How clinical and research failures lead to suboptimal prescribing: the example of chronic gout
BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d7459 (Published 01 December 2011) Cite this as: BMJ 2011;343:d7459All rapid responses
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There is here more concentration of thought on treatment and less on prevention.
Colchicine with Benzbromarone (if still available) are basic treatments with minimal use of a Steroid in acute cases.
It seemed coincidental that, as Allopurinol initially came on the market many years ago that there was an article published somewhat entitled "Diet plays little or no part in the treatment of Gout" and doctors perhaps were persuaded to rely upon their prescribing talents and Allopurinol was recommended.
Was this a coincidence?
Diet of course is the main cause of Gout and the relationship has been recognised for some centuries.
The Pundits will maintain that there is a "Normal" Uric Acid level when there is no such thing. It is well known that the variations in an Uric Acid level threshold, above which one gets pain and below one does not, makes a "Normal" level baseless.
For example. One patient with double parental rheumatic genes develops Gout when his Uric Acid level rises above 2.3mg/dl. (0.24 mmol/l) and another, a Spanish seaman from Corunna with inherited good fisherman stock behind him has 25 mg/dl and develops neither kidney stones or attacks of Gout.
The Uric Acid level depends upon the genes of one's parents and ancestors.
These are anecdotal cases from general practice but significant nevertheless.
There are two elements with regard to Diet.
One is Input and the other whatever delays the Output of Uric Acid from the kidney.
Think then of the intake of Nucleoprotein content of luxury foods. That dense nuclear content per cubic centimetre in offal meats, brain and foie gras, of shellfish and the growing tips of young vegetables and the tea bush. Their nucleo-protein breaks down via Alanine and Guanine to Uric Acid, unless interrupted by Allopurinol and stopped at the Xanthine stage.
Think also of the delay in excretion, the blocking action by the kidney caused by (a) alcohol in any form and (b) the action of Fructose variably present in most fruit.
Another curious anecdote: A patient developed her Gout as a result of a sudden dietary excursion into eating six sweet bananas for her breakfast and the same for her supper. (She had a tree in her garden and didn't want to waste them.)
Shell-fish are notorious, (an historic surfeit of lampreys) as are scampi, squid, calamare, oysters in quantity, lobster and scallops in initiating those acute attacks and maintaining Tophaceous Gout.
The remedy, for a long time if not forever, will involve returning to the most simple diet of adequately nutritious natural plain food, with home-baked bread and other home-made foods, omitting the luxuries and retaining a supply of Colchicine and Benzbromarone (when available again) and Allopurinol for those who cannot deny themselves that rich diet, with fruit, and alcohol.
Competing interests: No competing interests
Gout management is suboptimal in a variety of settings for a variety of reasons. Lipworth and colleagues correctly suggest that one of the reasons for under-treatment is that the doctors who manage chronic gout are often not specialist rheumatologists, and might be unfamiliar with guidelines developed by specialist organisations (1). However, this does not conversely mean that management in rheumatology units is currently optimal, as the evidence is, in fact, otherwise (2).
In 2010, we audited consecutive patients with synovial fluid confirmed gout attending our department who completed at least 12 months of follow up (2005-2010). Median duration from symptom onset to first Rheumatology appointment was 12 months (range 1-180). Of 37 patients (32 male, 5 female), 14 (38%) achieved target serum urate <0.36mmol/L, 11 (30%) within 12 months (median 6.5, range 2-25). Target urate level was not achieved in 6, and status not known in 17 at data collection. This is despite the fact that allopurinol dose increase was documented in 31 (84%), reflecting a high awareness of the relevant clinical guidelines amongst clinicians in our department. One possibility is the well known poor concordance with prescribed treatment (3).
Another important issue not commented on by Lipworth and colleagues is that women particularly may be diagnosed late, have greater co-morbidity and do less well compared to men (4, 5). In our audit women had a higher median age at diagnosis (M:F = 49.5 : 66 yrs, not significant). In women baseline serum urate was significantly higher (median M:F = 0.51 : 0.60 mmol/L, P=0.011), and eGFR significantly lower (median M:F = 84 : 49.5 ml/min, P=0.008). After including age in a multivariate regression, higher urate (P=0.024) and lower eGFR (P=0.011) remained independently associated with female sex.
We therefore recommend that a high index of suspicion and awareness is maintained to achieve early referral and diagnosis. Following diagnosis, health education and agreeing a management plan with the patient regarding achieving and maintaining target serum urate levels are essential and this should be followed through with repeat serum urate measurements for confirmation. While Lipworth and colleagues attempt a broader analysis of the reasons for the current status of management, we feel concentrating on these core clinical measures is essential to achieve better outcomes in chronic gout.
References:
1. Lipworth W, Kerridge I, Brett J, Day R. How clinical and research failures lead to suboptimal prescribing: the example of chronic gout. BMJ. 2011 Dec 1;343:d7459. doi: 10.1136/bmj.d7459.
2. Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis. 2009;68(8):1265-70.
3. Harrold LR, Andrade SE, Briesacher BA, Raebel MA, Fouayzi H, Yood RA, Ockene IS. Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther. 2009;11(2):R46. Epub 2009 Mar 27.
4. Dirken-Heukensfeldt KJ, Teunissen TA, van de Lisdonk H, Lagro-Janssen AL. Clinical features of women with gout arthritis. A systematic review. Clin Rheumatol 2010;29:575-82.
5. De Vera MA, Rahman MM, Bhole V, Kopec JA, Choi HK. Independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study. Ann Rheum Dis 2010; 69:1162-4.
Competing interests: No competing interests
Suboptimal prescribing: chronic gout
The article by Lipworth at al (1) highlights the variation in practice in managing gout, and the poor quality of care provided for most patients. Although there are guidelines available for managing gout (2, 3, 4 ), these are rarely followed (5). This may be because they are too complicated, or published in specialist journals that most GPs do not access (1). There is an urgent need in the UK for NICE Clinical Guidelines, because the disease ticks all the appropriate boxes:
1.Lipworth et al state that gout is the most common inflammatory arthritis in older men, but could simply have said that gout is the most common inflammatory arthritis (1,6). Furthermore it is becoming more common, with increasing obesity, alcohol consumption and the metabolic syndrome (6).
2. Gout is associated with significant co-morbidities, and significant all cause and cardiovascular mortality, much of which is preventable (6).
3. Gout is often poorly managed, resulting in unnecessary irreversible joint damage, as well as other co-morbidities (1).
4. The management of resistant gout is becoming much more expensive, with drugs such as canakinumab and pegloticase coming under the radar of NICE technology appraisals (7,8). Prompt intervention and better early management might decrease the need for some patients to need these costly interventions.
We would encourage NICE to provide national guidelines for the management of gout. Both authors can testify to the power of NICE Guidelines having been on the Guideline Development Group for the NICE rheumatoid arthritis management guidelines. NICE clinical management guidelines go well beyond existing guidelines, because they;
1. Are well funded to provide excellent up to date evidence based guidelines, with a transparent methodology, and easy to follow trail from evidence to recommendation.
2. Include consideration of health economics so that not only is effectiveness of interventions considered, but also cost effectiveness.
3. Include formats at different levels of complexity, from the full guideline to brief summaries and clinical pathways, with commissioning guidelines to assist their implementation.
4. Now incorporate quality standards, with statements of what constitutes good care, to assist commissioning of high quality outcome based services.
Gout is crying out for NICE Guidelines. Patients with gout are crying out for them to be implemented.
References
1. Lipworth W, Kerridge I, Brett J, Day R. Suboptimal prescribing: chronic gout. BMJ 2011;343:d7459
2. Jordan MM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl JR, et al. British Society for Rheumatology and British Health Professionals in Rheumatolgy guideline for the management of gout. Rheumatology 2007;46:1372-4.
3. EULAR guidelines
4. Map of Medicine
5. Roddy E, Zhang W, Doherty M. Concordance of the management of chronic gout in a UK primary care population with the EULAR gout recommendations. Ann Rheum Dis 2007;66:1311-5.
6. Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007;3:443-9.
7. Canakinumab NICE TA ref
8. Pegloticase NICE TA ref
Competing interests: No competing interests
The treatment of gout remains sub-optimal despite recommendations from international guideline groups, which advocate the use of urate-lowering therapies (ULT) such as allopurinol to lower uric acid levels, shrink tophi and prevent acute attacks of gout (1). Only 30% of patients take definitive treatment (e.g. allopurinol) for gout in primary care (2, 3). Lipworth et al (4) highlight some important reasons for the under-prescribing of ULT such as the potential for drug toxicity, treatment by non-rheumatologists (who may not be aware of up to date treatment guidelines) and poor patient compliance due to gout attacks provoked by the introduction of ULT.
However, Lipworth et al overlook another potentially important explanation for poor uptake of ULT in primary care – the views and beliefs of patients about gout and ULT. From our experience of treating gout in primary and secondary care, patients are often reluctant to commence potentially life-long ULT as long as they have access to medications such as non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine to treat acute attacks of gout when they arise. This behaviour may stem from a lack of understanding that in addition to preventing recurrent attacks, one aim of ULT is to prevent long-term irreversible joint damage associated with gout (5). Thus clinicians should explain to patients the impact of ULT on all aspects of gout, not simply prevention of acute attacks.
It is also likely that consultation patterns may help to explain suboptimal management. Our clinical experience suggests that patients infrequently re-consult after an acute attack of gout has been treated. Further acute attacks are often treated with over-the-counter medications such as ibuprofen or other NSAIDs or colchicine available on repeat prescription. The stigma attached to the condition may also deter patients from re-consultation (6). Hence, GPs may not be aware that patients are experiencing recurrent acute attacks of gout, denying them the opportunity to consider the appropriateness of ULT as well as address adverse life-style factors and screen for traditional cardiovascular risk factors in these high-risk patients (7). Following consultation in primary care with an acute attack of gout, we recommend that a further review is scheduled once that attack has resolved to consider these issues and explain the indications and rationale for ULT.
Irrational prescribing is just one factor leading to the suboptimal management of this common condition but patient-related-factors should not be over-looked.
References
1. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65(10):1312-24.
2. Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Schumacher HR Jr., Saag KG. Gout epidemiology: Results from the UK general practice research database, 1990–1999. Ann Rheum Dis. 2005; 64:267-72.
3. Roddy E, Zhang W, Doherty M. Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations. Ann Rheum Dis. 2007; 66(10):1311-5.
4. Lipworth W, Kerridge I, Brett J, Day R. How clinical and research failures lead to suboptimal prescribing: The example of chronic gout. BMJ. 2011; 343:d7459.
5. Jordan KM, Cameron JS, Snaith M, Zhang W, Doherty M, Seckl J, et al. British society for rheumatology and British health professionals in rheumatology guideline for the management of gout. Rheumatology. 2007; 46(8): 1372-4.
6. Lindsay K, Gow P, Vanderpyl J, Logo P, Dalbeth N. The experience and impact of living with gout: A study of men with chronic gout using a qualitative grounded theory approach. Journal of Clinical Rheumatology. 2011; 17(1):1-6.
7. Roddy E, Doherty M. Epidemiology of gout. Arthritis Research & Therapy. 2010; 12:223.
Competing interests: No competing interests
Lipman and colleagues raise the issue of under-prescription of anti-gout drugs due to the failure of clinical practice and drug development [1]. It is probably as important to understand the long-term consequences of untreated high serum uric acid levels and treat gout as a risk factor for different diseases. Gout has been associated with an increased risk of hypertension, metabolic syndrome, cardiovascular disease and kidney disease [2]. Interestingly, it is not just higher than normal uric acid levels which are contributory to these common complications but also levels within the higher range of normal [3]. Despite this, it is surprising that the harmful consequences of hyperuricemia have not become wider knowledge. This is especially so, since serum uric acid levels can be easily measured and monitored, and cheap and relatively safe drugs like allopurinol are available to decrease the uric acid levels.
With respect to hypertension, elevated uric acid levels correlate with primary hypertension, especially in younger individuals (over 90% in one study) [4]. The relationship between hyper-uricaemia and metabolic syndrome (even in the absence of obesity) is interesting since increase in fructose intake can lead to increase in uric acid generation explaining partly the increasing incidence of hypertension with higher body mass index [5]. Although gout can lead to kidney disease, the histological pattern of the gout kidneys that mimic hypertension rather than uric acid crystal deposition once again demonstrates the “causative” role for uric acid in vascular disease [6].
A beneficial effect for uric acid lowering has been noted in adolescent hypertension and kidney disease but not extensively studied in the metabolic syndrome or vascular disease [7,8]. It is time that we are aware of these important risks with gout and be pro-active in prescribing anti-uricaemic drugs much in the same way as we do statins.
1.Lipworth W, Kerridge I, Brett J, et al. How clinical and research failures lead to suboptimal prescribing: the example of chronic gout. BMJ. 2011 Dec 1
2.Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359:1811–21.
3.Niskanen LK, Laaksonen DE, Nyyssonen K, et al. Uric acid level as a risk factor for cardiovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern Med 2004; 164: 1546-51.
4.Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension 2003; 42: 247-52.
5.Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose induced metabolic syndrome. Am J Physiol Renal Physiol 2006; 290: F625-F631.
6.Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002; 13: 2888-97.
7.Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on the blood pressure of adolescents with newly diagnosed essential hypertension. JAMA 2008; 300: 924–32.
8.Kanbay M, Ozkara A, Selcoki Y, et al. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions. Int Urol Nephrol 2007; 39: 1227-33.
Competing interests: No competing interests
In my experience the major reason why I use less allopurinol than I would like is because patients choose not to take it. If you do a Google search for allopurinol the number one article that comes up is a personal account by a retired member of the Royal College of Physicians saying how his allopurinol gave him diabetes.
The teaching of gout management has also changed radically over the past 20 years and only now seems to have reached some sort of consensus (although target irate level still seems to be different in different parts of Europe). And the role of diet? Mmmm
Competing interests: No competing interests
Re: How clinical and research failures lead to suboptimal prescribing: the example of chronic gout
Sir,
The recent analysis by Lipworth(1) highlights important aspects of prescribing in gout. However, a number of aspects require clarification.
First, while gout is recognised as the commonest inflammatory arthritis in men,(2) chronic tophaceous disease is a small subset of that disease burden. There is no validated evidence of the growth of tophaceous disease, indeed the only published study showed a decline in incidence.(3)
Second, use of probenecid is often impractical. It reduces excretion of a host of drugs including NSAIDS leading to potential toxicity, requires avoidance of salicylates, is contra-indicated in renal impairment and can only be sourced via ‘special order’ in the UK.(4)
Finally, many clinicians are delighted that newer drugs such as febuxostat are available given the paucity of therapeutic options for gout. As outlined elsewhere (5) allopurinol must be properly tried with desensitisation programmes if necessary, and fears allayed over hypersensitivity.(6) Nevertheless, the authors assertion that febuxostat is being used unnecessarily is speculative. Clinicians have embraced drug development precisely because properly trialled drugs offer robust safety profiles with proven efficacy for patients. In that regard, I am certainly looking forward to the day when I no longer require to prescribe rat poison for anticoagulation in atrial fibrillation.
1. Lipworth W, Kerridge I, Brett J, Day R. Suboptimal prescribing: chronic gout. BMJ 2011;343 d7459
2. Roddy E, Zhang W Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007;3:443-9
3. O’Duffy JD, Hunder GG, Kelly PJ. Decreasing prevalence of tophaceous gout. Mayo Clin Proc 1975; 50(5) 227-8
4. British National Formulary No 62. Section 10.1.4
5. Perry ME, Madhok R. Treatment failure gout- failure to treat? Rheumatology 2010; 49(12) 2233-4
6. Perry ME. Allopurinol and Stevens-Johnson Risk. J R Coll Phys Edinb 2009; 39:284-6. Letter to the Editor.
Competing interests: Equipment, speaking and travel grants from Menarini Pharma.