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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

of bleeding.

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.


Fourthly, INR

measurements are reported up to 10 with values above 10 being

reported as


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.



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