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Rapid Responses: Rapid Responses published:
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Anti-platelets in acute coronary syndromes: too much of a good thing?
- Damian J Kelly, Anthony H Gershlick, Consultant Cardiologist (2 April 2007)
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Increased bleeding, recurrent myocardial infarction and death with glycoprotein IIb/IIIa inhibitor-induced thrombocytopenia
- Amit Patel (3 April 2007)
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GP2b/3a blockers do not save lives.
- David L Murdoch (5 April 2007)
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Perhaps now and again more represents less
- Dr. Filip Konecny (3 July 2007)
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Damian J Kelly, Clinical Research Fellow in Cardiology Glenfield Hospital, Leicester LE3 9QP., Anthony H Gershlick, Consultant Cardiologist
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Dear Sir, The editorial comment by Khavandi and Walker provides a timely reminder of the need for careful assessment of risk in patients presenting with an acute coronary syndrome to identify those would benefit from early angiography and revascularization.1 Their conclusion that glycoprotein IIb/IIIa inhibitors (GPI) are underused in high-risk patients is however based on outdated trial data. All the landmark trials establishing the role of GPI in non ST-segment elevation acute coronary syndrome were conducted in the era before the routine use of clopidogrel. Whereas the benefits of clopidogrel in patients with acute coronary syndrome have been demonstrated across all levels of risk, irrespective of PCI, the benefits of GPI appear more pronounced in those managed invasively. Clinical outcome data on initial or ‘upstream’ use of GPI in the era of clopidogrel are lacking. The National Institute for Clinical Excellence (NICE) guidance on the use of GPI of September 2002 recommends the use of a small-molecule GPI (tirofiban or eptifibatide) in addition to aspirin and unfractionated heparin in high-risk acute coronary syndrome patients, with no mention of the role of concomitant clopidogrel.2 The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial and its PCI sub-study were published in August 2001, too late to inform NICE guidance.3,4 The high-risk group of acute coronary syndrome patients in whom post-hoc analysis showed benefit from upstream use of GPI were entirely clopidogrel naïve.5 The Boersma meta-analysis on the use of GPI in acute coronary syndromes quoted in the editorial was influential in forming guidance, but none of the six landmark trials analysed patients treated with clopidogrel.6 Furthermore, the relatively modest benefit in terms of reduction in recurrent MI was confined to a group of troponin positive patients, most of whom subsequently underwent PCI. Indeed addition of GPI to aspirin and heparin conferred less protection from death or myocardial infarction (1% absolute reduction from 11.8% to 10.8%) than did addition of clopidogrel to aspirin in CURE (8.6% death or recurrent MI for clopidogrel and aspirin versus 10.5% aspirin alone, relative risk , 0.81, p<0.001).3 In his conclusions Boersma comments that data are insufficient to comment on the ‘medical’ role of upstream GPI use in patients not going forward to PCI. Maximizing platelet inhibition may seem intuitively correct, however all anti-platelet medications increase the risk of bleeding. No randomized, controlled clinical trial has specifically addressed the issue of upstream ‘quadruple’ anti-platelet therapy (aspirin, low molecular- weight heparin, clopidogrel plus upstream GPI). The US National registry of 38,000 patients with non ST-segment myocardial infarction has cast doubt on the benefits of upstream GPI: the addition of upstream glycoprotein IIb/IIIa inhibitor to aspirin, heparin and clopidogrel significantly increased the combined risk of mortality, re-infarction or major bleeding compared to aspirin, heparin and clopidogrel alone in conservatively managed patients (17.8% versus 12.4%, OR 1.61, p<0.0001). There was also a strong trend towards worse outcomes with ‘quadruple’ compared to 'triple' anti-platelet therapy in those undergoing PCI.7 We agree with the authors that risk stratification of patients with acute coronary syndrome is vital to ensure prompt access to PCI where required, a strategy that is firmly rooted in evidence. In contrast, it is important to realise that there are no direct data to support he addition of upstream GPI to contemporary management with aspirin, low molecular-weight heparin and clopidogrel, irrespective of clinical risk. There may be benefit over 'triple therapy' in higher-risk patients, most of whom will subsequently undergo PCI, but the financial and clinical costs of upstream GPI use must be weighed on an individual patient basis given the paucity of contemporary data. 1 Khavandi A, Walker PR. Acute coronary syndrome. BMJ 2007;334:647 -8. (31 March) 2 National Institute for Clinical Excellence Technology Appraisal No. 47: Guidance on the use of Glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE September 2002 3 Yusuf S, Zhao F, Mehta SR et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) investigators. Effect of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med 2001 Aug 16;345(7):494-502. 4 Mehta SR, Yusuf S, Peters RJ, et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001 Aug18;358(9281):527-33. 5 Morrow D, Sabatine M, Antman E, Cannon C, Braunwald E, Theroux P. Usefulness of tirofiban among patients treated without percutaneous coronary intervention (TIMI high risk patients in PRISM-PLUS). Am J Cardiol 2004;94:774-6 6 Boersma E, Harrington RA, Moliterno DJ, White H, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002:360:342 -3. 7 Bromberg-Marin G, Marin-Neto JA, Parsons LS, Canto JG, Rogers WJ. Effectiveness and safety of glycoprotein IIb/IIIa inhibitors and clopidogrel alone and in combination in non ST-segment elevation myocardial infarction (from the National Registry of Myocardial Infarction-4). Am J Cardiol 2006 Nov1;98(9):1125-31. Competing interests: None declared |
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Amit Patel, Academic Clinical Fellow & Specialist Registrar in Haematology Imperial College London & Hammersmith Hospitals NHS Trust, Charing Cross Hospital, London, W6 8RF
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Khavandi[1] highlights suboptimal use of glycoprotein (GP) IIb/IIIa inhibitors, particularly in district general hospitals and in high risk groups admitted by medical teams awaiting troponin estimation. These drugs are often used in combination with aspirin, clopidogrel and heparin. However, adjusted registry data from 18,821 percutaneous coronary intervention (PCI) procedures suggest that they increase the risk of bleeding at least twofold in these patients, particularly when combined with heparin.[2] Indeed, combined aspirin and clopidogrel therapy also increases the risk of adverse events from bleeding, including upper gastrointestinal. Both heparin and GP IIb/IIIa inhibitors can cause thrombocytopenia and increase the risk of mucosal, gastrointestinal and intracranial bleeding. The reported incidence of thrombocytopenia associated with GP IIb/IIIa inhibitors varies depending on the route, agent, dose and platelet threshold definition used, but estimates range from 0-15%.[3][4]. A pooled retrospective analysis of eight randomised multi-centre trials comparing GP IIb/IIIa inhibitors with placebo suggest that higher molecular weight agents, such as abciximab, were more frequently implicated than smaller molecular weight agents, such as eptifibatide and tirofiban.[3][4] When it does occur it is associated with an increase in severe bleeding, a higher risk of recurrent myocardial infarction, a greater transfusion requirement, and an increased 30-day[3] and one-year risk of death.[5] Platelet transfusion maybe hazardous, resulting in stent thrombosis with GP IIb/IIIa inhibitors, and more widespread thrombosis in the case of heparin-induced thrombocytopenia (HIT). Platelet transfusion is contraindicated in HIT, and the 2006 UK national British Society for Haematology guideline suggests that conversion from heparin to lepirudin may improve the platelet count. References [1] Khavandi A, Walker PR. Acute coronary syndrome. BMJ 2007;334:647- 8. [2] Horwitz PA, Berlin JA, Sauer WH, Laskey WK, Krone RJ, Kimmel SE. Bleeding risk of platelet glycoprotein IIb/IIIa receptor antagonists in broad-based practice (results from the Society for Cardiac Angiography and Interventions Registry). Am J Cardiol 2003;91:803-6. [3] Merlini PA, Rossi M, Menozzi A, Buratti S, Brennan DM, Moliterno DJ, Topol EJ, Ardissino D. Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting. Circulation 2004;109:2203-6. [4] Dasgupta H, Blankenship JC, Wood GC, Frey CM, Demko SL, Menapace FJ. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis. Am Heart J 2000;140:206- 11. [5] Scirica BM, Cannon CP, Cooper R, Aster RH, Brassard J, McCabe CH, Charlesworth A, Skene AM, Braunwald E. Drug-induced thrombocytopenia and thrombosis: Evidence from patients receiving an oral glycoprotein IIb/IIIa inhibitor in the Orbofiban in Patients with Unstable coronary Syndromes- (OPUS-TIMI 16) trial. J Thromb Thrombolysis 2006;22:95-102. Competing interests: None declared |
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David L Murdoch, Consultant Cardiologist Southern General Hospital, Glasgow G51 4TF
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After reading the editorial by Khavandi and Walker (BMJ 31 March 2007), you could be forgiven for thinking that ignorant physicians and cardiologists were witholding life saving drugs from acute coronary syndrome (ACS) patients . In reality, these doctors have made an evidence based judgement and are reluctant to prescribe these expensive drugs outwith the cath lab where they have minimal benefit but potentially serious adverse effects. None of the glycoprotein inhibitors have been shown to save lives in patients not undergoing PCI. In fact, one study not mentioned showed a trend towards increased incidence of death and MI in the treatment group(1). Even the absolute benefits in reduced myocardial infarction and refractory ischaemia are disappointingly modest. Never mind the lack of mortality benefit but there is also consistent evidence of increased bleeding events in those patients treated with glycoprotein blockers. It would be hard to think of another set of eagerly awaited trial results that were as disappointing as those involving the glycoprotein inhibitors especially in ACS patients not undergoing percutaneous ntervention. Guidelines and scores are a useful adjunct to clinical judgement but do not replace it. 1. Simoons, ML for the GUSTO-IV investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV- ACS randomised trial. Lancet 2001;357:1915-24. Competing interests: None declared |
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Dr. Filip Konecny, PDF cardiovascular surgery TMDT, TGH , M5G 1L7
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Reading the article by Khavandi and Walker (1) and the rapid responses to this article about the suboptimal use of glycoprotein (GP) IIb/IIIa inhibitors, made me think how much we still do not know about the acute coronary syndrome (ACS), -but as always we are ready to treat. The authors conclusion that glycoprotein IIb/IIIa inhibitors are underused in high-risk patients is not clinically well-thought out. As discussed, any anti-thrombotic treatment following an ACS has to be based on solid clinical and functional knowledge of the treatment that is prescribed, and WHEN is prescribed. Concentrating only on some aspects of coronary artery circulation and treating with all proposed agents, not assessing the time critical changes, usually leads to many therapeutic mistakes and induction of multi-organ bleeding. Mechanistically then, if we consider that thrombus, which develops on the site of the injury (in further discussion-the region of coronary artery) is partially built from the platelet thrombus; one has to consider that : After an injury the mechanism that taking place (cell to vessel wall and plasma interactions) instigate the coagulation processes. Thus the aspects of platelet initial interaction with subendothelial collagens under high shear conditions, (in)directly mediated by von Willebrand factor, which binds collagen and platelet GPIb, leads to platelets adhesion, which is fast outmoded by more-stable binding to collagen. Platelet then secrete many prothrombotic factors (3 types of granula-alpha , dense, lysosomal) with e.g. PF4 inhibiting Heparin, Coagulation f. (f. V., f. XI. F.VIII) - Coagulation Factors V and VIII participate in the formation of thrombin. Taken together production of thrombin does not cease with heparin treatment, moreover locally produced thrombin and consequently enzymatically activated fibrinogen helps build bridges that occupy the (GP) IIb/IIIa receptors, causing local platelet aggregation and its incorporation into developing fibrin network. The question then becomes obvious: What would be the best treatment scenario? Are then the (GP) IIb/IIIa inhibitors underused or even necessary to consider at ACS, when the treatment has to rather concentrate on direct inhibition of multi-coagulation active thrombin and the inhibition of an inflammation? There is no clear answer to this question, Clopidogrel and other ADP inhibitors are however welcome in early stages of platelet adhesion, but again maybe the coagulation factors and thrombin -fibrin initiation and its local inhibition would be considered as a PRIORITY? There is long list of other platelet inhibitors that could be sensible to employ, not only(GP) IIb/IIIa inhibitors, however risk of bleeding, while applied systemically or even locally with combination with others, is high. Equally, there are no time frame-critical-systemic studies of anti- thrombotic dosage-regimen of therapeutics, which would clearly point out and differentiate the gradual importance and what to commence with e.g. at (0-2h), (2-12h), (12h-3days), (and 3d-and subsequent) post-ACS. And I still did not mention the side effects of the therapeutics and its combinations with its negative systemic interactions. Are we ready for direct and selective (GP) IIb/IIIa inhibitors? (1) Khavandi A, Walker PR. Acute coronary syndrome. BMJ 2007; 334:647 - 8. Competing interests: None Declared |
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