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Drug regimens and compliance
- Alan M W Porter (24 September 2001)
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Self-evident?
- Dominic McDermott (24 September 2001)
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Was Bloom's article and editorial or an advertisement?
- Patrick Vallance (25 September 2001)
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Compliance with treatment for tuberculosis
- Graham F Cope, Ruth Whitfield (3 October 2001)
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Conflicting evidence for effect of dosing schedules on compliance
- Knut Schroeder (4 October 2001)
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Low-dose thiazide diuretics and beta-blockers are as well tolerated as the newer antihypertensives
- Briegeen Girvin (25 October 2001)
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Evidence that newer drugs improve compliance is biased
- Peter Jackson (26 October 2001)
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Alan M W Porter, retired n/a
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Sir, In respect of his editorial (Daily regimen and compliance with treatment 2001;323:647) Professor Bernnard Bloom implies that he only searched the literature since the year 1980. Most of the factors influencing compliance had been identified and published by that time. I had provided evidence in a paper published in this journal in 1969 (Drug defaulting in a general practice 1:218-22) that compliance was better with a once a day dose than with divided ones and confirmed the findings of a number of other workers that old age was not a factor. It is wrong to ignore the large body of literature which predates 1980. Alan Porter |
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Dominic McDermott, Locality Pharmaceutical Adviser Newcastle PCT
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Concluding remarks from the abstract of the only paper cited by Professor Bloom that has anything to say about supposedly better compliance with newer antihypertensive drugs(ref 10): "Additional studies are needed to explain why more patients continued with the same A-II antagonist therapy at 12 months compared with the other classes of antihypertensive drugs; whether these findings are explained by drug tolerability, financial incentives, newness of the product, selection bias, or other factors; whether these differences will be maintained in the following years; and whether the differences are associated with better health outcomes." |
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Patrick Vallance, Professor of Clinical Pharmacology & Therapeutics University College London, 5 University St, WC1E 6JJ
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In his Editorial of 22 September Professor Bloom raises the important and often forgotten issue of whether patients actually take the medicines they are prescribed. He suggests that patients adhere to newer treatments better than they do to older drugs and therefore "newer and higher quality products are usually more expensive, but their value, or the trade off to quality cost, is also higher". He concludes that the best treatment is usually the most expensive and that doctors and health care organisations usually deny patients the better option as first line treatment. The case is built on examples of treatments for hypertension and arthritis. For anti-hypertensives he argues that the new and old drugs are of equal efficacy but that newer drugs have fewer side effects and that adherence to therapy, or persistence with therapy, is much better for the newer drugs compared to older drugs. If correct, these would indeed be important things to take into account when prescribing or formulating policy. His bold assertions are based on two papers [1,2]. These papers both describe unblinded retrospective studies. One appears in a non peer-reviewed supplement [1] funded by SmithKlineFrench and seems not to deal directly with the issues raised in the editorial. The other concludes that more patients continued with angiotensin II antagonists than with other treatments but warns "whether these findings are explained by drug tolerability, financial incentives of the product, selection bias; whether these differences are maintained and whether these differences will be associated with better health outcomes" is not known [2]. The author of these "two studies with similar results"? Professor BS Bloom. Professor Bloom chooses to ignore the large prospective randomised outcome studies with intention to treat analyses [see for example ref 3] that suggest that each class of anti-hypertensive (new or old) is equally likely to achieve a similar degree of blood pressure lowering, that the side effects, whilst different between drugs, are not fewer for new drugs nor is there evidence for greater drop-out rates for older drugs. Why did the BMJ commission an editorial from an individual in which he simply describes two of his own papers and ignores large parts of the literature? How does this fit in with the BMJ's desire to promote evidence-based practice and avoid undue influence of the pharmaceutical industry? Perhaps the most telling sentence in this editorial is that "persistence with a drug was related to the year in which it was first marketed". Might this indicate something about the way doctors communicate information about medicines to their patients and the external influences on this process? References 1. Bloom BS. Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis. Am.J.Med. 1988;84 (suppl 2A):20-24 2. Bloom BS Continuation of initial antihypertensive medication after 1 year of therapy. Clin.Ther. 1998;20:1-11. 3. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in patients: cardiovascular mortality and morbidity the Swedish Trial of Old Patients with Hypertension-2 study. Lancet 1999;354:1751- 1756. Competing interests: I am a member of the Advisory Board of Drug and Therapeutic Bulletin (Consumers Association). I have occasionally received travel funds from pharmaceutical companies when speaking at academic meetings. |
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Graham F Cope, Honorary Senior Research Fellow, Associate Specialist University of Birmingham, Croydon Chest Clinic, Mayday University Hospital, Ruth Whitfield
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We welcome the editorial (BMJ 2001: 323: 647-50) highlighting the problems of compliance with treatment. One disease not mentioned in the report, where failure to adhere to prescribed medication can have extremely serious consequences, is tuberculosis. Over the last few years there has been a worrying increase in cases of tuberculosis globally, and particularly in larger cities such as London, where it has increased 57% between 1990 & 1999. The current increase is exacerbated by the problem of drug resistance, including multi-drug resistant TB (MDR-TB). Poor patient adherence to treatment regimens leads to drug resistance. Directly observed treatment (DOT) can prevent this, but is expensive and not suitable for all patients with TB. One of the measures available to check adherence is examination of the urine for the typical orange colour seen after ingestion of rifampicin. However, this is only visible for a few hours each day and so fully adherent patients often do not have orange urine. To detect poor adherence to treatment, additional methods are needed. One alternative is to test the urine for isoniazid metabolites, but this test needs to be quick to perform and the result rapidly available. A laboratory test exists, but is expensive and time consuming, and not readily accessible in areas with high incidence of the disease. To overcome these problems work at the University of Birmingham developed a rapid point-of-care colour test kit to detect isoniazid in urine - turning blue if the metabolites of the drug are present. The test is currently being used at the Mayday University Hospital to audit adherence to treatment and to compare it with the use of the rifampicin test alone. We included patients on isoniazid (either for treatment or chemoprophylaxis). So far urine samples have been collected from 52 patients who were on daily therapy with isoniazid, with 94% receiving it in combination with rifampicin. Of these only 54% had orange-stained urine. The time from last reported dose varied from 40 minutes to 24 hours. Positive tests for isoniazid were obtained from 48 (92%) of patients with the remaining 4 (8%) producing a colour change indicating partial or non-adherence. The test is easy to use, with a positive colour change within 60 seconds of sample addition, which stabilised after 5 minutes. The test has proved to be a useful guide to which patients required extra monitoring, further education as to the importance of taking their drugs every day, or directly observed treatment. Dr Graham F. Cope, Dr Ruth Whitfield, Financial support from the Sir Halley Stewart Trust. |
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Knut Schroeder, MRC Training Fellow in Health Services Research Division of Primary Health Care, University of Bristol, Cotham House, Cotham Hill, Bristol BS6 6JL
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Dear Editor Bloom's editorial is a surprising contribution to the important discussion about how best to improve compliance to treatment in chronic diseases.[1] His assertion that fewer daily doses increase compliance, and his notion that the least expensive drugs are usually the least effective and have the highest rate of side effects cannot go unchallenged. Bloom cites one of his own studies, funded by a pharmaceutical company, to support the idea that fewer daily doses improve compliance.[2] This study was a retrospective analysis of prescription records which showed higher rates of prescription refill at one year among those treated with once daily versus more frequent dosing, and those treated with newer, more expensive drugs. The study was confined to supposedly hypertensive people under the age of 71 years, but no initial blood pressure levels were available and none of them were evaluated in a standardised manner. Moreover, none of the following were recorded: follow up records of blood pressure, non-pharmacological interventions used, side effects, and reasons for stopping treatment. Allocation to different drugs was at the discretion of the physician. During the time period covered by the study, growing awareness of the limited benefits of treating mild hypertension in younger patients was occurring among physicians and patients. Furthermore, it might be expected that a new drug undergoing post-marketing surveillance would be more likely to be continued if financial benefits accrued to the prescriber. Most serious investigators would have been deterred from using such a dataset to tackle the question of compliance, and it is telling that in discussing his findings, Bloom locates one of the landmark United States trials in the treatment of hypertension (the Hypertension Detection & Follow Up Program) to the United Kingdom! We reviewed the literature on compliance with anti-hypertensive drugs from 1966 to 1996, [3] and have recently updated our work. To our knowledge there are at least six randomised controlled trials that have investigated the effects of dosing schedules on compliance, with conflicting results. The notion that the least expensive drugs are the least effective would be a very convenient marketing strategy for the pharmaceutical industry, but it is simply untrue in the two areas Bloom considers. Low dose thiazide diuretics are as effective as more expensive antihypertensives,[4] and have a better side effect profile than newer drugs.[5] In osteoarthritis, a Cochrane systematic review has reported that paracetamol (acetaminophen) is as effective in relieving pain as newer and more expensive non-steroidal anti-inflammatory drugs.[6] Improving compliance is important - and will undoubtedly involve balancing considerations of efficacy, side effects and convenience - but better clinical practice will only result from rigorous evaluation of all the available evidence. Knut Schroeder, MRC Training Fellow in HSR, Division of Primary Health Care, University of Bristol, Cotham House, Cotham Hill, Bristol BS6 6JL, email k.schroeder@bristol.ac.uk Shah Ebrahim, Professor in Epidemiology of Ageing, Department of Social Medicine, University of Bristol Tom Fahey, Senior Lecturer in General Practice, Division of Primary Health Care, University of Bristol Alan Montgomery, MRC Training Fellow in HSR, Division of Primary Health Care, University of Bristol Tim Peters,Reader in Medical Statistics, Department of Social Medicine, University of Bristol References: 1. Bloom BS. Daily regimen and compliance with treatment. BMJ 2001;323:647 2. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:1-11 3. Ebrahim S. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review. Health Technology Assessment 1998;2(11):1-78 4. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-1756. 5. Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE Trial Research Group Br.Med.J. 1997;315:154-159. 6. Towheed, T. Shea, B. Wells, G. Hochberg, M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. Cochrane Musculoskeletal Group. Cochrane Database of Systematic Reviews. Issue 3, 2001. Conflict of interest: none |
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Briegeen Girvin, Prescribing Information Pharmacist Regional Prescribing Information Unit, Dept. Therapeutics & Pharmacology, Queen's University Belfast
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Low-dose thiazide diuretics and beta-blockers are as well tolerated as the newer antihypertensive agents In his editorial on discontinuation of antihypertensive therapy, Professor Bloom makes a number of unwarranted assumptions about the adverse effects of antihypertensive agents and their relationship to compliance with drug therapy [1]. Little is known about why patients stop taking their antihypertensive therapy, but Professor Bloom assumes the reason to be adverse effects. Reasons for stopping therapy are varied and complex and may range from forgetfulness to factors involving patient beliefs - such as fears of drug addiction or not realising that antihypertensive agents need to be taken long-term. Professor Bloom found that the rate of drug discontinuation was lower with newer drugs, (such as angiotensin-II receptor antagonists, ACE inhibitors and calcium-channel blockers) than with older agents (diuretics and beta-blockers) [2]. However, lower numbers in the new drug groups (e.g. only 2.6% of patients in the study received losartan), mean the results should be viewed with some caution. Other studies have found no significant difference in discontinuation rates among the 4 major classes of antihypertensive agents - diuretics, beta-blockers, calcium-channel blockers and ACE inhibitors [3] and have found that older drugs are not discontinued any sooner than newer drugs [4]. In three long-term double blind studies (TOMHS, HANE and Veterans Affairs) with the 4 major classes of antihypertensive agents, no important differences have been identified in terms of adverse effects or quality of life [5]. Despite this, the Pharmaceutical Industry continually reinforces the excellent tolerability of calcium-channel blockers and ACE inhibitors, which can profoundly influence doctors and patients alike. Limited post-marketing experience with new drugs means that in many cases adverse effects have yet to be identified. When used in low doses, the adverse effects of thiazide diuretics and beta-blockers are minimal and they are among the most cost-effective treatments for hypertension. The majority of outcome data are still from studies using the older agents and recent trials are showing that the newer drugs are no more effective than the older ones [5]. For all of these reasons and in the absence of contraindications or compelling indications for other antihypertensives, low dose thiazide diuretics and beta-blockers still remain the first line choice in the treatment of hypertension for most patients. 1. Bloom BS. Daily regimen and compliance with treatment: Fewer daily doses and drugs with fewer side effects improve compliance. BMJ 2001; 323: 647. 2. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998; 20: 1-11. 3. Jones JK; Gorkin L; Lian JF et al. Discontinuation of and changes in treatment after start of new courses of antihypertensive drugs: a study of a United Kingdom population. BMJ 1995; 311: 293-5. 4. Benson S; Vance-Bryan K; Raddatz J. Time to patient discontinuation of antihypertensive drugs in different classes. Am J Health-Syst Pharm 2000; 57: 51-4. 5. Ramsay LE; Williams B; Johnston GD et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertension 1999; 13: 569-92. Authors (we have no competing interests) Briegeen Girvin
G Dennis Johnston
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Peter Jackson, Reader in Clin Pharm & Ther, University of Sheffield Royal Hallamshire Hospital, Sheffield
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Sir Bloom [Sept 22nd, p647] is right to raise the issues of compliance and withdrawal from treatment as critical in the management of long-term disorders. However his suggestion that we should use more modern antihypertensive drugs to limit discontinuations because of fewer adverse-effects is wrong. In studies looking at withdrawal from long-term treatment about one half of the patients cite adverse-effects as their reason for quitting. Amongst those who believe they have adverse-effects many symptoms are not due to any pharmacological action of the drug. This is illustrated by the substantial withdrawal rate due to “adverse-effects” of placebo treatment. We have shown a significant relationship between drug withdrawals or dose reduction attributed to adverse-effects and indices of psychiatric morbidity [1], again suggesting that some “adverse- effects” are not truly drug related. The study Bloom cites [2] to support the contention that newer drugs are better tolerated was uncontrolled and open to bias. Persistence on treatment correlated with the year of introduction, and undoubtedly with the promotional budget for each drug or drug class. Doctors who are bombarded with information about the superior tolerability of newer agents are inevitably less likely to attribute unexplained symptoms to these drugs. This alone will lead to fewer withdrawals in response to patient’s symptoms. Compare the outcome of such open studies, which are biased, with those of carefully controlled double-blind studies [3,4]. These show equal and even superior tolerability and quality of life on older drugs when compared to new drug classes or placebo. This evidence of equal tolerability from carefully controlled studies negates unreliable suggestions of superiority of newer drugs from biased studies. There is now sound evidence that drugs which are equally effective in lowering blood pressure may vary in their ability to prevent cardiovascular complications [5]. Even if newer drugs were better tolerated and less likely to be stopped we should demand evidence that they are equally effective in preventing disease before preferring them to older drugs of proven value. 1 Davies SJC, Ghahramani P, Jackson PR, Ramsay LE. Psychiatric aspects of multiple intolerance to antihypertensive drugs. J Hypertens 2001;19(Suppl2):S101. 2 Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:1-11. 3 Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-21. 4 Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study. Final results. JAMA. 1993;270:713-24. 5 Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;356:1955-64. 6 PR Jackson1, SJC Davies2, LE Ramsay1. 1 - Clinical Pharmacology & Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF, 2 – Psychopharmacology Unit, University Walk, University of Bristol, Bristol BS8 1TD. |
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