CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
The average cost to treat a patient with warfarin toxicity was
calculated at R10 578. The largest contributors to treatment
costs were cost to be admitted and the use of blood and blood
products when required (see Table 6).
To the best of our knowledge, this is the first review of warfarin
toxicity in South Africa looking at causes, management and
treatment cost implications. We found that the cause of warfarin
toxicity was not identified in the majority of patients. DDIs
were identified to be the cause of warfarin toxicity in only
three cases, while we identified that 77% (97/126) of patients
were using concomitant medication known to have a DDI with
warfarin. The most frequently prescribed interacting medicines
were cardiovascular medicines. Major DDIs with antimicrobial,
antiretroviral and central nervous system medicines were also
Our patients presented with significant morbidity, with
nearly half of the patients presenting with bleeding, while 28%
presented with major bleeding. Although many unrecorded
DDIs with warfarin were identified, we could not prove a
statistically significant relationship for the presence of DDIs
and the occurrence of bleeding. Furthermore we could not
prove a statistically significant relationship between the usage of
antiplatelet medicines together with warfarin and the occurrence
Patients were admitted for a median of eight days and the
average total cost to treat a patient with warfarin toxicity was
estimated at R10 578. Of concern is that some patients were
treated with high-cost interventions, which do not address the
pathophysiology of warfarin toxicity. We also recognised a
significant mortality rate associated with warfarin toxicity as
15% of patients died, although the final cause of death could not
be attributed with certainty to warfarin toxicity.
The low pick-up rate for the cause of warfarin toxicity
could be explained by physicians not documenting the cause
of warfarin toxicity, however this is unlikely. Furthermore, it
could be postulated that physicians are not aware of or unable
to determine all the drug interactions with warfarin. Medicines
found to have major DDIs with warfarin are used over a variety
of disciplines and within a tertiary setting could result in the
addition of medications to a patient’s treatment regime without
adequate knowledge of already prescribed medication by other
disciplines. Difficulty in dose adjustment could be explained by
the availability of only 5-mg oral tablets in the public sector,
limiting physicians in the degree that they can adjust warfarin
Our study has a number of limitations. Firstly, this was a
retrospective study and relied on the availability of clinical
records and the quality of available records. We were unable
to obtain access to the clinical records of 55 raised INR
measurements. Secondly, it is possible that we excluded patients
presenting with warfarin toxicity complicated by major bleeding
using our inclusion criteria. We identified 19 patients who died
with only one INR measurement having been done, but who
were excluded from our analysis due to insufficient clinical
information and our inclusion criteria.
Thirdly, we were unable to determine the impact of genetics
on warfarin toxicity. However, genotype-guided dosing is only
of value when initiating warfarin therapy.
measurements are reported up to 10 with values above 10 being
10 by the NHLS. For statistical analysis, values
greater than 10 were processed as 10, and underestimated the
association between INR and bleeding severity of warfarin
toxicity. Lastly, we were not able to determine prolonged
admission to hospital for concomitant medical or surgical
conditions after correction of warfarin toxicity.
We found that the cause of warfarin toxicity is frequently not
identified by physicians and is therefore rarely addressed. We
found that warfarin toxicity carries a significant morbidity
rate and significant resources to treat. Future prospective
research should study the causes of patients who are stable on
warfarin treatment and present with warfarin toxicity, and target
interventions to address this.
Sonuga BO, Hellenberg DA, Cupido CS, Jaeger C. Profile and antico-
agulation outcomes of patients on warfarin therapy in an urban hospital
in Cape Town, South Africa.
Afr J Prim Health Care Fam Med
Rossiter D (ed).
South African Medicines Formulary
. Cape Town:
Health and Medical Publishing Group of the South African Medical
Association, 2014: 102–103.
Jonas DE, McLeod HL. Genetic and clinical factors relating to warfarin
Trends Pharmacol Sci
Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee
. Warfarin pharmacogenetics: a single
phism is predictive of dose across 3 racial groups.
Westaway K, Cruickshank M, Roberts GW, Esterman AJ. Factors
influencing over-anticoagulation and bleeding warfarin therapy during
the initial five months of treatment.
Austr Nursing J
Gage BF, Fihn SD, White RH. Management and dosing of warfarin
Am J Med
Hull RD, Garcia DA. Correcting excess anticoagulation after warfarin
[Online] 2015 [access 2015, April 23]; Available:http://www.uptodate
Mezin J, Hoesche J, Friedman M, Nichols C, Bergman C, Crowther M,
. Failure to correct international normalized ratio and mortality
among patients with warfarin-related major bleeding: an analysis of
electronic health records.
J Thromb Haemostasis
. Interactive Drug Interactions database (Truven
Health Analytics Inc. Micromedex
Healthcare Series) 2016. [Online].
expert/PFActionId/evidencexpert.FindDrugI [2016, July]
10. Primohamed M, Burnside G, Eriksson N, Jorgensen AL, Hock Toh C,
. A randomized trial of genotype-guided dosing of
New Engl J Med