ISSN 1178-6124 Re - Research Review€¦ · Re Research Review TM Making Education Easy Issue 63 – 2012 1 In this issue: a RESEARCH REVIEW publication ISSN 1178-6124 Welcome

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Making Education Easy Issue 63 – 2012

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Welcome to the sixty-third issue of GP Research Review. Research has investigated the risk for venous thromboembolism among users of hormonal contraception, but less is known about the risk for arterial complications. The first study that we discuss in this issue analysed data from 1.6 million Danish women followed over 15 years, in an investigation designed to establish whether different contraceptives differentially affect risk for arterial thrombosis. Although the absolute risks of thrombotic stroke and MI associated with the use of hormonal contraception were low, these events were more likely to occur with oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 µg than those that included ethinyl estradiol at a dose of 20 µg; differences in risk were relatively small with different progestogens.

If, in our last study the “best case scenario analysis” modelling proves to be correct, daily dark chocolate consumption would be a cost-effective and – as the study authors put it – “a pleasant, and hence sustainable” means of preventing adverse CV events in patients with metabolic syndrome.

I hope you enjoy this issue and I welcome your comments and feedback. Kind Regards, Jim Associate Professor Jim Reid [email protected]

Thrombotic stroke and myocardial infarction with hormonal contraceptionAuthors: Lidegaard Ø et al

Summary: This retrospective cohort study used data from 1,626,158 Danish nonpregnant women aged 15–49 years with no history of cardiovascular disease or cancer, to examine whether different contraceptives differentially affect the risk for thrombotic stroke and MI. During 15 years of follow-up, 1051 thrombotic strokes (21.4 per 100,000 person-years) and 497 MIs (10.1 per 100,000 person-years) occurred among hormonal contraception users, whereas 2260 thrombotic strokes (24.2 per 100,000 woman-years) and 1228 MIs (13.2 per 100,000 woman-years) occurred among nonusers. Compared with nonusers of hormonal contraception, women who used progestogen-only pills, contraceptive implants, or levonorgestrel intrauterine devices had no excess risk for stroke or MI; women who used combined hormonal contraceptives had approximately twice the risk for stroke or MI, irrespective of progestogen formulation. Oral contraceptives including ethinyl estradiol at a dose of 30 µg to 40 µg were more likely to cause arterial thrombosis than those including ethinyl estradiol at a dose of 20 µg.

Comment: As the authors say, while there have been several large and comprehensive studies assessing the risk of thromboembolism with hormonal contraception, there has been little published on the risk of myocardial infarction and thrombotic stroke. This is a large study, over a period of 15 years, involving women aged 15 to 49 years. Myocardial infarction as such is rare among women of this age group, but stroke is more common by a factor of 2 x. This study demonstrated that risk was increased only slightly with doses of both 20 and 30 µg, with little difference being created by different progestogens. The message is reassuring but it is a reminder that prescribers must be vigilant for other risk factors when prescribing oral contraceptives, even in young women.

Reference: N Engl J Med. 2012;366(24):2257-66.http://www.nejm.org/doi/full/10.1056/NEJMoa1111840

Hormonal contraception: risk for arterial complications

Low-dose aspirin is not benign

Pioglitazone: excess risk of bladder cancer

Giant cell arteritis diagnosis with ESR, CRP

Gout: an independent risk factor for mortality

Obesity, hypertension and sleep disorders

Changing aetiology of peptic ulcers

Faecal calprotectin in suspected paediatric IBD

Diabetes: not a predictor of atypical MI symptoms

Opioids for refractory dyspnoea

Probiotics reduce antibiotic-associated diarrhoea

Daily dark chocolate cardioprotective?

Abbreviations used in this issueCOPD = chronic obstructive pulmonary diseaseCV = cardiovascularMI = myocardial infarctionNNT = number needed to treatNSAIDs = nonsteroidal anti-inflammatory drugs

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Association of aspirin use with major bleeding in patients with and without diabetes Authors: De Berardis G et al

Summary: These researchers sought to determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes taking aspirin. Administrative data were analysed from 4.1 million citizens in 12 local health authorities in Puglia, Italy. 186,425 individuals with new prescriptions for low-dose aspirin (≤300 mg) were identified during the index period from January 2003 to December 2008, and were matched with 186,425 individuals who did not take aspirin during this period. During a median follow-up of 5.7 years, the overall incidence rate of haemorrhagic events was 5.58 per 1000 person-years for aspirin users and 3.60 per 1000 person-years for those without aspirin use (incidence rate ratio [IRR], 1.55). The use of aspirin was associated with a greater risk of major bleeding in most of the subgroups investigated but not in individuals with diabetes (IRR, 1.09). Diabetes was independently associated with a 36% increased relative risk of major bleeding episodes, irrespective of aspirin use.

Comment: The use of aspirin is controversial. The very large recently published Scottish study did not demonstrate any benefit from the use of aspirin in primary prevention of cardiovascular disease, and a more recent study reported similar results with diabetes. This study demonstrates that the risk of bleeding for those on aspirin is actually increased in groups without diabetes, but diabetics had an increased risk themselves, with or without aspirin. The message – low-dose aspirin is not benign treatment. Look carefully at the risk / benefit ratio!

Reference: JAMA. 2012;307(21):2286-94.

http://jama.jamanetwork.com/article.aspx?articleid=1172042

The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control studyAuthors: Azoulay L et al

Summary: The risk of incident bladder cancer associated with use of pioglitazone was assessed in a cohort of 115,727 patients with type 2 diabetes who were newly treated with oral hypoglycaemic agents between January 1988 and December 2009. A total of 470 patients were diagnosed as having bladder cancer during follow-up (rate 89.4 per 100,000 person years). The 376 cases of bladder cancer that were diagnosed beyond 1 year of follow-up were matched to 6699 controls. Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99) and in those with a cumulative dosage greater than 28,000 mg (2.54).

Comment: Another potential red flag for glitazone users. First it was rosiglitazone with cardiovascular side effects and now pioglitazone (which till now has had a relatively clean slate) with, according to this study, an increased risk of bladder cancer. Virtually all medications have some sort of potential side or unwanted effect, and it is a risk vs benefit every time a doctor writes a prescription. The “ever” use of pioglitazone doubled the incidence of bladder cancer, with an increase in the rate depending on length of exposure and cumulative dose. The message – this is only one study but if you have your back to the wall in trying to achieve diabetic control, the possible dangers of pioglitazone need to be brought to the attention of patients. The alternative may be insulin!

Reference: BMJ. 2012;344:e3645.

http://www.bmj.com/content/344/bmj.e3645

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Utility of erythrocyte sedimentation rate and C-reactive protein for the diagnosis of giant cell arteritisAuthors: Kermani TA et al

Summary: These US researchers evaluated the utility of ESR and CRP for the diagnosis of giant cell arteritis (GCA) and the frequency of normal ESR and CRP at diagnosis of GCA in 764 patients undergoing temporal artery biopsy (TAB) between 2000 and 2008. Biopsy was consistent with GCA in 177 patients (23%), 159 of whom had elevated ESR and/or CRP (89.8%), while 18 (10.2%) had a normal ESR and CRP at diagnosis. Elevated CRP and elevated ESR provided a sensitivity of 86.9% and 84.1%, respectively, for a positive TAB. The odds ratio of a concordantly elevated ESR and CRP for positive TAB was 3.06 (95% CI, 2.03 to 4.62), whereas the odds ratio for concordantly normal ESR and CRP was 0.49 (95% CI, 0.29 to 0.83). Seven patients (4%) with a positive TAB for GCA had a normal ESR and CRP at diagnosis. These patients tended to be younger, have a longer duration of symptoms, and fewer constitutional symptoms than GCA patients with elevated ESR and/or CRP. In addition, a greater proportion of patients with normal ESR and CRP at the time of diagnosis had symptoms of polymyalgia rheumatic as well as a significantly lower platelet count and higher haemoglobin at the time of diagnosis compared with patients with an elevated ESR or CRP. In contrast, constitutional symptoms, anaemia and thrombocytosis, were observed less often in patients with normal ESR and CRP at diagnosis.

Comment: This paper demonstrates that a small but significant cohort of patients (4%) with temporal artery biopsy have normal inflammatory markers. Those who had a positive biopsy with elevated inflammatory markers had a higher prevalence of symptoms consistent with polymyalgia rheumatica. It would be interesting to know of the percentage of patients with polymyalgia symptoms, negative inflammatory markers, and negative biopsy. Perhaps a small number of patients have a reciprocal diagnosis? The message – consider temporal artery biopsy (it is not difficult to do in primary care with appropriate training) in patients who have polymyalgia rheumatica symptoms and normal inflammatory markers. We may be missing more than we realise.

Reference: Semin Arthritis Rheum. 2012;41(6):866-71.

http://www.semarthritisrheumatism.com/article/S0049-0172(11)00337-4/abstract

Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study Authors: Teng GG et al

Summary: Data were examined from the prospective Singapore Chinese Health Study, in this assessment of the association between gout and mortality. A total of 63,257 Singapore Chinese individuals aged 45–74 years were enrolled during 1993–1998 and interviewed in person on lifestyle factors, current diet and medical histories. Surviving cohort members were contacted by telephone during 1999–2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Among 52,322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean 8.1-year follow-up, there were 6660 deaths. Compared with non-gout subjects, subjects with gout had a higher risk of death (HR, 1.18), and specifically from death due to coronary heart disease (HR, 1.38) and kidney disease (HR 5.81). All gout-mortality risk associations were present in both genders but the risk estimates appeared higher for women.

Comment: While the association between gout and cardiovascular disease has been known for a long time, kidney disease with gout has been associated with renal failure secondary to uncontrolled gout. This study demonstrates and reinforces the association between gout and a higher risk of death especially from cardiovascular disease, but also from kidney disease, and not end-stage renal failure from uncontrolled disease. This study has major implications, especially for Māori and Pacific peoples, who have a high incidence of gout. The message – be aware of the total cardiovascular and renal risk factors involved in patients who have gout and make efforts to minimise these.

Reference: Ann Rheum Dis. 2012;71(6):924-8.http://ard.bmj.com/content/71/6/924.abstract

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The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel diseaseAuthors: Henderson P et al

Summary: This UK study evaluated the diagnostic accuracy of faecal calprotectin (FC) in a large regional paediatric cohort (190 patients aged <18 years) undergoing full upper and lower endoscopy for suspected inflammatory bowel disease (IBD). Ninety-one patients had IBD; 99 non-IBD patients served as controls. Median FC at diagnosis was significantly higher for the IBD group compared with the control group (1,265 μg/g vs 65 μg/g; p<0.001). FC levels did not vary significantly between patients with Crohn’s disease, ulcerative colitis, and IBD unclassified and were not influenced by age or disease location. FC was clearly superior to commonly utilised blood parameters such as C-reactive protein and white cell count (both p<0.01), with an area under the curve of 0.93.

Comment: Faecal calprotectin is an expensive test, so it is gratifying to see that this study demonstrates that it is superior to inflammatory markers, and white blood cell count. The message – if inflammatory bowel disease is suspected in children under the age of 18, a faecal calprotectin is worthwhile.

Reference: Am J Gastroenterol. 2012;107(6):941-9.

http://tinyurl.com/7w5meuj

Sleep, blood pressure and obesity in 22 389 New ZealandersAuthors: Wilsmore BR et al

Summary: Data were examined from 22,389 volunteer blood donors in New Zealand aged 16–84 years, who underwent height, weight, neck circumference and blood pressure measurements, and completed a validated self-administered questionnaire on sleep and other factors. Even in this relatively young (60% aged <40 years), healthy sample, 1 in 3 participants reported snoring (33%) or lack of sleep (34%). In addition, 1 in 5 had high blood pressure (20%) and 1 in 5 were obese (19%). After adjusting for a wide range of potential confounders, there was a strong association between sleep apnoea and high blood pressure, but only in participants aged ≥40 years. Both very low and very high quantities of sleep were associated with high blood pressure. Even after controlling for neck circumference, self-reported sleep apnoea, sleep dissatisfaction and low amounts of sleep were associated with a higher body mass index.

Comment: Sleep medicine is a relatively new discipline, and the importance of appropriate sleep is rapidly gaining acceptance as part of a healthy lifestyle, and healthy being. It has long been recognised that sleep apnoea is associated with an increased risk of cardiovascular disease, stroke, high blood pressure, arrhythmias, diabetes, and sleep-deprived driving accidents. More recently, angiogenesis and increased tumour growth have come into the picture. This study reinforces many of these findings, with the relationship between obesity and high blood pressure (above the age of 40) again being demonstrated. The burning question is, however – which came first – the obesity or the sleep apnoea. The message – look out for sleep disorders – they are worth addressing.

Reference: Intern Med J. 2012;42(6):634-41.

http://tinyurl.com/8xpfxqn

The relative contribution of NSAIDs and Helicobacter pylori to the aetiology of endoscopically-diagnosed peptic ulcer disease: observations from a tertiary referral hospital in the UK between 2005 and 2010Authors: Musumba C et al

Summary: Recent research from Western studies indicates a dramatic change in the epidemiology of peptic ulcer disease, with the overall incidence falling, and the proportion of Helicobacter pylori-negative peptic ulcer disease increasing. This trend has been attributed to the decreasing prevalence of H. pylori infection due to increasing eradication efforts as well as the increasing use of proton pump inhibitors (PPIs) for gastroprotection in NSAID-users. At the same time the use of NSAIDs including low-dose aspirin (≤325 mg/day) has increased. This study investigated the changing trends in the epidemiology of peptic ulcer disease in a phenotypically well-defined cohort of 386 patients at a large tertiary hospital in the UK between 2005 and 2010. The majority (57%) used NSAIDs (51% low-dose aspirin only) and 43% were non-users. Overall, 57% were H. pylori-positive; the prevalence was higher in those with duodenal ulcers (66%) than in those with gastric ulcers (47%). Compared with non-users, NSAID-users were older (mean age 68 vs 61 years) and fewer were H. pylori-positive (52% vs 63%). Low-dose aspirin users were older (mean age 71 vs 62 years) and more likely to be H. pylori-positive (61% vs 41%) than those using non-aspirin NSAIDs. Twelve per cent of the patients were neither using NSAIDs nor were H. pylori-positive.

Comment: Gone are the days of “stress” being the primary cause of peptic ulceration as it was commonly taught during my medical school days. Along came H. pylori and the world changed forever! Now it seems that along came aspirin prophylaxis for ischaemic heart disease, and nonsteroidals for musculoskeletal disorders! While it seems that 12% of peptic ulceration suffers were neither H. pylori-positive nor on NSAIDs yet another cause can be considered – perhaps back to stress???? The message – low-dose aspirin (which can be bought over the counter) is not necessarily benign treatment. As I have stated before in this Review – consider the risk / benefit ratio.

Reference: Aliment Pharmacol Ther. 2012;36(1):48-56.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2012.05118.x/abstract

Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time.Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits.

Independent commentary by Associate Professor Jim Reid, Head of Department of General Practice at the Dunedin School of Medicine and Deputy Dean of the School.

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Patients with diabetes are not more likely to have atypical symptoms when seeking care of a first myocardial infarction. An analysis of 4028 patients in the Northern Sweden MONICA StudyAuthors: Hellström AK et al

Summary: These researchers conducted a population-based study of 4028 people aged 25–74 years with first MI registered in the Northern Sweden Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) myocardial infarction registry between 2000 and 2006. Among patients with diabetes, 90.1% reported typical symptoms of MI; the corresponding proportion among patients without diabetes was 91.5%. In the diabetes group, 88.8% of women and 90.8% of men had typical symptoms of MI. There were no sex differences in symptoms of MI between individuals with and those without diabetes. Atypical symptoms were more prevalent in the older age groups (>65 years) than in the younger age groups (<65 years). The increases were approximately equal among men and women, with and without diabetes. Diabetes was not an independent predictor of atypical symptoms of MI.

Comment: This paper runs contrary to what has to now been generally believed – that diabetic patients frequently have atypical symptoms of myocardial infarction, or in fact frequently have “silent” infarcts. This large study (4000 patients) demonstrated that there was no difference in presentation of myocardial infarct between males and females, nor was there any difference between diabetics and nondiabetics. The message – another sacred cow bites the dust.

Reference: Diabet Med. 2012;29(7):e82-7.http://onlinelibrary.wiley.com/doi/10.1111/j.1464-5491.2011.03561.x/abstract

Perspectives of patients, family caregivers and physicians about the use of opioids for refractory dyspnea in advanced chronic obstructive pulmonary disease Authors: Rocker G et al

Summary: Emergent themes are reported in this paper from two qualitative studies that explored the experiences of patients and family caregivers with opioids for refractory COPD-related dyspnoea and the perspectives and attitudes of physicians toward opioids in this context. The studies involved 8 patients, their 12 caregivers, and 28 physicians. All patients reported that opioids provided substantial improvements to their quality of life, relief of their dyspnoea, or both, and that opioids provided a sense of calm and relief from severe dyspnoea. Family caregivers described opioids as helping patients to breathe more “normally”, observed improvements in patients’ symptoms of anxiety and depression, and experienced reductions in their own stress. All patients and family caregivers wanted opioid therapy to continue. Most physicians were reluctant to prescribe opioids for advanced COPD, citing a lack of education and knowledge about opioids, and fears related to the potential adverse effects and possible legal censure.

Comment: A number of guidelines now advocate the use of low-dose opioids in advanced COPD. Such use is well recognised in the transition in attitude by doctors and patients in moving from maintenance therapy to a palliative care approach to management. Basically, the current difficulty in the decision to utilise opioids is how much, and when. A relatively low dose of morphine (5mg of a long-acting product twice daily) can bring great symptomatic relief from air hunger. It is important the pros and cons of such treatment need to be discussed with the patient and the caregiver / family. The message – in end-stage, or near end-stage COPD, a small dose of long-acting opioid can bring significant symptom relief.

Reference: CMAJ. 2012;184(9):E497-504.http://www.cmaj.ca/content/184/9/E497.abstract

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Dr Christopher TofieldDr Tofield completed his medical training at St Bartholomew’s and the Royal London Hospital in London and is now a fulltime General Practitioner in Tauranga. Chris has extensive experience in medical writing and editing and while at medical school published a medical textbook on pharmacology. He is responsible for sourcing studies for all Research Review journals.

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Meta-analysis: probiotics in antibiotic-associated diarrhoeaAuthors: Videlock EJ, Cremonini F

Summary: This meta-analysis evaluated data from 34 randomised, double-blinded, placebo-controlled trials involving 4138 patients treated with antibiotics and administered a probiotic for at least the duration of the antibiotic treatment. The pooled relative risk (RR) for antibiotic-associated diarrhoea (AAD) in the probiotic group vs placebo was 0.53, corresponding to a NNT of 8. The preventive effect of probiotics remained significant when grouped by probiotic species, population age group, relative duration of antibiotics and probiotics, study risk of bias and probiotic administered. The pooled RR for AAD during treatment for Helicobacter pylori was 0.37, corresponding to a NNT of 5.

Comment: Old hat, but worth reiterating the beneficial effects of probiotics for antibiotic-associated diarrhoea, a problem we see fairly often. Unfortunately, the good quality probiotics can be well outside many patients’ budgets, but nonetheless I regularly inform patients of this option.

Reference: Aliment Pharmacol Ther. 2012;35(12):1355-69.http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2012.05104.x/abstract

The effectiveness and cost effectiveness of dark chocolate consumption as prevention therapy in people at high risk of cardiovascular disease: best case scenario analysis using a Markov modelAuthors: Zomer E et al

Summary: This “best case scenario analysis” modelled the long-term effects of daily dark chocolate consumption in 2013 patients with untreated hypertension and metabolic syndrome, but without diabetes or CV disease. Risks for CV disease and death were calculated using established algorithms and registries. The effects of dark chocolate consumption (polyphenol content equivalent to 100 g of dark chocolate daily) were based on prior meta-analyses; the systolic blood pressure-lowering effect was assumed to be –5.0 mm Hg and the LDL cholesterol-lowering effect was assumed to be –8.1 mg/dL. Given these assumptions, 100% adherence with daily dark chocolate consumption would prevent 70 nonfatal and 15 fatal CV events per 10,000 persons treated over 10 years. Costs associated with CV events and treatments were applied to determine the potential amount of funding required for dark chocolate therapy to be considered cost effective. $A40 (£25; €31; $US42) could be cost effectively spent per person per year on prevention strategies using dark chocolate.

Comment: These results will please chocolate lovers. The downside is that 10,000 people would need to consume 100 g of dark chocolate each and every day for 10 years to prevent 85 CV events. Still, that may be more palatable than taking a daily statin or beta-blocker.

Reference: BMJ. 2012;344:e3657.http://www.bmj.com/content/344/bmj.e3657