Cardiovascular Journal of Africa: Vol 24 No 2 (March 2013)

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CARDIOVASCULAR JOURNAL OF AFRICA • Vol 24, No 2, March 2013 22 AFRICA
substrates and inhibitors of various CYP isoforms including
CYP3A4.34 Pharmacokinetic interaction at the metabolic level
with these antibiotics can inhibit warfarin metabolism, leading
to increased INR, as observed in this study.
Various other studies have reported an interaction between
warfarin and the quinolones, metronidazole and other
antibacterial drugs, leading to bleeding complications. Therefore
it is reasonable to infer that drug–drug interactions could have
been responsible for the observed increase in INR in the month
of concurrent administration with warfarin.
The observations presented in this study reflect the complexity
of the many factors to be considered in warfarin therapy. A
comprehensive overview of such considerations by McMillin and
co-workers35 concluded that pharmacogenetic testing is important
in personalised warfarin therapy. While new anticoagulant drugs
are entering the drug market and clinical practice, warfarin will
continue to be the reference oral anticoagulant.
This is more so in Africa, where cost and accessibility are
important considerations. Therefore, studies that will add to
current knowledge and improve warfarin therapy among African
populations will benefit clinicians, patients, researchers and
policy makers in the health sector.
Conclusions
This study confirmed the variability in patient response to
warfarin therapy, with race, gender, weight, and concurrent
morbidity and medications as some of the important factors.
Over a third of the patients had at least one record of an INR
above 3.5 in Gugulethu Hospital, compared to over half in
Wesfleur Hospital. Differences in the control of INR values were
observed with race, weight and age.
Warfarin remains the oral anticoagulant of choice in South
Africa. Its use should be closely monitored. Health practitioners
must be aware of the various factors responsible for variations
in inter-individual responses to warfarin therapy. INR values
should be monitored frequently and closely in high-risk patients,
including those on co-medications and with cardiovascular
co-morbidities.
References
1. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism
of action, clinical effectiveness, and optimal therapeutic range. Chest
2001; 119: 8–21s.
2. Chaves CJ, Caplan LR. Heparin and oral anticoagulants in the treatment
of brain ischemia. J Neurol Sci 2000; 173: 3–9.
3. Lemos Silva R, Carvalho de Sousa J, Calisto C, Braz Nogueira JM,
Ravara L. Oral anticoagulant therapy. Fundamentals, clinical practice
and recommendations. Rev Port Cardiol 2007; 26: 769–788.
4. Hill CE, Duncan A. Overview of pharmacogenetics in anticoagulation
therapy. Clin Lab Med 2008; 28: 513–524.
5. Shikata E, Ieiri I, Ishiguro S, Aono H, Inoue K, Koide T, et al.
Association of pharmacokinetic (CYP2C9) and pharmacodynamic
(factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl
carboxylase) gene variants with warfarin sensitivity. Blood 2004;
103(7): 2630–2635.
6. Shek KL, Chan LN, Nutescu E. Warfarin-acetaminophen drug interac-
tion revisited. Pharmacotherapy 1999; 19: 1153–1158.
7. Daly AK, Day PC, Guruprasad PA. CYP2C9 polymorphism and warfa-
rin dose requirements. Br J Clin Pharmacol 2002; 53(4): 408–409.
8. Kealy C, Chen Z, Christie J, Thorn CF. Warfarin and cytochrome
P450 2C9 genotype: possible ethnic variation in warfarin sensitivity.
Pharmacogenomics 2007; 8(3): 217–225.
9. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current
status and future challenges. Pharmacogenomics 2007; 53: 99–111.
10. Le DT, Weibert RT, Sevilla BK, Donnelly KJ, Rapaport SI. The inter-
national normalized ratio (INR) for monitoring warfarin therapy: reli-
ability and relation to other monitoring methods. Ann Intern Med 1994;
120: 552–558.
11. Gage BF, Fihn SD, White RH. Management and dosing of warfarin
therapy. Am J Med 2000; 109: 481–488.
12. Odén A, Fahlén M. Oral anticoagulation and risk of death: a medical
record linkage study. Br Med J 2002; 325: 1073–1075.
13. Srivastava A, Hudson M, Hamoud I, Cavalcante J, Pai C, Kaatz S.
Examining warfarin underutilization rates in patients with atrial fibril-
lation: Detailed chart review essential to capture contraindications to
warfarin therapy. Thromb J 2008; 6: 6.
14. Hirsh J, Dalen JE, Anderson DR, Poller L. Oral Anticoagulants: mecha-
nism of action, clinical effectiveness, and optimal therapeutic range.
Chest 2001; 119: 8S–21S.
15. Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A,
et al. Interindividual variability in sensitivity to warfarin – nature or
nurture? Clin Pharmacol Ther 2001; 70: 159–164.
16. Miao L, Yang J, Huang C, Shen Z. Contribution of age, body weight,
and CYP2C9 and VKORC1 genotype to the anticoagulant response to
warfarin: proposal for a new dosing regimen in Chinese patients. Eur J
Clin Pharmacol 2007; 63: 1135–1141.
17. Schwarz UI, Ritchie MD, BradfordY, Li C, Dudek SM, Frye-Anderson
A, et al. Genetic determinants of response to warfarin during initial
anticoagulation. N Engl J Med 2008; 358: 999–1008.
18. Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou G,
et al. Clinical and genetic determinants of warfarin pharmacokinetics
and pharmacodynamics during treatment initiation. PLoS One 2011;
6(11): e27808.
19. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD,
Crowther M, Wells PS. Systematic overview of warfarin and its drug
and food interactions. Arch Intern Med 2005; 165: 1095–1106.
20. Tadros R, Shakib S. Warfarin – indications, risks and drug interactions.
Aust Fam Physician 2010; 39: 476–479.
21. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interac-
tions of warfarin and novel oral anticoagulants: an update. J Thromb
Thrombolysis 2011; 31: 326–343.
22. Sands CD, Chan ES, Welty TE. Revisiting the significance of warfarin
protein-binding displacement interactions. Ann Pharmacother 2002;
36: 1642–1644.
23. Knijff-Dutmer EA, Schut GA, van de Laar MA. Concomitant
coumarin–NSAID therapy and risk for bleeding. Ann Pharmacother
2003; 37(1): 12–16.
24. Davydov L, Yermolnik M, Cuni LJ. Warfarin and amoxicillin/clavula-
nate drug interaction. Ann Pharmacother 2003; 37: 367–370.
25. Zhou SF, Xue CC, Yu XQ, Li C, Wang G. Clinically important
drug interactions potentially involving mechanism-based inhibition of
cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther
Drug Monit 2007; 29: 687–710.
26. Scott SA, Khasawneh R, Peter I, Kornreich R, Desnick RJ. Combined
CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic
groups. Pharmacogenomics J 2010; 11(6): 781–791.
27. Momary KM, Shapiro NL, Viana MA, Nutescu EA, Helgason CM,
Cavallari LH. Factors influencing warfarin dose requirements in
African-Americans. Pharmacogenomics 2007; 8(11): 1535–1544.
28. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current
status and future challenges. Pharmacogenomics 2007; 7: 99–111
29. Limdi NA, Beasley TM, Crowley MR, Goldstein JA, Rieder MJ,
Flockhart DA, et al. VKORC1 polymorphisms, haplotypes and haplo-
type groups on warfarin dose among African-Americans and European-
Americans. Pharmacogenomics 2008; 9(10): 1445–1458.
30. Schelleman H, Brensinger CM, Chen J, Finkelman BS, Rieder MJ,
Kimmel SE. New genetic variant that might improve warfarin dose
prediction in African Americans. Br J Clin Pharmacol 2010; 70(3):
393–399.
31. Casimire T, Carter R, Peters S, Tweedle J, Charles KS. Establishing