Impact of treatment algorithms on the prescribing of antithrombotic therapy in patients with suspected acute coronary syndrome a prospective audit

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1 British Journal of Clinical Pharmacology DOI: /bcp Impact of treatment algorithms on the prescribing of antithrombotic therapy in patients with suspected acute coronary syndrome a prospective audit Alan C. Cameron, 1 Linsay McCallum, 2 Thomas Gardiner, 3 Claire Darroch, 3 Matthew R. Walters 4 &KeithG.Oldroyd 5 1 Department of Cardiology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, Correspondence Dr Alan C. Cameron, Clinical Research Fellow, Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, 126 University Place, Glasgow, United Kingdom, G12 8TA. Tel.: +44 (0) Fax: +44 (0) alan.cameron.2@glasgow.ac.uk Keywords acute coronary syndrome, antithrombotic therapy, chest pain, ticagrelor Received 24 February 2015 Accepted 30 June 2015 Accepted Article Published Online 5 July Department of Clinical Pharmacology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, 3 Department of Cardiology, Queen Elizabeth University Hospital, Glasgow, 4 Department of Clinical Pharmacology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, and 5 Department of Cardiology, University of Glasgow and Queen Elizabeth University Hospital, Glasgow, UK WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Chestpainisacommonpresentation although most patients do not have an acute coronary syndrome. Novel and increasingly potent antithrombotic agents have recently been introduced into clinical practice. Inappropriate administration of potent anti-thrombotic therapy to low risk patients may lead to avoidable adverse events, primarily bleeding. WHAT THIS STUDY ADDS Only one-fifth of patients presenting with suspected ACS have this as their final diagnosis. Our new guideline proposal would minimize inappropriate administration of potent anti-thrombotic therapy to low risk patients. Itmaybeappropriatetoreserveticagrelorfor use only in patients with troponin positive ACS or after formal cardiological review. AIMS Chestpainpresentationsarecommonalthoughmostpatientsdonot have an acute coronary syndrome (ACS). We hypothesized that our local therapeutic guideline was leading to many low risk patients being inappropriately treated with potent anti-thrombotic therapy for ACS. METHODS We conducted a prospective analysis of patients presenting with suspected ACS to the Western Infirmary Glasgow over a 2 month period between 6/10/13 3/11/13 and 5/4/14 2/5/14. We collated data on demographics, investigation, initial management and final diagnosis. Patients taking warfarin were excluded. We calculated sensitivity, specificity and receiver operating characteristic (ROC) curves for our local guideline, the SIGN guideline and a new guideline proposal. RESULTS We studied 202 patients of whom 112 (55%) were male with mean (SD) age 60 (15) years. Full anti-thrombotic therapy for ACS was recommended in 91 patients (45%) according to the NHS GG&C guideline, 37 (18%) by the SIGN guideline and 30 (15%) by our new guideline proposal. The final diagnosis was ACS in 39 patients (19%). The current NHS GG&C guideline had a sensitivity of 80%, specificity 63% and AUROC 0.71 (95% CI 0.63, 0.80). The respective values were 62%, 92% and 0.77 (95% CI 0.67, 0.86) for the SIGN guideline and 54%, 94% and 0.74 (95% CI 0.64, 0.84) for our new proposed guideline. CONCLUSIONS Only one-fifth of patients who present with chest pain or suspected ACS have ACS as their final diagnosis. Our new guideline proposal is highly specific and would minimize unnecessary administration of potent anti-thrombotic therapy to low risk patients / / 80:5 / Br J Clin Pharmacol 2015 The British Pharmacological Society

2 Treatment algorithms and antithrombotic prescribing in suspected ACS Introduction Chest pain is a common reason for presentation and referral to secondary care [1, 2]. Early administration of anti-thrombotic therapy improves outcome in patients with acute coronary syndromes (ACS) [3 7]. However, most patients who present with chest pain do not have an ACS [8]. Novel and increasingly potent antithrombotic agents have recently been introduced into clinical practice for management of patients with ACS [3]. Ticagrelor is a new oral antiplatelet therapy that offers greater, quicker and more consistent inhibition of platelet aggregation than clopidogrel. The PLATO trial demonstrated that ticagrelor is associated with a 16% relative risk reduction in major adverse cardiovascular events (MACE) when compared with clopidogrel in patients with ACS [3]. Ticagrelor was therefore introduced within NHS Greater Glasgow and Clyde in April 2013 as the first line oral antiplatelet agent to be used in conjunction with aspirin in patients who present with ACS. Whilst there was no difference in the overall rates of major bleeding in patients treated with ticagrelor or clopidogrel in the PLATO trial, ticagrelor was associated with significantly higher rates of fatal intracranial bleeding and major bleeding not related to coronary artery bypass graft (CABG). Ticagrelor was also associated with a significantly higher incidence of dyspnoea [3]. The introduction of ticagrelor therefore necessitates increased awareness of the risk of potential adverse events, primarily bleeding, when managing patients who present with chest pain or suspected ACS. Risk stratification tools are required to guide appropriate administration of anti-thrombotic therapy to patients with moderate to high risk of ACS whilst minimizing unnecessary administration to low risk patients. We hypothesized that our local therapeutic guideline (Figure 1) was leading to low risk patients being inappropriately treated with full anti-thrombotic therapy for ACS. In order to test this hypothesis we conducted a prospective analysis of all patients presenting to our unit with suspected ACS. Methods We conducted a prospective analysis of all patients presenting to the Western Infirmary Glasgow with chest pain of suspected cardiac origin or who had troponin I checked for possible ACS over a 2 month period between Figure 1 NHS Greater Glasgow and Clyde Guideline Br J Clin Pharmacol / 80:5 / 1177

3 A. C. Cameron et al. 6 October 2013 to 3 November 2013 and 5 April 2014 to 2 May Patients taking warfarin were excluded. We collated data on demographics, investigation, initial management and final diagnosis after review by a consultant cardiologist, consultant physician or senior cardiology trainee. We defined previous cardiovascular risk factors as known ischaemic heart disease, hypertension, diabetes mellitus, peripheral vascular disease or hypercholesterolaemia. New ischaemic changes on electrocardiography were defined as transient ST segment elevation of 1 mm in two contiguous leads, ST segment depression of 1 mm, new T-wave inversion of 1 mm or pseudo-normalization of previously inverted T waves [9, 10]. Our local laboratory uses a troponin I assay and defines a value of <0.04 μg l 1 as negative. We defined ACS as type 1 myocardial infarction or unstable angina defined as a clinical syndrome consistent with myocardial ischaemia with negative biomarkers and previous or newly documented coronary artery disease [9, 10]. We calculated sensitivity, specificity, positive and negative predictive values and constructed receiver operating characteristic (ROC) curves for our local NHS Greater Glasgow and Clyde (NHS GG&C) guideline (Table 1, Figure 1), the Scottish Intercollegiate Guideline Network (SIGN) guideline (Figure 2) and a new guideline proposal based upon that used in Sheffield and derived from the PLATO trial (Figure 3) [3]. Data were analyzed and ROC curves constructed using SPSS. We reviewed electronic patient records to identify adverse events or complications that occurred during 6 months of follow-up after index hospital admission. Adverse events were defined using criteria from the PLATO trial: major bleeding (fatal bleeding, intracranial bleeding, intra-pericardial bleeding with cardiac tamponade, hypovolaemic shock or severe hypotension due to bleeding requiring pressors or surgery, fall in Hb of at least 5 g dl 1, transfusion of at least 2 units of packed red cells, bleeding with associated clinically significant disability, fall in Hb of at least 3 g dl 1 in the context of bleeding), minor bleeding (hospital admission with bleeding not meeting criteria for major bleeding), any bleeding (major or minor bleeding), hospital admission due to dyspnoea and death from any cause [3]. This was a departmental audit that did not require research ethics committee approval. Table 1 Diagnostic coding used in sensitivity analyses Final diagnosis ACS Final diagnosis not ACS Guideline would recommend full anti-thrombotic therapy for ACS True positive False positive Guideline would not recommend full anti-thrombotic therapy for ACS False negative True negative Figure 2 Scottish Intercollegiate Guidelines Network (SIGN) Guideline [9] 1178 / 80:5 / Br J Clin Pharmacol

4 Treatment algorithms and antithrombotic prescribing in suspected ACS Figure 3 New Guideline Proposal Results Demographics We studied 202 patients of whom 112 (55%) were male with mean (SD) age 60 (15) years. The presenting features were typical of cardiac chest pain in 76 patients (36%) and atypical in 126 (63%). Cardiovascular risk factor(s) were present in 126 patients (62%) and 72 patients (36%) had a history of ischaemic heart disease. Prior to admission, 96 patients were taking anti-platelet therapy and 106 were taking no anti-thrombotic therapy (Table 2). We excluded 16 patients who were taking warfarin. Investigations and initial management All 202 patients had an electrocardiogram on admission. One hundred and forty-three (71%) had no features of ischaemia, 24 (12%) had new ischaemic changes and 35 (17%) had changes consistent with previous ischaemia. Troponin I was Table 2 Anti-thrombotic therapy patients were taking on admission Anti-thrombotic therapy n (%) (n = 202) None 108 (53%) Aspirin 68 (34%) Clopidogrel 10 (5%) Aspirin and clopidogrel 12 (6%) Aspirin and ticagrelor 4(2%) checked on admission in all 202 patients and 40 (20%) were above the reference range. Thirteen patients (6%) had new ischaemic ECG changes and a positive troponin on admission. The anti-thrombotic medication administered on presentation are detailed in Table 3. Br J Clin Pharmacol / 80:5 / 1179

5 A. C. Cameron et al. Table 3 Anti-thrombotic medication administered on presentation n (%) Anti-thrombotic therapy (n = 202) No anti-thrombotic agent 67 (33.0%) Aspirin 88 (43.5%) Aspirin and ticagrelor 2 (1.0%) Ticagrelor and fondaparinux 3 (1.5%) Fondaparinux 2 (1.0%) Aspirin, clopidogrel and fondaparinux 2 (1.0%) Aspirin, ticagrelor and fondaparinux 36 (18%) Aspirin, clopidogrel, ticagrelor and fondaparinux 1 (0.5%) Treatment dose enoxaparin 1 (0.5%) Sensitivity analyses Current local guideline This protocol would have recommended that 91 patients (45%) should be treated with full anti-thrombotic therapy for ACS. The final diagnosis was ACS in 31 (34%) of these patients. Of the 111 patients in whom the local guideline would not have recommended initially treating with full anti-thrombotic therapy, eight (7%) had ACS as their final diagnosis. The current local guideline had a sensitivity of 80%, specificity 63% and AUROC (95% CI) 0.71 (0.63, 0.80) (Table 4 and Figure 4). The positive predictive value (PPV) was 34% and negative predictive value (NPV) 93%. Figure 4 Receiver operator characteristic (ROC) curves by therapeutic guideline., Current NHS GGC guideline;, SIGN guideline;, New proposed guideline;, any TNI positive;, initial TNI positive;, 12 h TNI positive. TNI, troponin I SIGN guideline This protocol would have recommended that 37 patients (18%) should receive full anti-thrombotic therapy for ACS. The final diagnosis was ACS in 24 (65%) of these patients. Of the 165 patients in whom the SIGN guideline would not have recommended initially treating with full anti-thrombotic therapy, 15 patients (9%) had ACS as their final diagnosis. The SIGN guideline had a sensitivity of 62%, specificity 92% and AUROC (95% CI) 0.77 (0.67, 0.86). The PPV was 65% and NPV 91%. Proposed new guideline This protocol would have recommended that 30 patients (15%) should be treated with full anti-thrombotic therapy for ACS. The final diagnosis was ACS in 21 of these patients (70%). Of the 172 patients in whom the new guideline proposal would not have recommended initially treating with full anti-thrombotic therapy, 18 patients (10%) had ACS as Table 4 Diagnostic performance of NHS GG&C guideline, SIGN guideline and new proposed guideline NHS GG&C guideline SIGN guideline New proposed guideline Initial TNI + ve 12 h TNI + ve Any TNI + ve AUROC (95% CI) 0.71 (0.63, 0.80) 0.77 (0.67, 0.86) 0.74 (0.64, 0.84) 0.74 (0.64, 0.84) 0.85 (0.77, 0.93) 0.87 (0.80, 0.93) Sensitivity 80% 62% 54% 59% 80% 87% Specificity 63% 92% 94% 90% 90% 86% PPV 34% 65% 70% 58% 66% 60% NPV 93% 91% 90% 90% 95% 97% PPV, positive predictive value; NPV, negative predictive value; TNI, troponin I 1180 / 80:5 / Br J Clin Pharmacol

6 Treatment algorithms and antithrombotic prescribing in suspected ACS their final diagnosis. The new guideline proposal had a sensitivity of 54%, specificity 94% and AUROC (95% CI) 0.74 (0.64, 0.84). The PPV was 70% and NPV 90%. Troponin Usingapositiveadmissiontroponinastheonlyindication for full ACS treatment would result in an AUROC of 0.74 (95% CI 0.64, 0.84) with sensitivity 59%, specificity 90%, PPV 58% and NPV 90%. Using positive 12 h troponin as the only indication for full ACS treatment, the respective figures would be 0.85 (95% CI 0.77, 0.93), 80%, 90%, 66% and 95%. Finally for any positive troponin the respective figures would be 0.87 (95% CI 0.80, 0.93), 87%, 86%, 60%, 97%. Adverse events and complications Eleven patients experienced bleeding in the 6 months after index hospital admission. Major bleeding occurred in 10 and minor bleeding in 1. Of the 10 patients who experienced major bleeding, six had been treated with ticagrelor and three of these patients did not have ACS as their final diagnosis. Dyspnoea was reported in 14 patients during follow-up, of whom three had been treated with ticagrelor. Seven patients died during follow-up, four of whom had been treated with ticagrelor. Discussion Chest pain is a common reason for presentation and referral to secondary care and has been reported as the second commonest cause of Accident and Emergency department attendance [1, 2]. Optimal administration of anti-thrombotic therapy improves outcomes in patients who present with ACS [1]. Ticagrelor is a potent anti-platelet that has greater and more rapid platelet inhibition than clopidogrel and is superior in reducing the risk of major adverse cardiovascular event after ACS [3]. Ticagrelor was therefore introduced into clinical practice in 2013 for the management of this group of patients [3]. However, ticagrelor is associated with significantly higher rates of major bleeding when CABG related bleeds are excluded [3]. Ticagrelor has an incremental cost effectiveness ratio (ICER) of 7897 per quality adjusted life year (QALY) when compared with clopidogrel in the management of ACS [11]. Given that the majority of patients who present with chest pain are low risk and do not have an ACS [1], the management of these patients must balance the rapid, optimal administration of antithrombotic therapy for the minority who have ACS against the recognition of low risk patients for whom such an approach would be unnecessary, expensive, potentially dangerous and an ineffective use of resources [1]. Several methods can be used to identify safely and accurately patients who present with chest pain and have minimal risk of ACS. The most important features are history, examination, electrocardiogram and cardiac markers. Diagnostic protocols use these features to risk stratify patients and guide management [1, 4]. NHS Greater Glasgow and Clyde has a guideline for the management of patients with suspected ACS (Figure 1). Currently, this guideline recommends treating all patients with aspirin, ticagrelor and fondaparinux even in the context of a normal electrocardiogram and before a cardiac biomarker is available. We hypothesized that this was contributing to a number of low risk patients being unnecessarily treated with a potent, expensive and potentially dangerous combination of anti-thrombotic agents. The Scottish Intercollegiate Guidelines Network guideline recommends that patients who present with chest pain or suspected ACS should receive a second anti-platelet agent and subcutaneous anticoagulant if they have new ischaemic electrocardiogram changes or a positive cardiac biomarker (Figure 2) [9]. The Cardiology Department in Sheffield use a protocol derived from the PLATO trial [3]. We adapted the current NHS Greater Glasgow and Clyde guideline to produce a new guideline proposal that incorporates the main points from the Sheffield protocol (Figure 3). We sought to assess the diagnostic accuracy of each guideline in terms of sensitivity, specificity and AUROC. The Western Infirmary Glasgow is a University teaching hospital with a cardiology unit that offers daily consultant review for all patients admitted under cardiology or admitted under general medicine if the receiving physician requests cardiology review. The majority of patients in our cohort presented with features atypical for ACS. A small minority had new ischaemic changes on their admission electrocardiogram and only around one-fifth had a positive cardiac biomarker on admission. The initial diagnosis of ACS may, in part, be a subjective decision, particularly in the absence of clear ischaemic ECG changes. A number of factors must therefore be considered when assessing a patient who presents with chest pain or suspected ACS. Almost half of the 40 patients with a positive admission troponin had a final diagnosis that was not ACS (Table 5). There are a large number of potential causes of troponin elevation, as well as conditions that may fulfil diagnostic criteria for ACS but which would not benefit from anti-thrombotic therapy, such as myocarditis. Guidelines should be used to assist clinicians in the appropriate diagnosis and management of patients presenting with chest pain but must be applied to the individual clinical context, particularly the history, and our data emphasize the importance of not solely attributing an elevated troponin to a diagnosis of ACS. Br J Clin Pharmacol / 80:5 / 1181

7 A. C. Cameron et al. Table 5 Non-ACS diagnoses in patients with positive admission troponin Diagnosis Number of patients (n (%)) (n = 17) Acute confusion 1(6%) Alcohol excess or withdrawal 2 (12%) Cardiac dysrhythmia 2 (12%) Coronary spasm secondary to recreational 1(6%) drug use Heart failure 2 (12%) Infection 6 (35%) Pleurisy 1(6%) Pulmonary thromboembolism 1(6%) Renal impairment 2 (12%) Stable angina with chronic and persistently 1(6%) elevated troponin Takotsubo cardiomyopathy 1(6%) Type 2 myocardial infarction secondary to 1(6%) anaemia Chest pain with elevated troponin secondary to recent successful coronary angioplasty 1(6%) We identified a heterogeneous range of management strategies amongst our cohort. All patients with suspected ACS should receive aspirin yet a third of our patients received no anti-thrombotic therapy. Nine patients received a combination of anti-thrombotic therapy that no guideline recommends. It is concerning that one patient received three antiplatelet agents and subcutaneous anticoagulation. The heterogeneous management strategies we identified demonstrate that there is uncertainty amongst medical staff about how to apply the current NHS GG&C guideline. Only one third of patients that the NHS GG&C guideline recommended should be treated for ACS had this as their final diagnosis, supporting our hypothesis that the guideline is contributing to a number of low risk patients being inappropriately treated with full antithrombotic therapy. The inclusive nature of this guideline is reflected in its moderate sensitivity (80%) at the expense of poor specificity (63%) and PPV (34%). The SIGN guideline and the new guideline proposal both demonstrate improved specificity and PPV (92% and 65%, 94% and 70%, respectively) with NPV similar to the NHS GG&C guideline. All guidelines have similar AUROCs, although the SIGN guideline and new guideline proposal would reduce unnecessary administration of anti-thrombotic therapy to low risk patients with the new proposed guideline demonstrating greatest specificity. The new proposed guideline does have a relatively low sensitivity; however, given the underlying principle that we should first do no harm, it could be considered the most overall appropriate in view of its greatest specificity and PPV. It is interesting that using a positive initial troponin as the only indication for full ACS treatment results in an AUROC similar to the new proposed guideline with relatively maintained sensitivity and specificity. Using a positive 12 h troponin as the only indication for full ACS treatment would result in an AUROC greater than any of the three guidelines with similar or improved sensitivity, specificity, PPV and NPV. Patients with a negative initial troponin did not benefit from ticagrelor over clopidogrel in subgroup analyses of the PLATO trial [3]. It could therefore be suggested that ticagrelor is reserved for patients with a positive troponin and that clopidogrel should be used in those without. The European Society of Cardiology and American College of Cardiology-American Heart Association recommend antiplatelet preloading in patients with moderate to high risk non-st elevation ACS (e.g. elevated troponin) [12, 13]. This reduces ischaemic events if clopidogrel [14, 15] or ticagrelor [3] are used, although preloading with prasugrel increased bleeding with no reduction in ischaemic events in the ACCOAST trial [16]. Recent data have demonstrated that the average delay from hospital admission to coronary angiography in the United Kingdom is 48 to 72 h [17]. It would therefore be unreasonable to wait until coronary angiography before antiplatelet preloading in patients in whom an invasive strategy is planned. It may, however, be reasonable to wait until cardiology review and confirmation of a diagnosis of moderate to high risk ACS before loading with ticagrelor. Clopidogrel could be used as an alternative if there is delay to cardiology review or if the patient is troponin negative. We studied a large number of consecutive patients admitted over two 4 week periods, which should reduce bias introduced by variation in medical staffing. The final diagnosis was assigned after review by a consultant cardiologist, consultant physician or senior cardiology trainee, which may introduce between observer variability in data analysis. We sought to minimize this by ensuring final diagnoses had been made by senior and experienced clinicians. Our data represent a prospective audit of practice in a single centre with findings that are not currently generalizable to other centres but which highlight important issues that would benefit from a larger analysis of practice over several sites and regions. In conclusion, only one-fifth of patients who present with chest pain or suspected ACS have ACS as their final diagnosis. Management algorithms should be used alongside clinical judgement to balance optimal administration of anti-thrombotic therapy for high risk patients against inappropriate prescribing in low 1182 / 80:5 / Br J Clin Pharmacol

8 Treatment algorithms and antithrombotic prescribing in suspected ACS risk patients for whom this approach would be unnecessary, expensive and potentially dangerous. Our new guideline proposal, although not particularly sensitive, is highly specific, has robust positive and negative predictive values, and would minimize unnecessary administration of potent anti-thrombotic therapy to low risk patients. Competing Interests All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare no support from any organization for the submitted work. KGO reports personal fees, outside the submitted work with Astra Zeneca and ACC has delivered educational lectures with Astra Zeneca in the previous 3 years. There are no other relationships or activities that could appear to have influenced the submitted work. 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