Risk Factors Associated with the Requirement for Pharmaceutical Intervention in the Hospital Setting: A Systematic Review of the Literature

The ten risk factors most frequently associated with DRPs, ADEs, ADRs, drug errors, and MRPs are not surprising and yet are poorly documented as such in the literature. The identity of the drugs themselves and the associated class effects are the single largest risk factor and yet it is not possible from the literature to quantify the risk associated with the use of an individual drug or drug class. For example, intravenous antibiotics are the most frequently reported drug class linked with medicines-related problems, while thrombolytics and anticoagulants constitute the second most prevalent group. However, none of the review papers quantify those risks. Further research would be beneficial to identify a risk score for each drug class to facilitate comparisons and measures for prevention. Similarly, there is no information comparing the risks associated with drugs within each class.

The four most commonly named drug groups associated with issues were antimicrobials (mainly intravenous antibiotics), anticoagulants and thrombolytics, cardiovascular drugs, and drugs acting on the CNS. Definitions of these classes of drugs are unclear in almost all of the papers reviewed, making interpretation of the findings and further research problematic. In most papers, the researchers did not consider whether the drug was an independent risk factor. For example, in the case of antimicrobials, none of the researchers considered the possibility that the presence of infection may have been the causative factor leading to an adverse event.

It is important that any conclusions made from this review are interpreted in general medical and surgical settings only. In order to obtain meaningful data, researchers have examined groups of patients taking widely available and frequently prescribed medicines in hospital. None of the review papers reported the frequency of prescribing for a particular drug class, i.e. there was no reported denominator. It is possible that the large number of issues associated with diuretics, for example, is associated with their widespread use. Some newer drugs to the market such as monoclonal antibodies, anti-retrovirals and anti-rejection drugs, which might be expected to be associated with a large number of problems associated with the use of medicines compared with the number of prescriptions, are not included in any of the review papers, and therefore the results do not necessarily mirror alerts for high-risk drugs issued nationally and internationally [13‐15].

The present review identified papers within the limitation of date restrictions of the databases searched, which included papers from 1966 to the close of search (July 2013). Despite concerns that this might have a direct impact on the range of drugs identified as high risk, only the inclusion of diuretics as a high-risk category was unexpected. On review of the date of the articles citing diuretics as a high-risk drug category, four of the eight publications were published post 2005; should all papers prior to 2005 in the review be excluded, diuretics would remain as a top 10 high-risk drug.

Since undertaking the present review, another systematic review of high-risk drugs associated with medication errors has been published [17]. The drugs highlighted as high risk in the review are different to those identified in the present review. The review [56] only searched for risks associated with preventable problems, with the assumption that intervention prior to a non-preventable problem would be futile. The present review examines risks associated with both preventable and non-preventable issues with medicines since in cases where problems may not be preventable, prompt recognition and possible removal of the causative agent seems sensible.

One approach to increasing awareness of the risks associated with individual medicines could be that in the future, all drugs are risk assessed before reaching the market as part of the clinical trial process. Products could be assigned a risk score prior to the issue of market authorisation, using a process similar to that undertaken for intravenous medication under UK NPSA Alert 20 [13]. In light of post-marketing studies and national incident reporting systems, modifications of risk scores could accompany national patient safety alerts.

It is widely accepted that polypharmacy has a direct effect on the number of DRPs, ADEs, ADRs, drug errors, and MRPs. This not only seems a logical assumption, but it is also undisputed in the literature where polypharmacy has been shown to be an independent risk factor for the development of problems related to medicines [18, 24, 25, 28, 29, 32‐34, 46, 54, 56]. Various definitions of polypharmacy exist, ranging from prescription of three to six or more medicines. However, it is more likely that there is a continuous relationship [56], possibly exponential [57], between the number of drugs taken and the risk of a problem developing.

Older age (definitions vary from 60 years to over 75 years) was reported as a risk factor in 14 studies; however, a further six studies [24, 25, 28, 29, 34, 55] reported that age is not an independent risk factor for medicines-related issues. The six studies that demonstrated that age is unlikely to be an independent risk factor used multi-variant analysis and logistic regression to show that the association of older age with medication problems is more likely to be associated with the increased incidence of multiple comorbidities, multiple medications, poor renal function, and compliance issues in elderly persons rather than a direct association with their age per se. This was supported by a literature review [36] over 20 years ago, which recognised that most studies examining age and ADRs (including all definitions) failed to control for multiple drugs and multiple comorbidities. As the elderly population increases and research in this area continues, it is likely that the risks associated with the use of drugs in old age will become clearer. However, it seems logical that as life expectancy increases, exceeding age 65 years is unlikely to influence the likelihood of suffering an ADR, whereas, the prevailing general state of health will.

One study [31] reported that the age group 18–50 years was a risk factor for ADEs, but it is likely that this was due to the fact that the study group comprised only diabetic patients.

Poor renal function was the fourth most frequently reported risk factor, listed in nine papers [18, 23‐25, 35, 44, 46, 47, 51]. However, as long ago as 1966, Smith et al. [51] recognised that this risk factor is only likely to increase the rate of ADRs when using certain groups of drugs that are eliminated renally. However, any patient with poor renal function may potentially be prescribed one of these drugs and, as such, may already be deemed at risk of a problem related to drugs prior to prescription. The recommended dosage or frequency adjustments in renal failure are well documented for affected agents so that this risk may be minimised if appropriately identified. This was supported by Fields et al. [35], who recognised the importance of early estimation of creatinine clearance (CrCl) through computerised order entry to identify renal function as a risk factor for preventable ADEs.

Female gender is the fifth most frequently reported risk factor for DRPs, ADEs, ADRs, drug errors, and MRPs, with nine papers reporting an association [25, 26, 31‐34, 38, 44, 57]. However, it is possible that the link with female gender may be weak since one paper demonstrated that gender was not an independent risk factor for ADRs [28], while another reported that ADEs occurred more often in men than in women [40]. However, numbers in the later study [40] were small and most adverse events were due to drug errors, which are unlikely to be affected by the gender of the patient. Further detailed research is required to define the precise relationship.

Seven papers included multiple comorbidities as a risk factor for problems associated with the use of medicines [21, 24, 26, 28, 30, 44, 55]. However, Camargo et al. [28] used multivariate logistic regression and identified that multiple diagnoses were unlikely to be an independent risk factor for ADRs. It is possible that the increased number of medicines taken by patients with multiple comorbidities could have a bearing on the number of problems experienced by patients. Conversely, it is also possible that a patient’s susceptibility to ADRs is increased by their poor overall health and that drug metabolism may be affected by their condition or additional unknown factors. It would be advisable for more research to be carried out in this area.

Length of hospital stay was also reported as a risk factor [26, 28‐30, 33]. This seems a logical connection in that any adverse event (drug related or otherwise) is more likely to occur the longer the patient is observed, which in the case of hospital inpatients, would be dependent on their length of stay. However, one paper [28] reported that there is an association with follow-up period (period of time as an inpatient after an ADR). In this case, it is possible that the occurrence of an ADR caused the increase in length of stay through treatment failure, drug toxicity, or other factors. None of the review papers reported that patients were more likely statistically to experience a problem the longer the patient stayed in hospital, i.e. the intra-patient risk at any point in time does not increase with the length of inpatient stay. However, it is also likely that patients who have longer hospital stays suffer from complex conditions or are more unwell, making them more susceptible to DRPs throughout their stay; under such circumstances, length of stay is not an independent risk factor.

Other risk factors for DRPs, ADEs, ADRs, drug errors, and MRPs included in the literature were a previous history of allergy or ADR and compliance issues, which were listed as risk factors in four [18, 24, 38, 47] and three [24, 29, 57] papers, respectively. Patients who may have a genetic predisposition to ADRs or who display atopic characteristics may be more likely to experience ADRs. One paper [51] noted that although there was not an overall increase of ADRs in this group, there was an increase in allergic reactions.

Compliance issues included assumed non-compliance, low cognition, and other factors affecting patients taking their medicines such as alcohol abuse and swallowing difficulties. Such barriers to compliance intuitively would predispose patients to problems with medication regimens.

The association of deteriorating liver function with DRPs, ADEs, ADRs, drug errors, and MRPs is less well documented. Only three papers [18, 24, 51] list deteriorating liver function as a risk factor. In an analogous situation to renal impairment, poor liver function is likely to only be associated with an increased risk when certain drugs are used, i.e. those whose elimination or distribution is hepatic or affected by the reduction in protein metabolism, which accompanies deterioration of liver function. Again this relationship was recognised by Smith et al. [51], who noted in his study that although the overall rate of ADRs was not increased by decreasing liver function, the rate for certain groups of drugs was increased slightly.

Drug management in hepatic failure generally differs to therapy in renal failure. Often the risks of hepatotoxicity drive the decision to treat with a drug or not, in contrast to dosage or frequency adjustments required to avoid immediate toxicity or treatment failure encountered in renal failure. Prescribers often only have one of two options when considering a drug for use in liver failure—“To use or not to use?”—essentially a 50 % chance of making the correct decision and avoiding toxicity that may (or may not) result in an adverse event related to the use of medicines. The likelihood of ADEs in patients with renal failure as opposed to liver failure seems much greater owing to errors in prescribing. These issues are compounded in renal failure owing to drug accumulation or treatment failure as CrCl reduces.

Other risk factors that were uniquely identified (and were therefore not tabulated as top 10 risk factors in this review) included admission to a medical ward [32], geriatric ward, rheumatology ward or gastroenterology ward [33], source of admission (e.g. from home, general practitioner, clinic, etc.) [40], insurance class (US) [40], infection [51], changes in patient’s biochemical/haematological parameters [53], new drug initiation in hospital [54], single marital status [31], use of drugs with a narrow therapeutic index [44], and TDM requirement in the absence of a pharmacokinetics service [47]. Since these associations were only reported in single studies, there may have been explanations for the reported risk factors. It seems likely that drugs with a narrow therapeutic index or requiring TDM are indeed generic risk factors in all specialities and that starting a new drug in any setting poses a risk owing to drug error or poor compliance. However, it is less obvious that factors such as single marital status are independent risk factors for DRPs. Perhaps married patients may be older and their lifestyle more predictable, providing a supportive environment for improved compliance.

The present review methods relied on the use of a number of electronic databases, all of which used English as the primary language, and all of the journals searched were publications in the English language. As a consequence, although the databases included citations from international journals, it is likely that there is a bias towards publications in English and that other work, in particular from the Far East, may have been overlooked. However, the review did not exclude publications from non-English outputs. When the full texts were received, 44 citations were identified from cross-referencing. It was found that 30 of these papers were available through databases listed in the review, indicating that the online database search had not captured all relevant papers. However, these databases have been rechecked using various other combinations of the search terms listed in an attempt to confirm that no other papers remain. In particular, cross-referencing identified a number of older articles that have been included in this review but whose significance may be debatable owing to differences in drug treatments available historically.

No outputs listing risk factors requiring intervention by a pharmacist were detected using these methods. It is possible that research into pharmacist interventions would assume a direct correlation between pharmacist intervention and an ADE. Researchers may deem it more appropriate to assess risk factors leading to the latter since the presence of an adverse event indicates that either there has been no preventative intervention or an intervention has been unsuccessful in prevention of the adverse event. Whichever is the case, without a proven correlation between pharmaceutical intervention and the outcome of an adverse event, research methodology may be better directed at risk factors leading to adverse events caused by medicines use.

Similarly, as research into pharmacist interventions is more likely to be carried out by pharmacists themselves who already target patients perceived to be at risk, this may result in bias. Intervention research is more likely to be targeted at those areas pharmacists may be missing, i.e. actual reported problems associated with medicines rather than pharmacist interventions, i.e. the near miss. Pharmacists may wish to determine whether problems are preventable, non-preventable, or partially preventable through pharmaceutical intervention before targeting clinical pharmacy services to patients with risk factors for medicines-related issues. Certainly, research in this area is lacking and has resulted in difficulties in quantifying the worth of clinical pharmacy services.