Adverse drug reactions in older Australians, 1981–2002

The World Health Organization (WHO) has defined an adverse drug reaction (ADR) as a “response to a medicine that is noxious and unintended, and that occurs at doses normally used in humans”.1 Iatrogenic factors that lead to ADRs can include inappropriate dosages, inappropriate combinations of drugs, and use of drugs not recommended for a particular age group.2 However, most ADRs occur in patients who are prescribed treatment within the limits of accepted clinical practice.

A 1994 study found that the rate of ADR-related hospital stays in people aged 70 years and over in Western Australia doubled between 1980 and 1991, with the main classes of drugs responsible being cardiovascular agents, antirheumatics and cytotoxics.3 Since then, several Australian Government education and service initiatives have endeavoured to reduce ADRs in older Australians. These include the Quality Use of Medicines Program and the National Prescribing Service.4,5 While the hospital morbidity rate from ADRs is not the only basis on which to evaluate such programs, it offers one criterion by which to judge their success.

This study examines recent trends in ADR-related hospital stays in people aged 60 years and over in WA to determine if these trends and the profile of drugs responsible have changed.

Rates of ADR-related hospital stays continued to increase between 1991 and 2002, with rates doubling since the earlier study in 1991.3 The increase was especially marked in those aged 80 years and over, where cardiovascular agents continue to be the largest problem. The profile of responsible drugs has changed, with an increase in ADRs from anticoagulants and a continued rise in those from NSAIDs and other antirheumatics.

The study was limited to ADRs of sufficient severity to warrant or extend hospitalisation. Thus, the results represent only the extreme end of a continuum of ADRs, most of which occur in the community and are managed on an ambulatory basis. Unfortunately, although the burden of ADRs managed in the community is likely to be significant,9,10 reliable estimates of rates of these ADRs were unavailable. The study was also unable to distinguish ADRs leading to hospitalisation from those arising during inpatient stay and serious enough to become the principal condition managed.

Another limitation was imposed by the necessary reliance on hospital morbidity classification systems and coding practices, which may have changed over time. In the only available validation study, Dawes found that her review of 377 hospital charts was consistent with a real increase in hospital morbidity caused by ADRs, although the administrative hospital data tended to underascertain cases.3

A previous review of 14 Australian studies found that ADRs occurred in 2.4%–3.6% of hospital admissions.9 ADRs were associated with 1.8% of 14 000 admissions to 28 hospitals in New South Wales and South Australia.11 We found that 0.8% of hospital stays in the total WA population were ADR related. Apart from real differences in incidence rates across time and place, results have varied because of bias from hospital selection and differences in ascertainment criteria. Some studies counted any ADR observed at admission or during hospital stay, whereas, along with others, we focused on hospital admissions where the ADR was sufficiently severe to cause the admission or extend hospital stay.

The Pharmaceutical Benefits Scheme (which subsidises about three-quarters of prescriptions dispensed in Australia) paid benefits for 155 million prescriptions in 2001–2002, an increase of 4.7% over 2000–2001.12 This increase exceeded population growth, suggesting either a larger population at risk or a higher average level of drug exposure. Our results suggest that the factors responsible for the increasing incidence rate of ADRs have combined with the ageing of the population, as it is well established that risks of side effects are much higher in older age and worsened by polypharmacy.13

Anticoagulants were the most common drugs implicated in ADRs causing hospitalisation in 2002 and had undergone the greatest increase over time. In 1996, draft guidelines were prepared by the National Health and Medical Research Council (NHMRC) on the role of anticoagulants in stroke prevention.14 Many substances interact adversely with anticoagulants. Older adults are more susceptible to these interactions, have a higher risk of haemorrhage, and therefore require lower anticoagulant doses and careful monitoring. In addition, the increasing use of alternative or complementary therapies raises the potential for adverse interactions with anticoagulants.15

Chemotherapy has become better tolerated because of advances in the management of side effects. Opposing this are the increasing number of cytotoxic agents in use and the increase in active prevalence of cancer in the WA population — from 0.51% in 1990 to 0.74% in 1998 — because of longer survival of patients with active disease.16

NSAID use continues to be a major reason for hospital admission, despite evidence from previous studies indicating the large size of the problem.3,9,17,18 Celecoxib (Pharmacia), an NSAID introduced to the market in 1999, was seventh among the top 10 most prescribed drugs in Australia in 2000 (Box 4).19 Elderly patients taking NSAIDS are at increased risk of gastrointestinal ulceration and renal impairment.17

Cardiovascular agents have been consistently identified as the drug group that causes the most ADRs.10,11,17,18 The antihypertensives enalapril and amlodipine held ninth and tenth positions among Australia’s top 10 most prescribed drugs in 2002 (Box 4). In fact, there was a fall from 1996 in ADR admissions from antihypertensives, suggesting that they no longer warrant urgent attention. Although the lipid-lowering agents atorvastatin and simvastatin were the first and third most frequently used drugs (Box 4), this group is seldom implicated in ADRs causing hospital admissions.

Our findings have policy implications. It has been estimated that at least 80 000 hospital admissions each year in Australia are medication related, at an annual cost of $350 million.9 Despite significant investment of resources by the Australian Government in targeted interventions to empower prescribers, pharmacists and consumers, efforts to reduce the burden of ADRs appear to be faltering against the increasing use of a wider range of medications, especially in older Australians. Arguably, the situation would be worse with no interventions, but our results bring into question their effectiveness and the adequacy of funding.

Particular drug classes, especially anticoagulants, warrant updated clinical guidelines, with increased attention to careful patient monitoring. The NHMRC and the National Medication Safety Breakthrough Collaborative of the Australian Council for Quality and Safety in Health Care provide opportunities to support new initiatives and related needs, such as research into the role of alternative therapies in adverse drug interactions.

Concerns over the rising costs of ADRs in the United States have led to updating of the criteria for potentially inappropriate medication use in older adults.20 The new criteria identify 48 classes of medication to avoid in older adults and a further 20 assessed as potentially inappropriate in the presence of certain comorbid conditions.20 The adoption of such explicit criteria presents a challenge for continuing professional education, behaviour change and medical informatics.

The medical data linkage system in WA is being enhanced by the addition of links between the Pharmaceutical Benefits Scheme and Medicare benefits, paid to or on behalf of WA residents, and the hospital morbidity, cancer, congenital anomaly and death data collections. The system will provide infrastructure for postmarketing surveillance for serious and longer-term ADRs, more detailed characterisation of patients at high risk of ADRs, and an accurate baseline for the evaluation of further intervention.

Ultimately, the risk of side effects must be balanced against the benefits to patients of the increased use of powerful pharmaceutical agents in treating diseases. Even the most well-resourced and carefully designed intervention program imaginable will not prevent all ADRs.

1 Rates of hospital stays related to adverse drug reactions in people aged 60 + years in Western Australia

3 Drug-specific rates of hospital stays from adverse drug reactions in people aged 60 + years in Western Australia