BJA 22 Wessel JR, Danielmeier C, Ullsperger M. Error awareness revisited: accumulation of multi-modal evidence from central and autonomic nervous systems. J Cog Neurosci 2010; 23: 3021– 36 23 Manser T, Dieckmann P, Wehner T, Rall M. Comparison of anaesthetists’ activity patterns in the operating room and during simulation. Ergonomics 2007; 50: 246–60
Editorial IV
24 van Schie HT, Mars RB, Coles MG, Bekkering H. Modulation of activity in medial frontal and motor cortices during error observation. Nat Neurosci 2004; 7: 549– 54 25 Wascher E, Heppner H, Hoffmann S. Towards the measurement of event-related EEG activity in real life working environments. Int J Psychophysiol Advance Access published on October 19, 2013, doi:10.1016/j.ijpsycho.2013.10.006
British Journal of Anaesthesia 112 (6): 964–7 (2014) Advance Access publication 24 February 2014 . doi:10.1093/bja/aeu011
EDITORIAL IV
D. A. Coventry1 and N. R. Webster1,2* 1 2
Anaesthesia and Intensive Care, University of Aberdeen, Aberdeen, UK Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
* Corresponding author. E-mail: [email protected]
Thrombocytopenia is encountered not infrequently in the critically ill patient. Determining the cause is vital to ensure that the patient gets the right treatment at the right time. Heparin-induced thrombocytopenia (HIT) is one of the differential diagnoses requiring treatment rapidly because it is a prothrombotic condition compared with the other causes of thrombocytopenia. An anticoagulant useful in HIT has recently been introduced in the UK but has been used in many other countries for many years. After a brief introduction to HIT, we discuss the value of this ‘new’ agent and other licensed alternatives along with the barriers put in its way to impede its introduction when other potential treatments disappeared. HIT exists in one of two forms, type I (non-immune) or type II (immune). Type I can also be described as heparinassociated thrombocytopenia, typically occurs within the first 5 days of heparin treatment, it results in minimal reduction in platelets (unlikely ,100 000 mm3), and is thought to be a result of a direct non-immune interaction between the surface of platelets and heparin.1 No treatment is necessary and heparin should be continued.2 Conversely, type II (which is the form of HIT we are now concentrating on in this editorial) has a much more progressive thrombotic profile. It results from a stimulation of the immune system leading to the formation of IgG antibodies against platelet factor 4 (PF4) and heparin complex. IgG binds to PF4– heparin complex, leading to platelet activation, thrombosis, and thrombocytopenia.3 4 There are a number of separate risk factors for HIT. At a structural level, porcine, rather than bovine sourced, is less likely to lead to HIT. Low molecular weight heparin when used for thromboprophylaxis is also less likely than unfractionated heparin to
964
lead to HIT.5 Overall, the incidence is higher in surgical rather than medical patients, and cardiac and orthopaedic patients are the most at risk. Curiously, women have double the risk of men.6 Calculating the overall incidence of HIT is difficult due to the requirement to delineate the studies between simply the presence of antibodies, antibodies with thrombocytopenia, and antibodies with thrombosis. Diagnosing HIT relies on a combination of both a high clinical pre-test probability score and an assay.7 The probability scoring system most commonly used is the ‘4T’ score, composed of Thrombocytopenia, Timing of onset of thrombocytopenia, presence of Thrombosis, and oTher possible causes of thrombocytopenia being ruled out. A low score in the ‘4T’ scoring system has a high negative predictive value for the presence of HIT.8 A clinician has to strike the balance between waiting for the assay confirmation and continuing or stopping heparin in the meantime. An alternative anticoagulant could be used pending the results of the assay; however, they are more expensive, unfamiliar to staff, and often are difficult to source immediately. The laboratory tests can either be a platelet activation assay or be an antigen assay, both are highly sensitive, with a negative test therefore making HIT unlikely.4 However, the specificity is not as high resulting in overtreatment of patients who do not have HIT.8 On diagnosis of HIT, type II heparin should be discontinued. The aim is to stop the prothrombotic cycle that can lead to catastrophic venous and arterial thrombotic events.9 Although the platelet count may be low, prophylactic platelets are not indicated in patients not bleeding as they potentially increase the thrombotic risk. However, platelet transfusion may have
Downloaded from http://bja.oxfordjournals.org/ at The Edward G Miner Library on June 3, 2014
Heparin-induced thrombocytopenia and the health economic analysis of argatroban
Editorial IV
In the UK, there are a number of different organizations involved in assessing cost-effectiveness—the National Institute of Health and Clinical Excellence (NICE), the all Wales Medicines Strategy Group (AWMSG), a Regional Group on Specialist Medicines for Northern Ireland, and the Scottish Medicines Consortium (SMC). NICE provides guidance on a variety of different areas of healthcare beyond medicines, with the technology appraisal arm reviewing the use of medicines. The AWMSG evaluates medicines for Wales, aiming to avoid duplication with NICE but can make recommendations before NICE appraisal has been carried out. In Northern Ireland, since 2006, health technology appraisal guidance issue by NICE has been accepted and any additional medicines can be analysed by the Regional Group on Specialist Medicines.21 22 In NICE, the technology appraisal topics are generally identified by the National Institute for Health Research Horizon Scanning Centre. This resource then informs the Department of Health of an emerging health technology. The Secretary of State for Health would then formally refer for NICE appraisal. For pharmaceutical products, it would then subsequently be through a Single Technology Assessment (STA)23 or Multiple Technology Assessment (MTA).24 If argatroban were to undergo a formalized NICE process, it would go through an STA review, which would be based upon clinical and financial information provided by the manufacturer. An appraisal committee would convene to decide if a medicine was suitable both clinically and in a financial manner. Importantly, NICE does not review all new medications, but somewhere around 25% of all new products. The SMC operates in quite a different manner and brings together all of the Area Drug and Therapeutics Committees (ADTCs) throughout Scotland to assess the clinical and costeffectiveness of all newly licensed medicines, medicines where the formulation has been altered, and medication where the indications for its usage have altered. One of the key targets of the SMC is to provide swift recommendations for the clinician in Scotland.25 NICE appraisals tend to be more detailed and as a result generally take longer to reach a recommendation, averaging 21 months for all drugs to 7 months for all drugs approved by the SMC. Recent alterations to the NICE appraisal process from mostly MTAs to STAs have increased the speed of approval.22 Because all newly licensed medicines have to be approved by the SMC to be prescribed in Scotland and because the review process is relatively rapid, many countries outside the UK use the recommendations of SMC to guide cost-effectiveness decisions when thinking of allowing new drugs onto their own formularies. Pharmaceutical companies submit a report to SMC, outlining the clinical and economic evidence. Initially, the smaller New Drugs Committee (NDC) analyses the submission in a very scientific way before it comes before the larger SMC committee. A more pragmatic viewpoint may occur at this point leading to approval. The SMC committee has representatives from all of the ADTCs, which helps increase the speed of delivery of new medicines to clinicians when approved by the SMC. All Health Boards in Scotland should comply with SMC advice where clinically appropriate.
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a role in the patient with HIT who is actively bleeding.4 Guidelines from North America also suggest the use of platelets in patients with HIT if they are about to undergo an invasive proceedure.10 There are two main classes of drugs that are established therapy for HIT, heparinoids, and direct thrombin inhibitors. Danaparoid, a heparinoid, works by indirectly inhibiting factor Xa. This agent has a long half-life and monitoring of anticoagulation is advisable in patients who have both renal impairment and a weight .90 kg. A calibrated anti-Xa assay to danaparoid is the investigation of choice if monitoring is advised, due to the minimal effects this drug has on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT).4 Three direct thrombin inhibitors have been used as an anticoagulant when heparin has been stopped—lepirudin, bivalirudin, and argatroban. Lepirudin was permanently discontinued by the manufacturer and removed from the market in April 2012, not due to safety concerns but for business reasons.11 Bivalirudin is a synthetic thrombin inhibitor with an extremely short half-life, ,30 min in patients with normal renal function.12 Currently, bivalirudin is used extensively in percutaneous coronary interventions and is recommended as an alternative anticoagulant for patients requiring surgery with cardiopulmonary bypass.4 10 Monitoring of the degree of anticoagulation requires the use of an activated clotting time. Primarily, clearance is via enzymatic proteolysis, but 20% of the drug is cleared through the renal tract, so if renal function develops, there can be a problem with excess anticoagulation. No reversal agent exists. Argatroban is metabolized in the liver and eliminated largely via biliary excretion, unlike the other alternative anticoagulants to heparin that are at least partly metabolized in the kidney.13 Anticoagulation with argatroban is targeted towards an aPTT 1.5–3 times the baseline. Unsurprisingly, because of the thrombus generation in patients with HIT, it is not unusual to see renal impairment14 and the lack of renal interaction makes this drug particularly useful.15 Also being able to monitor the degree of anticoagulation with the widely available aPTT makes the clinical use of this agent much more relevant. In critically ill patients and patients with hepatic impairment, it is advised to reduce starting concentration, 0.5 mg kg21min21 as opposed to 2 mg kg21 min21 (which is the usual recommended initial concentration). Steady-state anticoagulation should be achievable within 3–4.5 h.16 The pharmacoeconomics of medicines prescribed continues to be a pressing concern—expenditure, on branded medicines in the UK for the year 2011/2 exceeded £12 billion.17 Mechanisms are required to evaluate medicines not only for efficacy but to ensure equitable distribution of a finite resource. In the early 1990s, Australia were the first to incorporate formalized economic evaluation before approval for public funding of a drug and inclusion in its formulary.18 19 Clearly, an appreciation of the cost of developing new drugs by the pharmaceutical industry has to be acknowledged— but how do we determine the cost of a new drug on its release? One systematic review estimated equivalent costs and suggests that drug development costs increased eightfold from the 1960 –1970s to the 2000s.20
BJA
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Clinicians’ understanding of health economics remains poor. When detailed analysis of health economics is required, the ‘everyday’ clinician in all likelihood will struggle. Yet when is the appropriate time to learn? It is clear the teaching on the subject at undergraduate level varies across medical schools, but when it is taught, then health economists should deliver this.31 The post-graduate syllabus in Anaesthesia and Intensive Care Medicine cover this domain in little detail and almost certainly the candidate will never be examined in their professional examinations on the topic. A recent survey to US physicians suggested only one-third believed they had a major responsibility to reduce healthcare costs.32 We need to accept our role in critically appraising cost-effectiveness since resource is finite and without this knowledge, our role in the future for making choices will diminish. In the case of argatroban, the use of an agent to treat a potentially lifethreatening condition, which has proven its value in many other countries, was potentially denied to those living in the UK. With rare conditions such as HIT, it is clearly going to be difficult to demonstrate both clinical and cost-effectiveness superiority of one agent vs another—as was the case with argatroban. In the end, approval came when the cost of transport of samples and their analysis was taken into account.
Declaration of interest N.R.W. has acted as a consultant for Mitsubishi Pharma Europe and is the Chairman of the Board of the BJA.
References 1 Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J 2007; 83: 575– 82 2 Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care 2011; 15: 211 3 Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7(Suppl. 1): 9– 12 4 Watson H, Davidson S, Keeling D. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012; 159: 528–40 5 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710– 5 6 Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108: 2937– 41 7 Nellen V, Sulzer I, Barizzi G, La¨mmle B, Alberio L. Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a singlecenter experience with 1,291 patients. Haematologica 2012; 97: 89– 97 8 Crowther MA, Cook DJ, Albert M, et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical– surgical intensive care unit patients. J Crit Care 2010; 25: 287–93 9 Kelton JG, Arnold DM, Bates SM. Non-heparin anticoagulants for heparin-induced thrombocytopenia. N Engl J Med 2013; 368: 737– 44 10 Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia, treatment of HIT antithrombotic therapy and prevention of thrombosis, 9th ed: American
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Wales has the AWMSG, which works side by side with NICE. AWMSG would not plan to carry out an appraisal of medicine if NICE were planning to carry out an STA or MTA within the following year. NICE recommendations would succeed that of AWMSG advice, with regard to health technology assessments. The purpose of the AWMSG currently is to review all medicines not awaiting NICE review.26 27 New medicines go before the New Medicines Group (NMG) with information provided by the relevant company. Clinical and cost-effectiveness analysis occurs, along with clinical experts views and written views from patients, carers, and patient organizations. The NMG makes an initial report to the AWMSG who then decide whether to approve it and then forward it on towards ministerial ratification. Argatroban now has approval both from the SMC and the AWMSG, for anticoagulation in adult patients with HIT. AWMSG approval occurred in January 2013 after clinical opinion sought had found argatroban to be the preferred treatment, primarily due to the ease of monitoring and availability. Cost analysis was not so clear with regard to how advantageous argatroban was over the alternative danaparoid. A 5 day course of argatroban is more expensive by some £200 than danaparoid. The cost-effectiveness analysis, submitted by Mitsubishi Pharma Europe Ltd, suggested less Quality Adjusted Life Years (QALYs) with argatroban vs danaparoid; therefore, the incremental cost-effectiveness ratio of argatroban would be higher. AWMSG when analysing these two differences went with the clinical recommendation of superiority and accepted the financial downside of argatroban usage.28 The SMC, when initially reviewing argatroban in October 2012 for HIT type 2, did not recommend its use within NHS Scotland. It was felt that ‘the submitting company did not present a sufficiently robust clinical and economic analysis to gain acceptance by SMC’.29 This was despite the fact that it could be argued that there was now no alternative treatment available for at least some patients with a life-threatening disease. The license holder was allowed to resubmit with additional information and in July 2013, argatroban was accepted for use within Scotland.30 What additional information was provided to result in a change in recommendation? Mitsubishi Pharma concentrated its resubmission on the monitoring costs of patients receiving either argatroban or danaparoid, respectively, either aPTT ratios or anti-Xa tests. One of the major weaknesses of danaparoid usage has been the availability of the anti-Xa test that is advisable in patients with renal impairment (glomerular filtration rate ,30 ml min21) and a body weight .90 kg.4 It is estimated that there may be ,20 UK laboratories suitably calibrated to monitor anticoagulation with danaparoid (personal communication). The costs involved in transportation of haematological samples for the anti-Xa assay from the treating hospital to the laboratory capable of carrying out the assay was one of the major factors leading to the altered advice of SMC and argatroban’s approval for usage in Scotland. The resubmission could not be based on clinical superiority of this agent over any other since the robust evidence did not exist and nor could any further trial possibly now take place.
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21 http://www.dhsspsni.gov.uk/nice_guidance_01-06.pdf (accessed 5 December 2013) 22 Ford JA, Waugh N, Sharma P, Sculpher M, Walker A. NICE guidance: a comparative study of the introduction of the single technology appraisal process and comparison with guidance from Scottish Medicines Consortium. BMJ Open 2012; 2: e000671 23 http://www.nice.org.uk/media/42D/B3/STAGuideLrFinal.pdf (accessed 5 December 2013) 24 http://www.nice.org.uk/media/42D/8C/MTAGuideLRFINAL.pdf (accessed 5 July 2014) 25 Dear J, O’Dowd C, Timoney A, Paterson R, Walker A, Webb J. Scottish Medicines Consortium: an overview of rapid new drug assessment in Scotland. Scott Med J 2007; 52: 20 –6 26 Linley WG, Hughes DA. Reimbursement decisions of the all Wales medicines strategy group: influence of policy and clinical and economic factors. Pharmacoeconomics 2012; 30: 779–94 27 http://www.awmsg.org/docs/awmsg/appraisaldocs/inforandforms/ AWMSG%20appraisal%20FAQs.pdf (accessed 5 December 2013) 28 http://www.awmsg.org/awmsgonline/app/appraisalinfo/1405; jsessionid=00f9e76a1513f2188ea8e896a135 (accessed 5 December 2013) 29 http://www.scottishmedicines.org.uk/files/advice/argatroban_ Exembol_FINAL_October_2012_for_website.pdf (accessed 5 December 2013) 30 http://www.scottishmedicines.org.uk/files/advice/argatroban__ Exembol__RESUBMISSION_FINAL_July_2013_for_website.pdf (accessed 5 December 2013) 31 Gray E, Lorgelly PK. Health economics education in undergraduate medical degrees: an assessment of curricula content and student knowledge. Med Teach 2010; 32: 392– 9 32 Tilburt JC, Wynia MK, Sheeler RD, et al. Views of US physicians about controlling health care costs. J Am Med Assoc 2013; 310: 380– 9
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college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(2 Suppl.): e495–530S http://www.mhra.gov.uk/home/groups/pl-p/documents/websitere sources/con134765.pdf (accessed 5 December 2013) Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830–9 Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129: 1167–75 Alatri A, Armstrong A-E, Greinacher A, et al. Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy—a European perspective. Thromb Res 2012; 129: 426– 33 Guzzi LM, McCollum DA, Hursting MJ. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2006; 22: 169– 76 Saugel B, Phillip V, Moessmer G, Schmid RM, Huber W. Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study. Crit Care 2010; 14: R90 Wise J. NHS spending on drugs is frozen for two years under price deal. Br Med J 2013; 347: f6731 Taylor RS, Drummond MF, Salkeld G, Sullivan SD. Inclusion of cost effectiveness in licensing requirements of new drugs: the fourth hurdle. Br Med J 2004; 329: 972–5 Hill SR, Mitchell AS, Henry DA. Problems with the interpretation of pharmacoeconomic analyses: a review of submissions to the Australian Pharmaceutical Benefits Scheme. J Am Med Assoc 2000; 283: 2116–21 Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: a systematic review. Health Policy 2011; 100: 4– 17
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Editorial IV
24 van Schie HT, Mars RB, Coles MG, Bekkering H. Modulation of activity in medial frontal and motor cortices during error observation. Nat Neurosci 2004; 7: 549– 54 25 Wascher E, Heppner H, Hoffmann S. Towards the measurement of event-related EEG activity in real life working environments. Int J Psychophysiol Advance Access published on October 19, 2013, doi:10.1016/j.ijpsycho.2013.10.006
British Journal of Anaesthesia 112 (6): 964–7 (2014) Advance Access publication 24 February 2014 . doi:10.1093/bja/aeu011
EDITORIAL IV
D. A. Coventry1 and N. R. Webster1,2* 1 2
Anaesthesia and Intensive Care, University of Aberdeen, Aberdeen, UK Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
* Corresponding author. E-mail: [email protected]
Thrombocytopenia is encountered not infrequently in the critically ill patient. Determining the cause is vital to ensure that the patient gets the right treatment at the right time. Heparin-induced thrombocytopenia (HIT) is one of the differential diagnoses requiring treatment rapidly because it is a prothrombotic condition compared with the other causes of thrombocytopenia. An anticoagulant useful in HIT has recently been introduced in the UK but has been used in many other countries for many years. After a brief introduction to HIT, we discuss the value of this ‘new’ agent and other licensed alternatives along with the barriers put in its way to impede its introduction when other potential treatments disappeared. HIT exists in one of two forms, type I (non-immune) or type II (immune). Type I can also be described as heparinassociated thrombocytopenia, typically occurs within the first 5 days of heparin treatment, it results in minimal reduction in platelets (unlikely ,100 000 mm3), and is thought to be a result of a direct non-immune interaction between the surface of platelets and heparin.1 No treatment is necessary and heparin should be continued.2 Conversely, type II (which is the form of HIT we are now concentrating on in this editorial) has a much more progressive thrombotic profile. It results from a stimulation of the immune system leading to the formation of IgG antibodies against platelet factor 4 (PF4) and heparin complex. IgG binds to PF4– heparin complex, leading to platelet activation, thrombosis, and thrombocytopenia.3 4 There are a number of separate risk factors for HIT. At a structural level, porcine, rather than bovine sourced, is less likely to lead to HIT. Low molecular weight heparin when used for thromboprophylaxis is also less likely than unfractionated heparin to
964
lead to HIT.5 Overall, the incidence is higher in surgical rather than medical patients, and cardiac and orthopaedic patients are the most at risk. Curiously, women have double the risk of men.6 Calculating the overall incidence of HIT is difficult due to the requirement to delineate the studies between simply the presence of antibodies, antibodies with thrombocytopenia, and antibodies with thrombosis. Diagnosing HIT relies on a combination of both a high clinical pre-test probability score and an assay.7 The probability scoring system most commonly used is the ‘4T’ score, composed of Thrombocytopenia, Timing of onset of thrombocytopenia, presence of Thrombosis, and oTher possible causes of thrombocytopenia being ruled out. A low score in the ‘4T’ scoring system has a high negative predictive value for the presence of HIT.8 A clinician has to strike the balance between waiting for the assay confirmation and continuing or stopping heparin in the meantime. An alternative anticoagulant could be used pending the results of the assay; however, they are more expensive, unfamiliar to staff, and often are difficult to source immediately. The laboratory tests can either be a platelet activation assay or be an antigen assay, both are highly sensitive, with a negative test therefore making HIT unlikely.4 However, the specificity is not as high resulting in overtreatment of patients who do not have HIT.8 On diagnosis of HIT, type II heparin should be discontinued. The aim is to stop the prothrombotic cycle that can lead to catastrophic venous and arterial thrombotic events.9 Although the platelet count may be low, prophylactic platelets are not indicated in patients not bleeding as they potentially increase the thrombotic risk. However, platelet transfusion may have
Downloaded from http://bja.oxfordjournals.org/ at The Edward G Miner Library on June 3, 2014
Heparin-induced thrombocytopenia and the health economic analysis of argatroban
Editorial IV
In the UK, there are a number of different organizations involved in assessing cost-effectiveness—the National Institute of Health and Clinical Excellence (NICE), the all Wales Medicines Strategy Group (AWMSG), a Regional Group on Specialist Medicines for Northern Ireland, and the Scottish Medicines Consortium (SMC). NICE provides guidance on a variety of different areas of healthcare beyond medicines, with the technology appraisal arm reviewing the use of medicines. The AWMSG evaluates medicines for Wales, aiming to avoid duplication with NICE but can make recommendations before NICE appraisal has been carried out. In Northern Ireland, since 2006, health technology appraisal guidance issue by NICE has been accepted and any additional medicines can be analysed by the Regional Group on Specialist Medicines.21 22 In NICE, the technology appraisal topics are generally identified by the National Institute for Health Research Horizon Scanning Centre. This resource then informs the Department of Health of an emerging health technology. The Secretary of State for Health would then formally refer for NICE appraisal. For pharmaceutical products, it would then subsequently be through a Single Technology Assessment (STA)23 or Multiple Technology Assessment (MTA).24 If argatroban were to undergo a formalized NICE process, it would go through an STA review, which would be based upon clinical and financial information provided by the manufacturer. An appraisal committee would convene to decide if a medicine was suitable both clinically and in a financial manner. Importantly, NICE does not review all new medications, but somewhere around 25% of all new products. The SMC operates in quite a different manner and brings together all of the Area Drug and Therapeutics Committees (ADTCs) throughout Scotland to assess the clinical and costeffectiveness of all newly licensed medicines, medicines where the formulation has been altered, and medication where the indications for its usage have altered. One of the key targets of the SMC is to provide swift recommendations for the clinician in Scotland.25 NICE appraisals tend to be more detailed and as a result generally take longer to reach a recommendation, averaging 21 months for all drugs to 7 months for all drugs approved by the SMC. Recent alterations to the NICE appraisal process from mostly MTAs to STAs have increased the speed of approval.22 Because all newly licensed medicines have to be approved by the SMC to be prescribed in Scotland and because the review process is relatively rapid, many countries outside the UK use the recommendations of SMC to guide cost-effectiveness decisions when thinking of allowing new drugs onto their own formularies. Pharmaceutical companies submit a report to SMC, outlining the clinical and economic evidence. Initially, the smaller New Drugs Committee (NDC) analyses the submission in a very scientific way before it comes before the larger SMC committee. A more pragmatic viewpoint may occur at this point leading to approval. The SMC committee has representatives from all of the ADTCs, which helps increase the speed of delivery of new medicines to clinicians when approved by the SMC. All Health Boards in Scotland should comply with SMC advice where clinically appropriate.
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a role in the patient with HIT who is actively bleeding.4 Guidelines from North America also suggest the use of platelets in patients with HIT if they are about to undergo an invasive proceedure.10 There are two main classes of drugs that are established therapy for HIT, heparinoids, and direct thrombin inhibitors. Danaparoid, a heparinoid, works by indirectly inhibiting factor Xa. This agent has a long half-life and monitoring of anticoagulation is advisable in patients who have both renal impairment and a weight .90 kg. A calibrated anti-Xa assay to danaparoid is the investigation of choice if monitoring is advised, due to the minimal effects this drug has on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT).4 Three direct thrombin inhibitors have been used as an anticoagulant when heparin has been stopped—lepirudin, bivalirudin, and argatroban. Lepirudin was permanently discontinued by the manufacturer and removed from the market in April 2012, not due to safety concerns but for business reasons.11 Bivalirudin is a synthetic thrombin inhibitor with an extremely short half-life, ,30 min in patients with normal renal function.12 Currently, bivalirudin is used extensively in percutaneous coronary interventions and is recommended as an alternative anticoagulant for patients requiring surgery with cardiopulmonary bypass.4 10 Monitoring of the degree of anticoagulation requires the use of an activated clotting time. Primarily, clearance is via enzymatic proteolysis, but 20% of the drug is cleared through the renal tract, so if renal function develops, there can be a problem with excess anticoagulation. No reversal agent exists. Argatroban is metabolized in the liver and eliminated largely via biliary excretion, unlike the other alternative anticoagulants to heparin that are at least partly metabolized in the kidney.13 Anticoagulation with argatroban is targeted towards an aPTT 1.5–3 times the baseline. Unsurprisingly, because of the thrombus generation in patients with HIT, it is not unusual to see renal impairment14 and the lack of renal interaction makes this drug particularly useful.15 Also being able to monitor the degree of anticoagulation with the widely available aPTT makes the clinical use of this agent much more relevant. In critically ill patients and patients with hepatic impairment, it is advised to reduce starting concentration, 0.5 mg kg21min21 as opposed to 2 mg kg21 min21 (which is the usual recommended initial concentration). Steady-state anticoagulation should be achievable within 3–4.5 h.16 The pharmacoeconomics of medicines prescribed continues to be a pressing concern—expenditure, on branded medicines in the UK for the year 2011/2 exceeded £12 billion.17 Mechanisms are required to evaluate medicines not only for efficacy but to ensure equitable distribution of a finite resource. In the early 1990s, Australia were the first to incorporate formalized economic evaluation before approval for public funding of a drug and inclusion in its formulary.18 19 Clearly, an appreciation of the cost of developing new drugs by the pharmaceutical industry has to be acknowledged— but how do we determine the cost of a new drug on its release? One systematic review estimated equivalent costs and suggests that drug development costs increased eightfold from the 1960 –1970s to the 2000s.20
BJA
BJA
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Clinicians’ understanding of health economics remains poor. When detailed analysis of health economics is required, the ‘everyday’ clinician in all likelihood will struggle. Yet when is the appropriate time to learn? It is clear the teaching on the subject at undergraduate level varies across medical schools, but when it is taught, then health economists should deliver this.31 The post-graduate syllabus in Anaesthesia and Intensive Care Medicine cover this domain in little detail and almost certainly the candidate will never be examined in their professional examinations on the topic. A recent survey to US physicians suggested only one-third believed they had a major responsibility to reduce healthcare costs.32 We need to accept our role in critically appraising cost-effectiveness since resource is finite and without this knowledge, our role in the future for making choices will diminish. In the case of argatroban, the use of an agent to treat a potentially lifethreatening condition, which has proven its value in many other countries, was potentially denied to those living in the UK. With rare conditions such as HIT, it is clearly going to be difficult to demonstrate both clinical and cost-effectiveness superiority of one agent vs another—as was the case with argatroban. In the end, approval came when the cost of transport of samples and their analysis was taken into account.
Declaration of interest N.R.W. has acted as a consultant for Mitsubishi Pharma Europe and is the Chairman of the Board of the BJA.
References 1 Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J 2007; 83: 575– 82 2 Sakr Y. Heparin-induced thrombocytopenia in the ICU: an overview. Crit Care 2011; 15: 211 3 Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009; 7(Suppl. 1): 9– 12 4 Watson H, Davidson S, Keeling D. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol 2012; 159: 528–40 5 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106: 2710– 5 6 Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108: 2937– 41 7 Nellen V, Sulzer I, Barizzi G, La¨mmle B, Alberio L. Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a singlecenter experience with 1,291 patients. Haematologica 2012; 97: 89– 97 8 Crowther MA, Cook DJ, Albert M, et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical– surgical intensive care unit patients. J Crit Care 2010; 25: 287–93 9 Kelton JG, Arnold DM, Bates SM. Non-heparin anticoagulants for heparin-induced thrombocytopenia. N Engl J Med 2013; 368: 737– 44 10 Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia, treatment of HIT antithrombotic therapy and prevention of thrombosis, 9th ed: American
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Wales has the AWMSG, which works side by side with NICE. AWMSG would not plan to carry out an appraisal of medicine if NICE were planning to carry out an STA or MTA within the following year. NICE recommendations would succeed that of AWMSG advice, with regard to health technology assessments. The purpose of the AWMSG currently is to review all medicines not awaiting NICE review.26 27 New medicines go before the New Medicines Group (NMG) with information provided by the relevant company. Clinical and cost-effectiveness analysis occurs, along with clinical experts views and written views from patients, carers, and patient organizations. The NMG makes an initial report to the AWMSG who then decide whether to approve it and then forward it on towards ministerial ratification. Argatroban now has approval both from the SMC and the AWMSG, for anticoagulation in adult patients with HIT. AWMSG approval occurred in January 2013 after clinical opinion sought had found argatroban to be the preferred treatment, primarily due to the ease of monitoring and availability. Cost analysis was not so clear with regard to how advantageous argatroban was over the alternative danaparoid. A 5 day course of argatroban is more expensive by some £200 than danaparoid. The cost-effectiveness analysis, submitted by Mitsubishi Pharma Europe Ltd, suggested less Quality Adjusted Life Years (QALYs) with argatroban vs danaparoid; therefore, the incremental cost-effectiveness ratio of argatroban would be higher. AWMSG when analysing these two differences went with the clinical recommendation of superiority and accepted the financial downside of argatroban usage.28 The SMC, when initially reviewing argatroban in October 2012 for HIT type 2, did not recommend its use within NHS Scotland. It was felt that ‘the submitting company did not present a sufficiently robust clinical and economic analysis to gain acceptance by SMC’.29 This was despite the fact that it could be argued that there was now no alternative treatment available for at least some patients with a life-threatening disease. The license holder was allowed to resubmit with additional information and in July 2013, argatroban was accepted for use within Scotland.30 What additional information was provided to result in a change in recommendation? Mitsubishi Pharma concentrated its resubmission on the monitoring costs of patients receiving either argatroban or danaparoid, respectively, either aPTT ratios or anti-Xa tests. One of the major weaknesses of danaparoid usage has been the availability of the anti-Xa test that is advisable in patients with renal impairment (glomerular filtration rate ,30 ml min21) and a body weight .90 kg.4 It is estimated that there may be ,20 UK laboratories suitably calibrated to monitor anticoagulation with danaparoid (personal communication). The costs involved in transportation of haematological samples for the anti-Xa assay from the treating hospital to the laboratory capable of carrying out the assay was one of the major factors leading to the altered advice of SMC and argatroban’s approval for usage in Scotland. The resubmission could not be based on clinical superiority of this agent over any other since the robust evidence did not exist and nor could any further trial possibly now take place.
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Editorial IV
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21 http://www.dhsspsni.gov.uk/nice_guidance_01-06.pdf (accessed 5 December 2013) 22 Ford JA, Waugh N, Sharma P, Sculpher M, Walker A. NICE guidance: a comparative study of the introduction of the single technology appraisal process and comparison with guidance from Scottish Medicines Consortium. BMJ Open 2012; 2: e000671 23 http://www.nice.org.uk/media/42D/B3/STAGuideLrFinal.pdf (accessed 5 December 2013) 24 http://www.nice.org.uk/media/42D/8C/MTAGuideLRFINAL.pdf (accessed 5 July 2014) 25 Dear J, O’Dowd C, Timoney A, Paterson R, Walker A, Webb J. Scottish Medicines Consortium: an overview of rapid new drug assessment in Scotland. Scott Med J 2007; 52: 20 –6 26 Linley WG, Hughes DA. Reimbursement decisions of the all Wales medicines strategy group: influence of policy and clinical and economic factors. Pharmacoeconomics 2012; 30: 779–94 27 http://www.awmsg.org/docs/awmsg/appraisaldocs/inforandforms/ AWMSG%20appraisal%20FAQs.pdf (accessed 5 December 2013) 28 http://www.awmsg.org/awmsgonline/app/appraisalinfo/1405; jsessionid=00f9e76a1513f2188ea8e896a135 (accessed 5 December 2013) 29 http://www.scottishmedicines.org.uk/files/advice/argatroban_ Exembol_FINAL_October_2012_for_website.pdf (accessed 5 December 2013) 30 http://www.scottishmedicines.org.uk/files/advice/argatroban__ Exembol__RESUBMISSION_FINAL_July_2013_for_website.pdf (accessed 5 December 2013) 31 Gray E, Lorgelly PK. Health economics education in undergraduate medical degrees: an assessment of curricula content and student knowledge. Med Teach 2010; 32: 392– 9 32 Tilburt JC, Wynia MK, Sheeler RD, et al. Views of US physicians about controlling health care costs. J Am Med Assoc 2013; 310: 380– 9
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college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(2 Suppl.): e495–530S http://www.mhra.gov.uk/home/groups/pl-p/documents/websitere sources/con134765.pdf (accessed 5 December 2013) Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99: 830–9 Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction. Chest 2006; 129: 1167–75 Alatri A, Armstrong A-E, Greinacher A, et al. Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy—a European perspective. Thromb Res 2012; 129: 426– 33 Guzzi LM, McCollum DA, Hursting MJ. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2006; 22: 169– 76 Saugel B, Phillip V, Moessmer G, Schmid RM, Huber W. Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study. Crit Care 2010; 14: R90 Wise J. NHS spending on drugs is frozen for two years under price deal. Br Med J 2013; 347: f6731 Taylor RS, Drummond MF, Salkeld G, Sullivan SD. Inclusion of cost effectiveness in licensing requirements of new drugs: the fourth hurdle. Br Med J 2004; 329: 972–5 Hill SR, Mitchell AS, Henry DA. Problems with the interpretation of pharmacoeconomic analyses: a review of submissions to the Australian Pharmaceutical Benefits Scheme. J Am Med Assoc 2000; 283: 2116–21 Morgan S, Grootendorst P, Lexchin J, Cunningham C, Greyson D. The cost of drug development: a systematic review. Health Policy 2011; 100: 4– 17
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