Skip to content
2000
image of Clinical Predictors of Warfarin Response Among Patients with Atrial Fibrillation: Evidence from the Middle Eastern JoFib Study

Abstract

Objective

To describe clinical factors predictive of warfarin response in atrial fibrillation (AF) patients and to evaluate its association with adverse outcomes.

Methods

Patients in the Middle Eastern JoFib study, a prospective, multicenter registry of AF patients, using warfarin with at least one international normalized ratio (INR) reading, were enrolled. We used the most recent INR as a measure of warfarin control.

Results

Out of the total 2020 patients, 544 (26.9%) were using warfarin. Multivariable logistic regression analysis demonstrated that heart failure (adjusted OR 0.55, 95%CI 0.36-0.86) and increasing HAS-BLED score (adjusted OR 0.73, 95%CI 0.58-0.92) decreased the odds of having a therapeutic INR. Chronic kidney disease (adjusted OR 3.11, 95%CI 1.46-6.62), heart failure (adjusted OR 2.37, 95%CI 1.4-4.01), and cancer (adjusted OR 2.48, 95%CI 1.03-6.01) were independently predictive of having INR less than 2.0. The first episode of AF was independently predictive of having INR above 3.0 (adjusted OR 2.48, 95%CI 1.39-4.42). Multivariable Cox regression analysis demonstrated that INR below the therapeutic range (aHR 4.36, 95%CI 2.19-8.68) and INR above the therapeutic range (aHR 3.03, 95%CI 1.33-6.92) were predictive of all-cause mortality. Below-range INR also predicted cardiovascular mortality (aHR 3.69, 95%CI 1.66-8.16).

Conclusion

Clinical factors predictive of sub-optimal INR in Middle Eastern AF patients using warfarin include chronic kidney disease, heart failure, cancer, high HAS-BLED score, and first episode of AF. Furthermore, sub-optimal INR is predictive of all-cause and cardiovascular mortality.

Loading

Article metrics loading...

/content/journals/cvp/10.2174/0115701611297687250221010411
2025-02-26
2025-04-12
Loading full text...

Full text loading...

References

  1. Go A.S. Hylek E.M. Phillips K.A. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001 285 18 2370 2375 10.1001/jama.285.18.2370 11343485
    [Google Scholar]
  2. Tsao C.W. Aday A.W. Almarzooq Z.I. Heart disease and stroke statistics—2023 update: A report from the american heart association. Circulation 2023 147 8 e93 e621 10.1161/CIR.0000000000001123 36695182
    [Google Scholar]
  3. Staerk L. Sherer J.A. Ko D. Benjamin E.J. Helm R.H. Atrial fibrillation. Circ. Res. 2017 120 9 1501 1517 10.1161/CIRCRESAHA.117.309732 28450367
    [Google Scholar]
  4. Nesheiwat Z. Goyal A. Jagtap M. Atrial Fibrillation. StatPearls. Treasure Island, FL: StatPearls Publishing 2023. Available from: www.ncbi.nlm.nih.gov/books/NBK526072/
    [Google Scholar]
  5. Kannel W.B. Benjamin E.J. Current perceptions of the epidemiology of atrial fibrillation. Cardiol. Clin. 2009 27 1 13 24 10.1016/j.ccl.2008.09.015 19111760
    [Google Scholar]
  6. Roth G.A. Mensah G.A. Johnson C.O. Global burden of cardiovascular diseases and risk factors, 1990-2019. J. Am. Coll. Cardiol. 2020 76 25 2982 3021 10.1016/j.jacc.2020.11.010 33309175
    [Google Scholar]
  7. Chugh S.S. Blackshear J.L. Shen W.K. Hammill S.C. Gersh B.J. Epidemiology and natural history of atrial fibrillation: Clinical implications. J. Am. Coll. Cardiol. 2001 37 2 371 378 10.1016/S0735‑1097(00)01107‑4 11216949
    [Google Scholar]
  8. Mkoko P. Bahiru E. Ajijola O.A. Bonny A. Chin A. Cardiac arrhythmias in low- and middle-income countries. Available from 2019 http://cdt.amegroups.org/article/view/31223
    [Google Scholar]
  9. Vinter N. Huang Q. Fenger-Grøn M. Frost L. Benjamin E.J. Trinquart L. Trends in excess mortality associated with atrial fibrillation over 45 years (Framingham Heart Study): Community based cohort study. BMJ 2020 370 m2724 10.1136/bmj.m2724 32784208
    [Google Scholar]
  10. Benjamin E.J. Wolf P.A. D’Agostino R.B. Silbershatz H. Kannel W.B. Levy D. Impact of atrial fibrillation on the risk of death: The Framingham Heart Study. Circulation 1998 98 10 946 952 10.1161/01.CIR.98.10.946 9737513
    [Google Scholar]
  11. Schnabel R.B. Yin X. Gona P. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: A cohort study. Lancet 2015 386 9989 154 162 10.1016/S0140‑6736(14)61774‑8 25960110
    [Google Scholar]
  12. Tanaka Y. Shah N.S. Passman R. Greenland P. Lloyd-Jones D.M. Khan S.S. Trends in cardiovascular mortality related to atrial fibrillation in the United States, 2011 to 2018. J. Am. Heart Assoc. 2021 10 15 e020163 10.1161/JAHA.120.020163 34320819
    [Google Scholar]
  13. Kanagasundram A. Stevenson W.G. Atrial fibrillation related mortality: Another curve to bend. J. Am. Heart Assoc. 2021 10 15 e022555 10.1161/JAHA.121.022555 34320818
    [Google Scholar]
  14. Cavallari I. Patti G. Early risk of mortality, cardiovascular events, and bleeding in patients with newly diagnosed atrial fibrillation. Eur. Heart J. Suppl. 2020 22 Suppl. L L110 L113 10.1093/eurheartj/suaa147 33239983
    [Google Scholar]
  15. Wolf P.A. Abbott R.D. Kannel W.B. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991 22 8 983 988 10.1161/01.STR.22.8.983 1866765
    [Google Scholar]
  16. Shi M. Chen L.Y. Bekwelem W. Association of atrial fibrillation with incidence of extracranial systemic embolic events: The ARIC study. J. Am. Heart Assoc. 2020 9 18 e016724 10.1161/JAHA.120.016724 32865122
    [Google Scholar]
  17. Migdady I. Russman A. Buletko A.B. Atrial fibrillation and ischemic stroke: A clinical review. Semin. Neurol. 2021 41 4 348 364 10.1055/s‑0041‑1726332 33851396
    [Google Scholar]
  18. Choi S.E. Sagris D. Hill A. Lip G.Y.H. Abdul-Rahim A.H. Atrial fibrillation and stroke. Expert Rev. Cardiovasc. Ther. 2023 21 1 35 56 10.1080/14779072.2023.2160319 36537565
    [Google Scholar]
  19. Ozdemir H. Sagris D. Lip G.Y.H. Abdul-Rahim A.H. Stroke in atrial fibrillation and other atrial dysrhythmias. Curr. Cardiol. Rep. 2023 25 5 357 369 10.1007/s11886‑023‑01862‑1 36976496
    [Google Scholar]
  20. Chatterjee N.A. Lubitz S.A. Systemic Embolic Events (SEE) in atrial fibrillation. Circulation 2015 132 9 787 789 10.1161/CIRCULATIONAHA.115.018172 26224812
    [Google Scholar]
  21. Lim G.B. Risk of systemic emboli in AF. Nat. Rev. Cardiol. 2015 12 10 561 10.1038/nrcardio.2015.126 26283268
    [Google Scholar]
  22. Bekwelem W. Connolly S.J. Halperin J.L. Extracranial systemic embolic events in patients with nonvalvular atrial fibrillation. Circulation 2015 132 9 796 803 10.1161/CIRCULATIONAHA.114.013243 26224811
    [Google Scholar]
  23. January C.T. Wann L.S. Calkins H. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J. Am. Coll. Cardiol. 2019 74 1 104 132 10.1016/j.jacc.2019.01.011 30703431
    [Google Scholar]
  24. Andrade J.G. Aguilar M. Atzema C. The 2020 Canadian cardiovascular society/Canadian heart rhythm society comprehensive guidelines for the management of atrial fibrillation. Can. J. Cardiol. 2020 36 12 1847 1948 10.1016/j.cjca.2020.09.001 33191198
    [Google Scholar]
  25. Hindricks G. Potpara T. Dagres N. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J. 2021 42 5 373 498 10.1093/eurheartj/ehaa612 32860505
    [Google Scholar]
  26. Giugliano R.P. Ruff C.T. Braunwald E. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2013 369 22 2093 2104 10.1056/NEJMoa1310907 24251359
    [Google Scholar]
  27. Granger C.B. Alexander J.H. McMurray J.J.V. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011 365 11 981 992 10.1056/NEJMoa1107039 21870978
    [Google Scholar]
  28. Patel M.R. Mahaffey K.W. Garg J. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011 365 10 883 891 10.1056/NEJMoa1009638 21830957
    [Google Scholar]
  29. Connolly S.J. Ezekowitz M.D. Yusuf S. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009 361 12 1139 1151 10.1056/NEJMoa0905561 19717844
    [Google Scholar]
  30. Wadsworth D. Sullivan E. Jacky T. Sprague T. Feinman H. Kim J. A review of indications and comorbidities in which warfarin may be the preferred oral anticoagulant. J. Clin. Pharm. Ther. 2021 46 3 560 570 10.1111/jcpt.13343 33393699
    [Google Scholar]
  31. Hadlock G.C. Burnett A.E. Nutescu E.A. Warfarin BT - Anticoagulation Therapy. Cham Springer International Publishing 2018 9 30 10.1007/978‑3‑319‑73709‑6_2
    [Google Scholar]
  32. Carnicelli A.P. Hong H. Connolly S.J. Direct oral anticoagulants versus warfarin in patients with atrial fibrillation: Patient-level network meta-analyses of randomized clinical trials with interaction testing by age and sex. Circulation 2022 145 4 242 255 10.1161/CIRCULATIONAHA.121.056355 34985309
    [Google Scholar]
  33. Tahaineh L. Ali T. Community pharmacists’ knowledge of direct oral anticoagulants and warfarin in the North of Jordan: A cross sectional study. Eur. Rev. Med. Pharmacol. Sci. 2022 26 4 1215 1223 35253177
    [Google Scholar]
  34. White P.J. Patient factors that influence warfarin dose response. J. Pharm. Pract. 2010 23 3 194 204 10.1177/0897190010362177 21507814
    [Google Scholar]
  35. Self T.H. Owens R.E. Sakaan S.A. Wallace J.L. Sands C.W. Howard-Thompson A. Effect of diseases on response to vitamin K antagonists. Curr. Med. Res. Opin. 2016 32 4 613 620 10.1185/03007995.2015.1134464 26695107
    [Google Scholar]
  36. Lee S.L. Ong T.J. Mazlan-Kepli W. Patients’ time in therapeutic range on warfarin among atrial fibrillation patients in Warfarin Medication Therapy Adherence Clinic. World J. Cardiol. 2021 13 9 483 492 10.4330/wjc.v13.i9.483 34621493
    [Google Scholar]
  37. Gurwitz J.H. Avorn J. Ross-Degnan D. Choodnovskiy I. Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann. Intern. Med. 1992 116 11 901 904 10.7326/0003‑4819‑116‑11‑901 1580446
    [Google Scholar]
  38. Absher R.K. Moore M.E. Parker M.H. Patient-specific factors predictive of warfarin dosage requirements. Ann. Pharmacother. 2002 36 10 1512 1517 10.1345/aph.1C025 12243598
    [Google Scholar]
  39. Whitley H.P. Fermo J.D. Chumney E.C. Brzezinski W.A. Effect of patient-specific factors on weekly warfarin dose. Ther. Clin. Risk Manag. 2007 3 3 499 504 18488070
    [Google Scholar]
  40. Hammoudeh A.J. Khader Y. Kadri N. Al-Mousa E. Badaineh Y. Habahbeh L. Adherence to the 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline on the use of oral anticoagulant agents in middle eastern patients with atrial fibrillation: The Jordan atrial fibrillation (JoFib) study. Int. J. Vasc. Med. 2021 2021 5515089 10.1155/2021/5515089 33898065
    [Google Scholar]
  41. Alrabadi N. Al-Nusair M. El-zubi K.F. Evaluation of clinical, echocardiographic, and therapeutic characteristics, and prognostic outcomes of coexisting heart failure among patients with atrial fibrillation: The Jordan Atrial Fibrillation (JoFib) study. Curr. Vasc. Pharmacol. 2024 22 58 66 10.2174/0115701611260211231115094716 38038004
    [Google Scholar]
  42. Pokorney S.D. Holmes D.N. Thomas L. Association between warfarin control metrics and atrial fibrillation outcomes in the outcomes registry for better informed treatment of atrial fibrillation. JAMA Cardiol. 2019 4 8 756 764 10.1001/jamacardio.2019.1960 31268487
    [Google Scholar]
  43. Holbrook A. Schulman S. Witt D.M. Evidence-based management of anticoagulant therapy. Chest 2012 141 2 Suppl. e152S e184S 10.1378/chest.11‑2295 22315259
    [Google Scholar]
  44. Nutescu E. Chuatrisorn I. Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: An update. J. Thromb. Thrombolysis 2011 31 3 326 343 10.1007/s11239‑011‑0561‑1 21359645
    [Google Scholar]
  45. Juurlink D.N. Drug interactions with warfarin: What clinicians need to know. CMAJ 2007 177 4 369 371 10.1503/cmaj.070946 17698826
    [Google Scholar]
  46. Limdi N.A. Beasley T.M. Baird M.F. Kidney function influences warfarin responsiveness and hemorrhagic complications. J. Am. Soc. Nephrol. 2009 20 4 912 921 10.1681/ASN.2008070802 19225037
    [Google Scholar]
  47. Limdi N.A. Limdi M.A. Cavallari L. Warfarin dosing in patients with impaired kidney function. Am. J. Kidney Dis. 2010 56 5 823 831 10.1053/j.ajkd.2010.05.023 20709439
    [Google Scholar]
  48. Kleinow M.E. Garwood C.L. Clemente J.L. Whittaker P. Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic. J. Manag. Care Pharm. 2011 17 7 523 530 10.18553/jmcp.2011.17.7.523 21870893
    [Google Scholar]
  49. Sakaan S.A. Hudson J.Q. Oliphant C.S. Evaluation of warfarin dose requirements in patients with chronic kidney disease and end-stage renal disease. Pharmacotherapy 2014 34 7 695 702 10.1002/phar.1445 24851819
    [Google Scholar]
  50. Nolin T.D. Frye R.F. Matzke G.R. Hepatic drug metabolism and transport in patients with kidney disease. Am. J. Kidney Dis. 2003 42 5 906 925 10.1016/j.ajkd.2003.07.019 14582035
    [Google Scholar]
  51. Yeung C.K. Shen D.D. Thummel K.E. Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 2014 85 3 522 528 10.1038/ki.2013.399 24132209
    [Google Scholar]
  52. Gallego P. Roldán V. Torregrosa J.M. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ. Arrhythm. Electrophysiol. 2012 5 2 312 318 10.1161/CIRCEP.111.967000 22319005
    [Google Scholar]
  53. Penning-van Beest F. Meegen E. Rosendaal F. Stricker B. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb. Haemost. 2001 86 8 569 574 10.1055/s‑0037‑1616088 11522005
    [Google Scholar]
  54. del Campo M. Roberts G. Changes in warfarin sensitivity during decompensated heart failure and chronic obstructive pulmonary disease. Ann. Pharmacother. 2015 49 9 962 968 10.1177/1060028015590438 26104049
    [Google Scholar]
  55. Ather S. Shendre A. Beasley T.M. Effect of left ventricular systolic dysfunction on response to warfarin. Am. J. Cardiol. 2016 118 2 232 236 10.1016/j.amjcard.2016.04.047 27241839
    [Google Scholar]
  56. Rose A.J. Sharman J.P. Ozonoff A. Henault L.E. Hylek E.M. Effectiveness of warfarin among patients with cancer. J. Gen. Intern. Med. 2007 22 7 997 1002 10.1007/s11606‑007‑0228‑y 17476542
    [Google Scholar]
  57. Bona R.D. Sivjee K.Y. Hickey A.D. Wallace D.M. Wajcs S.B. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb. Haemost. 1995 74 4 1055 1058 10.1055/s‑0038‑1649881 8560413
    [Google Scholar]
  58. Hutten B.A. Prins M.H. Gent M. Ginsberg J. Tijssen J.G.P. Büller H.R. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: A retrospective analysis. J. Clin. Oncol. 2000 18 17 3078 3083 10.1200/JCO.2000.18.17.3078 10963635
    [Google Scholar]
  59. Koopman M.M.W. Prandoni P. Piovella F. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N. Engl. J. Med. 1996 334 11 682 687 10.1056/NEJM199603143341102 8594426
    [Google Scholar]
  60. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N. Engl. J. Med. 1997 337 10 657 662 10.1056/NEJM199709043371001 9280815
    [Google Scholar]
  61. Kamaraju S. Mohan M. Zaharova S. Interactions between cardiology and oncology drugs in precision cardio-oncology. Clin. Sci. (Lond.) 2021 135 11 1333 1351 10.1042/CS20200309 34076246
    [Google Scholar]
  62. Saccullo G. Malato A. Raso S. Cancer patients requiring interruption of long‐term warfarin because of surgery or chemotherapy induced thrombocytopenia: The use of fixed sub‐therapeutic doses of low‐molecular weight heparin. Am. J. Hematol. 2012 87 4 388 391 10.1002/ajh.23122 22374861
    [Google Scholar]
  63. Avvisati G. Tirindelli M.C. Annibali O. Thrombocytopenia and hemorrhagic risk in cancer patients. Crit. Rev. Oncol. Hematol. 2003 48 Suppl. S13 S16 10.1016/j.critrevonc.2003.04.001 14563516
    [Google Scholar]
  64. Caine G.J. Stonelake P.S. Lip G.Y.H. Kehoe S.T. The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 2002 4 6 465 473 10.1038/sj.neo.7900263 12407439
    [Google Scholar]
  65. Pisters R. Lane D.A. Nieuwlaat R. de Vos C.B. Crijns H.J.G.M. Lip G.Y.H. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro heart survey. Chest 2010 138 5 1093 1100 10.1378/chest.10‑0134 20299623
    [Google Scholar]
  66. Garcia D. Regan S. Crowther M. Hughes R.A. Hylek E.M. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005 127 6 2049 2056 10.1378/chest.127.6.2049 15947319
    [Google Scholar]
  67. DeRemer C.E. McMichael B. Young H.N. Warfarin patients with anemia show trend of out-of-range international normalized ratio frequency with point-of-care testing in an anticoagulation clinic. J. Pharm. Pract. 2019 32 5 499 502 10.1177/0897190018768114 29642733
    [Google Scholar]
  68. Weathermon R. Crabb D.W. Alcohol and medication interactions. Alcohol Res. Health 1999 23 1 40 54 10890797
    [Google Scholar]
  69. Shendre A. Parmar G.M. Dillon C. Beasley T.M. Limdi N.A. Influence of age on warfarin dose, anticoagulation control, and risk of hemorrhage. Pharmacotherapy 2018 38 6 588 596 10.1002/phar.2089 29393514
    [Google Scholar]
  70. Crooks J. OʼMalley K, Stevenson IH. Pharmacokinetics in the elderly. Clin. Pharmacokinet. 1976 1 4 280 296 10.2165/00003088‑197601040‑00003 797500
    [Google Scholar]
  71. McLachlan A.J. Pont L.G. Drug metabolism in older people--a key consideration in achieving optimal outcomes with medicines. J. Gerontol. A Biol. Sci. Med. Sci. 2012 67A 2 175 180 10.1093/gerona/glr118 21835808
    [Google Scholar]
  72. Shepherd A.M. Hewick D.S. Moreland T.A. Stevenson I.H. Age as a determinant of sensitivity to warfarin. Br. J. Clin. Pharmacol. 1977 4 3 315 320 10.1111/j.1365‑2125.1977.tb00719.x 901699
    [Google Scholar]
  73. Amsterdam E.A. Wenger N.K. Brindis R.G. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014 130 25 e344 e426 10.1161/CIR.0000000000000134 25249585
    [Google Scholar]
  74. O’Gara P.T. Kushner F.G. Ascheim D.D. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013 127 4 529 555 10.1161/CIR.0b013e3182742c84 23247303
    [Google Scholar]
  75. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2022 79 2 e21 e129 10.1016/j.jacc.2021.09.006
    [Google Scholar]
  76. Wan Y. Heneghan C. Perera R. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: A systematic review. Circ. Cardiovasc. Qual. Outcomes 2008 1 2 84 91 10.1161/CIRCOUTCOMES.108.796185 20031794
    [Google Scholar]
  77. Björck F. Renlund H. Lip G.Y.H. Wester P. Svensson P.J. Själander A. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol. 2016 1 2 172 180 10.1001/jamacardio.2016.0199 27437888
    [Google Scholar]
  78. Turk U.O. Tuncer E. Alioglu E. Evaluation of the impact of warfarin time in therapeutic range on outcomes of patients with atrial fibrillation in Turkey: Perspectives from the observational, prospective WATER Registry. Cardiol. J. 2015 22 5 567 575 10.5603/CJ.a2015.0035 26100825
    [Google Scholar]
/content/journals/cvp/10.2174/0115701611297687250221010411
Loading
/content/journals/cvp/10.2174/0115701611297687250221010411
Loading

Data & Media loading...


  • Article Type:
    Research Article
Keywords: cardiovascular ; Atrial fibrillation ; INR ; warfarin ; anticoagulants ; JoFib study
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test