National Institute for Health and Clinical Excellence. Clinical guideline: Acute coronary syndromes PRE-PUBLICATION CHECK ERROR TABLE

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1 National Institute for Health and Clinical Excellence Clinical guideline: Acute coronary syndromes PRE-PUBLICATION CHECK ERROR TABLE Organisation Order number Section number in FULL guideline Page number ERROR REPORT Response from developers Department of Health Royal Pharmaceutical Society of Great Britain Royal College of Nursing 1 General General Just to confirm that my policy colleagues in the department have no comments to make regarding NICE's pre-publication check of factual errors Thank you. 1 General General We are not responding on this occasion Thank you. 1 General General Thank you for the opportunity to carry out a pre-publication check on this guideline. Thank you. There are no further comments to make on this on behalf of the Royal College of Nursing. DISN UK Group 1 General General I sent this to a few selected members as it is not my main field of expertise. Nobody highlighted any factual errors from what I could see, but the following comments were made: The authors of the NICE document, Unstable Angina and NSTEMI: The early management of unstable angina and non- ST-segment elevation myocardial infarction update for the management of patients with ST-elevation myocardial infarction deal with several key issues related to this group of individuals. 1 None of these comments pertain to factual accuracy. The management of hypoglycaemia was not included in the scope of the guidance. This scope was put to public consultation in accordance with the NICE Technical Manual 2009.

2 However, in a similar fashion to the recent ACC/AHA consensus document, they fail to address the big white elephant in the room the management of hyperglycaemia (1). This may, of course be due to the lack of consensus on this issue due to the conflicting results from large outcome trials. (2-4) Despite these disagreements, as the discussions in these studies highlight, the current treatments available to patients who have a myocardial infarction or acute coronary syndrome with concurrent hyperglycaemia result in poorer outcomes than in people with normal blood glucose levels on admission and throughout their hospital stay.(5) It is a pity that the writing committee did not take the opportunity to address this issue at all if only to acknowledge recently issued guidance.(6) Until then, practicing clinicians are at risk of remaining in limbo about how this increasingly prevalent group of patients should be optimally managed. (1) Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 writing group to review new evidence and update the 2

3 ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction, writing on behalf of the 2004 writing committee. Circulation 2008; 117(2): (2) The CREATE-ECLA Trial Group. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: The CREATE-ECLA randomized controlled trial. JAMA 2005; 293(4): (3) Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Br Med J 1997; 314(7093): (4) Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein K, Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K, Laakso M, Torp-Pedersen C, Waldenstrom A, for the DIGAMI. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005; 26(7): (5) Norhammar A, Lindback J, Ryden L, Wallentin L, Stenestrand U, on behalf of the Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA). Improved but still high short- and longterm mortality rates after myocardial 3

4 infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission. Heart 2007; 93(12): (6) Anonymous. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007; 28(1): The Medicines (MDCO) Page 32 Line Key messages of the Guideline: Omission of recommended interventions Currently the summary draft guideline only includes discussion of eptifibatide or tirofiban for the management of patients who have an intermediate or higher risk of adverse cardiovascular events (predicted 6-month mortality above 3.0%). Please refer to section 9.4 of the NICE Technical Manual (2009) for details about key priorities for implementation. This recommendation was not prioritised for inclusion in the list. [MDCO]: There are no data in the key messages section, referencing the detailed recommendations in the body of the guideline for interventions and practice in early angiography and for the optimal timing of abciximab and bivalirudin. Recommendations relating to bivalirudin can be found on Page 168: Draft Guideline: PAGE 168 R22: Once risk of adverse cardiovascular events is known, consider 4

5 switching to bivalirudin, rather than adding a GPI to an alternative antithrombin, for patients who: are at intermediate or higher risk of adverse cardiovascular events (predicted 6-month mortality above 3%), and are not already receiving a GPI or fondaparinux, and are scheduled to undergo angiography (with follow-on PCI if indicated) within 24 hours of admission. R23: Consider bivalirudin at the time of PCI as an alternative to the combination of another antithrombin plus a GPI for patients not already receiving a GPI or fondaparinux. The Medicines (MDCO) Page 139, line Updated Summary of Product Characteristics for bivalirudin [MDCO]: Please note that the labelled indication for bivalirudin has recently been updated. At the end of November 2009, the EMEA fully approved an extended label for ANGIOX (bivalirudin). Section 4.1 now states: As this summary of product characteristics does not pertain to the population considered by this guideline, this amendment has not been accepted. [SmPC]: Angiox is indicated as an anticoagulant for adult patients undergoing percutaneous coronary intervention (PCI) including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Angiox is also indicated for the treatment of adult patients with unstable angina / non-st segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention. 5

6 Angiox should be administered with aspirin and clopidogrel Draft Guideline: In current UK practice bivalirudin is used as an anticoagulant during percutaneous coronary intervention (PCI), as an alternative to the combination of heparin and a GPI, (initiated at the time of PCI). It is also approved for use in UA/NSTEMI patients planned for urgent or early invasive intervention (coronary angiography with PCI/CABG/medical management as indicated), and is initiated prior to angiography in combination with aspirin and clopidogrel and continued through PCI in those who undergo this procedure... [MDCO]: For factual accuracy, the underlined sentence above should read: It is also approved for use in STEMI patient undergoing Primary PCI, and in UA/NSTEMI patients planned for urgent or early invasive intervention... This extended indication for Angiox was granted on the basis of a statistically significant reduction in mortality and bleeding events at 30 days and one year in STEMI patients when compared against a heparin plus GPI strategy. We attach the latest SmPC for your reference. The Medicines (MDCO) Page 140 Line 1 Minor typographical error Draft Guideline: For patients who do are managed medically or go on to CABG Thank you. This has been amended. 6

7 following angiography... [MDCO]: Removal of do The Medicines (MDCO) Page 162 Line Factual error Draft Guideline: The ACUITY trial reflects practice in the USA and the time from hospital admission to angiography (around 19.5 hours), and the duration of treatment prior to angiography (median 4 hours), were short compared to UK practice. Thank you. This sentence has been amended to aid clarity of intention. [MDCO]: The ACUITY trial was a multinational trial reflecting international practice. It is of note that 35% of patients were enrolled from European centres. It is therefore factually incorrect that the trial reflects USA practice, and the above statement should read:..the ACUITY trial reflects international practice, with 35% of patient contribution from European centres... The Medicines (MDCO) British Society of Cardiovascular Magnetic Resonance Page 112 Line 29 Clarification [MDCO]: For clarity to the reviewer, the Incremental Net Benefit (INB) could be stated in full on first use and in the glossary of terms (page 13) with a reference to page 292 for definition / methodology. 1 Full General We are grateful to the committee for the opportunity to check the final recommendations and have no further comments on the issues that we have 7 Thank you. This has been added to the glossary of terms. Thank you.

8 (BSCMR) raised. We maintain that the assessment of ischaemia and myocardial viability is of paramount importance in patients presenting with ACS in order to guide appropriate, individual revascularisation decisions. We hope that NICE take onboard your recommendation for specific guidance on this issue in relation to the different cardiovascular imaging modalities available. GlaxoSmithKline 1 General General Further to your below, GlaxoSmithKline have reviewed the updated Acute coronary syndromes clinical guideline and have no further comment. Iroko Pharmaceuticals 1 General General Iroko would like to congratulate NICE and the guidelines committee for an excellent job on updating the ACS clinical guidance. Sanofi-aventis Lines 6-9 Please remove the inaccurate sentence regarding plan to submit for a clopidogrel hydrogen sulphate 600mg licence We do not currently anticipate any extensions to the current marketing authorisation (commercial in confidence). (Commercial in confidence information removed by NICE).The results of CURRENT OASIS 7 were presented at the ESC conference in August Sanofi-aventis Lines In line with previous footnotes regarding the licensed indications for other therapy classes (e.g. GPIs), a footnote should be added to state that the LMWHs with licensed indications for the treatment of UA and NSTEMI are enoxaparin and dalteparin. Thank you. Thank you. Thank you. This has been removed. Thank you but this is already discussed in the introduction to the chapter. 8

9 Sanofi-aventis Line 19 the incorrect drug name has been inserted, this arm was in fact for enoxaparin, as such the text should be amended as shown here: It 17 is possible that this difference in administration of additional heparin contributed to the 18 observation of higher bleeding in the enoxaparin arm of the trial. Eli Lilly and Limited Eli Lilly and Limited 1 We are very concerned at the extensive changes made to the ACS (UA & NSTEMI) guideline since the draft for consultation, without the opportunity to comment on them. The amended relative place of therapy of bivalirudin compared to abciximab is not clearly supported by the evidence base and may lead to confusing advice to clinicians. It is very important to have a full consultation on the proposed clinical guidance, particularly when clear head to head data is not available to establish the most appropriate position of a therapy. We therefore trust our comments below are given detailed consideration. 2 R15, section We supported the recommendation in the draft for consultation which stated: Consider offering abciximab as an adjunct to PCI to patients at intermediate or higher risk of adverse cardiovascular events who are not already receiving a GPI. Thank you. This has been amended. Thank you. The developers agree that there is no head to head data to support the use of bivalirudin ahead of abciximab and this was not the intention of the recommendation. The wording of the recommendation has now been changed to more accurately reflect this. Thank you. The developers agree with your comments, as stated above and agree with the limitations of the ACUITY and REPLACE2 trials. However, the recommendation R15 in the prepublication check version now states that abciximab should be considered as an adjunct to PCI for patients at 9

10 intermediate or higher risk of adverse cardiovascular events who are not already receiving a GPI or bivalirudin. The inclusion of bivalirudin in this recommendation is not supported by the literature and no justification is provided in the evidence to recommendations section. There is no head to head data to support the use of bivalirudin ahead of abciximab. There are various limitations with ACUITY, the registration trial for Angiomax (bivalirudin), which compared heparin + GPI vs. bivalirudin + GPI vs. bivalirudin alone in medium to high-risk patients undergoing an early invasive strategy: The study was open-label and designed as a non-inferiority trial, with a generous non-inferiority margin of 25% The trial was not restricted to patients undergoing PCI - only 56% of patients underwent PCI The study was not in a truly high risk cohort as troponin levels were only elevated in 58% of patients. The study was not a direct comparison with abciximab, the choice of GPI was at the operators discretion. Abciximab was used in only 17.8% and 16.3% of cases in the GPI arms only. {A published substudy of ACUITY (presented by Kirtane AJ et al., at AHA 2007 (Circulation. 2007;116:II_629-10

11 II_630.) showed significant differences in ischaemic event rates between eptifibatide and abciximab, favouring abciximab. Whilst there are limitations with the ACUITY study, the benefit seen with abciximab in the ACUITY substudy was consistent with the benefit seen in the head-to-head TARGET ACS-PCI subgroup analysis from TARGET (Stone GW, Circulation 2002;105: )} 9.1% of patients in the bivalirudin arm required a GPI ( bail-out use) as well Since there are many limitations to this trial, the results should be treated with caution and any recommendations made on the basis of this study should be carefully considered. There are also limitations with the REPLACE 2 trial which enrolled unstable and stable patients undergoing PCI Three-quarters of the patients in this study were stable patients. only 42.9% of patients in REPLACE 2 received abciximab as a GPI Unfractionated heparin plus planned abciximab treated patients trended to better ischemic outcomes compared to bivalirudin + provisional abciximab. There was no difference seen between eptifibatide vs. bivalirudin plus provisional eptifibatide which 11

12 suggests that abciximab may be more effective than a small molecule. {These findings are consistent with the TARGET trial, that showed the superiority of abciximab over a small molecule GPI (tirofiban) in the overall PCI study population and more profound in the ACS-PCI subgroup (Stone GW, Circulation 2002;105: )}. To date, no trial has compared bivalirudin to abciximab in NSTEMI patients undergoing PCI. The ISAR REACT 4 trial is still ongoing (ClinicalTrials.gov Identifier NCT ). Due to the lack of data, we think it would be inappropriate, to prefer one or the other. Furthermore, the most current SPC for Angiomax (bivalirudin) 1 doesn t exclude Angiomax (bivalirudin) from being used together with a glycoprotein IIb/IIIa receptor antagonist ent/1861/bivalirudin/ Eli Lilly and Limited 3 R22, section As discussed above, the evidence base does not support the prepublication guideline s preference for bivalirudin over GPI + heparin and contradicts the ESC guidelines for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes (Bassand et al. European Heart Journal 2007; 28, ) which recommend bivalirudin [only] as an alternative to GPIs (see Recommendations for GPIs [page 1621]) Thank you. The developers agree with your comments and the recommendations have been amended to reflect this. It was never the intended that bivalirudin should be recommended in preference to a heparin plus GPI. 12

13 The ISAR-REACT 3 trial showed that bivalirudin is not better than heparin. Bivalirudin and unfractionated heparin had opposite effects on the individual components of the composite endpoint. Patients treated with bivalirudin had significantly less bleeding, and those treated with heparin tended to have fewer myocardial infarctions than with bivalirudin (Kastrati et al N Engl J Med 2008; 359: ). There is an interesting substudy (Iijama, EHJ 2009, 30, ) which concludes, that "Compared with heparin, bivalirudin was associated with a reduction in major bleeding, but mostly in low-risk patients. A reduction in the bleeding risk inversely correlated with an increase in the risk of myocardial infarction with bivalirudin." Eli Lilly and Limited 4 R23, section Again the preference for bivalirudin over GPIs is not supported by the literature. See above. Thank you. The developers agree. 13