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\begin{document}

\title{Improving anticoagulation in sub-Saharan Africa -- what are the
challenges, and how can we overcome them?}



\author[1]{Johannes Mouton}%
\author[1]{Marc Blockman}%
\author[2]{Christine Sekaggya-Wiltshire}%
\author[2]{Jerome Semakula}%
\author[3]{Catriona Waitt}%
\author[3,4]{Munir Pirmohamed}%
\author[5]{Karen Cohen}%
\affil[1]{University of Cape Town}%
\affil[2]{Makerere University College of Health Sciences}%
\affil[3]{University of Liverpool Institute of Translational Medicine}%
\affil[4]{University of Liverpool}%
\affil[5]{Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.}%


\vspace{-1em}



  
  \date{June 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Patients in sub-Saharan Africa generally have poor anticoagulation
control. We review the potential reasons for this poor control, as well
as the potential solutions. Challenges include the affordability and
centralisation of anticoagulation care, problems with access to
medicines and INR monitoring, the lack of locally-validated standardized
dosing protocols, and low levels of anticoagulation knowledge among
health care workers and patients. Increasing numbers of patients will
need anticoagulation in the future because of the epidemiological
transition in the region. We propose that locally-developed ``warfarin
care bundles'' which address multiple anticoagulation challenges in
combination may be the most appropriate solution in this setting
currently.%
\end{abstract}%



\sloppy




\textbf{INTRODUCTION}

Anticoagulation is used to treat and prevent venous thrombosis and to
prevent intracardiac thrombosis due to some structural heart diseases or
dysrhythmias. Depending on the indication, treatment may be lifelong.
Over-anticoagulation may result in bleeding and under-coagulation in
thrombotic complications, including stroke. With the advent of direct
oral anticoagulants (DOACs), there is increased choice of drugs
available. However, vitamin K antagonists such as warfarin remain the
most widely used oral anticoagulants, and form the focus of this
article.

When using vitamin K antagonists, the degree of anticoagulation is
measured by the international normalised ratio (INR), and a patient's
longitudinal anticoagulation control can be described by the proportion
of INRs which fall in the therapeutic range (PTR), or by the proportion
of time spent in the therapeutic range (TTR), interpolating INR results
for the time between actual INR measurements. Patients in sub-Saharan
Africa (SSA) have poor anticoagulation control as measured by their
PTR/TTR, which is evident from trials,{[}1--3{]} large multisite
registries,{[}4,5{]} and smaller observational studies (Table 1).

\{Table 1 here\}

In this review, we explore potential reasons for this poor
anticoagulation control.

\textbf{METHODS}

For this narrative review, we searched Pubmed and Africa-Wide
Information through EBSCOhost, using index terms and free text around
four themes: (1) burden of anticoagulation indications, (2) challenges
accessing anticoagulation, (3) challenges with selecting and adjusting
anticoagulant dose, and (4) patient-related challenges including
adherence, knowledge, attitudes, and beliefs, and genetic factors. We
also searched Google and various dissertation databases for grey
literature from SSA on these issues. Further reports were found by
handsearching reference lists of included studies.

\textbf{CHALLENGES IN THE DISEASE BURDEN}

SSA is undergoing an epidemiological transition: with increasing life
expectancy the increasing burden of non-communicable disease is
colliding with the pre-existing burden of infectious diseases. In the
context of anticoagulation, this transition is evident in the increasing
prevalence of (non-valvular) atrial fibrillation (AF), adding to the
large number of people requiring anticoagulation for valvular heart
disease (VHD), which in SSA is still mostly caused by rheumatic heart
disease (RHD).{[}23{]} This increase in indications for anticoagulation
is occurring amidst an uneven distribution of limited resources. For
example, there were only 57 centres in SSA capable to perform regular
open heart operations in 2011/2012 (one per 15 million population); 35
of these were in South Africa.{[}24{]} Figure 1 shows some examples of
SSA anticoagulation studies mentioning resource limitations.

\{Figure 1 here\}

A recent systematic review suggested that AF prevalence in SSA may be
higher than previously thought,{[}33{]} up to 4.3\% in one Ethiopian
community-based survey.{[}34{]} Patients with AF in SSA have high
prevalence of concomitant stroke risk factors,{[}33,35{]} and should
therefore benefit from anticoagulation. However, despite clear
indications for anticoagulation, it is not always implemented in
SSA.{[}26,36--41{]} Indeed, in the multiregional RELY-AF
registry,{[}4{]} patients in Africa had the second-lowest use of oral
anticoagulation where indicated (19\%, second only to China), and the
lowest TTR (33\%).

RHD prevalence among school children in SSA is 1.5\% to
3.0\%.{[}42--47{]} In RHD registries, only two-thirds of patients with
an indication for oral anticoagulation received it,{[}5,37,48{]} and INR
control was in-range in only 28\%.{[}5{]}

Venous thromboembolism (VTE) epidemiology in SSA has not been well
described,{[}49{]} but HIV infection is a well-established risk factor,
associated with a 1.5-fold increased hazard (95\% confidence interval
1.1 to 2.0).{[}50{]} As the HIV pandemic epicentre, HIV-associated VTE
is commonly seen in SSA. In all the studies in Table 2, HIV prevalence
was higher among patients presenting with VTE than the background
prevalence. Interestingly, in a Ugandan study 9\% of patients on
antiretroviral therapy attending routine outpatient follow-up were found
to have incidental deep venous thrombosis.{[}51{]}

\{Table 2 here\}

\textbf{CHALLENGES ACCESSING ANTICOAGULATION}

Vitamin K antagonists appear on most SSA countries' essential medicine
lists.{[}64{]} Warfarin is the most commonly used, followed by
acenocoumarol.{[}64,65{]} Warfarin is cheap: a 5mg tablet cost 8 US
cents in rural Zambia{[}28{]} or 14 US cents in Uganda.{[}66{]} However,
being essential and cheap do not necessarily make medicines available or
accessible.{[}67{]} Essential medicines' availability ranged from 25\%
in public facilities to 49\% in private facilities in Cameroon,{[}68{]}
and from 49\% in public facilities to 71\% in retail pharmacies in
Malawi.{[}69{]} Anecdotally, frequent stock-outs of warfarin have been
mentioned in some SSA studies.{[}22,29,70{]} To our knowledge, the only
study to systematically evaluate warfarin availability in SSA was
conducted in Uganda in 2017,{[}66{]} and showed that warfarin was
available on the survey day at 75/100 private pharmacies, 15/23 (65\%)
private hospitals, and only 4/22 (18\%) public hospitals, all randomly
sampled.{[}66{]}

DOACs were only available in 14/33 African countries surveyed in
2018,{[}71{]} and are often beyond the means of patients and public
health services. In South Africa, which has statutory private sector
medicine ceiling prices, one month's supply of dabigatran, apixaban, or
rivaroxaban costs the equivalent of approximately 60 hours' minimum
wage.{[}72{]} To our knowledge, no DOAC has yet been shown to be
cost-effective in any SSA country's public health sector.{[}73{]}

A weak medicines regulatory environment in much of SSA means that
substandard and falsified medicines may be found on the market.{[}74{]}
We are not aware of any SSA data on the quality of warfarin on the
market, but in a medicines quality assessment across ten West and
Central African countries, there was fortunately no evidence of poor
quality acenocoumarol.{[}75{]}

Dedicated anticoagulation clinics (ACCs) using standardized approaches
may achieve better anticoagulation control than routine models of care,
where anticoagulation patients are seen as part of the general patient
mix.{[}76--81{]} Such ACCs are however not common in SSA;
anticoagulation is often managed in outpatient cardiology,
cardio-thoracic surgery, and haemato-oncology clinics{[}20,32,82{]} or
by individual health care workers who may not use standardized
approaches.{[}27,83{]} Prescribers of anticoagulation are often junior
with limited practice experience.{[}83{]}

A few studies investigated SSA health care workers' knowledge,
attitudes, and beliefs about anticoagulation. In one such study 164
doctors and pharmacists at an Ethiopian tertiary hospital completed a
self-administered questionnaire.{[}84{]} Participants' mean score on the
warfarin knowledge section was 10/15 correct answers, yet only 7\%
identified their own lack of knowledge on warfarin as a barrier to
effective patient counselling.{[}84{]} Specific knowledge gaps
identified included drug-drug interactions, and the target INR range
appropriate to specific indications.{[}84{]} In a second study at the
same hospital, investigators directly observed the counselling
pharmacists provided during warfarin dispensing and found that only 10\%
of patients were told what to do when they missed a dose, while
interactions and side effects were discussed in only 9\% and 3\% of
encounters, respectively.{[}85{]} In addition, just 24\% of patients
were given an opportunity to ask questions at the dispensing encounter,
and only 40\% of warfarin containers were labelled.{[}85{]} At a South
African academic hospital, in 86\% of admissions for
over-anticoagulation with warfarin the cause of toxicity was not
identified by attending clinicians.{[}86{]} Drug-drug interactions with
warfarin, which went unrecognised by the attending clinicians, were
retrospectively identified by study investigators in 77\% of these
patients.{[}86{]}

INR testing in centralised laboratories is the norm across SSA. As a
result, people living in rural settings often have no access to INR
monitoring. However, centralisation can even bypass people in urban
settings, as illustrated in some of the examples in Figure 1.
Centralised laboratory INR testing also means that results are delivered
with a long turn-around time,{[}27{]} and that patients may be required
to attend separate blood sampling and INR monitoring visits,{[}22,87{]}
driving up the expenses they incur.

The cost of INR testing has been identified as a barrier to
anticoagulation therapy in Zambian{[}88{]} and Ethiopian
reports.{[}29{]} We are aware of only one study systematically
investigating the availability and cost of coagulation profile testing
in SSA, conducted in Uganda in 2017.{[}66{]} At randomly sampled
facilities, coagulation profile testing was available at 13/22 (59\%)
private hospitals, and 3/22 (14\%) public hospitals,{[}66{]} at a median
price of US\$8.30.

At least two different point-of-care (POC) INR monitors have been
validated in South African patients,{[}89--91{]} and there have been
reports of using POC INR monitors in ACCs in Namibia,{[}19{]}
Kenya,{[}7,70,92,93{]} and Nigeria.{[}87{]} Considering only the cost
per test, POC testing is more expensive than laboratory monitoring;
however, it may be cost-effective in some settings.{[}94{]} In SSA, most
sites that reported using POC testing received the monitors and test
strips through donations, and offered POC tests at a subsidised cost to
patients.{[}7,87,93{]}

\textbf{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 \textgreater{}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.

\textbf{PATIENT-RELATED CHALLENGES}

The importance of pharmacogenetic variability on warfarin dose
requirements in SSA was demonstrated in a recent systematic
review.{[}104{]} For example, three variants that are more prevalent in
Black Africans than in other populations, \emph{CYP2C9*5}
,\emph{CYP2C9*6} , and \emph{CYP2C9*11} , affected warfarin dose
requirements by -13, -8, and -5 mg/week respectively.{[}104{]}

Potential drug-drug interactions between warfarin and co-prescribed
medications hinder good anticoagulation control. In SSA, antiretroviral
therapy is a significant source of potential drug-drug
interactions.{[}18,20,22,70,92,93,105{]} Tuberculosis is also common in
SSA, and rifampicin use induces multiple cytochrome P450 isoforms
resulting in a reduced warfarin effect. In a Kenyan case series of
patients on concurrent rifampicin and warfarin, the median warfarin dose
increase with rifampicin was 16\%, but some patients required dose
increases up to +441\%.{[}106{]} In a Ugandan case series, patients
concomitantly prescribed rifampicin, antiretroviral therapy, and
warfarin had highly labile INRs and warfarin dose requirements, and it
was not possible to predict the course of INR results in any individual
patient.{[}107{]} In Kenya, VTE patients with advanced HIV and
tuberculosis required a median 8 additional clinic visits to achieve or
maintain a therapeutic INR.{[}108{]}

Despite widespread herbal medicine use in SSA{[}109,110{]} there is very
little data on how this influences anticoagulation.{[}111,112{]}
Nevertheless, it is plausible that some herbal medicines may interact
with warfarin.

Anticoagulation patients in SSA are younger than those in high-income
settings. For example, in Uganda and South Africa the median age of
patients attending five anticoagulation services was 56 years,{[}22{]}
and in a Kenyan service the mean age was 43 years.{[}20{]} Younger
patients often show reduced adherence compared to older patients. Two
possible reasons for this are that they are economically active and
therefore may be unable to attend follow-up appointments, and that they
may have reproductive wishes and expectations and therefore
intentionally reduce their intake of a potentially teratogenic
medicine.{[}113,114{]}

Four studies reporting patients' self-reported adherence to
anticoagulants in SSA are summarised in Table 4. Notably, from these,
fewer than half of patients considered themselves highly adherent to
warfarin. One study suggested that warfarin non-availability may
contribute to poor adherence.{[}29{]} In an analysis of the ``care
cascade'' of RHD patients in Uganda, retention in care was the stage
with the highest patient drop-out.{[}48{]}

\{Table 4 here\}

We are not aware of any studies reporting SSA patients' attitudes and
beliefs about anticoagulation. A few studies (Table 5) reported on
patients' anticoagulation knowledge, with generally low levels of
knowledge found. Only two studies investigated whether participants'
anticoagulation knowledge correlated with their anticoagulation control,
and these reached conflicting results.{[}10,119{]} Levels of knowledge
were generally associated with participants' level of education and with
the provision of written educational materials. Topics on which
participants' knowledge was low were drug and food interactions, the
effect of missing a dose, the interpretation of INR values, recognizing
the symptoms of over- or underdosing, contraception, and pregnancy
planning.{[}10,82,120{]}

\{Table 5 here\}

\textbf{OVERCOMING THE CHALLENGES}

Overcoming the multitude of challenges faced by anticoagulation services
and patients requiring anticoagulation in SSA require a multifaceted
approach. ``Warfarin care bundles'' are effective and viable strategies,
as shown in a recent network meta-analysis of anticoagulation
interventions.{[}127{]} In SSA such a warfarin care bundle must include
both process-centred and patient-centred activities, the exact
combination of which will be specific to each setting and will depend on
cost-effectiveness to guide rational allocation of limited resources. In
making process changes, it will be important to leverage off existing
successful systems, such as HIV treatment programmes,{[}128{]} and to
ensure these changes are embedded in a quality-improvement framework,
with regular feedback to patients, clinicians, and managers.

First, we would propose patient-centred anticoagulation education and
adherence support. These interventions have shown benefit on patients'
knowledge, adherence, and INR control in a few individual SSA
studies{[}13,14,116{]} and may be of particular benefit in vulnerable
populations.{[}129{]} As pharmacists and doctors are a scarce resource
in Africa, these education and support tasks can be successfully shifted
to mid-level health care workers.{[}7{]} SSA has extensive expertise on
providing adherence support to patients with HIV, and education and
adherence support for patients with non-communicable diseases should
build on these already-existing systems.{[}130{]}

Process-centred activities may include decentralisation of
anticoagulation services, setting up of anticoagulation clinics,
improving access to warfarin (including formulations other than the 5 mg
tablet), improving access to laboratory testing and/or scaling up
point-of-care INR testing, task-shifting of anticoagulation care to
mid-level health care workers, staff training, and implementing locally
validated dose initiation and dose adjustment algorithms. Decentralised
anticoagulation clinics can be successfully implemented in SSA, with
improved outcomes (and better cost-effectiveness) compared to those
achieved at a central referral hospital.{[}93{]} Point-of-care INR
testing has also been successfully implemented in SSA, drastically
decreasing the number of visits patients have to make to the
clinic.{[}87{]} However, the high cost of test strips is problematic,
and relying on donations and subsidies is not sustainable. Localised
dose initiation and dose adjustment algorithms must consider the
comorbidities and potential drug interactions that are prevalent in SSA,
such as HIV, tuberculosis, antiretrovirals, antituberculosis therapy,
co-trimoxazole, and herbal / traditional medicines. These algorithms
must be easy to implement, for example being paper-based, and should
recommend small, percentage-based dose adjustments.{[}102{]}

One example of an effective anticoagulation programme combining multiple
interventions came from Rwanda.{[}131{]} In this programme, specialist
non-communicable disease nurses deliver post-operative care to VHD
patients in decentralised clinics. Standard dosing algorithms are used,
while nurses are supervised and supported by cardiologists, using mobile
communications. Adherence support, as well as financial support, is
offered to patients. While this small study did not report the effect of
this programme on TTR, low mortality was described, and there were no
bleeding or thrombotic complications.{[}131{]}

DOACs may be a solution to some anticoagulation challenges in SSA: while
they are still prohibitively expensive to most African patients and
health care systems, they will in the future come off patent, and
generics may be more affordable. DOACs have the benefit of being used at
fixed rather than individualised doses and do not require routine
monitoring.{[}73{]} However, DOACs come with their own set of
challenges. They are contra-indicated in valvular heart disease, a
significant group of patients in SSA, and require dose adjustment / are
contra-indicated in severe renal impairment. DOACs have shorter
half-lives than warfarin, making strict adherence more critical;
ironically, without regular monitoring, adherence problems may be missed
in patients on DOACs.{[}73{]} DOACs are also subject to drug-drug
interactions: notably for SSA, these include interactions with
rifampicin and many antiretroviral agents.{[}132{]} Finally, the
management of major bleeding occurring with DOACs will require specific
protocols, localised for SSA.{[}73{]}

\textbf{CONCLUSION}

There is significant room for improvement of anticoagulation control in
countries across SSA. Increasing numbers of patients will need
anticoagulation in the future because of the epidemiological transition
in the region. Despite the many challenges faced by patients, health
care providers, and health systems in these resource-limited settings,
several opportunities for improvement exist. Decentralisation of
anticoagulation care, together with expanded access to medicines and
monitoring, and enhanced support to practitioners and patients, are
pivotal in achieving better control. Dose initiation and dose adjustment
protocols that have been developed taking locally relevant factors into
account can also contribute to better anticoagulation control. With the
cost of DOACs still prohibitive, locally-developed ``warfarin care
bundles'' which address multiple anticoagulation challenges in
combination, particularly when they leverage off systems that are
already functional in SSA, currently appear to be the most appropriate
strategy to improve anticoagulation control in this setting.

\textbf{FUNDING}

This research was funded by the National Institute for Health Research
(NIHR) (project ref:16/137/101) using UK aid from the UK Government to
support global health research. The views expressed in this publication
are those of the author(s) and not necessarily those of the NIHR or the
UK Department of Health and Social Care.

\textbf{CONFLICT OF INTEREST}

MP receives research funding from various organisations including the
Governmental bodies such as the MRC, EU Commission and Health Education
England. MP also received partnership funding for the following: MRC
Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB,
Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and
Astra Zeneca; and grant funding from Vistagen Therapeutics. MP also
received unrestricted educational grant support for the UK
Pharmacogenetics and Stratified Medicine Network from Bristol-Myers
Squibb and UCB. MP held a joint grant from NIHR with MC Diagnostics for
the development of a HLA panel. None of the funding MP received is
related to the current paper.

The remaining authors declare no conflicts of interest.

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doi:10.1016/j.jacc.2019.12.068

Table 1. Observational studies from sub-Saharan Africa which measured
time in therapeutic range (TTR) or proportion of INR results in
therapeutic range (PTR) among patients on anticoagulation.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Study, publication year} & \textbf{Setting} & \textbf{Sample
characteristics} & \textbf{Sample size} & \textbf{Mean or median TTR} &
\textbf{Mean or median PTR}\tabularnewline
\midrule
\endhead
Makubi,{[}6{]} 2008 & Dar es Salaam, Tanzania. National referral
hospital. & Patients with mechanical heart valves attending the ACC. &
189 & & 36\%\tabularnewline
Manji,{[}7{]} 2011 & Eldoret, Kenya. Teaching hospital. & Adults
attending ACC. & 178 & 65\% &\tabularnewline
Menanga,{[}8{]} 2015 & Yaound\selectlanguage{ngerman}é, Cameroon. A general and a central
hospital. & Adult inpatients and outpatients with AF on VKA. & 27 & 48\%
&\tabularnewline
Daba,{[}9{]} 2016 & Addis Ababa, Ethiopia. Teaching hospital. & Adults
with VTE on anticoagulation. & 91 & & 34\%\tabularnewline
Mariita,{[}10{]} 2016 & Nairobi, Kenya. Teaching hospital. & Adults
attending cardiac, cardiothoracic, or hemato-oncology clinic for
anticoagulation monitoring. & 147 & & 44\%\tabularnewline
Sadhabiriss,{[}11{]} 2016 & Durban, South Africa. District-level
hospital. & Patients with non-valvular AF or prosthetic heart valves
attending outpatient department on warfarin for \textgreater{}= 12
months. & 177 & 30\% &\tabularnewline
Sonuga,{[}12{]} 2016 & Cape Town, South Africa. District hospital. &
Adults attending ACC and on warfarin for \textgreater{}= 30 days. & 136
& & 49\%\tabularnewline
Ahmed,{[}13{]} 2017 & Khartoum, Sudan. Specialist hospital. & Adults
attending ACC and on warfarin for \textgreater{}= 1 year. & 135 & &
52\%\tabularnewline
Fenta,{[}14{]} 2017 & Addis Ababa, Ethiopia. Teaching hospital. & Adults
attending cardiology or hematology outpatient clinics on warfarin for
\textgreater{}= 3 months. & 360 & & 29\%\tabularnewline
Nyamu,{[}15{]} 2017 & Nairobi, Kenya. Teaching hospital. & Adults
attending cardiac, cardiothoracic, or hemato-oncology clinics on
warfarin. & 102 & & 28\%\tabularnewline
Coulibaly,{[}16{]} 2018 & Abidjan, C\selectlanguage{ngerman}ôte d'Ivoire. Specialist hospital. &
Adults with non-valvular AF on VKA for \textgreater{}= 6 months and with
\textgreater{}= 6 INR measurements. & 100 & & 44\%\tabularnewline
Ebrahim,{[}17{]} 2018 & Cape Town, South Africa. A specialist hospital
and a community health centre. & Patients attending two ACCs and on
warfarin for \textgreater{}= 27 months with regular INR monitoring. &
363 & 47\% &\tabularnewline
Mwita,{[}18{]} 2018 & Gaborone, Botswana. Tertiary hospital. & Patients
attending medical outpatient clinics on warfarin for \textgreater{}= 1
month with \textgreater{}= 4 INR measurements. & 410 & 31\%
&\tabularnewline
Jonkman,{[}19{]} 2019 & Windhoek, Namibia. Central hospital. & Patients
attending ACC with \textgreater{}= 3 INR values. & 215 & 29\% &
25\%\tabularnewline
Karuri,{[}20{]} 2019 & Nairobi, Kenya. Teaching hospital. & Patients
attending cardiac, cardiothoracic, or hemato-oncology clinics on
warfarin for \textgreater{}= 1 month with \textgreater{}= 2 INR
measurements. & 406 & 31\% &\tabularnewline
Botsile,{[}21{]} 2020 & Gaborone, Botswana. Tertiary hospital. & Adults
with mechanical heart valves attending ACC on warfarin for
\textgreater{}= 1 month with \textgreater{}= 3 INR measurements. & 142 &
30\% &\tabularnewline
Semakula,{[}22{]} 2020 & Kampala, Uganda \& Cape Town, South Africa. A
primary level health centre and four secondary and tertiary level
hospitals. & Patients attending five ACCs. & 229 & 41\% &\tabularnewline
\bottomrule
\end{longtable}

ACC: anticoagulation clinic; AF: atrial fibrillation; PTR: proportion of
INR results in therapeutic range; TTR: time in therapeutic range; VKA:
vitamin K antagonist; VTE: venous thromboembolism.

Table 2. Studies from sub-Saharan Africa reporting the prevalence of HIV
and tuberculosis among patients presenting to hospitals for venous
thromboembolism\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Study} & \textbf{Setting} & \textbf{Population HIV
prevalence\textsuperscript{a}} & \textbf{Proportion HIV-infected} &
\textbf{Proportion TB-infected}\tabularnewline
\midrule
\endhead
Mampuya{[}52{]} & Regional / tertiary hospital, Kimberley, Northern
Cape, South Africa, 2010-2014. & 11.0\% & 443/852 (52\%) & 106/852
(12\%)\tabularnewline
Louw{[}53{]} & Tertiary hospital, Johannesburg, Gauteng, South Africa,
date NR. & 16.9\% & 11/24 (46\%) & NR\tabularnewline
Goldstein{[}54{]} & Tertiary hospital emergency centre, Johannesburg,
Gauteng, South Africa, 2012-2013. & 17.8\% & 35/70 (50\%) & 21/70
(30\%)\tabularnewline
Awolesi{[}55{]} & Urban district hospital, KwaZulu-Natal, South Africa,
2013. & 27.0\% & 42/81 (52\%) & 29/81 (36\%)\tabularnewline
Olubanwo{[}56{]} & Tertiary hospital, Mthatha, Eastern Cape, South
Africa, 2010. & 18.0\% & 81/102 (79\%) & 42/102 (41\%)\tabularnewline
Alshehri{[}57{]} & District hospital, Cape Town, Western Cape, South
Africa, 2008-2011. & 8.9\% & 393/610 (64\%) & 339/610
(56\%)\tabularnewline
Kamdem{[}58{]} & Tertiary urban hospital, Douala, Cameroon, 2008-2016. &
3.6\% & 11/78 (14\%) & 3/78 (3.8\%)\tabularnewline
Nkoke{[}59{]} & Semi-urban regional hospital, Buea, Cameroon, 2016-2017.
& 3.6\% & 5/22 (23\%) & 4/22 (18\%)\tabularnewline
Abah{[}60{]} & Semi-urban military hospital, Bamenda, Cameroon,
2010-2013. & 3.6\% & 17/79 (22\%) & NR\tabularnewline
Ogeng'o{[}61{]} & National referral hospital, Nairobi, Kenya, date NR. &
4.7\% & 14/128 (11\%) & 16/128 (13\%)\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} HIV prevalence among adults 15 to 49 years old. For
South Africa, these are provincial estimates from the Thembisa
model{[}62{]} for the final year of study data collection (or
publication, if not reported). For other countries, these are 2018
national estimates by UNAIDS.{[}63{]}

Table 3. Examples of warfarin dose initiation and dose adjustment
guidelines for venous thromboembolism by SSA countries' departments or
ministries of health\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Guideline}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Warfarin dose initiation guideline}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Warfarin dose adjustment guideline}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ghana Standard Treatment Guidelines 2010{[}96{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Warfarin, oral, adults: 10 mg daily at 6pm for 2 days, then 5 mg
daily''\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``regular dose adjustment and monitoring of INR until target of 2.0 and
3.0 is attained''\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Namibia Standard Treatment Guidelines 2011{[}97{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Warfarin: 5 to 10 mg orally; start at same time as heparin''\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``adjust dose according to INR''\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ethiopia Standard Treatment Guidelines for General Hospitals
2014{[}98{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Warfarin (starting simultaneously with heparin), 5 mg orally,
daily''\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``dose adjusted to achieve target INR of 2.0 to 3.0''\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Uganda Clinical Guidelines. National Guidelines for Management of Common
Conditions 2016{[}99{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``\ldots{} plus warfarin 5mg single dose given in the evening,
commencing on the same day as heparin''\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Maintenance dose 2.5 to 7.5 mg single dose daily, adjusted according
to the INR 2 to 3''\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Kenya National Guidelines for Cardiovascular Diseases Management
2018{[}100{]}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Recommended starting dose: 5 mg orally once a day''\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
``Typical maintenance dose: 2 to 10 mg orally once a day. Dosage must be
individualized according to the patient's INR''\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Standard Treatment Guidelines and Essential Medicines List for South
Africa, Hospital Level, Adults 2019{[}101{]}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Day 1}: 5 mg daily (2.5 mg daily for high sensitivity) \emph{2 to
3 days after initiation}: 5-7.5 mg/d if INR \textless{} 1.5; 2.5-5 mg/d
if INR 1.5 to 1.9; 2.5 mg/d if INR 2.0 to 2.5; hold warfarin if INR
\textgreater{} 2.5 \emph{2 to 3 days after last INR check:} 7.5-10 mg/d
if INR \textless{} 1.5; 5-10 mg/d if INR 1.5 to 1.9; 2.5-5 mg/d if INR
2.0 to 3.0; hold warfarin if INR \textgreater{} 3\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Increase weekly dose by 10\% if INR \textless{} 1.5; increase weekly
dose by 5\% if INR 1.5 to 1.9; no change to warfarin dose if INR 2.0 to
3.0; decrease weekly dose by 5\% if INR 3.1 to 4.0; decrease weekly dose
by 10\% if INR 4.1 to 5.0; decrease weekly dose by 20\% if INR 5.1 to
9.0\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 4. Sub-Saharan African studies of patients' self-reported
adherence to anticoagulation.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Study} & \textbf{Setting, sample} & \textbf{Adherence measure} &
\textbf{Outcome}\tabularnewline
\midrule
\endhead
Chalachew{[}29{]} & Addis Ababa, Ethiopia, 2019. Children and young
adults (11 to 25 years) with prosthetic valves on anticoagulation at a
teaching hospital & Not reported & 30/73 (41\%) reported perfect
adherence, 34/73 (47\%) missed 1 to 2 doses per week. 9/73 (12\%) missed
\textgreater{}2 doses per week. Most common reasons were forgetfulness
(30\%) and unavailability of warfarin (23\%). Association between
adherence and INR control not reported.\tabularnewline
Mariita{[}113{]} & Nairobi, Kenya, 2015. Consecutive sample at cardiac,
cardiothoracic, and hemato-oncology clinics of a teaching hospital &
Eight-item Morisky medication adherence scale (MMAS-8){[}115{]}. High
adherence if score = 8, moderate adherence if score 6 or 7, low
adherence if score \textless{}5. & 77/147 (52\%) high adherence, 53/147
(36\%) moderate adherence, 17/147 (12\%) low adherence. Association
between adherence and INR control not reported.\tabularnewline
Iqbal{[}116{]} & Nairobi, Kenya, 2017. Convenience sample at cardiac,
cardiothoracic, hemato-oncology, and DVT clinics of a teaching hospital
& MMAS-8{[}115{]}. High adherence if score = 8, moderate adherence if
score 6 or 7, low adherence if score \textless{}5. & 13/45 (29\%) high
adherence, 32/45 (71\%) low adherence. Association between adherence and
INR control not reported.\tabularnewline
Eltayeb{[}117{]} & Khartoum, Sudan, 2017. Convenience sample at
cardiothoracic clinic of a teaching hospital & Four-item MMAS{[}118{]}.
Considered adherent if score = 0, non-adherent if score \textgreater{} 0
& 5/93 (5.4\%) adherent. Association between adherence and INR control
not reported.\tabularnewline
\bottomrule
\end{longtable}

Table 5. Sub-Saharan African studies of patients' knowledge about
anticoagulation.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Study} & \textbf{Setting, sample} & \textbf{Knowledge measure} &
\textbf{Outcome}\tabularnewline
\midrule
\endhead
Dwamena{[}119{]} & Accra, Ghana, 2012. Systematic sample of outpatients
at anticoagulation clinic of a teaching hospital. & Own tool, adapted
from Taylor{[}121{]}, pass rate set at 70\% & 112/175 (64\%) passed.
Better knowledge was associated with better INR control.\tabularnewline
Assefa{[}82{]} & Addis Ababa, Ethiopia, 2014. Outpatients on warfarin at
teaching hospital. & Own tool, adapted from Anticoagulation Knowledge
Assessment (AKA){[}122{]}, pass rate set at 75\% & 18/130 (14\%) passed.
Mean score was 59\%. Association between knowledge and INR control not
reported.\tabularnewline
Mariita{[}10{]} & Nairobi, Kenya, 2016. Consecutive sample at cardiac,
cardiothoracic, and hemato-oncology clinics of a teaching hospital. &
Own tool, adapted from Oral Anticoagulation Knowledge test
(OAK){[}123{]}, pass rate set at 75\% & 15/147 (10\%) passed. Mean score
was 57\%. Knowledge was not associated with INR control.\tabularnewline
Iqbal{[}116{]} & Nairobi, Kenya, 2017. Convenience sample at cardiac,
cardiothoracic, hemato-oncology, and DVT clinics of a teaching hospital.
& Own tool, adapted from OAK{[}123{]}, ``satisfactory knowledge'' set at
\textgreater{}70\% & 12/45 (27\%) had satisfactory knowledge
pre-intervention. Association between knowledge and INR control not
reported.\tabularnewline
Hutheram{[}124{]} & Gauteng, South Africa, 2016. Convenience sample at
ten private sector INR clinics attached to a private pathology company.
& Own tool, adapted from OAK{[}123{]}, pass rate set at 50\% & 31/34
(91\%) passed. Association between knowledge and INR control not
reported.\tabularnewline
Samadoulougou{[}125{]} & Ouagadougou, Burkina Faso, 2014. Convenience
sample of patients in the cardiology clinic of a university hospital. &
Own tool, adapted from Janoly-Dum\selectlanguage{ngerman}énil{[}126{]} & Participants scored low
in questions relating to their ability to anticipate and make decisions
in risky situations. Association between knowledge and INR control not
reported.\tabularnewline
Maramba{[}32{]} & Harare, Zimbabwe, 2018. Convenience sample of
outpatients with thrombophilia on long-term warfarin. & Not clear &
29/47 (62\%) were not aware of the need for regular check-ups.
Association between knowledge and INR control not
reported.\tabularnewline
Gregersen{[}120{]} & Johannesburg, South Africa, 2006. Convenience
sample of women of childbearing age with valvular heart disease, who had
at least one pregnancy while on warfarin. & Own questionnaire & 38/124
(31\%) were not using contraception; misperceptions about ``the
contraceptive effect of warfarin'' were not uncommon. Knowledge about
effects of warfarin on the fetus was often inaccurate, and not specific
or detailed. Association between knowledge and INR control not
reported.\tabularnewline
\bottomrule
\end{longtable}

Figure 1. Example observational studies from sub-Saharan Africa which
described resource limitations\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig1/Fig1}

\end{center}
\end{figure}

\selectlanguage{english}
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