Download PDF
Thromb Haemost 2014; 112(03): 522-536
DOI: 10.1160/TH13-11-0941
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Pharmacogenetics role in the safety of acenocoumarol therapy

Enrique Jiménez-Varo
1   Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Granada, Spain
3   University of Granada, Department of Pharmacology, Faculty of Pharmacy, Campus Universitario de Cartuja, Granada, Spain
,
Marisa Cañadas-Garre
1   Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Granada, Spain
,
Cristina Isabel Henriques   *
1   Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Granada, Spain
,
Ana Margarida Pinheiro   *
1   Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Granada, Spain
,
María José Gutiérrez-Pimentel
2   Haematology Department, Complejo Hospitalario de Granada, Granada, Spain
,
Miguel Ángel Calleja-Hernández
1   Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario de Granada, Granada, Spain
3   University of Granada, Department of Pharmacology, Faculty of Pharmacy, Campus Universitario de Cartuja, Granada, Spain
› Author Affiliations Financial support: This work was partly supported by a contract for Marisa Cañadas-Garre (Técnicos de Apoyo Subprogram) from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad.
Further Information

Publication History

Received: 18 November 2013

Accepted after major revision: 23 April 2014

Publication Date:
02 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Vitamin K antagonists (VKAs) remain as the most prescribed drug for treatment and prevention of thrombotic disorders in many countries, despite the recent approval of the new oral anticoagulants (NOACs). Although effectiveness and safety of VKAs are tightly associated to maintaining the patient within the international normalised ratio (INR) therapeutic range (TWR), they have been likened to NOACs when patients are in good INR control (≥66% of TWR). Therefore, assessing the safety of patients should be a priority in the selection of the anticoagulation therapy. The aim of this study was to evaluate the association between CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2*3, ABCB1 C3435T, APOE, CYP2C19*2 and CYP2C19*17 gene polymorphisms and treatment safety in 128 patients diagnosed with atrial fibrillation or venous thromboembolism during the initial first seven months of acenocoumarol therapy. After the first month, VKORC1-Tallele and APOE-E3/E3 genotype were independently associated to higher time above therapeutic range (TAR) and lower time below the therapeutic range (TBR). After seven months, VKORC1 T-allele predicted higher TAR, and was also associated to increased INR>4, particularly the TT-genotype (odds ratio [OR]: 32; 95% confidence interval [CI95%]: 6–175; p=810–5). C-alleles for CYP2C9*3 (OR: 5.5; CI95%: 1.8–17; p=0.003) and ABCB1 (OR: 8.9;CI95%: 1.1–70; p=0.039) independently influenced on INR>6 . Patients VKORC1-TT/ABCB1-C remained 26.8% [19.7–38.9] TAR, with associated relative risk (RR) for INR>4 1.8 higher (CI95%: 1.2–2.5; p=0.015). Patients VKORC1-TT also presented the highest risk of bleeding events (RR: 3.5;CI95%: 1.4–8.4; p=0,010). In conclusion, VKORC1, CYP2C9*3, APOE and ABCB1 genotypes should be considered in prevention of overanticoagulation and bleeding events in the initiation of acenocoumarol therapy.

Keywords

Pharmacogenetics - VKORC1 - safety - CYP2C9 - atrial fibrillation - acenocoumarol

* Cristina Isabel Henriques and Ana Margarida Pinheiro contributed equally to this work.


 

  • References

  • 1 You JJ, Singer DE, Howard PA. et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) Suppl e531S-75S.
    CrossrefPubMedSearch in Google Scholar
  • 2 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) Suppl e419S-94S.
    CrossrefPubMedSearch in Google Scholar
  • 3 Pengo V, Pegoraro C, Cucchini U. et al. Worldwide management of oral anticoagulant therapy: the ISAM study. J Thrombosis Thrombol 2006; 21: 73-77.
    PubMedSearch in Google Scholar
  • 4 Camm AJ, Kirchhof P, Lip GY. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
    CrossrefPubMedSearch in Google Scholar
  • 5 Jones M, McEwan P, Morgan CL. et al. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: 472-477.
    CrossrefPubMedSearch in Google Scholar
  • 6 Wallentin L, Yusuf S, Ezekowitz MD. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010; 376: 975-983.
    CrossrefPubMedSearch in Google Scholar
  • 7 FDA. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation. FDA, News & Events; 2010
    Search in Google Scholar
  • 8 FDA. FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm. FDA, News & Events; 2011
    Search in Google Scholar
  • 9 FDA. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation. FDA, News & Events; 2012
    Search in Google Scholar
  • 10 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedSearch in Google Scholar
  • 11 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedSearch in Google Scholar
  • 12 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedSearch in Google Scholar
  • 13 Larsen TB, Rasmussen LH, Skjoth F. et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013; 61: 73.
    CrossrefPubMedSearch in Google Scholar
  • 14 Johnson JA. Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation 2012; 125: 1964-1966.
    CrossrefPubMedSearch in Google Scholar
  • 15 Ministerio de Sanidad SSeI. Criterios y recomendaciones generales para el uso de nuevos anticoagulantes orales (NACO) en la prevención del ictus y la embolia sistémica en pacientes con fibrilación auricular no valvular. 2013
    PubMedSearch in Google Scholar
  • 16 Wells G CD, Cameron C, Steiner S. et al. Safety, Effectiveness, and Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarin in Preventing Stroke and Other Cardiovascular Events in Patients with Atrial Fibrillation. Available at: http://www.cadth.ca/media/pdf/NOAC_Therapeutic_Review_final_report.pdf . Accessed November 7, 2013.
    PubMed
  • 17 Schwarz UI, Ritchie MD, Bradford Y. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
    CrossrefPubMedSearch in Google Scholar
  • 18 Levine MN, Raskob G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119 (01) Suppl 108s-121s.
    CrossrefPubMedSearch in Google Scholar
  • 19 Hylek EM, Go AS, Chang Y. et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019-1026.
    CrossrefPubMedSearch in Google Scholar
  • 20 McMahan DA, Smith DM, Carey MA. et al. Risk of major hemorrhage for outpatients treated with warfarin. J General Int Med 1998; 13: 311-316.
    PubMedSearch in Google Scholar
  • 21 Schalekamp T, de Boer A. Pharmacogenetics of oral anticoagulant therapy. Curr Pharmaceut Design 2010; 16: 187-203.
    CrossrefPubMedSearch in Google Scholar
  • 22 Teichert M, Eijgelsheim M, Rivadeneira F. et al. A genome-wide association study of acenocoumarol maintenance dosage. Human Mol Gen 2009; 18: 3758-3768.
    CrossrefPubMedSearch in Google Scholar
  • 23 Bodin L, Verstuyft C, Tregouet DA. et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005; 106: 135-140.
    CrossrefPubMedSearch in Google Scholar
  • 24 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
    CrossrefPubMedSearch in Google Scholar
  • 25 Li C, Schwarz UI, Ritchie MD. et al. Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood 2009; 113: 3925-3930.
    CrossrefPubMedSearch in Google Scholar
  • 26 Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H. et al. Acenocoumarol stabilization is delayed in CYP2C93 carriers. Clin Pharmacol Therap 2004; 75: 394-402.
    CrossrefPubMedSearch in Google Scholar
  • 27 Spreafico M, Lodigiani C, van Leeuwen Y. et al. Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenom 2008; 09: 1237-1250.
    PubMedSearch in Google Scholar
  • 28 Schalekamp T, Brasse BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Therap 2006; 80: 13-22.
    CrossrefPubMedSearch in Google Scholar
  • 29 Ferder NS, Eby CS, Deych E. et al. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost 2010; 08: 95-100.
    CrossrefPubMedSearch in Google Scholar
  • 30 Visser LE, van Schaik RH, van Vliet M. et al. The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Thromb Haemost 2004; 92: 61-66.
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Takahashi H, Wilkinson GR, Padrini R. et al. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Therap 2004; 75: 376-380.
    CrossrefPubMedSearch in Google Scholar
  • 32 Limdi NA, Wiener H, Goldstein JA. et al. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 2009; 43: 119-128.
    CrossrefPubMedSearch in Google Scholar
  • 33 Meckley LM, Wittkowsky AK, Rieder MJ. et al. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 2008; 100: 229-239.
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Santos PC, Dinardo CL, Schettert IT. et al. CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability in patients on long-term anticoagulation. Eur J Clin Pharmacol 2013; 69: 789-797.
    CrossrefPubMedSearch in Google Scholar
  • 35 Horne BD, Lenzini PA, Wadelius M. et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost 2012; 107: 232-240.
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Zhong SL, Liu Y, Yu XY. et al. The influence of genetic polymorphisms and interacting drugs on initial response to warfarin in Chinese patients with heart valve replacement. Eur J Clin Pharmacol 2011; 67: 581-590.
    CrossrefPubMedSearch in Google Scholar
  • 37 Lund K, Gaffney D, Spooner R. et al. Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates. Br J Haematol 2012; 158: 256-261.
    CrossrefPubMedSearch in Google Scholar
  • 38 Teichert M, van Schaik RH, Hofman A. et al. Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatment period. Clin Pharmacol Therap 2009; 85: 379-386.
    CrossrefPubMedSearch in Google Scholar
  • 39 Gonzalez-Conejero R, Corral J, Roldan V. et al. The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol. J Thromb Haemost 2007; 05: 1701-1706.
    CrossrefPubMedSearch in Google Scholar
  • 40 Verhoef TI, Redekop WK, Buikema MM. et al. Long-term anticoagulant effects of the CYP2C9 and VKORC1 genotypes in acenocoumarol users. J Thromb Haemost 2012; 10: 606-614.
    CrossrefPubMedSearch in Google Scholar
  • 41 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112.
    CrossrefPubMedSearch in Google Scholar
  • 42 Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc 1997; 56: 915-937.
    CrossrefPubMedSearch in Google Scholar
  • 43 Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev 1992; 06: 92-104.
    CrossrefPubMedSearch in Google Scholar
  • 44 Zannis VI, Just PW, Breslow JL. Human apolipoprotein E isoprotein subclasses are genetically determined. Am J Human Gen 1981; 33: 11-24.
    PubMedSearch in Google Scholar
  • 45 Visser LE, Trienekens PH, De Smet PA. et al. Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genom 2005; 15: 69-74.
    CrossrefPubMedSearch in Google Scholar
  • 46 Hoffmeyer S, Burk O, von Richter O. et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473-3478.
    CrossrefPubMedSearch in Google Scholar
  • 47 Leschziner GD, Andrew T, Pirmohamed M. et al. ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenom J 2007; 07: 154-179.
    CrossrefPubMedSearch in Google Scholar
  • 48 Wadelius M, Sorlin K, Wallerman O. et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenom J 2004; 04: 40-48.
    CrossrefPubMedSearch in Google Scholar
  • 49 Saraeva RB, Paskaleva ID, Doncheva E. et al. Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements. J Clin Pharm Therap 2007; 32: 641-649.
    CrossrefPubMedSearch in Google Scholar
  • 50 De Oliveira Almeida VC, De Souza Ferreira AC, Ribeiro DD. et al. Association of the C3435T polymorphism of the MDR1 gene and therapeutic doses of warfarin in thrombophilic patients. J Thromb Haemost 2011; 09: 2120-2122.
    CrossrefPubMedSearch in Google Scholar
  • 51 Godbillon J, Richard J, Gerardin A. et al. Pharmacokinetics of the enantiomers of acenocoumarol in man. Br J Clin Pharmacol 1981; 12: 621-629.
    CrossrefPubMedSearch in Google Scholar
  • 52 Teichert M, van Noord C, Uitterlinden AG. et al. Proton pump inhibitors and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Haematol 2011; 153: 379-385.
    CrossrefPubMedSearch in Google Scholar
  • 53 Thijssen HH, Verkooijen IW, Frank HL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogen 2000; 10: 757-760.
    CrossrefPubMedSearch in Google Scholar
  • 54 Rosendaal FR, Cannegieter SC, van der Meer FJ. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
    Thieme ConnectPubMedSearch in Google Scholar
  • 55 Scott SA, Khasawneh R, Peter I. et al. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenom 2010; 11: 781-791.
    PubMedSearch in Google Scholar
  • 56 Gage BF, Eby C, Johnson JA. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Therap 2008; 84: 326-331.
    CrossrefPubMedSearch in Google Scholar
  • 57 Voora D, Eby C, Linder MW. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005; 93: 700-705.
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Anderson JL, Horne BD, Stevens SM. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563-2570.
    CrossrefPubMedSearch in Google Scholar
  • 59 Wen MS, Lee M, Chen JJ. et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Therap 2008; 84: 83-89.
    CrossrefPubMedSearch in Google Scholar
  • 60 Huang SW, Chen HS, Wang XQ. et al. Validation of VKORC1 and CYP2C9 genotypes on inter-individual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogen Genom 2009; 19: 226-234.
    PubMedSearch in Google Scholar
  • 61 Lenzini P, Wadelius M, Kimmel S. et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Therap 2010; 87: 572-578.
    CrossrefPubMedSearch in Google Scholar
  • 62 Anderson JL, Horne BD, Stevens SM. et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012; 125: 1997-2005.
    CrossrefPubMedSearch in Google Scholar
  • 63 Mark L, Marki-Zay J, Fodor L. et al. [Significance of cytochrome P450 2C9 genotype for the bleeding complications in patients treated with acenocoumarol]. Orvosi hetilap 2005; 146: 739-743.
    PubMedSearch in Google Scholar
  • 64 Gadisseur AP, van der Meer FJ, Adriaansen HJ. et al. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon. Br J Haematol 2002; 117: 940-946.
    CrossrefPubMedSearch in Google Scholar
  • 65 Verhoef TI, Ragia G, de Boer A. et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013; 369: 2304-2312.
    CrossrefPubMedSearch in Google Scholar
  • 66 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Therap 2008; 83: 460-470.
    CrossrefPubMedSearch in Google Scholar
  • 67 Burmester JK, Berg RL, Yale SH. et al. A randomized controlled trial of geno-type-based Coumadin initiation. Genetics Med 2011; 13: 509-518.
    PubMedSearch in Google Scholar
  • 68 Gong IY, Tirona RG, Schwarz UI. et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 2011; 118: 3163-3171.
    CrossrefPubMedSearch in Google Scholar
  • 69 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690-1698.
    CrossrefPubMedSearch in Google Scholar
  • 70 Limdi NA, Arnett DK, Goldstein JA. et al. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenom 2008; 09: 511-526.
    PubMedSearch in Google Scholar
  • 71 Wadelius M, Chen LY, Lindh JD. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784-792.
    CrossrefPubMedSearch in Google Scholar
  • 72 Tassies D, Freire C, Pijoan J. et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematologica 2002; 87: 1185-1191.
    PubMedSearch in Google Scholar
  • 73 Montes R, Nantes O, Alonso A. et al. The influence of polymorphisms of VKORC1 and CYP2C9 on major gastrointestinal bleeding risk in anticoagulated patients. Br J Haematol 2008; 143: 727-733.
    CrossrefPubMedSearch in Google Scholar
  • 74 McMillin GA, Melis R, Wilson A. et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Therap Drug Monitor 2010; 32: 338-345.
    PubMedSearch in Google Scholar
  • 75 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-428.
    CrossrefPubMedSearch in Google Scholar
  • 76 Jiménez-Varo E, Cañadas-Garre M, Calleja Hernández MA. VKORC1 in the selection of oral anticoagulant therapy for atrial fibrillation patients. Eur J Hosp Pharm Sci Pract. 2014 21. (Supp 1): in press.
    PubMedSearch in Google Scholar