Anticoagulation control among patients on vitamin K antagonists in nine countries in Sub-Saharan Africa

Vitamin K anticoagulants (VKAs) have been widely used for decades for treating and preventing thromboembolic complications of venous thromboembolism (VTE), atrial fibrillation (AF), and valvular heart disease [1]. Furthermore, VKAs are the only recommended anticoagulant treatment for patients with rheumatic heart disease-associated atrial fibrillation and mechanical heart valves [2]. However, VKA use can be challenging given the narrow therapeutic window, unpredictable response, and multiple interactions with other drugs and diets [3, 4]. Therefore, to attain the maximal therapeutic benefits of VKA while minimising bleeding complications, warfarin therapy must be tightly controlled and maintained within a narrow therapeutic range based on INR [5]. The recommended INR targets are 2.0–3.0 for VTE and AF and 2.5–3.5 for mechanical prosthetic valves [6, 7]. The safety and efficacy of warfarin depend on the extent to which anticoagulant regimens maintain patients in these therapeutic ranges. The average percentage of the time in the therapeutic range (TTR) and the percentage of INR values in the therapeutic range are ways to assess the quality of anticoagulation related to thrombotic and bleeding complications [5, 8]. Guideline-recommended thresholds for optimal anticoagulation are TTR ≥ 65% for the British National Institute for Health and Care Excellence and TTR ≥ 70% for the European Society of Cardiology [9, 10]. Achieving these thresholds has been challenging in most settings, leaving a substantial proportion of warfarin-treated patients sub-optimally anticoagulated and with an increased stroke, bleeding, and mortality risk [11‐15]. In the Global Anticoagulant Registry in the FIELD (GARFIELD) study, the proportion of patients with TTR ≥ 65% was low, varying from 16.7% in Asia to 49.4% in Europe [13]. The situation is worse in SSA, with the proportion of patients with optimal anticoagulation control as low as 15%. [16] The long travel distance to access the few unreliable centralised VKA services, leading to the low frequency of INR monitoring, out-of-pocket expenses for VKA services and other health system-related problems that affect the accessibility of VKA services, significantly impact anticoagulation control in these settings [13, 16‐18]. The resulting suboptimal quality of anticoagulation is a significant concern in SSA, given the high burden of rheumatic heart disease-associated AF and mechanical heart valve transplantation, for which VKA is the preferred oral anticoagulation strategy. Even for therapeutic indications that non-vitamin K oral anticoagulants (NOACs) are possible substitutes, VKAs remain the primary anticoagulant as the uptake of NOACs is limited by the high cost and accessibility in African settings. Consequently, VKAs could remain the primary anticoagulant in SSA for decades and efforts to achieve optimal VKA anticoagulation are crucial [13]. Evidence suggests that VKA at stable optimal anticoagulation has comparable efficacy and safety to NOACs [19‐21]. The current study aimed to describe the quality of anticoagulation control among patients using VKA in nine SSA countries.

The study included 1011 patients whose mean age was 51 years (Table 1). Most participants (64%) were females, half were from Nigeria and South Africa, and half had an out-of-pocket payment for their medical. Warfarin was prescribed in 99.3% of the patients (n = 1004). The most common VKA indications for warfarin were venous thromboembolism, atrial fibrillation, and mechanical heart valves.

We sought to determine the anticoagulation control among patients on VKA in SSA. Data from our study indicate that the proportions of INR values in the therapeutic range, the median TTR and the proportion of patients with TTR ≥ 65% are all low. In all nine countries, the median TTR values were below 65%, ranging from 0 to 44.6%. In addition, we consistently observed poor anticoagulation control in patients with all VKA indications (mechanical heart valves, atrial fibrillation, and venous thromboembolism). For those with suboptimal control, under-anticoagulation is more frequent than over-anticoagulation. Universal health coverage was more likely associated with optimal anticoagulation control. Our analysis also showed a lower frequency of INR measurements among the study participants.

The high burden of suboptimal anticoagulation control in the current study is consistent with the findings in similar studies in SSA, where the TTR values ranged from 13.7% to 47% and the proportion of patients with TTR ≥ 65% as low as 15% [16, 28]. Our findings are consistent with the global GARFIELD study, which also reported a low proportion of patients with TTR ≥ 65%, varying from 16.7% in Asia to 49.4% in Europe [13]. Therefore, real-world data, including ours, indicate that optimal anticoagulation is often not achieved in routine clinical practice. This apparent suboptimal anticoagulation in VKA-treated individuals is concerning, given the increased mortality risk of as much as fourfold when TTR falls below 30% [15]. Our findings strengthen the argument for improving anticoagulation quality, particularly in SSA, where VKAs are the primary anticoagulants [13]. Evidence suggests that VKA at stable optimal anticoagulation has comparable efficacy and safety to NOACs [19‐21].

The relatively high proportion of sub-therapeutic INRs is consistent with a previous meta-analysis and meta-regression conclusion, which reported predominantly under-anticoagulated in patients on VKA anticoagulation [14]. Although most studies typically report 25–36% of INRs below the range, the proportion of sub-therapeutic INRs in our cohorts was almost 50% [13, 14, 29‐32]. Our findings not only depict suboptimal anticoagulation control but also that when patients were out of range, they were more likely to be sub-therapeutic and at an increased risk of thrombosis than supratherapeutic with an increased risk of bleeding. This is a concern as subtherapeutic anticoagulation may cause up to a 16-fold increase in the rate of thromboembolism [33]. Though the reasons are unclear, subtherapeutic anticoagulation is likely related to a lack of dedicated anticoagulation clinics and less stringent monitoring, VKA non-adherence, dosage interruption for several reasons, a recent dose reduction in response to a previously recorded high INR value and clinicians' using low dosage due to fears of inducing a major haemorrhage [33]. Regardless of the reason, our results call for efforts to reduce or eliminate sub-therapeutic anticoagulation to improve patient outcomes.

Better anticoagulation control has been attained in clinical trials performed in the SSA [2]. In the Investigation of Rheumatic AF Treatment Using VKA, Rivaroxaban or Aspirin Studies (INVICTUS) trial that involved several African countries, 56.1% to 65.3% of INR tests were in the therapeutic range during the four years of follow-up, rising from 33.2% before the trial. The INVICTUS study reported a lower rate of a composite of stroke, systemic embolism or myocardial infarction, or death in patients with rheumatic heart disease–associated atrial fibrillation on warfarin than rivaroxaban therapy. The improved quality of anticoagulation is a significant determinant of thrombotic and bleeding events in patients receiving a vitamin K antagonist and likely influenced outcomes in the INVICTUS trial. Although these results show that optimal quality of anticoagulation can be achieved in resource-limited countries, the trial's rigorous follow-up and strict inclusion criteria make it difficult to extrapolate the results to real-life VKA-treated patients [2]. Due to frequent anticoagulation monitoring, patients in the VKA arm had frequent physician interactions, which could have resulted in better clinical outcomes. Our study analysed anticoagulation data routinely collected from different levels of healthcare and likely reflects the accurate picture of the quality of anticoagulation in non-trial clinical sub-Saharan African settings. Putting these results into perspective, the benefits seen in the INVICTUS trial are difficult to replicate in sub-Saharan Africa, where time, distance, economic or other access-to-care issues impede access to anticoagulation care.

Our analyses noted an association between optimal quality of anticoagulation and universal health coverage. This finding is consistent with previous evidence linking out-of-pocket expenses for VKA services and suboptimal quality of the anticoagulation [13, 16, 18]. Owing to the underfunding of the health systems in Africa, patients travel a long distance to access the few unreliably running centralised VKA services [17].

In conclusion, patients on VKAs for different therapeutic indications in SSA are frequently outside the therapeutic INR range and tend to be sub-therapeutic rather than over-anticoagulated. Anticoagulation care in settings without universal health is associated with suboptimal anticoagulation control. The evidence calls for efforts to improve the region’s anticoagulation control among patients in sub-Saharan Africa, including providing VKA services free of charge.