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an APEX trial substudy. J Am Heart Assoc 2017; 6 (07) 6
    Google Scholar
  • 68 Unger EF. Weighing benefits and risks--the FDA's review of prasugrel. N Engl J Med 2009; 361 (10) 942-945
    CrossrefPubMedGoogle Scholar
  • 69 Spyropoulos A, Ageno W, Albers G. , et al. Extended-duration Thromboprophylaxis with Rivaroxaban Reduces the Risk of Major and Fatal Vascular Events in Hospitalized Medically Ill Patients. Paper presented at: International Society on Thrombosis and Haemostasis (ISTH) 2019 Melbourne, Australia:
    PubMedGoogle Scholar
  • 70 Raskob G, Spyropoulos A, Cohen A. , et al. Abstract 12863: rivaroxaban for extended thromboprophylaxis after hospitalization for medical illness: pooled analysis of mortality and major thromboembolic events in 16,496 patients from the MAGELLAN and MARINER trials. Circulation 2019; 140
    PubMedGoogle Scholar
  • 71 Cohen AT. Extended thromboprophylaxis with betrixaban: a new standard for acute medically ill patients. Eur Heart J Suppl 2018; 20 (Suppl E): E1-E2
    CrossrefPubMedGoogle Scholar
  • 72 Shah NR, Seger AC, Seger DL. , et al. Improving acceptance of computerized prescribing alerts in ambulatory care. J Am Med Inform Assoc 2006; 13 (01) 5-11
    CrossrefPubMedGoogle Scholar
  • 73 McGinn TG, McCullagh L, Kannry J. , et al. Efficacy of an evidence-based clinical decision support in primary care practices: a randomized clinical trial. JAMA Intern Med 2013; 173 (17) 1584-1591
    CrossrefPubMedGoogle Scholar
  • 74 Kucher N, Koo S, Quiroz R. , et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med 2005; 352 (10) 969-977
    CrossrefPubMedGoogle Scholar
  • 75 Piazza G, Goldhaber SZ. Computerized decision support for the cardiovascular clinician: applications for venous thromboembolism prevention and beyond. Circulation 2009; 120 (12) 1133-1137
    CrossrefPubMedGoogle Scholar
  • 76 Piazza G, Anderson FA, Ortel TL. , et al. Randomized trial of physician alerts for thromboprophylaxis after discharge. Am J Med 2013; 126 (05) 435-442
    CrossrefPubMedGoogle Scholar
  • 77 FHIR H. SMART Application Launch Framework Implementation Guide Release 1.0.0. 2019
    PubMed
  • 78 Thromboembolic Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305 (6853): 567-574
    CrossrefPubMedGoogle Scholar
  • 79 Clagett GP, Anderson Jr FA, Geerts W. , et al. Prevention of venous thromboembolism. Chest 1998; 114 (5, Suppl): 531S-560S
    CrossrefPubMedGoogle Scholar
  • 80 Turpie AG, Chin BS, Lip GY. Venous thromboembolism: pathophysiology, clinical features, and prevention. BMJ 2002; 325 (7369): 887-890
    CrossrefPubMedGoogle Scholar