Preventable medication harm across health care settings: a systematic review and meta-analysis

The Institute of Medicine report ‘To Err is Human: Building a Safer health System’ helped generate the patient safety movement by reporting that up to 98,000 deaths were due to medication and at least some of them could have been preventable [1‐3]. On March 2017, the World Health Organisation (WHO) launched a global initiative to develop approaches to reduce severe, preventable medication harm in all countries by 50% over the next 5 years [4]. Similarly, in May 2018, the Institute for Healthcare Improvement of the USA launched a multi-organisation initiative to create a national action plan for the prevention of harm in healthcare [5].

In the USA alone, medication errors are the third most common cause of death behind heart disease and cancer [6] accounting for injuries to approximately 1.3 million people annually [7, 8]. Similarly, in the UK, it was estimated that there are 237 million medication errors in England over a year period [9, 10], and preventable adverse drug reactions were estimated to cost the National Health Service (NHS) £98.5 million per annum, consume 181,626 bed days, cause 712 deaths and contribute to 1708 deaths during initial hospitalisation.

It is important to underline that not all harms caused by medication errors are preventable. However, distinction between preventable and non-preventable harm is becoming increasingly important, because it provides an indication of where best to invest limited resources for healthcare improvement in order to have the greatest benefit. From a quality improvement perspective, measuring harm, particularly preventable harm, alongside medication error [11] is critical. This would help ensure efforts are more patient-centred; can target the system rather than the individual, with the aim of enhancing clinical outcomes; reduce punitive concerns associated with the reporting methodology; allow for analysis of unintended results and encourage learning from events to continually improve the processes for detecting preventable harm [12]. Practitioners should also supplement preventable medication harm assessment with the measurement of certain contributory factors such as the severity of harm, the source at which the harm occurred (i.e. prescribing, transcribing, dispensing, administering or monitoring) and classification of harm according to the ‘five rights’ (patient, drug, dose, route, and time). Each of these factors could significantly inform quality improvement efforts [13].

Due to the ongoing global challenges in this area, it is important that healthcare providers, researchers and policy makers have a better understanding about the current prevalence rates and nature of preventable medication harm. Therefore, we undertook a systematic review and meta-analysis to inform the identification of targets for improvement efforts on estimating the prevalence of preventable medication harm across medical care settings including hospitals, primary care and various specialties. We also examined the clinical severity of preventable medication harm, and the impact of the medication use, stage and high-risk medication groups by building on what is already known from previous research efforts [14‐16].

This systematic review was conducted and reported in accordance with the Reporting Checklist for Meta-analyses of Observational Studies (MOOSE). The completed MOOSE checklist is available in Additional file 1: Table S1. The review protocol is registered in PROSPERO under the review number: CRD42020164156.

The searches revealed 7868 articles, and after reviewing the full text screening, 81 studies met the inclusion criteria (see PRISMA flow chart in Fig. 1). A list of the eligible studies is included in Additional file 3: Table S3.

This meta-analysis found that preventable medication harm occurs in 3% of patients across medical care settings and that at least a quarter of preventable medication harm is severe or potentially life threatening. In our previous meta-analysis, the prevalence of preventable patient harm (e.g. adverse events due to any type medical errors—not only medication) was 6%, and only one tenth of this harm was severe or potentially life-threatening [50]. Thus, medication harm indeed accounts for half of the overall preventable harm in medical care. The present findings also align closely to a recent narrative meta-review of systematic reviews [51], which looked at the preventability of ADRs in patients receiving acute or ambulatory care—reporting a prevalence rate of 3.13%. However, this earlier narrative overview involved only 37 studies compared to the 81 studies in our meta-analysis, did not include patients in primary care or emergency care settings and did not examine thoroughly the severity of harm, patient age, stage of medication use and high-risk medication groups.

The highest prevalence rate of preventable medication harm was seen in studies based on elderly care units which often involve patients with high comorbidity and hence polypharmacy. The headline policy implication of this study therefore is that mitigation strategies for preventable medication harm are primarily needed for older people with multimorbidity/polypharmacy—which is indeed a key priority area of the WHO safety initiative [16, 52]. A recent review that tried to determine which interventions, alone or in combination, were effective in improving the appropriate use of polypharmacy and reducing medication related harms in older people [53], revealed great uncertainty about the effectiveness of comprehensive medicines reviews of patient prescriptions and urged for further research. Since the last update of this review, a Scottish working group has published a guidance document on polypharmacy, which included a seven-step process for standardised and structured medicines reviews that are holistic, patient-centred and consider non-pharmacological treatments [54], as well as a review of the quality of development of available guidelines to promote appropriate polypharmacy [55]. Further population-based research is needed to evaluate the implementation and effect of these resources on prescribing for older people.

Moreover, medication harm in ICUs [56] and acute specialised care settings involving surgery [57] was associate with higher volumes of preventable medication harm and should, therefore, also be considered as high-risk patient care settings. Evidence concerning the prevalence and severity of preventable medication harm in primary care and psychiatry was scarce. We only found four studies based in primary care, where over 80% of healthcare services are delivered internationally [58], and only one study was identified in psychiatry. It is therefore possible that certain types of preventable harm in psychiatry settings may remain undetected, as these harms often result from multiple interacting errors from violation provoking conditions and latent ‘system’ failures [22, 59]. Thus, there is a need for more research in both these care settings.

The prescribing and monitoring stages of medication use were key sources of preventable harm. The adoption of electronic health records and electronic prescribing has helped avert preventable harm at the prescribing and transcribing stages [14, 60‐66], but preventable harm persists across all pathways of medication use. This is most likely due to underlying system flaws that allow individual errors such as those in prescribing or medicines administration to reach the patient and cause serious harm [67]. Human factors play an important role in understanding these system flaws; for instance, there may be a lack of standard procedures for storage of medications that look alike, poor communication between different providers, lack of verification before medication administration and limited involvement of patients in their own care [68‐71]. Better safeguarding processes that acknowledge the contribution of human factors and systems thinking are required at the different points of medication use to ensure correct measures are contributing to healthcare improvement efforts [72].

We found that medication groups that gave rise to most preventable medication harm include; central nervous system, cardiovascular, hypnotics and sedatives, anti-inflammatory and antirheumatic, antibiotics and antibacterial drugs. Many of these medication groups have been previously assessed in relation to hazardous prescribing in the past [14, 15]. However, the interventions featured in these studies deliberately focused on potential medication errors rather than preventable harm, and therefore, available evidence has not yet determined whether these interventions will reduce harm to patients. This stresses further the urgency and need to focus on assessment of medication errors and harm in conjunction [13, 71], as well as new ways of reducing medication harms in older people [53].

Most efforts so far originate in developed countries [73], and so the rate of preventable medication harm from less developed countries remains relatively unknown. However, in one study, the preventability of adverse events across 26 hospitals in eight low-and middle-income countries showed an adverse event rate to be around 8%. Of these events, 83% were preventable, while about 30% were associated with death of the patient [74]. Although this is likely to be an underestimate with higher rates of excess death unaccounted for, it shows that patient safety is a much bigger problem in these developing and transitional countries, when judged by the preventability and severity of harm (number of preventable deaths). These results are somewhat contrasting with our results, with the higher rate of preventable harm being found in studies from Europe. However, these findings might reflect the limitations that exist in assessing preventable medication harm in developing countries. Moreover, the prevention of medication harm is often complex and involves improving basic clinical processes and does not simply depend on the provision of more resources [75].

Despite this being the first large meta-analysis to assess the prevalence of preventable medication harm across healthcare settings, there still remain several limitations. First, a considerable proportion of the high heterogeneity remained unexplained in meta-regressions. Several other factors such as differences in systems, procedures and variations in timeframe used to evaluate medication harm remain largely unknown and may be responsible for this unexplained heterogeneity.

Second, whilst we performed exhaustive searches for unpublished studies, the exclusion of non-English written studies and the presence of publication bias that forms of selection bias or system bias is likely [76]. We tried to account for this in the analysis by adjusting for sample size, but some of the causal factors remain unexplained.

Third, studies not reporting data on preventable medication harm were excluded from the analyses. Among the included studies, only 36% of studies provided an analysis of severity and even the classification system used was unclear at times so a pragmatic judgement was made to group some of the severity categories. Furthermore, discussions of causality assessment were limited with few studies reporting the exact assessment tool used, and only 22% of studies provided the stage of medication use, and whilst harm was reported by medication group in 78% of the studies, only one fifth of these provided data at the preventable level. The use of different preventability scales may also incur a level of ‘hindsight bias’, where healthcare professionals may be subject to overestimation of their ability to predict preventable harm events [77, 78]. However, adjustment for this in observation research can be a significant challenge in evidence synthesis.

Finally, more than two thirds of preventable medication harm were examined retrospectively through medical case notes and chart reviews. Although case note reviews are the most universally used method for assessing medication harm to date, patients and healthcare providers suggest that case reviews still lack the robustness to detect diagnostic error and are susceptible to time-delay issues in the absence of regular patient consultation [79]. Combining methods that prospectively uncover preventable harm by use of the ‘failure mode and effect analysis’, ‘structured what-if technique’ [13], pharmacist screening, or patient surveys along with retrospective error detection methods including trigger tools, voluntary reporting systems, root cause analysis or mortality reviews [76, 80] would provide better and more promising approaches for enhancing the detection of preventable medication harm.

Our study findings confirm that preventable medication-related harm is a frequent and enduring serious problem, causing severe or potentially life-threatening outcomes in over a quarter of all preventable harm cases. A highly problematic healthcare setting was in geriatric care, specialised care settings, intensive care or those in emergency departments. Elderly patients are at greater risk of polypharmacy, and patients in other specialised or emergency medicine settings may be exposed to higher-risk mediation groups. As both are priority areas of the WHO’s safety initiative, we have gone some way in this review to providing a basis of evidence to support future policy developments in this area. Nevertheless, further research is needed in primary care and psychiatry settings where up to 80% of healthcare service is delivered, alongside efforts to better understand where improvements can be made in less-developed countries.