Hematologic diseases

We report a case of compassionate use of a haemoglobin-based oxygen carrier in a severely injured Jehovah’s Witness patient, for whom survival was considered unlikely. Severe anaemia and cardiac hypoxia were reversed after slow infusion of this agent. No vasoactive side effects were associated with the treatment, possibly due to the slow infusion, and the patient survived. (MJA 2011; 194: 471-473) Clinical recordA healthy 32-year-old woman was a passenger in a vehicle involved in a high-speed collision with a truck, and she was entrapped for 2 hours. Initially, her heart rate was 100 beats/min, blood pressure was 90/50 mmHg, respiratory rate was 28 breaths/min and oxygen saturation measured by pulse oximetry (SpO2) was 92% on air. Her Glasgow Coma Scale score was 9 (eye opening, 2; verbal response, 1; motor response, 6) and her pupils were equal and reactive to light. Her family indicated that she was a Jehovah’s Witness and would not accept the units of blood that had been transported to the accident site. Paramedics performed endotracheal intubation, immobilisation, left femoral splinting and resuscitation with a 7000 mL crystalloid infusion, and applied dressings to wounds. The patient was transported by helicopter to The Alfred’s trauma centre. On arrival at the trauma centre, she was ventilated, her heart rate was 120 beats/min, blood pressure was 62/26 mmHg and SpO2 was 79% on 100% fraction of inspired oxygen (FiO2). Following discussions with the family, the trauma team agreed not to treat the patient with packed red cells, platelets or fresh frozen plasma. Thoracostomies for a right tension pneumothorax and a left pneumothorax were performed, which increased her blood pressure to 105/65 mmHg and SpO2 to 100% on FiO2 100%. Intercostal drains were inserted and connected to a cell salvage device. She was administered 1400 mL of succinylated gelatin, 10 units of cryoprecipitate and 5 mg of recombinant factor VIIa. Bleeding was controlled with direct pressure, and a scalp wound was closed. Ultrasonography demonstrated a moderate pericardial effusion with systolic right ventricular collapse and free intraperitoneal fluid. Electrocardiography demonstrated sinus tachycardia with no ST segment changes. Initial blood tests showed a haemoglobin (Hb) level of 67 g/L (reference range [RR], 113–159 g/L), activated partial thromboplastin time of 44.3 s (RR, 26–38 s), international normalised ratio of 1.9 (RR, 1.0–1.3), serum fibrinogen level of 3.2 μmol/L (RR, 5.9–11.8 μmol/L, lactate level of 3.9 mmol/L (RR, 0.6–2.2 mmol/L) and serum creatinine level of 55 μmol/L (RR, 60–105 μmol/L). Imaging showed a fractured right orbit and maxilla, bilateral rib fractures, a grade 4 splenic laceration, a likely jejunal injury with intramural haematoma, a left distal humerus fracture, a comminuted open left femoral shaft fracture, an unstable T12/L1 fracture dislocation (60% off-ended), and multilevel spinous process and transverse process fractures. Laparotomy and fixation of the patient’s thoracolumbar injury were deferred because of the likelihood of associated bleeding. Instead, she underwent splenic embolisation, external fixation of her open left femoral shaft fracture and debridement of her left humerus injury. She received 1000 mL of 4% albumin and 1000 mL of crystalloid fluid during these procedures, and 10 mg of intravenous vitamin K afterwards. On postoperative admission to the intensive care unit, her Hb level was 36 g/L and her coagulation profile was normal. Low-dose noradrenaline was required to support her blood pressure until Day 2. Her urine output over the first 24 hours was 4500 mL. A follow-up transthoracic ultrasound showed abatement of the pericardial effusion. An abdominal computed tomography (CT) scan with oral contrast excluded jejunal injury. To protect renal function, intravenous contrast was not used. Placement of an inferior vena cava filter was deferred because of anatomical distortion secondary to the thoracolumbar injury. Several strategies were used to manage the patient’s anaemia. Sedation minimised metabolic demand. A ventilation cycle of 2 hours of 90% FiO2, followed by 2 hours of 90% SpO2 and then 20 hours of 95% SpO2 was used. This was employed to maximise oxygen delivery while minimising shunt from absorption atelectasis and to promote erythropoiesis. Recombinant erythropoietin (36 000 units daily for 6 days), folic acid (5 mg daily continued until discharge), vitamin B12 (1 mg daily for 6 days) and a single iron infusion of 500 mg were administered to maximise haematopoiesis. Menses was inhibited with progesterone. Blood testing was performed using paediatric-sized samples. Pneumatic calf compressors were applied and regular lower-limb sonography was performed to exclude venous thrombosis. The trauma team considered using a synthetic haemoglobin-based oxygen carrier (HBOC) to increase oxygen delivery to the patient’s tissues. On Day 3, OPK Biotech (Cambridge, Mass, USA), the Therapeutic Goods Administration (TGA), the Australian Quarantine and Inspection Service and airline carriers were contacted to determine availability and import permissions. HBOC-201 was supplied by OPK Biotech without charge. Informed consent for use of HBOC-201 was obtained from the patient’s family. Approval for emergency compassionate use of HBOC-201 was obtained from The Alfred Ethics Committee on Day 4. The published and unpublished in-vivo and in-vitro research into HBOC-201 was reviewed at a multidisciplinary meeting, and its use was agreed to. Ten 250 mL units of HBOC-201 were imported under Category A of the TGA’s Special Access Scheme. By Day 5, the patient’s Hb level had dropped to 29 g/L and her serum troponin I level was 0.33 μg/L (RR, < 0.10 μg/L), indicating cardiac hypoxia (Box). An electrocardiogram showed widespread ST depression and an episode of non-sustained ventricular tachycardia was documented. Survival with this degree of metabolic demand, the associated anaemia, and resultant end-organ hypoxia was considered unlikely. Following advice from experienced United States physicians, 3 units of HBOC-201 were administered on Day 5, and a further 2 units were administered on Day 6 with ascorbic acid (1 g twice daily continued until discharge). Each unit of HBOC-201 was infused over 8 hours to minimise any adverse effects related to volume overload, vasoactivity or methaemoglobin. Intravenous glyceryl trinitrate was the agreed treatment in the event of hypertension,1 but this was not necessary. After the slow administration of 5 units of HBOC-201, the patient’s Hb level increased from 35 g/L to 62 g/L (Box). Echocardiography performed before and after HBOC-201 treatment showed a reduction in cardiac output from 6.8 L/min to 5.0 L/min. Electrocardiography findings and troponin I levels returned to normal and no further arrhythmias were noted. Somatosensory evoked potentials revealed intact lower-limb neurological pathways. On Day 7, closed reduction was performed and a body cast was applied to treat the T12/L1 fracture dislocation. Imaging showed improved alignment, and an inferior vena cava filter was placed. From Day 6, the patient’s temperature began spiking, secondary to femoral pin site infections and pneumonia. Despite treatment with antibiotics, temperature spiking continued. Cooling was commenced to minimise metabolic demand. A transoesophageal echocardiogram on Day 11 showed right ventricular regional wall motion abnormality but no evidence of endocarditis. A CT scan showed persistent bilateral pneumothoraces, a left pleural effusion and an epidural haematoma at L1 level. Bilateral tube thoracostomies were re-performed and an antifungal was added to the anti-infective regimen. A percutaneous tracheostomy was performed on Day 12. Low-dose heparin therapy for thromboprophylaxis was deferred until Day 17. By Day 21, the infections had resolved and the tracheostomy tube was removed. The femoral and humeral fractures were internally fixed on Day 20 with minimal blood loss. On Day 30, the patient’s Hb level was 107 g/L and operative reduction and internal fixation of her thoracolumbar spine was performed. She was well when discharged to a rehabilitation facility on Day 43 — her cognition was formally assessed as normal, lower-limb neurological pathways were intact and Hb level was 101 g/L. DiscussionWe have described compassionate use of HBOC-201 in a severely injured Jehovah’s Witness patient. To our knowledge, this is the first report to describe reversal of documented cardiac hypoxia secondary to anaemia following trauma. Haemorrhagic shock is responsible for one-third of deaths following high-energy trauma.2 Integrated trauma care systems coordinate rapid haemorrhage control, shock recognition and surgical interventions to minimise blood loss and coagulopathy.3 Healthy volunteers can tolerate Hb levels of 50 g/L without evidence of end-organ hypoxia.4 However, it is estimated that the median Hb concentration associated with mortality is about 25 g/L.5 During the phase of increased metabolic demand in our patient, there was evidence of cardiac hypoxia when her Hb level reached 29 g/L. This prevented further operative interventions and placed her at high risk of cardiac dysrhythmias and death. HBOC-201 is a modified lactated Ringer’s solution containing 130 g/L of polymerised Hb of bovine origin. It is compatible with all blood types, stable for 3 years when stored at 2–30°C and stable for 2 years when stored at 40°C. When fully saturated, HBOC-201 has the same oxygen-carrying capacity as whole blood with the same Hb concentration. The partial pressure of oxygen at which HBOC-201 is 50% saturated (40 mmHg) is higher than that for cellular Hb (27 mmHg), which facilitates oxygen delivery to tissues. The half-life of HBOC-201 is approximately 20 hours.6 Polymerisation of the Hb reduces its glomerular diffusion and nephrotoxicity. A potential complication of HBOC-201 administration is hypertension and increased left ventricular afterload. Infusing each unit slowly (over 8 hours) in our patient may have diminished any vasoactive side effects. Two case reports of using HBOC-201 to treat severe anaemia following blunt trauma have been published. The first described improved cerebral oxygen delivery, but not survival, in a patient with head injuries.7 The second described successful reversal of haemorrhagic shock in a patient whose Hb level dropped to 45 g/L before HBOC-201 administration.8 However, the lack of clear HBOC-201 transfusion indications and end points, as well as the lack of data to support widespread use of HBOCs, has been criticised.9 A meta-analysis of data from HBOC trials has demonstrated an increased incidence of myocardial infarction and death in anaemic patients without life-threatening haemorrhagic shock.10 However, the analysis did not address the issue of “risk versus benefit” for use of these agents, including HBOC-201, in cases where blood transfusion for severely anaemic patients is not possible. A subsequent series of 54 consenting non-trauma patients with a median Hb level of 40 g/L demonstrated improved chances of survival with no serious adverse events following HBOC-201 administration.11 When blood transfusion is not possible, HBOCs can sustain oxygen delivery to hypoxic tissues.12 Such treatment may represent a life-saving intervention for patients with acute anaemia.13 Interest in safe and effective red blood cell substitutes for oxygen transport is increasing. Agents such as HBOC-201 show particular promise and could make a large difference to survival of trauma patients when blood is not accessible, available or acceptable. Haemoglobin and troponin I levels of a woman who was treated with a haemoglobin-based oxygen carrier (HBOC) following severe trauma * Troponin I levels were measured using the Architect i2000 immunoassay analyser (Abbott Diagnostics, Abbott Park, Ill, USA).

Mark C Fitzgerald MB BS, FACEM · Julie Y Chan MB BS(Hons), BMedSci · Andrew W Ross MB BS, FANZCA · Susan M Liew MB BS(Hons), FRACS(Orth) · Warwick W Butt MB BS, FCICM, FRACP · David Baguley MB ChB, BSc(Hons) · Hatem H Salem MB BS, FRACP · Matthias K Russ Orthopaedic and Trauma Surgeon (Germany) · Conor Deasy FACEM, FCEM, MB BCh BAO · Katherine E Martin MB BS, BMedSci, FRACS · Joseph K Mathew MB BS, MS · Jeffrey V Rosenfeld FRACS, FRCS(Edin), FACS

To the Editor: The levels of ferritin and folate in the blood are regarded as the “gold standards” for measuring deficiencies in iron and folate, but they are complex and expensive tests. The red cell distribution width (RDW-CV%) measures variability in red blood cell (RBC) size, helps in early detection of deficiencies and is available in all automated analyses of RBCs. It is seldom listed on haematology reports, though it can be printed out at no extra cost. A raised RDW-CV% should prompt the treating doctor to consider underlying latent deficiencies and to order specific tests. Pasricha and colleagues outlined the most efficient ways of diagnosing and managing iron deficiency anaemia.1 However, they did not mention RDW-CV%. Haemoanalysers measure the haemoglobin (Hb) content and size of individual RBCs. The average RBC size is the mean cell volume (MCV), and the variation in sizes is calculated as a standard deviation (SD). The haemoanalyser converts the MCV and SD to a coefficient of variation (CV) using the formula: Normal RBCs vary slightly in size, so the normal value of the RDW-CV% is 10%–15%. Greater variability gives a higher RDW-CV%. When a person becomes iron deficient, he or she forms small RBCs. The circulation will then contain a mixture of older normal RBCs and increasing numbers of newer small cells, until all the normal cells reach the end of their 120-day lifespan. It therefore takes several weeks for the Hb level and MCV to drop low enough to diagnostic levels for iron deficiency. However, the mixture of normal and small RBCs rapidly increases the variability in the size of circulating RBCs, so the RDW-CV% reaches pathological levels before other RBC measurements do.2 A raised RDW-CV% is the first haematological sign of iron deficiency. My computer model demonstrating the mechanism and timing of changes in Hb level and RDW-CV% showed a large and early rise in the initial stages of iron deficiency before anaemia (Box).3 In the anaemia of thalassaemia, the RDW-CV% is usually normal. In combination with other parameters, the RDW-CV% helps to classify anaemias. The sensitivity and specificity for diagnoses is about 80%,4 so the RDW-CV% result should be used as a screening tool to alert the clinician to a possible disorder that can be investigated using standard tests. I recommend the RDW-CV% be included in all routine blood reports. Computer model of changes in haemoglobin (Hb) levels and red cell distribution width (RDW-CV%) in developing iron deficiency anaemia. Iron deficient red blood cells were formed from Day 0

Alan E Dugdale

To the Editor: Hereditary haemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu syndrome manifests as vascular dysplasia involving the nose, skin, lung, brain and gastrointestinal tract. It is an inherited disorder manifesting as unbalanced angiogenesis.1 Bevacizumab is a recombinant, humanised monoclonal antibody that binds to and neutralises vascular endothelial growth factor (VEGF), preventing its association with endothelial receptors. VEGF binding initiates angiogenesis (endothelial proliferation and the formation of new blood vessels). VEGF and transforming growth factor β play a role in the pathogenesis of HHT, with affected patients having increased levels of these factors.2 Anecdotal reports have demonstrated the effectiveness of bevacizumab in patients with HHT. To date, good responses have been documented in patients presenting with epistaxis, haemoptysis, anaemia,3 pancreatic arteriovenous malformations4 and hepatic vascular abnormalities.5 We were referred a 71-year-old man who related a 45-year history of recurrent nose bleeds, pulmonary and gastrointestinal haemorrhage and significant facial and oral telangiectasias. He had a history of multiple hospital admissions for haemoptysis and malaena necessitating blood and iron transfusions. The patient averaged three blood transfusions and four iron infusions a year, and his haemoglobin level ranged from 90 to 120 g/L. The patient also received argon laser treatment for his gastric and duodenal telangiectasias, and was taking bovine colostrum for nosebleeds with minimal effect. Shaving resulted in regular bleeding as a result of his facial telangiectasias. Because of his significant morbidity, the patient was referred for a trial of bevacizumab therapy and underwent six cycles at 5 mg/kg by means of fortnightly intravenous infusion from March to May 2010. This treatment has resulted in an effective and tangible response. Since completing the treatment, the patient has been followed up monthly, and he reports only two nosebleeds compared with daily bouts before therapy. Further, the telangiectasias on his face and in his mouth have reduced considerably, and he has had only one gastrointestinal bleed, which occurred after heavy lifting. His haemoglobin level 2 weeks after treatment was 163 g/L and has remained stable since that time. A follow-up gastroscopy in November 2010 showed that his multiple vascular lesions had reduced to just one angiodysplastic lesion in his gastric body (Box). The only adverse effect he experienced from the bevacizumab was poor sleep with associated tiredness, but the patient was able to tolerate this in light of the amelioration of the symptoms of his HHT. Other reported side effects of bevacizumab such as hypertension, proteinuria and thrombosis did not manifest in this patient. With growing anecdotal evidence of the effectiveness of bevacizumab in treating symptomatic HHT, an argument for using bevacizumab as an adjunctive or even first-line treatment for HHT is becoming stronger. Gastroscopic images of the patient’s stomach before and after treatment with bevacizumab

Ross P Cruikshank · Boris W Chern

Clinical record A 57-year-old woman underwent an uncomplicated vaginal hysterectomy for vaginal prolapse. Three days later, she re-presented with ischaemic chest pain associated with inferior ST-segment elevation. Thrombolysis was not initiated, due to her recent operation. The patient was transferred to a tertiary hospital for an urgent coronary angiogram, which showed normal, smooth coronary arteries and a thrombus in the right posterolateral branch. The patient was conservatively managed. Investigations for a paradoxical embolus were unrevealing: the results of a bilateral lower limb Doppler ultrasound examination were negative, and a transthoracic echocardiogram showed no evidence of a patent foramen ovale. The patient was discharged home. Three days after discharge, she presented to our hospital with an acute, painless loss of vision in the superior medial quadrant of her right eye. An urgent ophthalmological consultation led to a diagnosis of retinal artery thrombosis. A bilateral carotid Doppler ultrasound result was unremarkable. This second thrombotic event within a short time prompted an examination for underlying thrombophilia. A screening test result for antiphospholipid antibodies was strongly positive: anticardiolipin IgG antibody, 143 units (reference range [RR], < 20 units); β2-glycoprotein IgG antibody, 185 units (RR, < 20 units); lupus anticoagulant, 1.5 (RR, < 1.3). Results of tests for factor V Leiden (R506Q) and prothrombin gene (20210) mutations and antithrombin III, protein C and protein S deficiencies were negative. On further questioning, our patient revealed that she had experienced intermittent visual blurriness in the right eye since 1992. She had previously been treated for a lupus-like condition with hydroxychloroquine. She had Raynaud’s phenomenon affecting her fingers, and chronic shoulder and limb pain. Interestingly, the patient also had Dupuytren’s contracture bilaterally in her hands and feet; this may have been part of her connective tissue disorder. While she was being treated, the patient’s visual symptoms resolved. Her hydroxychloroquine treatment had been discontinued several years previously because her test results for serum antinuclear antibody (ANA) became negative. A screen for autoimmune disease at our hospital showed a strongly positive ANA titre of 1/1280 (RR, < 1/160) with a finely speckled homogeneous pattern, consistent with a lupus-like connective tissue disorder. Additional screening test results for autoimmune disease (anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Scl-70, anti-Jo 1, anti-PCNA, antiribosomal P, anti-PM-Scl, and antismooth muscle) were negative. To prevent recurrent thrombotic events, warfarin treatment was commenced, aiming to achieve a target international normalised ratio of 2.5–3.5, and therapeutic enoxaparin was administered during the warfarin titration period. Hydroxychloroquine treatment was also begun, at a dose of 200 mg orally twice a day. We hypothesise that our patient had longstanding untreated connective tissue disease associated with antiphospholipid syndrome (APS). Her previous intermittent visual blurriness may have been caused by microthrombotic events. Her recent hysterectomy was the only major operation our patient had undergone (she had previously had a repair of Dupuytren’s contracture in her right foot). The recent surgery and associated release of inflammatory mediators may have been the trigger that caused endothelial activation in her coronary and retinal arteries, causing myocardial infarction and visual loss, respectively. APS can have multiorgan manifestations, and is commonly associated with a connective tissue disorder such as systemic lupus erythematosus (SLE).1 Unrecognised APS can have life-threatening consequences. It is a rare cause of myocardial infarction and, conversely, myocardial infarction is not an uncommon presentation of APS. In a cohort of 1000 patients with APS, 2.8% first presented with myocardial infarction.2 Recurrent coronary arterial thromboses have also been reported in patients with primary APS.3,4 Myocardial infarction due to APS is often undiagnosed initially, because the association between myocardial infarction and APS is under-recognised. Our case illustrates the importance of screening patients with SLE for APS, and highlights the importance of recognising and treating APS in patients with unusual recurrent thrombotic events. Lessons from practice Myocardial infarction associated with antiphospholipid syndrome is under-recognised. Antiphospholipid syndrome should be suspected in patients with unexplained, recurrent thrombotic events. Patients with systemic lupus erythematosus should be screened for antiphospholipid antibodies at baseline, with repeat screening when new thromboembolic risk factors arise. Low-dose aspirin should be considered in patients with systemic lupus erythematosus who test positive for antiphospholipid antibodies, as primary prevention of thrombosis and pregnancy loss. The European League Against Rheumatism (EULAR) recommends screening patients with SLE at baseline for antiphospholipid (aPL) antibodies, and to repeat screening in previously negative patients when there are new risk factors for thromboembolism, such as pregnancy, surgery, transplantation and use of oestrogen-containing treatments.5 The other indications for screening patients for aPL antibodies are recurrent venous and/or arterial thromboses, especially in patients younger than 50 years, recurrent miscarriages or fetal loss and early or severe pre-eclampsia.1 SLE and a positive test result for aPL antibodies, especially persistent anticardiolipin antibodies and lupus anticoagulant, increase the risk of thrombosis.1 Data on primary prevention in asymptomatic patients are limited. EULAR recommends consideration of low-dose aspirin in patients with SLE for primary prevention of thrombosis and pregnancy loss.6 However, asymptomatic individuals testing positive for aPL antibodies do not appear to benefit from aspirin.7 For patients with SLE or a lupus-like connective tissue disease who test positive for aPL antibodies, we recommend making a case-by-case decision on primary prevention, based on an assessment of each patient’s thromboembolic risk profile.

Bo Xu MB BS(Hons) · John Hounsell FRACP

Objective: To determine the impact that mandatory fortification with folic acid of wheat flour used in breadmaking has had on the blood folate levels of an Australian population since it was introduced in September 2009.Design, setting and patients: A retrospective analysis of serum and red blood cell (RBC) folate levels of 20 592 blood samples collected between April 2007 and April 2010 from a wide variety of inpatients and outpatients and analysed in a large public hospital diagnostic pathology laboratory.Main outcome measures: Prevalences of low levels of serum and RBC folate and monthly mean levels before and after introduction of mandatory fortification.Results: Between April 2009 and April 2010, there was a 77% reduction in the prevalence of low serum folate levels (from 9.3% to 2.1%) in all samples tested and an 85% reduction in the prevalence of low RBC folate levels (from 3.4% to 0.5%). In April 2010, the prevalence of low RBC folate levels for females of childbearing age was 0.16% for all samples. There was a 31% increase in mean serum folate level (from 17.7 nmol/L to 23.1 nmol/L; t = 9.3, P < 0.01), and a 22% increase in mean RBC folate level (from 881 nmol/L to 1071 nmol/L). The greatest increment in mean serum folate levels occurred in September 2009, the month that mandatory fortification was introduced, although there was evidence of a gradual change during the preceding months.Conclusion: The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia, including in women of childbearing age.

Ross D Brown PhD, MBA, FAIMS · Mark R Langshaw BAppSci, GradDipIT · Elaine J Uhr MSc(BiolSc) · John N Gibson PhD, FRACP, FRCPA · Douglas E Joshua DPhil, FRACP, FRCPA

Objective: To describe the clinical features and laboratory findings in patients with definite red-bellied black snake (RBBS; Pseudechis porphyriacus) bites, including correlation with results of venom assays. Design, patients and setting: Prospective cohort study of patients with definite RBBS bites, recruited to the Australian Snakebite Project from January 2002 to June 2010. Main outcome measures: Clinical and laboratory features of envenoming; peak venom concentrations and antivenom treatment. Results: There were 81 definite RBBS bites; systemic envenoming occurred in 57 patients (70%) and local envenoming alone occurred in one patient. Systemic envenoming was characterised by local envenoming in 55 patients (96%), systemic symptoms in 54 patients (95%), anticoagulant coagulopathy with a raised activated partial thromboplastin time (aPTT) in 35 patients (61%) and myotoxicity in seven patients (12%). One patient required non-invasive ventilation for severe myotoxicity that resulted in muscle weakness. Three patients developed local ulceration. There were no deaths. Twenty-two envenomed patients (39%) received tiger snake or black snake antivenom, and administration within 6 hours of the bite was associated with normalisation of the aPTT. Eight patients (36%) had immediate hypersensitivity reactions to antivenom, including one case of anaphylaxis. The median peak venom concentration in 37 systemically envenomed patients with serum available was 19 ng/mL (interquartile range, 12–50 ng/mL; range, 3–360 ng/mL), which did not correlate with clinical severity. In 17 patients who received antivenom and had venom concentration measured, no venom was detected in serum after the first antivenom dose, including nine who were given one vial of tiger snake antivenom. Conclusion: RBBS envenoming caused local effects, systemic symptoms, anticoagulant coagulopathy and, uncommonly, myotoxicity. One vial of tiger snake or black snake antivenom appears to be sufficient to remove venom and neutralise reversible effects, but hypersensitivity reactions occurred in over a third of patients.

Andrew Churchman BM BS(Hons) · Margaret A O’Leary PhD · Nicholas A Buckley BMed, FRACP, MD · Colin B Page MB ChB, FACEM, MMedSci(Clin Epi) · Alan Tankel BSc, MB ChB, FACEM · Chris Gavaghan MB BS, FACEM · Anna Holdgate MB BS, FACEM, MMed · Simon G A Brown MB BS, FACEM, PhD · Geoffrey K Isbister BSc, FACEM, MD

Iron deficiency anaemia (IDA) remains prevalent in Australia and worldwide, especially among high-risk groups. IDA may be effectively diagnosed in most cases by full blood examination and serum ferritin level. Serum iron levels should not be used to diagnose iron deficiency. Although iron deficiency may be due to physiological demands in growing children, adolescents and pregnant women, the underlying cause(s) should be sought. Patients without a clear physiological explanation for iron deficiency (especially men and postmenopausal women) should be evaluated by gastroscopy/colonoscopy to exclude a source of gastrointestinal bleeding, particularly a malignant lesion. Patients with IDA should be assessed for coeliac disease. Oral iron therapy, in appropriate doses and for a sufficient duration, is an effective first-line strategy for most patients. In selected patients for whom intravenous (IV) iron therapy is indicated, current formulations can be safely administered in outpatient treatment centres and are relatively inexpensive. Red cell transfusion is inappropriate therapy for IDA unless an immediate increase in oxygen delivery is required, such as when the patient is experiencing end-organ compromise (eg, angina pectoris or cardiac failure), or IDA is complicated by serious, acute ongoing bleeding. Consensus methods for administration of available IV iron products are needed to improve the utilisation of these formulations in Australia and reduce inappropriate transfusion. New-generation IV products, supported by high-quality evidence of safety and efficacy, may facilitate rapid administration of higher doses of iron, and may make it easier to integrate IV iron replacement into routine care.

Sant-Rayn S Pasricha MB BS, MPH · Stephen C Flecknoe-Brown MB BS, FRACP, FRCPA · Katrina J Allen MB BS, FRACP, PhD · Peter R Gibson MD, FRACP · Lawrence P McMahon MD, BS, FRACP · John K Olynyk MB BS, MD, FRACP · Simon D Roger MD, FRACP · Helen F Savoia MB BS, FRCPA · Ramdas Tampi MB ChB, FRACP, FRCPA · Amanda R Thomson MB BS, FRACP, FRCPA · Erica M Wood MB BS, FRACP, FRCPA · Kathryn L Robinson MB BS, FRACP, FRCPA

The take-home message is not only early intervention but education and teamwork I was due to fly out to the United States the next morning. I was bending down to clean the floor of my car when it happened. First my right hand wouldn’t respond and I fumbled picking up a spoon from the floor, then my right leg wouldn’t support my weight. I tried to call out to my wife but only grunts came out, except of course the f-word when I knew what had happened. I crawled to the front door of the house, my intensivist wife called 000 and the ambulance was there in 3 minutes! The paramedics ignored my pleas to go to the closer private hospital ... “no you’re off to the Stroke Unit at The Alfred” ... and wasted no time — scoop and run. I was in the resuscitation bay of the emergency department (ED) in 20 minutes and, despite it being late on a Friday night, I was assessed, I had my computed tomography (CT) scan to exclude an intracranial haemorrhage, and the intravenous thrombolytic therapy was running within 60 minutes. The next day a repeat CT scan and a magnetic resonance imaging scan confirmed multiple small infarcts in the insula consistent with an embolic stroke. A patent foramen ovale (PFO) showed up on the transoesophageal echocardiogram on Day 3 and the PFO was occluded, percutaneously, on Day 7. I was home the next day and back at work 3 weeks later, with no significant residual deficit. Bending over in the car may have been the trigger, with a Valsalva that opened up the PFO and caused the clot to flip up my left middle cerebral artery (MCA) into the insular cortex. It is pleasing when published data justifies one’s own teaching; it is even more encouraging when it justifies treatment that affects one’s own life and health. Every 10 minutes, up to 20 million neurones will die in a typical infarct in the MCA territory, if not recanalised.1 A recent updated pooled analysis of eight trials using multivariate logistic regression has been used to assess the relationship of onset-to-treatment time with 3-month morbidity, brain haemorrhage and mortality.2 When selected by symptoms and CT findings, the critical time from onset of symptoms to the intravenous infusion of recombinant tissue plasminogen activator (rt-PA) seems to be 3 hours, though that window of opportunity can be increased to 4.5 hours, after which risk may outweigh benefit. After 4.5 hours, the risk, particularly of reduced recovery of brain function, brain haemorrhage and death, increases. However, not all patients benefit. It was shown that about five patients need to be treated within 0–90 minutes of symptom onset, nine patients within 91–180 minutes or 15 patients within 181–270 minutes for one of them to have an excellent outcome attributed to treatment. Clearly rt-PA is not a panacea, and other interventions need to be analysed for the ultimate objective of reperfusion of 100% of patients rather than 40%. Other modalities need to be investigated, particularly the therapeutic combinations of thrombolytics, neuroprotectives and antithrombotics in addition to ultrasound and endovascular mechanical clot manipulation.1 My experience with swift prehospital assessment and efficient ED intervention with intravenous rt-PA, after sustaining an acute ischaemic stroke, with full recovery, emphasises that time is critical.1 However, the take-home message here is not only early intervention but education and teamwork, similar to the model in trauma care — the “golden hour” and a well trained trauma team.3 For stroke management, this means the development of stroke centres, training of prehospital and emergency staff, prioritisation of patients to achieve door-to-needle times of less than 60 minutes and public education programs on acting early with the onset of symptoms.1,4 For me, it may have been luck: stroking out at home and not in the air; having a medico wife who recognised the signs; a paramedic crew trained to scoop and run and to take me to an ED with a stroke unit, not just passing by the end of my street when they got the call; ED staff who wasted no time; a neurology registrar who started the rt-PA immediately, though pointing out to me and my wife the risks of intracranial haemorrhage; and having a well trained team of health professionals in the Stroke Unit. Some cynics might say I got red carpet treatment because I am a professor of surgery. I disagree. I believe it was not just a stroke of luck but that I benefited from the ideal model of care of stroke management that should be available to all Australians.

Bruce P Waxman FRACS, FACS, MRACMA

Objectives: To examine 5-year survival from haematological malignancies in children, adolescents and young adults in Australia and determine if there has been any improvement in survival for the older age groups compared with children (the age-related “survival gap”).Design, setting and participants: Population-based study of all Australian children (aged 0–14 years), adolescents (15–19 years) and young adults (20–29 years) diagnosed with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) between 1982 and 2004, with follow-up to 2006.Main outcome measures: 5-year survival from ALL, AML, HL and NHL analysed for four periods of diagnosis (1982–1989, 1990–1994, 1995–1999 and 2000–2004).Results: During 1982–2004, 13 015 people aged ≤ 29 years were diagnosed with primary leukaemia or lymphoma in Australia. For those with ALL, 5-year survival for adolescents improved from 40% (1982–1989) to 74% (2000–2004); the improvement for young adults was smaller (31% to 47%), and both these groups still had lower survival than children, whose 5-year survival improved from 74% to 88%. There was a larger narrowing of the gap for AML: for cases diagnosed in 2000–2004, 5-year survival was similar for young adults (63%), adolescents (74%) and children (69%). For lymphoma cases diagnosed in 2000–2004, 5-year survival in all age groups was greater than 95% for HL and greater than 81% for NHL, although children fared better than adolescents and young adults.Conclusions: These Australian population-based data confirm an improvement in survival from haematological malignancies across all three age groups, but an age-related survival gap remains for adolescents and young adults compared with children, especially for young adults with ALL. Greater participation of adolescents and young adults in clinical trials and more detailed data collection are needed to provide evidence about optimal treatment regimens in these age groups.

Ross Pinkerton MD, FRACP · Rachael-Anne Wills BAppSc(Hons) · Michael D Coory FAFPHM, PhD · Christopher J Fraser MB BS, FRACP, MPH

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

Dabigatran etexilate was recently approved by the Therapeutic Goods Administration for thromboprophylactic use in adults undergoing elective total hip or knee replacement. Dabigatran etexilate is the prodrug of the active moiety dabigatran, an orally active agent that could replace enoxaparin in some clinical indications. Dabigatran is a direct thrombin inhibitor; it has stable, predictable pharmacokinetics and does not require routine monitoring. Pooled efficacy data from large-scale phase III clinical trials of dabigatran use in orthopaedic thromboprophylaxis have shown non-inferiority to enoxaparin, with total venous thromboembolism results of 3.8% for dabigatran etexilate 150 mg and 3.0% for dabigatran etexilate 220 mg, compared with 3.3% for enoxaparin. Pooled safety results for dabigatran are similar to those for enoxaparin, with major bleeding rates of 1.1% for dabigatran etexilate 150 mg and 1.4% for dabigatran etexilate 220 mg, compared with 1.4% for enoxaparin. Dabigatran failed to demonstrate non-inferiority compared with enoxaparin 30 mg twice daily for orthopaedic thromboprophylaxis. Issues relating to the use of dabigatran include its lack of antidote, limited application in renal disease, and interaction with drugs such as amiodarone and verapamil. Several trials investigating the use of dabigatran for other indications, such as stroke prevention in atrial fibrillation and acute coronary syndromes, are underway. Given its safety profile, efficacy, oral bioavailability and stable pharmacokinetic properties, dabigatran may be a viable alternative to enoxaparin for thromboprophylaxis in orthopaedic surgery.

Abhishek K Verma BSc(Med), MB BS

As sickle cell disease is increasing in Australia, paediatricians and other health care providers need to be aware of the broad range of complications that can occur in this condition. Although the complications of splenic sequestration and chest crises are well recognised, the infrequent but equally dramatic complication of hyperhaemolysis is less well appreciated. Here, we report a case of hyperhaemolysis in a Victorian paediatric patient.11 Clinical recordA 12-year-old boy with sickle cell disease (homozygous haemoglobin S) presented in July 2006 with abdominal pain and fever — symptoms of a vaso-occlusive crisis. His usual baseline haemoglobin level ranged from 65 g/L to 75 g/L. He was thriving, but had a history of numerous vaso-occlusive crises. His past management included repeated transfusions with Rhesus and Kell phenotypically matched, leukocyte-depleted (LD) red cells. During this admission, he was managed with intravenous (IV) fluids, IV analgesia, antibiotics and a transfusion of 1 unit of phenoytpically matched, crossmatch compatible, LD red cells. His pain gradually resolved and he was discharged home. Twenty-four hours after discharge (7 days after the transfusion), he re-presented with marked lethargy, jaundice, tachycardia, and no increase in splenic size. His haemoglobin level was 45 g/L and reticulocyte count was increased, at 444 × 109/L (reference range, 20–200 × 109/L). He received a transfusion of a further 2 units of red cells (about 500 mL). However, he remained pale after the transfusion and his haemoglobin level had further decreased to 39 g/L. He also developed profuse haemoglobinuria. Based on his estimated blood volume of 2350 mL, the total transfusion of 750 mL during the two admissions would equate to an increase in haemoglobin of 55 g/L, so the observed drop in haemoglobin level was consistent with haemolysis of both recipient and donor red cells. No red cell alloantibodies or autoantibodies were detected. A presumptive diagnosis of sickle cell hyperhaemolysis syndrome was made. Further transfusions were avoided, and the patient was treated with IV immunoglobulin (IVIG) (1 g/kg) and high-dose IV steroids (methylprednisolone, 20 mg/kg/day). IV mannitol and hyperhydration were commenced to avoid free haemoglobinaemia-associated renal damage. The patient recovered after 1 week and was discharged, with a haemoglobin level of 71 g/L. Six months later, the patient experienced a further episode of marked haemolysis that occurred after a red cell transfusion for vaso-occlusive crisis. He presented to hospital 5 days after the transfusion with a 48-hour history of increasing pain, increased jaundice and discoloured urine. His bilirubin level was 129 μmol/L (reference range, < 10 μmol/L) (unconjugated, 125 μmol/L; conjugated, 4 μmol/L), which was greater than a previous measurement of 77 μmol/L. Again, no red cell alloantibodies or autoantibodies were detected, and his reticulocyte count was elevated, at 303 × 109/L. His haemoglobin level continued to fall after admission, reaching 24 g/L after 24 hours. He was managed with further IVIG and high-dose steroids. In view of his ongoing marked, symptomatic anaemia after 3 days of this treatment, he was transfused with 250 mL of phenotypically matched red cells, without complication, and was discharged 2 days later with a haemoglobin level of 71 g/L. He did not re-present with further haemolysis. Follow-up is ongoing, with management as clinically indicated. This was a prolonged and dramatic event for the child and his family. Placing him on a regular transfusion program was discussed, but the risks of repeated transfusions and the possibility, although small, of another hyperhaemolysis event were considered to outweigh the benefits of maintaining a higher haemoglobin level in a child who was thriving. If a regular transfusion program were to be considered again in the future, it would be prudent to assess the risks and benefits of exchange transfusion. Treatment with erythropoietin was also considered but deemed unnecessary at this time. Pretransfusion steroid treatment was considered an appropriate addition to the future management of this patient. DiscussionSickle cell disease is increasing in incidence in Australia due to immigration patterns involving increasing numbers of people from regions where the disease is common, such as Africa.1 Although hyperhaemolysis in sickle cell disease has been recognised for more than 20 years, this case highlights it as an uncommon but potentially life-threatening complication, involving destruction of both donor and recipient red cells after red cell transfusion.2-5 Haemolysis can be rapid and profound. Onset is usually within 7 days after transfusion and is characterised by severe intravascular haemolysis, haemoglobinuria, and anaemia to levels of haemoglobin lower than pretransfusion levels. Reticulocytopenia may be present. Hyperhaemolysis has also been reported in patients with β thalassaemia and myelofibrosis.6,7 Recurrent hyperhaemolysis is unusual in children, with few available data pertaining to this phenomenon in the paediatric population. The information provided by patients in whom recurrence occurs is particularly valuable. Human leukocyte antigen antibodies were not tested in the patient described here, nor were his haemoglobin S levels followed during these episodes. Measurement of these parameters in other affected patients would add to the body of data and knowledge on hyperhaemolysis. The exact mechanisms responsible for hyperhaemolysis are not fully understood. High-performance liquid chromatography analysis of urine in a patient with haemoglobinuria after red cell tranfusion demonstrates both donor and recipient haemoglobin.8 In typical haemolytic transfusion reactions, alloimmune mechanisms are responsible, with the development of red cell antibodies in the patient against antigens present on donor red cells. The antigens most commonly implicated are those of the Rhesus, Kell, Kidd, Duffy and MNSs blood group systems. Haemolytic reactions due to alloimmunisation are associated with haemolysis of donor red cells only, and laboratory testing usually leads to identification of the causative red cell antibodies. Suggested mechanisms for hyperhaemolysis include cytokine-mediated haemolysis or uncontrolled macrophage activation.9-11 Recommended treatment of hyperhaemolysis includes avoidance of transfusion where possible and immune modulation with steroids and IVIG.3,5,8 The mechanism of action of steroids and immunoglobulin has not been fully elucidated, but these treatments have been demonstrated to be effective in a number of patients. Repeated exposure to red cells after recovery may lead to recurrence of hyperhaemolysis, as seen in this case. Erythropoietin may be used in an attempt to reduce the need for further exposure to transfused red cells.3 Prompt referral for expert management is essential. Hyperhaemolysis is an uncommon but potentially fatal complication of sickle cell disease. Recognition of this unusual complication is important for medical staff who manage patients with sickle cell disease in Australia.

Ian C Stokes BSc(Hons), BM BS · Peter A Downie MB BS, FRACP · Erica M Wood MB BS, FRACP, FRCPA · Donald K Bowden MB BD, FRACP · Paul T Monagle MB BS, FRACP, FRCPA · Chris D Barnes MB BS, FRACP, FRCPA

To the Editor: The recent article by Lowthian and colleagues raises some important concerns regarding current management of warfarin therapy in Australia, especially the provision of quality warfarin education.1 While the study focused on the uncertainty surrounding who is responsible for this task, additional barriers to providing warfarin education include limited access to suitable resources and a tendency to rely on a single verbal counselling session and/or the supply of written material, often just before discharge from hospital.2 As Lowthian et al note, it is plausible that warfarin education was provided to the patients interviewed; it may simply have been inadequate to meet their needs or delivered at the wrong time or place. It is not always feasible for health care providers to reliably provide the necessary education in busy health care settings (eg, general practitioners when prescribing warfarin, pharmacists when supplying it). The authors note a potential role for practice nurses in providing this education; we would also like to highlight the role of accredited pharmacists, who can visit patients in their homes and provide targeted medication-related education. An annual Home Medicines Review can be provided for patients taking high-risk medications such as warfarin.3 Under the Fourth Community Pharmacy Agreement Research and Development Program, the Pharmacy Guild of Australia has funded two projects that are attempting to meet the education needs of patients taking warfarin. One project is trialling a comprehensive postdischarge service involving a series of follow-up home visits by trained accredited pharmacists, to provide not only warfarin education but also point-of-care international normalised ratio monitoring, in liaison with the patients’ GPs. The other project is piloting a process whereby community pharmacists can identify potential candidates for patient self-monitoring of warfarin and, with GP collaboration, organise suitable training, with ongoing support from the pharmacist and GP. Patient self-monitoring, although not widely practised in Australia, has been shown to provide the best clinical outcomes for suitable candidates.4 An important component of these two projects is a website, launched in late 2008, containing a range of free, downloadable educational resources for both consumers taking warfarin and health care professionals responsible for its management (http://www.anticoagulation.com.au). Education is crucial in achieving optimal health outcomes for patients taking warfarin, and health care professionals should cooperate to ensure their patients are well educated. This should involve regular reinforcement of consistent messages, and can also involve better use of existing services and educational tools.

Luke R E Bereznicki · Leanne Stafford · Ella C Jeffrey · Gregory M Peterson · Shane L Jackson

In reply: Bereznicki and colleagues have reinforced the importance of patient education in optimising warfarin safety, while highlighting the need for role clarification in its provision. We applaud the Pharmacy Guild of Australia’s sponsorship of research projects trialling different models of service delivery, such as the coordination of postdischarge warfarin home care by pharmacists and support of patient self-monitoring programs, where appropriate. The success of such care models will be enhanced by a collaborative partnership between the patient and all members of the warfarin care team.1 In addition, appraisal of patient suitability for programs such as patient self-monitoring requires systematic and regular evaluation of cognitive function, compliance and health literacy, to reduce the likelihood of adverse events.2-4 Likewise, ongoing education with resources tailored to individual patients’ capabilities will optimise patient safety.5

Judy A Lowthian · Basia O Diug · Sue M Evans · Ellen L Maxwell · Alison M Street · Leon Piterman · John J McNeil

To the Editor: Lowthian and colleagues ask who is responsible for the care of patients treated with warfarin therapy.1 In Melbourne, it seems that this devolves mainly upon the pathology laboratory, whereas in other states, general practitioners manage care for their own patients, in my own experience. Where management of warfarin dosing, based on the international normalised ratio (INR) result, is performed by the laboratory, this is done as a courtesy to GPs. This practice possibly evolved from competition between private laboratories and, as such, may have been intended to induce other pathology requests to the service provider. Larger metropolitan private pathology services may have sufficient pathologists with haematology training to provide warfarin dosing to patients, but this may not always apply in smaller laboratories. In some laboratories, warfarin dosing may be provided to patients by scientific staff. Although warfarin therapy can sometimes be challenging, its difficulties are not usually insurmountable. Problems for pathologists arise because they are expected to give a warfarin dose by telephone to a patient they do not know and have never seen. The patient’s phone number may be not supplied or incomplete, and the call may not be answered. If answered, a brief history of previous INR results, dosages and test intervals may or may not be elicited from a person who may have poor English, who may be the patient, a relative, friend or neighbour; or a message may have to be left. If the message is received, it may not be acted on, depending on memory, understanding or level of compliance. If the message is not received, the patient and the patient’s GP may be unreasonably irate, even though multiple attempts to contact the patient may have been made. It is not hard to understand why some GPs prefer to pass this often frustrating and time-consuming aspect of treatment to pathologists — who may also be pressed for time. Problems are further compounded if warfarin dosing devolves to pathology laboratory scientists, which may be required by their employer. Scientists would be, in effect, performing drug dosing without medical training or medical registration and may be exposing themselves to litigation risk, without carrying medical indemnity. In other Australian states, it seems that GPs do provide treatment and dosing of warfarin for their own patients. In my view, this is the safest and most satisfactory outcome for patients, pathologists and scientists. With the projected advent of point-of-care testing with reliable INR results2 and new anticoagulant alternatives1 that would enable easier management of anticoagulant therapy by GPs, this whole issue could potentially be resolved.

John C Roberts

To the Editor: I appreciated Brukner’s perspective on treatment of venous thromboembolism (VTE),1 but I do feel some additional considerations and clarifications are in order. Quotes from Kearon2 and Kearon and colleagues3 about the duration of therapy are missing an important caveat. The suggestion for longer duration and possibly “indefinite” anticoagulant therapy after a first deep vein thrombosis or pulmonary embolism is in reference to unprovoked VTE. Brukner1 mentions a plane flight from China to Australia 3 days before he experienced a symptomatic pulmonary embolism. According to guidelines issued by the American College of Chest Physicians, such a flight (although I cannot comment with certainty on its duration) is likely to represent a reversible minor risk factor for VTE — “prolonged travel (eg, > 8 h)”.3 Indeed, Kearon2 and the authors of a related research article to which he refers4 make the important distinction between provoked and unprovoked VTE. Kearon comments: For patients with a minor reversible risk factor, the risk of recurrence is about 5% in the first year after stopping anticoagulant therapy. This is considered low enough to justify stopping anticoagulant therapy at the end of 3 months.2 Additional factors and preferences are also important when considering prolonged anticoagulant therapy for individual patients. For instance, I can empathise with the 25-year-old who wants to discontinue warfarin therapy after 6 months following a first unprovoked VTE — another 50 years of warfarin therapy might seem a disheartening burden. And certainly we must take into account other variables that may increase a patient’s risk of bleeding complications while receiving warfarin therapy, such as older age, the presence of other acute or chronic illnesses and the use of other medications, particularly antiplatelet therapy.3 For someone such as Brukner,1 who claims that his anxiety about a recurrence of VTE is reduced by staying on warfarin therapy, I would probably say, “That’s OK by me, as long as you are aware of the risks and implications of provoked and unprovoked VTE”. For other patients with unprovoked VTE who may not want to continue indefinite anticoagulant therapy, there are other management options worth discussing. First, there is the possibility of further risk stratification for VTE recurrence by testing D-dimer levels. This strategy is receiving considerable study and validation as a useful tool for predicting VTE recurrence.5,6 Second, for patients who refuse to continue warfarin therapy but would consider other therapies for reducing their risk of having a recurrence of VTE, I would suggest taking a daily low dose of vitamin E, which has shown some benefit in reducing VTE.7 Finally, the ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) Trial, which is currently underway, should provide a definitive answer as to whether aspirin is a safe and effective option for secondary VTE prevention. If the trial supports the use of aspirin for this purpose, it would offer another VTE risk-reduction option for those who prefer not to take warfarin indefinitely.8

James A Fink

To the Editor: Brukner’s personal perspective in a recent issue of the Journal highlights the inherent difficulty of managing patients taking warfarin.1 Although Brukner advocates life-long warfarin therapy for patients who have experienced a pulmonary embolism, we believe few clinicians would be willing to expose their patients to the increased risk of haemorrhage associated with long-term warfarin therapy, especially if a transient risk factor for venous thromboembolism (VTE) existed (such as frequent air travel, in Brukner’s case). There is an abundance of conjecture regarding the appropriate duration of warfarin therapy for VTE, with guidelines and clinical intuition often differing. But it is possible that, in the future, decisions about the appropriate duration of warfarin therapy may be guided by the use of pharmacogenetics. Pharmacogenetics gives clinicians an insight into how a patient’s genetic profile affects his or her ability to metabolise drugs, thereby allowing doctors to better tailor the dose and duration of the patient’s medications. In the case of warfarin, metabolism of S-warfarin (the more potent enantiomer in the racemic warfarin mixture) occurs via the cytochrome P450 system, specifically enzyme CYP2C9.2 Studies have shown that patients who metabolise warfarin normally are homozygous for the wild-type allele CYP2C9*1, whereas patients with polymorphisms in the CYP2C9 allele have reduced warfarin metabolism and increased risk of bleeding.3 The anticoagulation effect of warfarin actually occurs via inhibition of the C1 subunit of the vitamin K 2,3-epoxide reductase complex (VKORC1).4 Numerous polymorphisms have been identified in VKORC1, and it is speculated that VKORC1 polymorphisms alone may account for a significant proportion of response variability to warfarin.4 Validated algorithms have been developed to combine information on a patient’s CYP2C9 and VKORC1 genotypes with factors such as age and body surface area to identify an appropriate warfarin regimen.5 Although the pharmacogenetic information required to employ this algorithm has not been assessed for cost-effectiveness, it is quite possible that clinicians will be able to use such pharmacogenetic information to their advantage in the future. This would allow doctors to identify with greater precision which patients are likely to benefit from warfarin (and how much is required, for how long), rather than relying on equivocal evidence and clinical intuition alone.

Amit K Verma · Ajai K Verma

Pregnancy and delivery are critical times for women with bleeding disorders, with mothers, and possibly their affected infants, being exposed to a variety of haemostatic challenges. Management of women with bleeding disorders during pregnancy involves a multidisciplinary team including, but not limited to, an obstetrician, an anaesthetist and a haematologist. This consensus document from the Australian Haemophilia Centre Directors’ Organisation (AHCDO) provides practical information for clinicians managing women with bleeding disorders during pregnancy. Included are: the expected physiological response in pregnancy in such women; management of pregnancy, labour and delivery, as well as obstetric anaesthesia issues, postpartum care, and reducing and treating postpartum haemorrhage; and management of infants at risk of a bleeding disorder and of bleeding in neonates. The guidelines were developed after extensive consultation, face-to-face meetings and revisions. The final document represents a consensus opinion of all AHCDO members. Where evidence is lacking, recommendations are based on clinical experience and consensus opinion.

on behalf of the Australian Haemophilia Centre Directors’ Organisation

Objective: To describe demographic, geographical and clinical features of envenoming by the rough-scaled snake (RSS) (Tropidechis carinatus).Design, setting and participants: Prospective cohort study of RSS snakebite victims, recruited between January 2004 and December 2008, as part of the Australian Snakebite Project. RSS envenoming cases were confirmed by snake identification and/or venom-specific enzyme immunoassay.Main outcome measures: Clinical and laboratory features of envenoming.Results: There were 24 confirmed cases of RSS envenoming, nearly all occurring in coastal areas between northern New South Wales and south-eastern Queensland. Twenty-three patients had local bite-site effects and 17 had at least three non-specific systemic effects (eg, nausea, headache). All 24 had venom-induced consumption coagulopathy (VICC), and 19 had an international normalised ratio > 3.0. Six had bleeding from the bite site or intravenous cannula site, 10 had blood detected on urinalysis, and one had a major intra-abdominal haemorrhage. Mild neurotoxicity developed in two patients, and one patient developed myotoxicity with generalised myalgia, myoglobinuria and a peak creatine kinase level of 59 700 IU/L. Twenty-three patients were treated with antivenom (21 with tiger snake antivenom, two with polyvalent antivenom). Free venom was undetectable in 19 of 20 blood samples taken after antivenom administration.Conclusion: RSS envenoming occurs predominantly in coastal areas of northern NSW and southern Queensland, and within this range, most envenoming is due to the RSS rather than tiger snakes. Clinically it is characterised by VICC, with mild neurotoxicity and myotoxicity in some cases. Tiger snake antivenom appears to be effective against RSS envenoming.

Melissa Gan MB BS · Margaret A O’Leary PhD · Simon G A Brown MB BS, FACEM, PhD · Tamara Jacoby BSc · David Spain MB BS, FACEM · Alan Tankel FACEM · Chris Gavaghan MB BS, FACEM · Peter Garrett MB BS, FACEM · Geoffrey K Isbister BSc, FACEM, MD

The risk of bleeding, as well as patient preferences, must be considered when deciding duration of warfarin therapy Venous thromboembolism (VTE) affects about 17 000 Australians each year, usually as deep vein thrombosis (DVT) of the legs or pulmonary embolism (PE).1 The sequelae of VTE include death, post-thrombotic syndrome, chronic pulmonary thromboembolic disease and recurrent VTE. Anticoagulation with an oral vitamin K antagonist (warfarin), overlapped for the first 5–7 days with unfractionated heparin, low-molecular-weight heparin or fondaparinux, prevents thrombus progression and reduces the risk of recurrent VTE and death during the acute phase.2,3 When treatment is continued beyond the acute phase, warfarin reduces the risk of recurrent VTE but increases the risk of bleeding and requires frequent laboratory monitoring, which is inconvenient for patients. Thus, decisions regarding the optimal duration of anticoagulant therapy must balance the increased risk and sequelae of recurrent VTE when warfarin is stopped against the risk of bleeding and the inconvenience of continuing treatment.3 Many randomised controlled trials have evaluated the optimal duration of anticoagulant therapy in patients with VTE, and their results can be summarised as follows: In patients with a first episode of VTE that is provoked by a reversible risk factor, 3 months of anticoagulant therapy halves the risk of recurrence compared with the level of risk achieved with 1 month of therapy.4 The risk of recurrence beyond 3 months is low.4 In patients with isolated provoked or unprovoked calf DVT, 6 weeks of anticoagulant therapy is as effective as 3 months’ therapy.5 In patients with a first episode of unprovoked VTE, 3 months of anticoagulant therapy is as effective as 6 months’ therapy,5,6 but there is a high rate of recurrence (about 10%) during the first year after stopping warfarin; in subsequent years, the recurrence rate decreases to 3%–4% per annum.7,8 Continuing warfarin treatment beyond the acute phase for 1–2 years reduces the risk of recurrence during treatment by as much as 90% compared with no warfarin, but a “catch-up” phenomenon occurs after stopping warfarin, so that after several years the risk of recurrence is similar in patients who are treated for 3 months compared with those treated for 12 months.9 Although the efficacy of long-term treatment with vitamin K antagonists for preventing recurrent VTE is impressive and consistent,7,8,10 pooled data from 10 trials involving 4833 participants provide no evidence that long-term anticoagulant therapy reduces fatal PE.8 Trial data show that continuing warfarin treatment beyond 3 months is associated with an annual risk of major bleeding of 1%–3%,11 and the incidence of major bleeding is likely to be even higher in unselected patients not enrolled in a clinical trial. Long-term warfarin therapy targeting an international normalised ratio (INR) of 1.5–2.0 is less effective for the prevention of recurrent VTE than warfarin therapy targeting an INR of 2.0–3.0; nor does the lower target ratio reduce the risk of bleeding.12 Several new oral anticoagulants (eg, rivaroxaban, apixaban, dabigatran etexilate) that selectively target coagulation factor Xa or factor IIa (thrombin) are in advanced stages of clinical development.13 These agents appear to be attractive alternatives to warfarin for long-term management of patients with VTE because they can be given in fixed daily or twice-daily doses without laboratory monitoring. However, it remains to be seen whether the new oral anticoagulants will provide a more favourable risk–benefit profile than warfarin during long-term treatment. Our recommendations for duration of anticoagulant therapy for VTE (Box) are generally consistent with those of the 2008 American College of Chest Physicians guidelines.14 The risk of bleeding and patient values and preferences must be taken into account when making treatment decisions. Patients with acute DVT or PE or both should receive warfarin for a minimum of 3 months. An exception is patients with isolated calf DVT, for whom 6 weeks of warfarin treatment is adequate. Patients whose first episode of proximal DVT or PE is provoked by a transient risk factor (eg, surgery) can stop treatment after 3 months because they have a relatively low risk of recurrence after warfarin is discontinued. Patients with a persisting reversible risk factor should continue taking warfarin until the risk is no longer present. Compared with those who experience provoked VTE, patients with a first episode of unprovoked proximal DVT or PE have a substantially higher risk of recurrence after warfarin treatment is discontinued, presumably because they have a chronic propensity to thrombus formation. However, there is little point in continuing treatment beyond 3–6 months in these patients unless a decision is made to treat indefinitely, as the benefits of extended treatment are lost when warfarin is discontinued. Long-term or indefinite warfarin therapy seems reasonable for patients with a history of limb- or life-threatening VTE, chronic pulmonary thromboembolism or severe post-thrombotic syndrome, and for patients who prefer to continue anticoagulant treatment. Indefinite treatment also seems reasonable for patients at very high risk of recurrence, such as those with a history of recurrent unprovoked VTE, high-risk thrombophilia (eg, antiphospholipid antibody syndrome, antithrombin deficiency, multiple thrombophilic defects) or active cancer (or those receiving treatment for cancer). Other tests (eg, for residual thrombus detected by compression sonography, or D-dimer) might also identify patients at increased risk of recurrence, but their utility in determining the optimal duration of anticoagulant therapy remains uncertain. Ultimately, the question of which patients will benefit from indefinite anticoagulant therapy requires evaluation in large randomised controlled trials that have sufficient power to show a worthwhile reduction in morbidity or mortality or an improvement in quality of life. Recommended duration of anticoagulant therapy Condition Recommended duration Evidence grade* Provoked VTE (transient risk factor) 3 months 1A Isolated calf DVT 6 weeks† 1B First unprovoked proximal DVT or PE Minimum 3 months Consider long-term‡ 1A 2B Recurrent unprovoked VTE Long-term 1A Cancer-related VTE Minimum 3 months§ Continue during treatment for cancer and while cancer is active 1A 1C VTE with high-risk thrombophilia¶ ** Minimum 3 months; consider long-term 2C Limb- or life-threatening VTE** Minimum 3 months; consider long-term 2C Chronic thromboembolic pulmonary disease Long-term 1C Severe post-thrombotic syndrome** Consider long-term 2C DVT = deep vein thrombosis. PE = pulmonary embolism. VTE = venous thromboembolism. * Based on the grading system used by the American College of Chest Physicians (ACCP) guidelines.13 Strong (Grade 1) recommendations can be applied uniformly to most patients. Weak (Grade 2) suggestions require more judicious application. Level A denotes high-quality evidence; Level B, moderate-quality evidence; and Level C, low-quality evidence. Risk of bleeding, as well as patient values and preferences, must be taken into account. † Unlike the ACCP guidelines, which do not provide a separate recommendation for calf vein thrombosis, we recommend 6 weeks, based on the results of the Durée Optimale du Traitement AntiVitamines K trial.5 There is no evidence to guide the treatment of calf vein thrombosis limited to muscle veins; if anticoagulants are used, we suggest that the duration of use does not exceed 6 weeks (Grade 2, Level C). ‡ Unlike the ACCP guidelines, we do not explicitly recommend long-term treatment after a first episode of unprovoked VTE. Our recommendation attaches a relatively high value to the burden of long-term anticoagulant therapy and a lower value to preventing recurrence beyond the acute phase. § Low-molecular-weight heparin is the preferred treatment. ¶ Includes patients with antiphospholipid antibody syndrome, antithrombin deficiency and multiple thrombophilic defects. ** The ACCP guidelines do not provide guidance for these categories of patients.

Nina C Raju MB BS, FRACP, FRCPA · Jack Hirsh MD, FRCPC, DSc · John W Eikelboom MB BS,MSc, FRCPC

I am a sports physician. Until recently, the only clots of any interest for me were sportspeople who missed easy goals, dropped catches or couldn’t hit a ball. Clinically, my only interest in thrombosis was in the differential diagnosis of calf tears. All that changed one morning 18 months ago. I was sitting at the kitchen table reading the paper, having just finished breakfast. Suddenly, I felt horrible, the worst feeling I had ever had, but one that is difficult to put into words. I remember calling out to my son in the adjoining room that I felt terrible. That was the last thing I remembered for a while. My son came into the room to find me slumped on the floor, not breathing. He tried unsuccessfully to lift me up and then called my wife who was in another part of the house. Together they were able to sit me up and, after a minute or two, I apparently made some choking sounds and commenced breathing again. A few minutes later, I regained consciousness, blissfully unaware that anything had happened. The ambulance arrived soon after and I was taken to hospital, where I was diagnosed, after a ventilation–perfusion lung scan, with a pulmonary embolus (PE). I had not had any calf swelling or pain and an ultrasound failed to demonstrate any calf thrombus. My only risk factor was that I had returned from a week-long trip to China 3 days previously. I do a lot of flying. I have been looking after national sporting teams for 25 years and have attended numerous world championships, Olympic, Commonwealth and university games, as well as doing many other tours. In all my flights with teams, the recent trip with the Socceroos to China was my first in business class. So much for “economy class syndrome”! I was placed on the usual regimen of short-term subcutaneous enoxaparin sodium therapy and oral warfarin, and my progress was quite uneventful. I was seen by a consultant haematologist, who suggested that I keep taking warfarin for 6 months, then stop taking it and have further blood tests to determine whether I have any risk factors. He also suggested that I subsequently use subcutaneous enoxaparin whenever I flew. As I knew very little about deep vein thrombosis or PE, I decided I would do some reading. I ascertained that my recommended treatment regimen of 6 months of oral warfarin and subsequent use of subcutaneous enoxaparin when travelling was almost universally recommended. Yet I felt uneasy. I felt very reassured while I was taking warfarin, particularly as all the literature says it is virtually impossible to have a recurrence of venous thromboembolism (VTE) while taking warfarin. The prospect of discontinuing warfarin did make me feel uneasy. The general consensus among medical people with whom I discussed my condition was that, as there was a “roughly similar chance” of having a haemorrhage while taking warfarin and having a recurrence of PE while not taking it, there was probably no point in staying on the drug. Interestingly, they always seemed to qualify their advice with the words “but of course it is up to you”. I was not totally convinced by that argument, for two reasons. Firstly, I had never had a haemorrhage, but I certainly had had a PE, and a near-fatal one at that. It’s amazing how such an experience concentrates the mind. If the risks were indeed 50:50 then I figured I would err on the side of preventing the PE rather than worrying about a haemorrhage. My second reason was more objectively based. When I looked further at the literature, I began to doubt the mantra that the chances of a warfarin-induced haemorrhage and a recurrence of VTE in the absence of warfarin were similar. The three major studies in this area1-3 all showed a significant risk of recurrence of VTE in the first year after cessation of oral anticoagulant therapy — in the order of 10%, rising to about 15% after the second year. Readers, I don’t know about you, but a 15% chance of having a potentially fatal event in the next 2 years is not a prospect I relish. I would much rather take the 1%–3% risk of a haemorrhage. Quite apart from playing the percentages, there is also the matter of peace of mind. I would feel extremely anxious about my health if I were not taking anticoagulants, and I would certainly not fly. This would involve giving up an important and enjoyable aspect of my job, including, I hope, accompanying the Socceroos to South Africa for the next World Cup, not to mention the prospect of overseas holidays and visits to children working and studying overseas. Clive Kearon, Chair of the American College of Chest Physicians (ACCP) evidence-based clinical practice guidelines on antithrombotic therapy for venous thromboembolic disease, stated recently that a general recommendation of 3–6 months of anticoagulant therapy is no longer appropriate.4 He quoted the 2008 ACCP guidelines, which strongly recommend that . . . in the absence of risk factors for bleeding, which include being older than 75 years . . . patients with a first episode of proximal deep venous thrombosis or pulmonary embolism remain on indefinite anticoagulant therapy, provided that good anticoagulant monitoring is achievable and indefinite treatment is consistent with patient preferences. I will certainly be following those guidelines and I strongly suggest that clinicians who are still giving out the “warfarin for 6 months” mantra reconsider their position in light of the clinical evidence and the potential to improve patients’ quality of life by reducing anxiety.

Peter D Brukner OAM, MB BS, FACSP

In June 2008, the ABC screened a television documentary involving a couple who decided to have an additional child in the hope of obtaining umbilical cord blood to treat their daughter who had leukaemia. The couple conceived naturally, meaning that there was a one in four chance that their child would be suitably matched. They seemed to be unaware of technologies that, if successful, could provide a near certainty that the next child would be a matched “saviour sibling”. This story raises questions about whether clinicians have an obligation to discuss emerging and morally contentious treatment options. Ignorance of technology, assumptions about availability, and medical assessment of burdens and benefits may affect attitudes towards treatment options, but they do not justify non-disclosure of information.

Kimberly A Strong BSc, GradDipGenCouns

Comment on Millar: The application of appropriate prophylaxis for venous thromboembolism (VTE) is recognised as an important patient safety measure. In a systematic review ranking 79 safety interventions, the Agency for Healthcare Research and Quality in the United States found that, based on the strength of overwhelming evidence that thromboprophylaxis reduces adverse patient outcomes and decreases overall costs, the highest-ranked safety practice was the appropriate use of prophylaxis to prevent VTE.1 However, it has been shown that, worldwide, the application of appropriate VTE prophylaxis is underutilised.2 The Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism first convened in 1997. It comprises a group of specialists from medical and surgical disciplines actively involved in VTE management and representing all Australian states and New Zealand. Its objective was to produce a practical, pocket-sized booklet summarising published evidence-based guidelines, drawing on those of the American College of Chest Physicians (ACCP)3 and the International Consensus Statement.4 The Working Party has never attempted to produce a new set of guidelines. The first edition of the Guidelines was published in 1998, with subsequent editions published in 2001, 2006 and 2008. Support from various companies in the medical industry was accepted to allay the cost of bringing Australian and New Zealand representatives to a meeting venue, usually an airport hotel meeting room on a Saturday. Members of the Working Party willingly gave of their time for these meetings, and none received payment. In return for their support and their assistance in distribution of the Guidelines, it was agreed that the companies could place their logo on the back cover of the booklets. It is erroneous to state that “the Guidelines are sponsored by a global pharmaceutical company and are professionally marketed”. The statement that “the current (fourth) edition of the Guidelines acknowledges commercial sponsorship by a ‘non directed’ grant from Sanofi-Aventis, the manufacturer of the LMWH enoxaparin” is incorrect. It is clearly stated in the Guidelines that “The Working Party members wish to acknowledge the support of the medical industry through their provision of non-directed educational grants. The opinions expressed in this booklet are entirely those of the expert clinicians on the Working Party”. The concern expressed in the article that “the Guidelines overstate the need for pharmacological prophylaxis in medical patients, and that patients at low risk of VTE will be exposed unnecessarily to the risk of bleeding complications” is at variance with the recommendation from the latest ACCP guidelines, which advocate low molecular weight heparin (Grade 1A recommendation), low-dose unfractionated heparin (Grade 1A), or fondaparinux (Grade 1A) for acutely ill medical patients admitted to hospital.5 The Working Party advocates that VTE risk assessment should become standard practice for all surgical and medical patients on admission to hospital. From experience since publication of the first edition of the Guidelines, it is anticipated that there will be an ongoing demand for a pocket-sized booklet that summarises current best practice in VTE prevention, and we will endeavour to continue to meet this need.

John P Fletcher

To the Editor: The timely article by Olver and Haines on industry-led versus investigator-led studies in cancer clearly outlines the importance of appropriate trial design.1 However, perhaps one aspect of this critical issue was underemphasised. In cancer trials, overall survival is typically seen as the primary endpoint. In fact, at time of relapse or disease progression, patients are generally treated in a non-uniform manner. In this scenario, treatment is frequently tailored depending on whether the aim of therapy is curative or palliative. Ad-hoc or experimental approaches are used for some patients with relapsed or refractory cancer. Thus, although survival is undoubtedly the most clinically relevant endpoint, the lack of standardisation of treatment at relapse inevitably confounds assessment of the impact of the study drug on survival. Furthermore, for many tumour types, full evaluation of time-to-event outcomes, such as event-free and overall survival, requires prolonged follow-up, resulting in studies taking many years to be completed. For these reasons, biomarkers that accurately serve as early surrogate endpoints to predict for clinical outcome are urgently needed. Yet a striking feature of much industry-led trial design is the paucity of correlative laboratory studies and tissue banking to identify and validate new biomolecular endpoints. Such studies are frequently seen as unnecessary and burdensome. By contrast, although investigator-led laboratory studies of novel biomarkers generate much interest from the clinical and scientific community, their resource and cost implications (chiefly data manager support) prevent many centres from participating. Lucrative company-sponsored trials will always take precedence unless state and/or federal initiatives to support investigator-led studies are enacted. Funding research nurses and data managers to help oncology units conduct non-industry trials that are well designed and incorporate laboratory-based biomolecular research would be an important beginning.

Maher K Gandhi

In reply: We support Gandhi’s contention about the value that can be added to clinical trials by performing correlative laboratory studies. The investigation of biomarkers as potential surrogate endpoints that may indicate efficacy, or lack thereof, earlier than the prolonged time sometimes required to reach a survival endpoint, is one such example. Such studies are often not funded by industry and the importance of funding these, which yield greater clinical benefit, should be recognised by government and non-government agencies. It is possible, but very unlikely, that a survival endpoint may be compromised by the lack of a standardised approach to second-line therapies. We believe that if a new first-line agent is associated with a clinically significant improvement in survival, this will be evident irrespective of subsequent therapies used, which will usually yield inferior results to first-line therapies and will most likely be distributed randomly across the treatment arms. The need for tissue banks as a resource required across trials in all tumours is something that governments could address by funding them as vital clinical research infrastructure. The same applies to data managers for non-industry sponsored trials that are well designed and incorporate laboratory-based research, as Gandhi suggests.

Ian N Olver · Ian E Haines