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Rapid Responses: Rapid Responses published:
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Antithrombotic therapy & gastrointestinal bleeding: further studies are required.
- Robert Stevenson, Melanie Halliday, Heather Dyson, and Nij Bhala (6 October 2006)
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Role of H.Pylori and other risk factors in GI bleeding in presence of anttithrombotics.
- Venkataswamy Narayana Mahesh (6 October 2006)
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Premature anti-platelet cessation may risk stent thrombosis and death
- Amit Patel (8 October 2006)
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Combination Antithrombotic Therapy - The Benefits
- Michael Poullis (10 October 2006)
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Combination anti-platelet therapy is also associated with sight loss due to spontaneous vitreous haemorrhage.
- Edward N Herbert, D. Alistair H. Laidlaw (17 October 2006)
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Additional analyses needed
- Jan P Vandenbroucke, Erik M van Driel (10 November 2006)
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Letter to the Editor
- D. Michael Humphreys, M.D., Ch.B.F.F.P.M., Manfred Haehl (5 December 2006)
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Aspirin-Clopidogrel Use and Upper Gastrointestinal Bleeding: A Causal Relationship?
- Anne L Grundy (5 December 2006)
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Robert Stevenson, Senior House Officer in General Medicine University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, Melanie Halliday, Heather Dyson, and Nij Bhala
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Hallas et al. deserve praise for highlighting the importance of gastrointestinal risks with antithrombotic therapy in their population- based study [1]. Of particular relevance to us was the significantly increased relative risk of combined aspirin and clopidogrel therapy (relative risk 7.4, 95% confidence interval 3.5 to 15). However, we feel this needs to be interpreted cautiously given that only thirteen cases of 1443 (0.009%) were exposed to dual antiplatelet therapy. There is a paucity of evidence regarding the gastrointestinal complications associated with dual therapy and we wholeheartedly agree further studies are required. Nevertheless, randomised trials have demonstrated an increased risk of bleeding in comparison with aspirin monotherapy [2,3]. This risk obviously needs to be counterbalanced with the benefits in both percutaneous coronary intervention and secondary prevention of cardiovascular disease (20% relative risk reduction in the CURE study). The co-prescription of proton pump inhibitors with aspirin has been shown to reduce gastrointestinal ulcers [4]. In contrast, there is a shortfall of evidence for the prevention and treatment of ulcers in the dual antiplatelet setting. Both clopidogrel and aspirin have a synergistic effect on platelet aggregation and thromboxane A2 production [5]. This appears to apply equally to gastrointestinal bleeding risk. Unfortunately, there are presently no plausible underlying mechanisms for this. As well as further clinical studies in this field, basic pathophysiological research is needed. Guidelines for the use of dual antiplatelet therapy in cardiovascular medicine are now well established. However, the apparent increased risks of gastrointestinal bleeding should not be ignored. The National Institute for Clinical Excellence recommends the use of gastroprotective proton pump inhibitors in combination with long term aspirin monotherapy. We acknowledge the lack of evidence for their use in dual antiplatelet therapy, but suggest that the addition of a proton pump inhibitor would reduce the bleeding risks. We strongly advocate that our cardiology colleagues consider such a triple therapy approach in high risk patients when instigating antiplatelet treatment. 1. Jesper Hallas, Michael Dall, Alin Andries, Birthe Søgaard Andersen, Claus Aalykke, Jane Møller Hansen, Morten Andersen and Annmarie Touborg Lassen. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607–21. 3. The CURE investigators. Effect of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation. N Engl J Med 2001;345:494-502. 4. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352: 238–44. 5. Mehta SR, Yusuf S. Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention. J Am Coll Cardiol. 2003 Feb 19;41(4 Suppl S):79S-88S. Competing interests: None declared |
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Venkataswamy Narayana Mahesh, SpR Gastroenterology University Hospital of North Durham, Durham, DH15TW
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Editor- I read with interest this very good study filling in the gaps of our knowledge especially regarding bleeding risks whilst on combination antithrombotic therapy. PRoFESS study(1) and MATCH trials(2) have shown that there is no statistically significant benefit of aspirin and clopidogrel therapy for prophylaxis in cerebrovascular disease, and their benefit as a combination have no clear answers as yet since CHARISMA trial which evaluated aspirin plus clopidogrel versus aspirin alone, showed that the combination therapy didnot improve the endpoints of MI, stroke or deatrh from cardiovascular events, compared to aspirin alone. I like to emphasize that , unless there is a clear risk benefit discussion with the patient, aspirin and clopidogrel combination therapy needs a cautious approach. Also in this study, the authors have tried to tackle the problem of smoking, NSAID and alcohol related markers as confounding variables and found no significant difference on the presented statistics, I would like to differ since we have enough evidence(3) to prove so far that H.Pylori and NSAID use(including low dose aspirin) are both independent and synergistic risk factors(17.5 times higher the risk). We also know that low dose aspirin(as low as 10mg/day) can cause inhibition of mucosal PG syntesis (4) and use of NSAIDs concurrently reduce the protective lipoxin synthesis(5) further increasing the risk of mucosal damage.Hence further clarifications regarding these confounding variables will be quite useful. References: 1. Sacco, RL, Diener, H-C, Yusuf, S, PRoFESS Steering Committee and Study Group. Prevention regimen for effectively avoiding second strokes (PRoFESS) 2. Diener, HC, Bogousslavsky, J, Brass, LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331. 3. Papatheodoridis, GV, Sougioultzis, S, Archimandritis, AJ. Effects of Helicobacter pylori and Nonsteroidal Anti-Inflammatory Drugs on Peptic Ulcer Disease: A Systematic Review. Clin Gastroenterol Hepatol 2006; 4:130. 4. Cryer, B, Feldman, M. Effect of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology 1999; 117:17. 5. Fiorucci, S, de Lima, OM, Mencarelli, A, et al. Cyclooxygenase-2- derived lipoxin A4 increases gastric resistance to aspirin-induced damage. Gastroenterology 2002; 123:1598. Competing interests: None declared |
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Amit Patel, Senior House Officer in Cardiology The Heart Hospital, UCLH NHS Foundation Trust, 16 - 18 Westmoreland Street, London, W1G 8PH, UK
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Hallas et al provide valuable case-control data on the risk of serious gastrointestinal bleeding from combined anti-platelet therapy.[1] Clinically important benefit from aspirin and increasingly higher loading doses of clopidogrel, 300 mg and 600 mg, has been demonstrated for both non-ST-elevation myocardial infarction (NSTEMI)[2] and ST-elevation myocardial infarction (STEMI). Emergency and elective percutaneous coronary intervention (PCI), with bare metal or drug-eluting stent placement is an increasingly popular and evidenced treatment strategy. Stent thrombosis is a serious and often underappreciated complication that has an estimated incidence of 0.5 to 0.6%.[3] It carries a thirty-day mortality of 15% and a 60% incidence of non-fatal myocardial infarction[4], with a six-month mortality of 31%.[5] Cessation of clopidogrel therapy is among the recognised associations[5] and should be remembered in the context of non-variceal gastrointestinal bleeding in these patients. [1] Jesper Hallas, Michael Dall, Alin Andries, Birthe Søgaard Andersen, Claus Aalykke, Jane Møller Hansen, Morten Andersen, Annmarie Touborg Lassen. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006;333:726-28. [2] Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, Lehmann A, Lambert M, Bonnet JL, Alessi MC. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339-45. [3] Moreno R, Fernandez C, Hernandez R, Alfonso F, Angiolillo DJ, Sabate M, Escaned J, Banuelos C, Fernandez-Ortiz A, Macaya C. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol 2005;45:954-9. [4] Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, Regar E, McFadden EP, Sianos G, van der Giessen WJ, de Jaegere PP, de Feyter P, van Domburg RT, Serruys PW. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare- metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol 2005;45:947-53. [5] Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113:1108-13. Competing interests: None declared |
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Michael Poullis, Consultant cardiothoracic Surgeon CTC, Liverpoool. L14
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Lassen et al1 present important data regarding combination antithrombotic therapy and the risk of serious upper gastrointestinal bleeding. This paper raises a number of important issues. Firstly the claim about sparse data is misleading, a number of papers about combination therapy document serious upper gastrointestinal bleeding, but still the superiority of combination therapy with regard to mortality is clearly demonstrated. Secondly, Lassen et al seem to have forgotten the indication for combination therapy after acute cardiac events, reduction in deaths in patients at high risk of suffering a fatal cardiovascular event. Use of the TIMI risk score system in ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) will enable identification of these high risk patients and subsequent targeting of combination therapy. Thirdly patency of drug eluting stents has been shown to be improved by the use of combination therapy. As drug eluting stents have higher patencey rates than bare metal stents their use has increased exponentially. 1. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, Andersen M, Lassen AT. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case -control study. BMJ. 2006;333(7571):726. Competing interests: None declared |
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Edward N Herbert, Vitreo-Retinal Surgeon St Thomas' Hospital. SE1 7EH, D. Alistair H. Laidlaw
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The experience of Hallas et al[1] in respect of serious upper GI bleeding mirrors our own findings of spontaneous vitreous haemorrhage associated with combination anti-platelet therapy[2]. In the last 3 years we have increasingly encountered spontaneous vitreous haemorrhage and also intra-operative haemorrhage during vitrectomy in patients on these agents as their use increases. We have seen further cases since our case series was submitted. In our experience the combination of clopidogrel and aspirin is most commonly encountered in these cases, and it is interesting that Hallas et al found this combination to be associated with the highest risk of upper GI haemorrhage. Patients presenting with spontaneous vitreous haemorrhage, whilst on combination treatment present a particular challenge. Early vitrectomy for spontaneous haemorrhage is advocated by many[3] to detect and treat associated retinal breaks (which may otherwise progress to retinal detachment), because undetected retinal detachment concealed by dense vitreous haemorrhage is associated with a poor outcome. Yet uncontrollable intra-operative bleeding can be encountered in patients on combined agents. Reverting to aspirin monotherapy[4], in consultation with the patient’s physicians, for the period of surgery may be an option, balanced against the cardiovascular risk of doing so. References: 1. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, Andersen M, Lassen AT Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006; 333: 726. 2. Herbert EN, Mokete B, Williamson TH, Laidlaw DAH. Haemorrhagic vitreoretinal complications associated combined antiplatelet agents. Br J Ophthalmol. 2006;90:1209-10. 3. Sarrafizadeh R. Hassan TS. Ruby AJ. Williams GA. Garretson BR. Capone A Jr. Trese MT. Margherio RR. Incidence of retinal detachment and visual outcome in eyes presenting with posterior vitreous separation and dense fundus-obscuring vitreous hemorrhage. Ophthalmology. 2001;108:2273- 8. 4. Narendran N, Williamson TH. The effects of aspirin and warfarin therapy on haemorrhage in vitreoretinal surgery. Acta Ophthalmol Scand 2003;81:38–40. Competing interests: None declared |
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Jan P Vandenbroucke, Professor of Clinical Epidemiology Leiden University Medical Center, Erik M van Driel
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In their excellent study on a timely topic, Hallas et al. have treated the use of NSAIDS, coxibs and SSRIs as “potential confounders”. However, if these drugs also interact with the study drugs, a statistical model that treats them as potential confounders will average out an interaction effect instead of removing it. Because numbers might become too small for separate analyses of the joint effects of more than two drugs, a clearer strategy might be to simply remove users of these drugs from the analysis: do the estimates for the main study drugs still remain the same? A similar question might be asked about previous peptic ulcer and/or previous gastro-intestinal bleeding. Competing interests: None declared |
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D. Michael Humphreys, M.D., Ch.B.F.F.P.M., Senior Medical Advisor Boehringer Ingelheim Boehringer Ingelheim GmbH, 55216 Ingelheim, Germany, Manfred Haehl
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Sir, Antithrombotic therapy is a mainstay of treatment for the prevention of thrombotic vascular events in patients with established vascular disease. Antithrombotic therapy includes antiplatelet and anticoagulant drugs and combinations of these, although the combination of an oral anticoagulant (Vitamin K antagonists, VKA) together with aspirin is not recommended because of the likely enhancement of bleeding risk from two agents each known to be associated with bleeding in its own right. The combination of the antiplatelet agents aspirin (ASA) and clopidogrel has recently been shown to provide no additional benefit but increased haemorrhagic risk in patients with prior stroke or T/A as evidence of cerebrovascular disease (1) (MATCH) and in patients at high risk of atherothrombotic events (2) (CHARISMA). Hallas et al (3) in their population based case-control study draw a general overall conclusion in stating that combined antithrombotic drug treatment confers particular risk and is associated with high rates of gastro-intestinal bleeding. That statement is not justified by the evidence available. Firstly, dipyridamole has been used for many years co- administered with VKA for the prevention of thromboembolism in patients with mechanical heart valves. Randomised, controlled trials of dipyridamole combined with warfarin versus warfarin alone have clearly shown no excess of bleeding over that seen with warfarin alone (4). In addition, the data from the randomised, placebo-controlled trials ESPS2 (5) involving some 6500 patients with cerebrovascular disease evidenced by prior stroke or TIA treated and followed for up to two years, and ESPRIT (6) which included more than 2700 prior stroke patients randomised to receive the combination of ASA plus dipyridamole or ASA alone and followed for up to four years, show that there was no excess of gastro-intestinal bleeding of any severity over that seen with ASA alone. ESPS2 also showed that any bleeding associated with dipyridamole was equal to that associated with placebo. In CAPRIE (7) (>19,000 patients) bleeding rates for ASA alone and clopidogrel alone were comparable at approximately 9.3 %, very similar to aspirin alone in ESPS2 (8.45%) and in ACTIVE W (8) the combination of clopidogrel and ASA was associated with more bleeding of all types than was warfarin alone (644 vs. 555, p<0.001). The study by Hallas et al appears to have methodological weaknesses. It would seem inappropriate to compare in-hospital patients with cardiovascular disease and exposed to antithrombotic regimen with control- patients who are not in hospital and have neither evidence of bleeding nor are hospitalised, i.e. a general population. It would seem more appropriate to take as controls hospitalised individuals at risk from cardiovascular disease. Secondly, the results for clopidogrel alone, clopidogrel plus ASA and ASA + VKA are fragile with very small numbers of exposed cases and controls as well as by the response of the estimates to adjustment. Finally, since the risk estimates for aspirin, dipyridamole, ASA + dipyridamole, clopidogrel alone and VKA alone all overlap almost completely, it cannot be inferred that the combination of ASA + dipyridamole poses more risk than ASA alone. It would appear that the substantial data available from very large-scale randomised, controlled trials provides much more definitive and consistent evidence as to the propensity for bleeding, particularly severe or serious bleeding, associated with any one of the agents singly as well as in combination and by no means are they all the same as Hallas et al. assert. D. Michael Humphreys, M.D., Ch.B. F.F.P.M.
Manfred Haehl, M.D.
References 1. Diener H-C et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCG): randomised, double-blind, placebo- controlled trial. Lancet 2004;364:331-37. 2. Bhatt DL et al. Clopidogrel and Aspirin versus Aspirin alone for the Prevention of Ahterothrombotic Events. N Engl J Med 2006;354:1-2. 3. Hallas J et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population-based case -control study. BMJ 2006;333:726-728. 4. Persantine (dipyridamole) Product Information. PDR 2005:1009-1010. 5. Diener H-C et al. European Stroke Prevention Study 2: Efficacy and Safety Data. J Neurol Sci 1997;151:51-77 6. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665-1673. 7. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39. 8. The ACTIVE Writing Group: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;363:1903-12. Competing interests: Company Employees |
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Anne L Grundy, MSc Candidate, Department of Community Health and Epidemiology Queen's University, Kingston, Ontario, Canada K7L 3N6
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Hallas et al (1) demonstrate a strong association between use of aspirin and clopidogrel combined, with a reported odds ratio of 7.4 (95% CI 3.5 – 15). When this result is compared with those of the individual drugs alone (OR = 1.8 (aspirin) and OR = 1.1 (clopidogrel)) the increase in risk appears even more staggering. Even at the lower bound of the 95% confidence interval, an odds ratio of 3.5, may still be considered a fairly strong association between drug use and bleeding. That this is a true relationship is supported by its consistency with data from several randomized clinical trials where the risk of bleeding is greater with the combination of aspirin and clopidogrel than in the group using aspirin alone. (2,3) A dose response relationship has been documented also for different doses of aspirin used in combination with clopidogrel, with higher doses being associated with more bleeding (2). Biologically, clopidogrel and aspirin act through different pathways to inhibit platelet activity, supporting the observed synergistic block in platelet action (4), which could lead to more bleeding as clotting is inhibited through multiple mechanisms. The evidence supporting the existence of a causal relationship between aspirin-clopidogrel use and gastrointestinal bleeding highlights a major downside to the use of these drugs in combination that should be brought to the attention of the public, beyond the readership of the British Medical Journal. (1) Hallas J, Dall M, Andries A, Anderson BS, Aalykke C, Hansen JM, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ 2006; 333:726-730. (2) Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108:1682-1687. (3) The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345(7):494-502. [Errata, N Engl J Med 2001;345:1506, 1716] (4) Chopra V, Marmur JD, Cavusoglu E. The Role of Clopidogrel in the Management of Patients with Ischemic Heart Disease. Cardiovasc Drugs Ther 2003; 17:467-477. Competing interests: None declared |
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