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.