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Keep taking the medicine

NSAID discontinuation in OA [1]
Immunosuppressants and renal transplant [3]
Compliance and contraception [4]

Bandolier has occasionally asked questions about compliance, or adherence, or concordance, because this is an important defining issue in healthcare, but one lacking some grip. It is partly because there are so many different definitions, and situations, that an over-arching summary is unlikely. Major differences may also crop up between clinical trials and clinical practice. In trials compliance may be good, but in practice adherence can be poor.

Bandolier 117 examined evidence both that there was better compliance with once or twice a day therapy, and that half of older people on statins had stopped taking them after five years. In clinical trials 90% of people remain on therapy, even in long duration studies.

Bandolier 122 examined a paper showing that half the people in Scotland prescribed low dose aspirin didn't take it, and 38% of people with psychosis didn't take their medicines. The situation is not necessarily better elsewhere, so a few other examples might help us think it through. Three more examples, then, of how initial treatment is not maintained, for NSAIDs in arthritis, immunosuppressants after renal transplants, and contraception.

NSAID discontinuation in OA [1]

A retrospective cohort analysed 1,405 patients aged 45 years or more receiving a new prescription for one of four NSAIDs, who were followed for 12 months in Washington state [1]. Patients had a unique identifier, and manual and electronic databases ensured excellent identification of the last date drugs could have been used, based on prescriptions filled, quantity dispensed and instructions for use.

Within a month about 30% of people had discontinued, in three months it was half, and by the end of a year fewer than 20% of patients were still using the NSAID prescribed (Figure 1 for ibuprofen). In a meta-analysis of randomised trials [2] at 12 weeks the discontinuation rate was 26-40%, somewhat less than in clinical trials than in this retrospective analysis in clinical practice.

Figure 1: Discontinuations over 12 months in patients on NSAIDs

Immunosuppressants and renal transplant [3]

Even in patients who have had a kidney transplant, adherence to immunosuppressant treatment can be a problem. A systematic review [3] found 36 cohort, cross-sectional studies, and case series looking at the problem. There were various definitions of non-adherence, and different ways of measuring it, but essentially what was looked at was the quantity and frequency of missed medicines assessed by questionnaire or interview.

Cross-sectional studies found a median of 22% of patients were non-adherent, and the cohort studies 15%. Non-adherence here is different in type and degree from discontinuation in other studies, perhaps relating to occasional missed doses, or doses wrongly timed. Even so, there was a big impact relating non-adherence to graft loss (Figure 2).

Figure 2: Graft loss in patients adherent and nonadherent to immunosuppressives

The number of transplant failures in non-adherent patients was 125/289 (43%), compared with 296/1724 (17%) in those patients who were adherent. The relative risk was 3.5 (95% CI 2.9 to 4.2). For every four renal transplant patients who were non-adherent to immunosuppressive medicines rather than being adherent, one more suffered a graft loss (NNH 3.8; 95% CI 3.1 to 5).

Compliance and contraception [4]

Another example where we can see outcomes relating to lack of compliance is in contraception. An analysis of perfect and imperfect use of patch and oral contraceptives in the context of a clinical trial [4] had pregnancy as an outcome. Here perfect use was 21 consecutive days of hormonal contraceptive patch use with every patch changed at a 7-day interval, and perfect hormonal oral contraceptive use was 21 consecutive days of tablet ingestion. Anything else was considered imperfect dosing. Information was gathered from diary cards on an ongoing basis.

The number of pregnancies and cycles is shown in Table 1. Imperfect use of the contraceptive increased the pregnancy rate by about 5-10 fold, though there were few pregnancies. In a comparative study 11% of patch cycles were imperfect, somewhat less than the 21% of cycles using oral contraceptive. There was no effect of age. The lesson may be that longer-acting hormonal contraceptives give better contraceptive protection for women in real life.

Table 1: Effect of perfect and imperfect dosing on contraceptive effectiveness

Pregnancies per 1000 cycles


Some patients do not keep taking the medicine. It may be understandable, because the medicine brings little benefit, and may do some harm. There may just seem not to be any benefit, as with a statin, where the results, after all, are statistical as much as personal. It will certainly be a bore, especially when there are lots of drugs to be taken at different times.

But there are costs. There are simple costs, like the tons of expensive medicines in medicine cabinets rather than people. There are costs because people do not benefit. A graft lost in a transplant patient is a tragedy.

The monetary value of non-adherence is huge. The cost of non-adherence in psychosis has been estimated to be £5,000 a year for a non-adherent patient [5]. A global figure for non-adherence costs in healthcare in the USA was a whopping US$300 billion (sic). So this is a topic worth re-visiting when more evidence emerges.


  1. D Scholes et al. Nonsteroidal anti-inflammatory drug discontinuation in patients with osteoarthritis. Journal of Rheumatology 1995 22: 708-712.
  2. JJ Deeks et al. Efficacy, tolerability and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 2002 325: 619-623.
  3. JA Butler et al. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation 2004 77: 769-789.
  4. DF Archer et al. The impact of improved compliance with a weekly contraceptive transdermal system (Ortho Evra®) in contraceptive efficacy. Contraception 2004 69: 189-195.
  5. M Knapp et al. Non-adherence to antipsychotic medication regimens: associations with resource use and costs. British Journal Psychiatry. 2004 184: 509-16.

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