DISCUSSION
A small number of relatively high-quality studies report that serious
ADRs contribute significantly to the burden of morbidity and mortality
in SSA hospitals. Fourteen studies included in this review reported that
a median 4.8% (IQR 1.5% to 7.0%) of admissions were attributed to
ADRs; three studies reported that between 2.5% and 16% of in-hospital
deaths were attributed to ADRs.
This systematic review demonstrated the paucity of drug safety data from
hospital settings in sub-Saharan Africa, and echoes the paucity of drug
safety data contributed from Africa to the global spontaneous reporting
database described by others63. Only fifteen studies
fulfilled the inclusion criteria, despite the fact that we searched
databases focused on Africa as well as grey literature, and despite
searching without language restrictions. Even given the overall low
number of studies included, there were regional and population
differences: two-thirds of the included studies came from just two
countries, South Africa and Nigeria, and none from a Central African
country; few studies were conducted in paediatric settings, and none
specifically in older adults. These are populations to be covered in
future ADR surveillance activities.
Study quality, as measured by the tool we applied, was generally high.
Nevertheless, to fully comprehend the context within which ADRs occur,
and the risk for their occurrence, it is essential to understand the
denominator study population, including their diseases and their drug
exposures64. Many studies included in this review did
not clearly describe the denominator study population, and had this been
included as a factor in the quality assessment, we may have reported
lower quality overall. A further quality concern among nearly all
studies included in this review is the high proportion of potential
participants excluded from the surveillance activity. Non-participation
was often over 50% and as high as 96% in one study, which may have
resulted in a biased sample. Again, although this is a serious quality
concern, it is not reflected in the quality assessment tool we used in
this review.
We found very high heterogeneity among the study results, which can be
attributed to high variability in study designs as described in Table 2,
and also to high variability in the study settings and populations,
potentially including some unreported differences. It is well
established that the reported prevalence of medication-related hospital
admissions depends on the setting, studied population, specific outcome
investigated, and surveillance method30.
Unfortunately, calls for greater standardisation in the methodology of
medicine safety studies8,61,64 have largely gone
unheeded.
Because of this high heterogeneity we did not conduct meta-analysis of
studies, but reported a median 4.8% (IQR 1.5% to 7.0%) as the
proportion of admissions attributed to ADRs. This estimate agrees with
the results of six earlier systematic reviews of ADR-related
admissions1-6, which estimated the proportion of
admissions attributable to ADRs to range between 3.1% and 6.3% (some
in sub-group analyses).
A 2018 systematic review of African studies of adverse drug events or
medication errors in hospitals33 differed from the
current review as it included only peer-reviewed publications, included
studies from North Africa and studies predating the ART era, and only
distinguished between serious and non-serious events in some ADE cases.
Moreover, despite defining ADRs as a subset of ADEs, the authors of that
systematic review reported “overlooking” this
factor33, in the end pooling studies reporting an
outcome of ADRs together with those reporting an outcome of ADEs. In
view of the methodological differences between the two systematic
reviews, it is not surprising that there is little overlap in the
studies included, and a very different result. For the comparable
outcome we described in our Group 1 studies (proportion of admissions
attributable to ADRs, n = 14 studies, median proportion 4.8%) and the
earlier review’s outcome of proportion of admissions as a direct result
of ADEs (n = 11 studies, median proportion 2.8%)33,
only six studies were included in both reviews.
Another previous systematic review, published in 2016, aimed to compare
adult ADR burdens in high-income countries and
LMICs16. The authors found the median proportion of
admissions attributed to ADRs to be lower in LMICs (5.5%) than in
high-income countries (6.3%)16. However, this review
included only three studies from SSA among the 13 LMIC
studies16. Our comparable estimate (median 6.4% among
nine adult active surveillance studies) is probably more representative,
and read together with the results from other systematic reviews
mentioned above1-6 probably dispels the idea that the
burden of ADR-related admissions in SSA is lower than in high-income
countries.
The proportion of in-hospital deaths attributed to ADRs in Europe was
the topic of a 2021 systematic review. Six studies contributed 657
drug-related deaths out of 7578 in-hospital deaths, with the
meta-analytic estimated proportion being 7.3% (95% CI 4.1% to
12.5%)65. This estimate appears to agree with an
earlier population-based study using linked databases in Sweden, in
which 6.4% of in-hospital deaths were attributed to
ADRs66. We identified only three studies conducted in
SSA to report this particular outcome, and these reported 2.5%, 13%,
and 16% of deaths in adult medical wards were attributed to ADRs. The
low number of SSA studies reporting this proportion as outcome precludes
any meaningful interpretation of this proportion. However, it is notable
that in two of the studies a large proportion of the deaths were
associated with preventable ADRs. In addition, it is notable that most
deaths were due to renal and liver injuries, with ART and
antituberculosis therapy most often implicated. This stands in contrast
to studies from Europe, which found haemorrhages to be most common fatal
ADRs.65,66
For several of our study objectives, we found limited data. Only two
studies reported on admissions prolonged by ADRs, and there were minimal
reports on admissions caused by or prolonged by preventable ADRs. These
are knowledge gaps to be filled by future research.
Another exploratory objective yielding little data was describing the
role played by HIV and ART in the serious ADR burden in SSA. Although
rarely reported, it was consistently reported that HIV prevalence among
patients with serious ADRs was higher than HIV prevalence among the
denominator population37,46,47,49,50,53. This
imbalance was most pronounced for the outcome of ADR-related deaths.
However, this finding should be interpreted with care. Where
antiretroviral therapy was implicated in causing ADRs, these were often
older antiretrovirals, including stavudine and efavirenz, and the ADRs
were often unpredictable and unavoidable events. ART programmes in SSA
are continuously improving and introducing newer drugs with fewer
toxicities: stavudine has been phased out as first-line ART option in
the period 2006 to 201167, and efavirenz is currently
being phased out in favour of dolutegravir. Tenofovir alafenamide has
better renal safety than tenofovir disoproxil
fumarate68 and may in future replace it in ART
programmes.