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Laurence A Goldberg
HPE Editorial Consultant
When assessing a drug, “benefit versus harm” would be a more meaningful comparison for us to make than “benefit versus risk”, as both concepts reflect patients’ experiences, according to Ralph Edwards (Director, Uppsala Monitoring Centre, Sweden). However, benefit to society is not always the same as benefit to an individual. Benefit should not be confused with effectiveness, he continued. Effectiveness is an indication that a drug works and is not the same as a benefit to an individual person or to society. Examples of interventions that are clearly beneficial to society include vaccination for measles, total abolition of tobacco advertising and discontinuation of the nonsteroidal anti-inflammatory drugs (NSAIDs) that cause the most gastrointestinal (GI) bleeding. Examples of interventions that are effective but not beneficial to society include prolongation of life in diabetes (although treatment has improved, diabetes mellitus is still a costly disease), treatment of HIV (which cannot be cured but can keep a patient in reasonable health for life) and use of Viagra (which is recreational rather than therapeutic).
In balancing the good and bad effects of drug treatment, “efficacy versus hazard” comparisons and “effectiveness versus risk” comparisons are helpful. Hazard is an intrinsic property of a given substance (eg, a hazardous chemical in a bottle), whereas a risk is present only when the product is in use. Thus, the effectiveness and risks of a drug can be assessed in postmarketing clinical use studies, when a drug is moved from controlled clinical trial situation to real-life situation. Problems in comparing the risks associated with drugs arise because many drugs have several adverse effects but only one therapeutic effect. There is also limited information about the frequency of adverse drug reactions (ADRs), because these data are based on spontaneous reports. Listing the three most serious and the three most frequent ADRs for products could be one way to make meaningful comparisons. A case in point was the withdrawal of Vioxx for a relatively low frequency of cardiac ADRs. This had to be balanced against the risk of GI bleeding, where Vioxx was superior to piroxicam, said Dr Edwards.
A meta-analysis of prospective studies for ADRs has shown that the overall incidence of serious ADRs was 6.7% and that ADRs were the fifth leading cause of death in hospitals in the USA.(1) Another study has shown that 50% of all ADRs were preventable.(2)
In 2004, the World Alliance for Patient Safety was established under the auspices of the World Health Organization (see Resources). A key role of this body will be to strengthen commitment to patient safety in healthcare. One of its first programmes will be concerned with identifying and supporting solutions for patient safety. The communication of risk will be a major challenge, predicted Dr Edwards. Doctors, patients, lawyers and media representatives are all potential audiences for risk information, and each has a different perspective. The risks with most drugs are more like the risks of flying, rather than the risks associated with driving a car, and yet they are popularly believed to be greater. One critical issue is the handling of changes in knowledge: for example, hormone replacement therapy for postmenopausal women was originally said to reduce the risk of myocardial infarction, but later evidence showed that this was not the case. Another issue is how much information to give, especially in complex cases. Sometimes, a “learned intermediary” to interpret the information could be helpful, he noted. Furthermore, there is unequal access to information, because those with internet access can find more information than those without. Failure to understand this complex but crucial situation and failure to communicate risks properly would be bad for patient care, concluded Dr Edwards.
The accepted classification of adverse drug reactions (ADRs) into type A and type B reactions does not help practitioners or patients to assess individual risks, Robin Ferner (Director, West Midlands Centre for Adverse Drug Reaction Reporting, UK) told the audience. Type A ADRs are predictable, dose-related, augmented pharmacological effects of the drug in question, such as a brain haemorrhage caused by a warfarin treatment. Type B ADRs are bizarre, not easily predictable and rare. An example is a case of abnormally increased libido caused by quinagolide, a dopamine agonist used for treatment of prolactin-secreting tumours. However, this simple classification does not work well in all situations. For example, gingival hypertrophy is common with phenytoin treatment but is not an augmented pharmacological effect. Another anomalous case is the bone marrow suppression caused by azathioprine, which used to be described as a type B reaction until the discovery that genetic variations in the levels of thiopurine methyl transferase (TPMT) were responsible, making it a predictable event.
A three-dimensional model of ADRs that takes into account dose, timing and susceptibility is useful, explained Dr Ferner. This has been described as the DoTS (dose, time, susceptibility) model.(3) Adverse reactions can occur in all regions of the dose–response curve – toxic effects are seen at the top, collateral effects in the rising portion and “hypersusceptibility” reactions at the bottom of the curve.
Some ADRs seen are time-dependent (ie, dependent on the duration of treatment) and can occur with the first dose, early or late during treatment, on withdrawal or even after withdrawal of the drug. Others are time-independent: for example, the risk of bleeding with warfarin is constant, as is the risk of GI haemorrhage with NSAIDs. The rate of administration can also be a factor: for example, the development of “red man syndrome” with vancomycin is related to rapid administration of the drug. Understanding the time course of adverse reactions is essential when it comes to warning patients about probable effects, said Dr Ferner. For example, it is helpful to explain about nitrate-induced headaches to prevent patients from discontinuing treatment.
Susceptibility to an adverse reaction depends on a number of factors, including genetics, age, sex and coexisting diseases. In addition, altered physiology or exogenous factors can play a role. Porphyria, cytochrome P450 polymorphisms and propensity to develop malignant hyperthermia are examples of genetic factors. Grey-baby syndrome with chloramphenicol and the greater sensitivity of elderly people to hypnotics are examples of age-related factors. Women are more susceptible to the psychiatric effects of mefloquine and more likely to develop a cough with angiotensin-converting enzyme (ACE) inhibitors. The volume of distribution for some drugs is changed during pregnancy, thereby altering the woman’s susceptibility to ADRs. An example of an exogenous factor is the way in which grapefruit juice can affect drugs metabolised by CYP3A4.
Using these concepts, it is possible to construct three- dimensional diagrams to illustrate the probability of a specific ADR in relation to the dose, time after administration and susceptibility level of the patient. This approach is easily applied in a clinical setting and is helpful in the prediction, prevention and palliation of adverse reactions, concluded
Self-management training (SMT) delivered by expert patients has resulted in a 15% increase in visits to community pharmacies (see Resources), according to Gill Dorer (Professional Development Manager, Medicines Partnership, UK). Ms Dorer explained that SMT relied on self-efficacy theory – the idea that “people with high assurance in their capabilities approach difficult tasks as challenges to be mastered rather than as threats to be avoided”. In the UK, it has been pioneered by Arthritis Care, a not-for-profit organisation. Patients attend a six-week training course (2.5 hours per week) led by tutors who are expert patients. Topics covered include symptom management, exercise and diet, relaxation, fatigue, depression and communication with healthcare professionals. Each week, participants are encouraged to set goals and make action plans. Outcomes included a 30% improvement in communications with healthcare professionals, 10% improvement in taking medicines as prescribed, 17% reduction in days off work and a reduction in the use of healthcare services.
The majority of patients want to be more involved in decisions about their treatment, and yet patients’ views and the ability to follow treatment regimens are rarely discussed during consultations, said Ms Dorer. “There is still scope for better patient involvement in decisions about care and treatment, particularly decisions about medication and information about side-effects,” she concluded.
Contradictory information about the safety of medicines in pregnancy is a major problem in the provision advice to expectant mothers, said Evelyn Schaafsma (Director, Science Shop for Medicines, Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, University of Groningen, the Netherlands). The contradictions arose because of differing classification systems. In the USA, the Food and Drug Administration (FDA) has classified 0.7% of all marketed drugs as “safe”, against 26% in Sweden. The FDA uses only controlled studies for evidence, whereas in Sweden “all reliable clinical data” are used. There is a tendency to consider only the potential risks to the fetus when considering drugs in pregnancy. However, Dr Schaafsma recommended a more balanced evaluation of the risks, taking into account the effects on both the mother and the fetus, with and without the drug (see Table).
Providing information to consumers on the risks of medicines is a difficult topic, and misunderstandings are common, explained Theo Rayner (Professor of Pharmacy Practice, University of Leeds, UK). The possible side-effects of a drug are simply listed in the patient information leaflets. No reference is made to the likelihood of their occurrence or to individual risk factors. Patients do not understand the difference between relative and absolute risk. In 1995, the UK media reported that third-generation oral contraceptives doubled the risk of thrombosis. However, the absolute risk of thrombosis rose from 5–10 per 100,000 users per year to 10–20 per 100,000 users per year. The absolute risk doubled, but this new figure still represented a very small risk. Nevertheless, many women stopped taking their contraceptive tablets, and there was a sharp rise in terminations and unwanted pregnancies. The risk of thrombosis in pregnancy is considerably higher, added Professor Rayner.
European guidelines recommended the use of the terms “very common”, “common”, “uncommon/rare” and “very rare” to describe levels of risk. The same guidelines recommended that side-effects should be reported “immediately” or “as soon as possible” for less urgent episodes. A study in Professor Raynor’s department using patients and members of the public showed marked differences in the interpretation of the terms. For example, “uncommon” was intended to indicate a frequency of 0.1–1.0%, whereas it was interpreted as 11% in the study.
In his concluding remarks, Professor Rayner recommended a list of five points compiled by Diane Berry (Professor of Psychology, University of Reading, UK):
World Health Organization – Patient Safety