CHALLENGES WITH DOSE SELECTION AND DOSE ADJUSTMENTS
Warfarin dose selection and adjustment can be divided into an initiation
phase, until a stable dose and INR is achieved, and a maintenance phase,
during which further dose adjustments may be required for clinical and
dietary reasons. Examples of dosing guidelines made by ministries /
departments of health in SSA countries are given in Table 3. Except for
the South African guideline, these are vague, with a large range of
warfarin initiation doses, and little detail about how often or by how
much doses should be adjusted. Aside from these national guidelines,
institution-specific anticoagulation protocols, guidelines, or
algorithms may be in use – in one Nigerian survey 11% of clinicians
reported using such guidelines in their institutions.[95] We did not
find any warfarin dose initiation or dose adjustment algorithms in use
in SSA that have been validated for the local population.
{Table 3 here}
Where detailed dose adjustment algorithms do not exist, clinicians may
make erroneous or even paradoxical dose adjustments. Reviews from
Cameroon,[8] Ethiopia,[9,14] and Namibia[19] report dose
increases after 4%-17% of supratherapeutic INRs and dose decreases
after 4%-15% of subtherapeutic INRs. In addition, dose adjustments are
often inappropriately large: While clinical trial evidence has shown
that warfarin dose adjustments of 10-15% were associated with better
outcomes,[102] the mean warfarin dose increase in one Ethiopian
review was 58% in response to an INR of 1.5 to 1.9 against a target of
2.0 to 3.0.[9] In the Namibian example, more than half of patients
with an INR >4 were over-corrected so that their subsequent
INR was subtherapeutic.[19]
Warfarin formulations other than 5mg are frequently not available in
SSA,[6,22] making precision dosing difficult. Complicated weekly
dosing schedules of alternating daily dosages which often require tablet
splitting (sometimes into quarters) are used, potentially compromising
the actual dose taken.[103] This may in turn influence adherence and
anticoagulation control. Reasons for the unavailability of alternative
formulations seem to be market-related as several SSA countries’
essential medicines lists follow the WHO model list which includes 1, 2,
and 5mg warfarin tablets. Even so, some Kenyan evidence suggests
prescribers may simply be unaware of the market availability of
alternatives to 5mg tablets.[83] Also, 1mg or 2mg formulations may
be priced close to 5mg tablets, making these alternative formulations
less cost-effective.