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.