A 90-year-old man presented to the emergency department with multiple symptoms including double vision, reduced mobility, dysphagia, recent rapid weight loss, ear discharge and deafness. He had diabetes and other chronic medical problems, including otitis media with mastoiditis. This case highlights the difficulty of investigating weight loss in older people, who may not show the usual clinical features of infection, and of distinguishing between infection and malignancy when radiological findings are inconclusive. His eventual diagnosis was osteomyelitis of the skull base with cranial nerve involvement. Clinical recordA 90-year-old, previously fit Estonian man was admitted to hospital from the emergency department (ED) with multiple symptoms including acute diplopia, difficulty with walking, several falls over 2 weeks, decreased taste sensation, dysphagia with solids over several months, a 10 kg weight loss over 5 months, and a 6-week history of otalgia, aural fullness, otorrhea, and deafness. Four months earlier, the patient had presented to the ED with acute onset of left facial nerve palsy, dysphonia and dysphagia. The facial nerve palsy had resolved spontaneously after 2 weeks without specific treatment. The patient had several significant background medical problems: late-onset diabetes mellitus of 17 years’ duration; peripheral neuropathy; chronic atrial fibrillation; hypertension; and chronic left otitis media with effusion and mastoiditis, for which he had been treated with insertion of a tympanostomy tube 5 months before admission, and a short course of a topical corticosteroid and an oral antibiotic 1 month before admission. The dysphagia was investigated before admission with a barium meal, oesophageal manometry and gastroscopy, which showed severe oesophageal dysmotility and no obstructive lesion. The patient was an ex-smoker with a 55 pack-year smoking history, regular moderate alcohol intake, and occasional salted fish but no areca (or “betel”) nut consumption (which have been linked to nasal and oral cancers, respectively). There was no family history of cancer. His regular medications included metformin, gliclazide, amiodarone, lercanidipine, frusemide and amitriptyline. The main findings on examination included failure of abduction (but no medial deviation) of the left eye consistent with abducens nerve palsy, bilateral haemoserous ear discharge, cachexia, and unsteady gait. No other localising neurological signs were found. The patient remained afebrile throughout the admission. A bedside swallowing assessment by a speech pathologist demonstrated moderate pharyngeal dysphagia. Communication with the patient was conducted through writing. The results of blood tests were unremarkable: his creatinine level was 100 μmol/L (reference range [RR], 70–110 μmol/L); leukocytes, 9.0 × 109/L (RR, 4.0–10.0 × 109/L); glycated haemoglobin, 7.1%; and C-reactive protein (CRP), 51 mg/L (RR, < 5.0 mg/L). One week later, the leukocyte count remained within the normal range and his CRP level had fallen to 35 mg/L, remaining at this level throughout the admission without any specific treatment. A computed tomography (CT) scan and magnetic resonance imaging (MRI) of the brain showed extensive skull base and prevertebral soft tissue thickening with contrast enhancement, bilateral mastoid air cell opacification, and bony destruction of the clivus and both petrous parts of the temporal bones (Box). Bone scintigraphy, performed using technetium-99m hydroxymethane diphosphonate, and a fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed intense tracer uptake in the nasopharynx, base of the skull and mastoid air cells. There was no evidence on the FDG-PET scan of distant uptake. A culture of ear discharge grew a mixture of Staphylococcus aureus and Pseudomonas aeruginosa that were sensitive to flucloxacillin and ciprofloxacin, respectively. Nasopharyngeal carcinoma was strongly suspected by the treating medical team on the basis of radiological findings, significant weight loss (even though the weight loss could be partially attributed to dysphagia), and only a moderate rise in the CRP level. However, the treating ear, nose and throat (ENT) surgeon was of the strong opinion that the abnormalities were due to an infective process and that nasopharyngeal biopsy was not necessary. In view of the radically different nature of the treatments for the two conditions, the divergent opinions about the diagnosis, and the patient’s family wanting more certainty, the opinion of a second ENT surgeon was sought. Subsequent nasopharyngeal biopsy results showed only submucosal chronic inflammation. A diagnosis of skull base osteomyelitis complicating otitis media was made. The patient was started on oral ciprofloxacin 500 mg twice a day (to be continued long term), rehabilitated (practice in transfers, ambulation and self-care), and discharged after 31 days, having shown improvements in weight, mobility and other functional status. At 4-month follow-up, diplopia and abducens nerve palsy had resolved, the patient’s CRP level was 0.3 mg/L and he had gained 8 kg in weight. At 7-month follow-up, there was no ear discharge, the patient’s weight was stable, he felt well and had returned to his previous level of activity. Using hearing aids, the patient was able to converse. Cessation of ciprofloxacin would be considered at 1-year follow-up if there were signs of resolution of osteomyelitis on gallium imaging and repeat bone scan and MRI. DiscussionOsteomyelitis of the base of the skull is commonly associated with malignant otitis externa. However, this patient had chronic otitis media and mastoiditis. Involvement of lower cranial nerves (VI to X) is common in skull base osteomyelitis due to their anatomical proximity to the clivus.1,2 Accurate diagnosis of abnormalities in the base of the skull is important but difficult. Both infection and malignancy can result in severe disability and death, but a good clinical outcome can be achieved with the correct treatment.2 The difficulty of diagnosing either infection or malignancy in similar cases has been reported previously.3-5 However, this patient’s case is unique because of his advanced age, complete resolution of symptoms, attainment of his ideal body weight and full return to his previous level of functioning. The diagnosis at discharge relied on the negative biopsy result for malignancy, the history of complicated chronic otitis media with effusion, and the patient’s improvement after antibiotic treatment. Subsequent clinical improvement at follow-up gave further support to the diagnosis of infection. Although weight loss was the major sign raising suspicion of malignancy, it is not a common feature of nasopharyngeal carcinoma without distant metastases.6 As occurs in many older patients, this patient did not have the usual clinical features of infection. CT, MRI and bone scans demonstrated the extent and location of abnormalities but could not distinguish between infection and malignancy. The FDG-PET scan indicated there were no metastases. Ciprofloxacin was chosen on the basis of the ear discharge culture result and because P. aeruginosa has been implicated as the major pathogen causing skull base osteomyelitis related to ear infections — especially in people with diabetes who have otitis externa.7 S. aureus was thought likely to be a colonising organism rather than a copathogen; the clinical response to the ciprofloxacin was consistent with this. A challenging question with this patient was the optimal duration of ciprofloxacin treatment, especially when the ear discharge persisted for up to 7 months. The decision to stop treatment with the antibiotic would be a matter of judgement based on clinical features, persistently normal CRP levels and improvements on serial scans. After cessation of antibiotic treatment, the patient would require regular and prolonged follow-up to detect early relapse of infection. Magnetic resonance image showing skull base osteomyelitis and otitis media Axial T1 weighted, fat suppressed contrast enhanced scan showing extensive skull base enhancement (white region) with extension anteriorly to the retropharyngeal space (thin white arrow) and posteriorly to dura at the left cerebellopontine angle cistern (thick white arrow).

Jenson C S Mak MB BS, FRACP, FAFRM(RACP) · Lawrence H Kim MB ChB · Lawrence T C Ong BPsych(Hons), MB BS · Triet M Bui MB BS, FRACP, MPH

Objectives: To assess the prevalence of and risk factors for claudication and its association with subsequent cardiovascular events.Design, setting and participants: Observational cohort study of 12 203 Western Australian men aged 65 years and over, recruited from 1996 to 1999, and followed up from 2001 to 2004.Main outcome measures: Prevalence of claudication and incidence of peripheral arterial disease (PAD); risk factors for claudication and its association with subsequent cardiovascular events.Results: The prevalence of claudication was 5.3% (638 of 11 970 men). At follow-up, after exclusion of 148 men with claudication at baseline and 76 with missing data at follow-up, the crude average annual incidence of new PAD (claudication or procedure for PAD) was 0.85% (95% CI, 0.72%–0.96%). The risk factors for prevalent claudication and incident PAD were similar, with age, smoking, hypertension, diabetes and history of cardiovascular disease dominating. Of the men with claudication at baseline, nearly half (47.5%; 303 of 638) were not taking aspirin. At follow-up, 42.5% (82 of 193) of the men with incident PAD were not taking aspirin. Claudication at baseline was associated with twice the risk of cardiovascular death (hazard ratio, 2.00; 95% CI, 1.52–2.64). There was a J-shaped relationship between aortic diameter, and both prevalent claudication and subsequent cardiovascular events.Conclusions: Among older men, claudication is prevalent and is associated with factors that can still be modified in older age, including smoking, exercise and diet. Relatively few men with claudication or at risk of PAD use aspirin. Claudication is a significant predictor of cardiovascular outcome.

Rahul Lakshmanan MB BS · Zoë Hyde BSc, PGradDipHlthProm, MPH · Konrad Jamrozik MB BS, DPhil · Graeme J Hankey MD, FRACP, FRCP · Paul E Norman BSc(Hons), DS, FRACP

To the Editor: Improving access to appropriate, good-quality care in the antenatal and postnatal period is a key part of closing the acknowledged gap between Indigenous and other Australians in perinatal outcomes.1 Previous research in a large Aboriginal medical service in Queensland demonstrated sustained improvements in perinatal outcomes associated with a quality improvement approach.2 Here we describe patterns of the delivery of maternity care and service gaps on a broad scale, using data from baseline clinical audits in 34 Indigenous primary health centres participating in a national quality improvement intervention.3 Participating services were located across the Northern Territory (Top End and Central Australia), North Queensland, Far West New South Wales and Western Australia. Details of the audit methods have been described previously.4 Briefly, a random sample of up to 30 clinical records in each service was assessed to determine the degree of adherence to recommended protocols and procedures in the antenatal and postnatal periods.5 Records of women with an infant aged 2–14 months and who had been resident in the community for at least 6 months of the infant’s gestation were considered eligible for our study. The study was approved by the human research ethics committees in each region, and their Indigenous subcommittees where required. Clinical records of 535 women were assessed. Eighty-nine per cent of the women were Indigenous. However, compared with services in the NT, WA and North Queensland, services in Far West NSW had a higher proportion of non-Indigenous women presenting for antenatal or postnatal care (34% v 0–6%; P < 0.05). Overall, less than half of all women presented for care in the first trimester of pregnancy (Box). Documentation of routine antenatal investigations and brief interventions or advice regarding health behaviour varied, but generally these services appeared to be underutilised. There was relatively good documentation of follow-up of identified problems relating to hypertension or diabetes, with over 70% of identified women being referred to a general practitioner or obstetrician. However, follow-up of other identified problems, such as inadequate rubella immunity, was poor. Although 53% of women had a recorded postnatal visit, documentation of advice regarding health risk factors during the postnatal period was poor. For about half of all women there was documentation about breastfeeding advice and contraception. But advice about smoking, nutrition or mood (depression) was recorded for only 19%–21% of all women, and advice about sudden infant death syndrome prevention, injury prevention or infection/hygiene was recorded for only 4%–5% of all women. The clinical audit data presented here indicate that participating services had both strengths and weaknesses in delivering maternal health care. Nevertheless, improving adherence to recommended screening investigations and brief interventions or advice about health behaviours, particularly smoking cessation, in the antenatal and postnatal period were identified as clear areas for improvement across all services. This information represents baseline data to inform the long-term monitoring of a quality improvement intervention. More broadly, it should be useful for informing local, regional and national efforts to promote and assess the quality of primary maternal health care for Indigenous women, and thus help address the persisting unacceptably high rates of poor Indigenous perinatal outcomes in Australia. Documented pregnancy care across regions Characteristic NT Top End NT Central Australia Far West NSW Western Australia North Queensland Total Number of health centres | number of client records audited 13 | 136 2 | 45 6 | 103 9 | 193 4 | 58 34 | 535 Proportion of women with estimated gestational age < 12 weeks at first antenatal visit 49% 44% 35% 42% 34% 42% Mean number of antenatal visits 9 10 5 6 7 7* Proportion of women with folate prescribed before 20 weeks 29% 49% 3% 33% 24% 27%* Any use of: Cigarettes 41% 40% 39% 42% 55% 43% Alcohol 12% 27% 19% 25% 31% 22%* Illicit drugs 7% 2% 17% 8% 7% 9% Brief interventions or counselling Smoking cessation† 48% 67% 35% 49% 41% 46% Antenatal education 51% 93% 51% 46% 47% 52%* Nutrition 53% 76% 18% 32% 59% 41%* Breastfeeding 21% 51% 17% 25% 19% 24% Alcohol and other substance abuse 37% 56% 12% 39% 34% 34%* Investigations at first antenatal assessment Blood group/Rh 96% 100% 65% 77% 79% 82%* Antibodies 93% 100% 66% 70% 78% 79%* Midstream urine (MSU) 91% 96% 40% 67% 76% 71%* Full blood examination (FBE) 95% 100% 64% 73% 79% 80%* Rubella 92% 100% 61% 70% 78% 77%* Hepatitis B surface antigen 91% 100% 56% 75% 79% 78%* Syphilis serology 94% 100% 58% 55% 81% 72%* HIV 80% 89% 14% 72% 59% 63%* Offered anomaly screening 6% 33% 17% 20% 0% 15%* Other investigations Ultrasound before 16 weeks 32% 49% 38% 39% 24% 36% Ultrasound at 16–20 weeks 47% 69% 31% 41% 34% 42% 50g or 75g glucose challenge test (GCT) or glucose tolerance test (GTT) 78% 49% 33% 38% 66% 51%* FBE (20–28 weeks) 82% 69% 24% 46% 60% 54%* Low vaginal swab for group B streptococcus (34–37 weeks) 49% 62% 31% 29% 10% 35%* Follow-up of abnormal findings Record of abnormal standard GCT 17% (23/136) 22% (10/45) 10% (10/103) 4% (7/193) 17% (10/58) 11% (60/535)* GTT undertaken 87% (20/23) 90% (9/10) 80% (8/10) 43% (3/7) 60% (6/10) 77% (46/60) Anaemia (Hb < 100 g/L) 14% (19/136) 22% (10/45) 11% (11/103) 12% (24/193) 3% (2/58) 12% (66/535)* Iron prescribed 84% (16/19) 100% (10/10) 91% (10/11) 75% (18/24) 50% (1/2) 83% (55/66) Follow-up FBE or Hb test done 42% (8/19) 90% (9/10) 36% (4/11) 46% (11/24) 50% (1/2) 50% (33/66) Nitrites detected by dipstick 21% (28/136) 33% (15/45) 5% (5/103) 24% (46/193) 10% (6/58) 19% (100/535)* Urine sent for culture and sensitivity 96% (27/28) 100% (15/15) 100% (5/5) 93% (43/46) 100% (6/6) 96% (96/100) Oral antibiotic prescribed 93% (26/28) 60% (9/15) 80% (4/5) 37% (17/46) 83% (5/6) 61% (61/100)* Record of a normal follow-up MSU 46% (13/28) 100% (15/15) 40% (2/5) 26% (12/46) 83% (5/6) 47% (47/100)* Rubella antibodies negative or low-titre 35% (47/136) 7% (3/45) 15% (15/103) 15% (28/193) 7% (4/58) 18% (97/535)* Rubella vaccination given postnatally 36% (17/47) 67% (2/3) 13% (2/15) 32% (9/28) 0 (0/4) 31% (30/97) GTT = glucose tolerance test. Hb = haemoglobin. NSW = New South Wales. NT = Northern Territory. * P < 0.05 for comparisons between regions. † Among those who used cigarettes: NT Top End (n = 56), NT Central Australia (n = 18), Far West NSW (n = 40), WA (n = 82), North Queensland (n = 32); total N = 228.

Alice R Rumbold · Ross S Bailie · Damin Si · Michelle C Dowden · Catherine M Kennedy · Rhonda J Cox · Lynette O’Donoghue · Helen E Liddle · Ru K Kwedza · Sandra C Thompson · Hugh P Burke · Alex D Brown · Tarun Weeramanthri · Christine M Connors

Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients The combined use of warfarin and dual antiplatelet therapy (aspirin plus clopidogrel) — so-called triple therapy — is a challenging management problem in patients with a coronary stent who also have an indication for oral anticoagulation. One of the most common clinical scenarios is a patient with atrial fibrillation (AF) who undergoes percutaneous coronary intervention with stenting. Guidelines for antithrombotic therapy recommend that patients with AF who are at high risk of stroke (ie, prior history of stroke or more than one of: age ≥ 75 years, hypertension, diabetes, and congestive cardiac failure) receive warfarin;1 and guidelines for percutaneous coronary intervention management recommend dual antiplatelet therapy in all stent patients to prevent stent thrombosis.2 Both warfarin and clopidogrel increase the risk of bleeding in patients treated with aspirin, and combining all three drugs can be expected to further increase bleeding risk. However, the efficacy and safety of triple therapy have not been evaluated in randomised controlled trials. What is the evidence concerning the efficacy of anticoagulation or antiplatelet therapy in patients with AF who have recently received a coronary artery stent? In patients with AF who are at risk of stroke, warfarin compared with placebo or no treatment reduces the risk of stroke by about two-thirds, whereas aspirin reduces the risk by about one-fifth.3 Adding clopidogrel to aspirin improves the effectiveness of antiplatelet therapy for stroke prevention,4 but warfarin is substantially more effective than dual antiplatelet therapy.5 In patients with a recent coronary artery stent, dual antiplatelet therapy compared with the combination of aspirin and warfarin reduces death or myocardial infarction by half.6 Premature discontinuation of clopidogrel (less than 3 months of treatment for sirolimus-eluting stents; less than 6 months for paclitaxel-eluting stents) is the single most important risk factor for stent thrombosis.7 The efficacy and safety of triple therapy have been examined in multiple observational studies. Meta-analysis of 10 observational studies involving 1349 patients with AF who received triple therapy after stent insertion revealed a weighted mean incidence of major bleeding at 30 days of 2.2% (95% CI, 0.7%–3.7%).8 Increasing the duration of triple therapy to longer than 6 months doubles the risk of major bleeding compared with 1 month of treatment.9 The guidelines recommend at least 4 weeks of dual antiplatelet therapy for patients who receive a bare metal stent and at least 1 year for those who receive a drug-eluting stent.2 What is the optimum antithrombotic management of patients with AF who undergo coronary stent insertion? Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients. Dual antiplatelet therapy alone is likely to be adequate for stent patients with AF if they are at low or moderate risk of stroke (CHADS2 stroke risk score [congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points10], 0–1), or if they are at high risk of stroke (CHADS2 stroke risk score, > 1) and deemed to be at unacceptably high risk of bleeding with triple therapy. The most important risk factors for bleeding are older age (eg, > 75 years), severe renal dysfunction (eg, creatinine clearance < 30 mL/min), recent gastrointestinal bleeding (eg, within 6 months), previous stroke, and uncontrolled hypertension (eg, systolic blood pressure > 160 mmHg, diastolic blood pressure > 110 mmHg).11 All other patients with AF who are at high risk of stroke (CHADS2 stroke risk score, > 1) and have recently undergone coronary artery stenting should probably receive warfarin in addition to dual antiplatelet therapy (Box).8 Cardiologists and primary care physicians should communicate closely to optimise antithrombotic therapy and minimise the risk of bleeding in patients who may be candidates for triple therapy. Firstly, the duration of exposure to triple therapy should be limited where possible by selecting a bare metal stent, which requires a shorter duration of antiplatelet therapy than a drug-eluting stent.2 Secondly, aspirin should be used at the lowest proven effective dose of 50–100 mg/day to minimise the risk of gastrointestinal bleeding.12 Thirdly, in patients at high risk of gastrointestinal bleeding, consideration should be given to the use of acid-suppressive therapy, either with a histamine H2-receptor antagonist (eg, ranitidine) or a proton-pump inhibitor.13 Retrospective analyses of administrative databases have suggested that the concomitant use of a proton-pump inhibitor (particularly omeprazole) reduced the efficacy of clopidogrel,14,15 but subsequent analyses of data from randomised controlled trials indicated no loss of benefit of clopidogrel when the two were used in combination.16 If a proton-pump inhibitor is used, it may be reasonable to avoid the use of omeprazole. Finally, warfarin therapy should, ideally, be monitored by an expert anticoagulation clinic to optimise the quality of international normalised ratio (INR) control (target INR, 2–3).11 What are the unresolved issues? Our recommendations for the use of triple antithrombotic therapy in patients with AF and a stent are based on observational studies8 and extrapolations of evidence from randomised controlled trials of antithrombotic therapy for prevention of stent thrombosis and thromboembolism in patients with AF. Dedicated randomised studies are urgently needed to obtain more reliable estimates of the risks and benefits of triple antithrombotic therapy in patients with a coronary artery stent who have AF, as well as in stent patients with other indications for warfarin therapy, such as mechanical heart valves or recent venous thromboembolism. Treatment decision algorithm for patients with atrial fibrillation and a coronary artery stent8 * CHADS2 stroke risk score (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points).10

Jeremy S Paikin MD · Shamir R Mehta MD, MSc, FRCPC · John W Eikelboom MB BS, MSc

Hype or hope? Although cancer receives a great deal of attention in the media, little is known about the main messages conveyed to readers. A content analysis of over 400 recent articles about cancer in several major US mainstream publications found that while more than half discussed “aggressive” treatments, 30% reported associated adverse effects and only 13% mentioned that these treatments can fail. End-of-life issues were rarely discussed, appearing in only 2.5% of articles. The most common articles were about breast or prostate cancer. The authors concluded that media portrayal of cancer may be inappropriately optimistic as, overall, about half of all cancer patients are known to eventually die from their disease or related complications. Arch Intern Med 2010; 170: 515-518 doi:10.1001/archintermed.2010.11 Donor survival According to results of a study in the United States, live kidney donors appear to survive as well as non-donors — in the longer term. Among a cohort of about 80 000 live kidney donors followed for a median of 6.3 years, survival was similar to that of a matched cohort of non-donors from one year after nephrectomy. However, during the 90-day postoperative period, there was a total of 25 deaths (equivalent to a mortality rate of 3.1 per 10 000) in the donor group; notably lower than the reported surgical mortality rate of about 18 per 10 000 for laparoscopic cholecystectomy and about 260 per 10 000 for non-donor nephrectomy. Surgical mortality was higher in male donors (RR 3.0, 95% CI 1.3−6.9) and in those with hypertension (RR 27.4, 95% CI 5−149.5), indicating the importance of appropriate donor selection. JAMA 2010; 303: 959-966 doi:10.1001/jama.2010.237 Poker face Can people tell what you are thinking by your eye movements? Melbourne researchers have put this to the test by assessing how often they were able to accurately predict the magnitude of a random number “thought of” by 12 test subjects, before they had actually spoken it. Working on the basis of the already recognised “mental number line” — that is, that looking up and to the right is usually associated with a larger number and down and to the left with a smaller number — they were able to predict the direction and magnitude of the next number correctly about 60% of the time (P< 0.001). The study authors state that “the eyes may not only reveal what is in a person’s mind, but also illustrate how abstract thoughts are grounded in basic sensory-neural processes.” Curr Biol 2010; 20: R264-R265 Motherhood and suicide risk In 1897, Durkheim hypothesised that parenthood conferred a protective effect against suicide. Now, more than 100 years later, a cohort study of more than 1 million Taiwanese women has found evidence in support of this hypothesis: having more than one child appears to lower suicide risk in mothers. Further, this apparent protective effect is more evident with increasing parity. The women were followed up for at least 20 years after a first live birth between 1978 and 1987. After adjusting for age, years of schooling and marital status, the estimated hazard ratio for suicide was 0.61 among women with two live births and 0.40 among those with three or more live births. While it is difficult to assume a direct cause-and-effect relationship, the researchers proposed factors such as increased self-worth, based on the mother’s perception of being needed, and enhanced social networks as possible explanations for this observation. CMAJ 2010 doi:10.1503/cmaj.090813 Diabetes burden Which country bears the highest diabetes-related disease burden? It may well be China. A large study involving glucose-tolerance testing of more than 46 000 adults in China has shown that about one in 10 have diabetes, while about 15% have pre-diabetes. This equates to about 50 million men and 42 million women in China with diabetes. Estimated prevalence increased with age, reaching about 1 in 5 among those aged over 60 years. Diabetes was more prevalent in urban than rural residents (11.4% vs 8.2%), and this was thought to be related to rapid changes in lifestyle factors such as diet and physical activity. However, the more troublesome finding was that in about 6 of every 10 cases, the diabetes was undiagnosed. N Engl J Med 362; 12: 1090-1100.

Alison Williams

Until the results of several statin trials are available, it is recommended that the current indications and usage of ezetimibe be continued Patients receiving statin therapy to reduce total and low-density lipoprotein cholesterol (LDL-C) levels still have a residual risk of cardiovascular (CV) events. In most statin trials, CV events are reduced by about 30% compared with placebo, leaving about 70% residual risk of CV events that occur in spite of statin therapy. Factors that may contribute to residual risk are listed in Box 1. The Treating to New Targets Study1 showed that residual risk of CV disease increased with low levels of high-density lipoprotein cholesterol (HDL-C), even in patients who had low levels of LDL-C as a result of statin therapy. This suggested that raising HDL-C levels may be beneficial for such patients, a hypothesis investigated in the recent ARBITER 6-HALTS trial (ARBITER [Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol]; HALTS [HDL and LDL Treatment Strategies in Atherosclerosis]). The ARBITER 6-HALTS trial was a study of carotid intima-media thickness (CIMT) in statin-treated patients who had achieved LDL-C goal levels. It compared an HDL-C-raising strategy (additional treatment with extended-release nicotinic acid titrated to 2 g daily) with an LDL-C-lowering strategy (additional treatment with ezetimibe 10 mg daily).2,3 The trial was stopped prematurely at its interim analysis of 180 of the planned 300 patients, on the basis of differences in the primary end point and other secondary analyses.4 The trial included subjects aged 30 years or over with coronary heart disease (CHD), known atherosclerotic vascular disease at other sites, diabetes, a 10-year CHD risk of > 20% (based on Framingham Heart Study criteria), or a coronary calcium score > 400 in men or > 200 in women, who were stabilised on statin therapy equivalent to simvastatin 20 mg/day, with LDL-C levels < 2.5 mmol/L and HDL-C levels < 1.3 mmol/L in men or < 1.4 mmol/L in women.2 Exclusion criteria included raised transaminase levels more than three times the upper limit of normal, current use of or intolerance to ezetimibe or nicotinic acid, a history of chronic liver disease, or the potential for pregnancy. Results of the ARBITER 6-HALTS trial showed that nicotinic acid reduced CIMT more effectively than ezetimibe (Box 2). Importantly, as no control group was included, no comparison can be made between ezetimibe and placebo with regard to their possible effects on CIMT. Atherogenic dyslipidaemia may be an important contributor to residual risk and is typically associated with obesity, the metabolic syndrome and type 2 diabetes. It is accompanied by impaired glycaemic control, hypertension, and procoagulant and inflammatory states, and is characterised by low HDL-C levels, high triglyceride levels, the presence of triglyceride-rich “remnant” lipoproteins, and a preponderance of small, dense, highly-oxidisable LDL particles. Levels of total cholesterol and LDL-C may be close to normal. Patients in the ARBITER 6-HALTS trial had a mean body mass index in the obese range (30.8–31.0 kg/m2) and a waist circumference above normal (mean, 103 cm and 104 cm in the two groups); 32%–40% were diabetic; and 85%–86% were hypertensive.2 Mean glucose levels (5.55–5.77 mmol/L) and triglyceride levels (1.38–1.42 mmol/L) were also in the high-normal range. Patients were selected for inclusion in the trial on the basis of low HDL-C levels. HDL-C levels increased, as expected, in the nicotinic acid treatment group (by about 18%), but unexpectedly decreased in the ezetimibe treatment group (by about 5%).2 The results of the trial may thus be partially explained by the fact that a significant proportion of patients had atherogenic dyslipidaemia, which responds to nicotinic acid therapy but not to ezetimibe therapy. Conclusions from the ARBITER 6-HALTS trial about the LDL-C-lowering effects of ezetimibe and the HDL-C-raising effects of nicotinic acid may be questioned, as ezetimibe and nicotinic acid affect different lipoproteins and metabolic pathways that may influence atherosclerosis. Nicotinic acid lowers levels of triglycerides and triglyceride-rich lipoproteins by reducing free fatty acid flux to the liver; it also lowers lipoprotein (a) and LDL-C levels. Ezetimibe has less pronounced effects on lowering triglyceride levels and raising HDL-C levels. In addition, the protective functions of HDL-C (including reverse cholesterol transport, anti-inflammatory and antioxidant effects) may not necessarily be reflected in HDL-C levels, and functional assessment of HDL-C may assist in assessing the potential benefits of intervention.5 The implication of the ARBITER 6-HALTS trial results is that targeting atherogenic dyslipidaemia with nicotinic acid therapy reduces CIMT and is likely to improve residual risk of CV events because CIMT is a validated surrogate marker for CV events — an important consideration for all patients receiving statins.6 The HATS (HDL-Atherosclerosis Treatment Study) trial demonstrated that CV events could be reduced by treating atherogenic dyslipidaemia with nicotinic acid.7 Previous CIMT studies (ARBITER 2 and 3) showed that a combination of nicotinic acid and statin therapy was superior to statin therapy alone for atherosclerosis stabilisation and regression.8 These results, together with those of the ARBITER 6-HALTS trial, indicate that nicotinic acid may be appropriate supplementary therapy for reducing residual risk in patients taking statins. The results also provide an evidence base for extended-release nicotinic acid to be made available once again under the Pharmaceutical Benefits Scheme. Long-term clinical outcomes trials are already underway to investigate the primary findings of the ARBITER 6-HALTS trial (Box 3).2 Until the results of these trials are available, it is recommended that the current indications and usage of ezetimibe be continued (Box 3). Lifestyle change is an important component of managing residual risk (Box 1). Stopping smoking, controlling weight and increasing physical exercise can all increase HDL-C levels and may contribute independently to reduction in residual risk of CV events. 1 Possible contributors to residual risk in patients receiving statin therapy Cigarette smoking Uncontrolled hypertension Impaired glucose tolerance Reduced physical exercise Central abdominal obesity Inflammation Prothrombotic tendency Proarrhythmic tendency Myocardial ischaemia Left ventricular dysfunction Reduced high-density lipoprotein cholesterol (HDL-C) level Increased low-density lipoprotein cholesterol (LDL-C) level Atherogenic dyslipidaemia: Increased apolipoprotein B and small, dense LDL particles Reduced HDL-C level Increased level of triglycerides and triglyceride-rich lipoproteins 2 Results of the ARBITER 6-HALTS trial2 Treatment group Ezetimibe (n = 111) Nicotinic acid (n = 97) P Baseline Mean CIMT (mm) (SE) 0.8957 (0.1484) 0.9001 (0.1558) 0.93 At 8 months* Mean change in CIMT (mm) (SE) 0.0014 (0.0020) – 0.0102 (0.1650) 0.90 P (change from baseline) 0.48 0.001 At 14 months* Mean change in CIMT (mm) (SE) – 0.0007 (0.0035) – 0.0142 (0.0041) 0.01 P (change from baseline) 0.84 0.001 ARBITER = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; HALTS = High-density Lipoprotein and Low-density Lipoprotein Treatment Strategies in Atherosclerosis. CIMT = carotid intima-media thickness. * Change compared with baseline. 3 Summary and future prospects The ARBITER 6-HALTS trial showed that a strategy of raising high-density lipoprotein cholesterol (HDL-C) levels using nicotinic acid therapy was more successful than a strategy of lowering low-density lipoprotein cholesterol (LDL-C) levels further with ezetimibe, at least with regard to reducing carotid intima-media thickness. Results of the trial are relevant to patients receiving statin therapy who have LDL-C levels < 2.5 mmol/L. Many of these patients have atherogenic dyslipidaemia, with low levels of HDL-C and high levels of triglycerides, as well as increased levels of apolipoprotein B and small dense atherogenic LDL particles. Despite having statin therapy, such patients may continue to experience a high rate of cardiovascular disease events — in part because of lack of control of atherogenic dyslipidaemia, which is not targeted by statins or ezetimibe but is alleviated by fibrates and nicotinic acid. The demonstrated superiority of nicotinic acid therapy in the ARBITER 6-HALTS trial is probably the result of improved control of atherogenic dyslipidaemia. Although the results of the trial are potentially important, their relevance to Australian practice is limited because extended-release nicotinic acid, although approved for prescription by the Therapeutic Goods Administration, is not reimbursed by the Pharmaceutical Benefits Scheme. The few patients who can tolerate non-extended-release nicotinic acid at doses of 2 g daily may benefit from this agent when added to statin therapy. An alternative strategy may be to combine statin therapy with fenofibrate therapy (the effectiveness of this approach will be determined by the results of the ACCORD trial, to be presented in early 2010). Other trials are in progress to determine the long-term clinical outcomes of statin therapy combined with ezetimibe (IMPROVE-IT [estimated completion date, 2015]) and with extended-release nicotinic acid (AIM HIGH and HPS2-THRIVE [estimated completion dates, 2011 and 2013, respectively]). Pending the results of these trials, the continued use of ezetimibe is recommended for patients unable to tolerate statins and for those whose LDL-C level is uncontrolled in spite of maximum-tolerated doses of statins. ACCORD = Action to Control Cardiovascular Risk in Diabetes. AIM HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes. ARBITER = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; HALTS = HDL and LDL Treatment Strategies in Atherosclerosis. HPS2-THRIVE = Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events. IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

Ian R Hamilton-Craig MB BS, FRACP, PhD

Objectives: To examine trends and predictors of prescription medications on discharge after first (index) hospitalisation for heart failure (HF), and the effect on all-cause mortality of evidence-based therapy.Design: A retrospective multicentre cohort study, with medical record review.Setting: Three tertiary-care hospitals in Perth, Western Australia.Patients: WA Hospital Morbidity Data were used to identify a random sample of 1006 patients with an index admission to hospital for HF between 1996 and 2006.Main outcome measures: Proportion of patients prescribed evidence-based therapy for HF on discharge from hospital; and 1-year all-cause mortality.Results: Among 944 patients surviving to hospital discharge, the prescription rate of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (74.3%) and loop diuretics (85.5%) remained high over the study period, whereas that of β-blockers and spironolactone increased (10.5% to 51.3% and 1.4% to 23.3%, respectively), and digoxin prescription decreased (38.1% to 20.7%). The temporal trends in use of β-blockers, spironolactone and digoxin were in line with clinical trial evidence. Age ≥ 75 years was a significant, negative predictor of β-blocker and spironolactone prescription. In-hospital echocardiography, performed in 53% of patients, was associated with a significantly greater likelihood of treatment with ACE inhibitors/ARBs, β-blockers and spironolactone. Both ACE inhibitors/ARBs and β-blockers prescribed on discharge were associated with a lower adjusted hazard ratio (HR) for mortality at 1-year (HR, 0.71; P = 0.003; and HR, 0.68; P = 0.002, respectively).Conclusion: ACE inhibitors/ARBs and β-blockers, prescribed during initial hospitalisation for HF, are associated with improved long-term survival. Therapy became more evidence based over the study period, but echocardiography, an important predictor of evidence-based therapy, was underutilised.

Tiew-Hwa Katherine Teng MPH · Joseph Hung MB BS(Hons), FRACP, FACC · Judith Finn RN, PhD, FRCNA

Childhood obesity and lifespan Obese children are far less likely to reach old age, according to US researchers. In a cohort of almost 5000 American Indians, they studied the effect of cardiovascular risk factors that were present in childhood on lifespan. A history of childhood obesity more than doubled the risk of dying from causes other than accident, suicide or homicide before the age of 55 years (incidence rate ratio 2.3). Although obesity conferred the strongest association with premature death, there were also significant associations between premature death and both impaired glucose tolerance and hypertension. Interestingly, no association with cholesterol levels was observed. The study was also of note because of its length — participants were followed up for a median of 24 years. N Engl J Med 2010; 362: 485-493 Ageing hearts Should octogenarians with acute coronary events undergo per-cutaneous coronary intervention (PCI)? The elderly are generally underrepresented in trials, but a recent Dutch study provides some insights. Of all patients with ST elevation myocardial infarction (STEMI) admitted to one institution for PCI, the proportion of octogenarians treated more than doubled over the 11-year study period, indicating that this is likely to be an ongoing dilemma. Unfortunately, mortality was high in this age group and did not improve (mortality at 30 days was 21.4% compared with 9.4% among 60-79-year-olds). As well as having more comorbidities, the octogenarians were less likely to have successful restoration of coronary perfusion — although this did improve over the study period, possibly reflecting better technology. Heart Online 4 Dec 2009 Haiti quake In two dispatches from Haiti, medical staff describe their experiences working in a collapsed infrastructure. While trying to restore a semblance of order, staff were faced with a lack of fuel, electricity and communication as well as threats of violence, with thousands of prisoners having escaped from the nearby national penitentiary. Hospitals across the city had varying capacities to provide services, with an urgent call for a centralised system informing people where to go for appropriate care. Meanwhile, another hospital about 60 km from the epicentre remained intact, allowing surgical teams to respond while operating rooms in Port-au-Prince were incapacitated. The acute management of the enormous number of injuries inflicted by this disaster is expected to evolve into wound care, fitting of prostheses and rehabilitation. N Engl J Med 2010; 362: 575-777 N Engl J Med 2010; 362: e19 (1)-e19 (2) The long and the short of it Are short babies really more likely to be shorter and weigh less when they grow up? A study involving almost 600 Israeli army recruits indicates that final adult height (at age 17 years) can be predicted by length at birth. In this retrospective study, those babies born short for gestational age (less than 48 cm at birth) were significantly more likely to be shorter and weigh less at their conscription medical than those with a normal birth length. This finding was apparent for both sexes. Arch Dis Child 2009; 94: 959-961 Pregnancy and pandemic flu Advanced pregnancy appears to be associated with an increased risk of severe complications of H1N1 influenza, according to analysis of the outcomes in 43 pregnant women with confirmed infection admitted to Melbourne hospitals during the 2009 pandemic. Of these, 65% were in the third trimester (of whom about half were at term), with 30% in their second trimester and only 5% in the first. Although about half had at least one associated comorbidity (including asthma, diabetes and obesity), half had no other risk factors. Antiviral therapy was prescribed in 77% and 8 women required admission to ICU. Median length of stay was 2 days, and 8 were hospitalised for more than 7 days.1 Although the mechanism by which pregnancy increases flu severity is unclear, a related study may shed some light. After finding a low level of IgG2 in one pregnant woman with severe H1N1 infection, levels were assessed in 39 other patients with confirmed infection (9 of whom were pregnant). Pregnant patients with H1N1 were found to have significantly lower levels compared with healthy pregnant controls, suggesting a possible role of IgG2 deficiency in the pathogenesis of H1N1 infection in pregnancy.2 1. Clin Infect Dis 2010; 50: 686-690 2. Clin Infect Dis 2010; 50: 672-678

Alison Williams

Objective: To examine the perception and management of cardiovascular disease (CVD) risk in Australian primary care.Design, setting and participants: The Australian Hypertension and Absolute Risk Study (AusHEART) was a nationally representative, cluster-stratified, cross-sectional survey of 322 general practitioners. Each GP was asked to collect data on CVD risk factors and their management in 15–20 consecutive patients aged ≥ 55 years who presented between April and June 2008, and to estimate each patient’s absolute risk of a cardiovascular event in the next 5 years.Main outcome measures: Estimated 5-year risk of a cardiovascular event, proportion of patients receiving appropriate treatment.Results: Among 5293 patients, 29% (1548) had established CVD. A further 22% (1145), when categorised according to the 2009 National Vascular Disease Prevention Alliance guideline, to 42% (2211), when categorised according to National Heart Foundation (NHF) 2004 guideline, had a high (≥ 15%) 5-year risk of a cardiovascular event. Of the 1548 patients with established CVD, 50% were prescribed a combination of a blood pressure (BP)-lowering medication, a statin and an antiplatelet agent, and 9% were prescribed a BP-lowering medication and a statin but not an antiplatelet agent. Among high-risk patients without established CVD, categorised using NHF 2004 adjustments, 34% were prescribed a combination of a BP-lowering medication and a statin. GPs estimated 60% of patients with established CVD as having a risk of less than 15%. The GPs’ estimates of risk among patients without established CVD agreed with the centrally calculated estimate (according to the NHF 2004 guideline) in 48% of instances (κ = 0.21).Conclusions: These data confirm substantial undertreatment of patients who are at high risk of a cardiovascular event. We recommend that GPs assess absolute risk for older patients and ensure that high-risk patients receive evidence-based pharmacotherapy.

Emma L Heeley BSc(Hons), MSc, PhD · David P Peiris MB BS, MIPH, FRACGP · Anushka A Patel MB BS, PhD, FRACP · Alan Cass MB BS, FRACP, PhD · Andrew Weekes BMedSci, BM BS · Claire Morgan BPhysio · Craig S Anderson MB BS, PhD, FRACP · John P Chalmers MD, PhD, FRACP

The 21st century has the most diabetogenic environment in human history with the number of people with diabetes worldwide increasing to 380 million by 2025. The fastest rate of increase will be in developing countries. Diabetes is now the major cause of end-stage kidney disease globally; 20%–40% of people on dialysis are diabetic. In Australia, the number of people with type 2 diabetes starting dialysis increased fivefold between 1993 and 2007. We must act now at local, national and international levels to prevent type 2 diabetes; screen for early diabetic kidney disease; increase public awareness of kidney disease; treat with medications proven to reduce kidney disease progression; and promote research into and trialling of new therapies. The problem is global yet requires local action. World Kidney Day on 11 March 2010 is a time to intensify action on diabetic kidney disease and to continue to do so until this huge but largely preventable health burden is controlled.

Robert C Atkins MSc, DSc, FRACP · Paul Z Zimmet PhD, MD, FRACP