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Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery
J Dörffler-Melly, HR Büller, MM Koopman, MH Prins
DOI:10.1002/14651858.CD000535
J Dörffler-Melly, HR Büller, MM Koopman, MH Prins
DOI:10.1002/14651858.CD000535
Date received: February 22, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9607#9607
I will comment on aspects of this review according to section.
Types of outcome measures
Comment: The first four outcome measures are surrogate endpoints. Conclusions and recommendations should not be based on them. Instead, the important outcome measures are the last four: (1) side effects of treatment, (2) limb salvage rate - survival rates with limb intact, (3) incidence of other cardiovascular events and mortality, and (4) patients' quality of life.
Results
Comment: Clinical endpoints were analyzed in a minority of trials. Below, I extract the evidence from this review concerning the available clinical endpoints for efficacy and side effects:
Aspirin (ASA) or aspirin/dipyridamol (ASA/DIP) versus no aspirin
Amputation
No statistically significant benefit.
Cardiovascular events
A borderline significant effect favoring ASA or ASA/DIP (OR: 0.71, 95% CI 0.47 – 1.08)
Comment: Of the four trials in this analysis, the three small ones all had ORs > 1.01-3 while the large one (McCollum) had a statistically significant reduction in heart attacks and strokes with ASA or ASA/DIP (OR: 0.55, 95% CI 0.35 – 0.88).4 By limiting the documentation of cardiovascular events to heart attacks and strokes, the McCollum trial may have missed other important cardiovascular events (e.g., hospitalizations for congestive heart failure). Patients with symptomatic PAD generally have advanced underlying cardiac disease. Many may be in heart failure and more will progress to heart failure within months to 1-2 years. For those in or near heart failure, aspirin may increase adverse events.5 The European Society of Cardiology guidelines state, “Aspirin should be avoided in patients with recurrent hospitalization with worsening heart failure (Class of recommendation IIb, level of evidence B).6 Similarly, American Heart Association / American College of Cardiology guidelines suggest avoiding ASA, “Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HF and reduced LVEF should be avoided or withdrawn whenever possible (e.g., nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and most calcium channel blocking drugs; see text). (Level of Evidence: B).”7
Long term use of antiplatelet drugs is potentially hazardous in the significant proportion of this PAD patient population that are prone to congestive heart failure.
Side effects
Gastrointestinal side effects: OR: 1.44; 95% CI 0.92 to 2.24
Major bleeding: OR: 1.88; 95% CI 0.85 to 4.16
Overall side effects: OR: 1.55: 95% CI 1.00 – 2.41
Comment: Given the absence of benefit demonstrated in any clinical endpoint, the significant increase in side effects is particularly notable.
Aspirin (ASA) or aspirin/dipyridamol (ASA/DIP) versus pentoxifylline (PTX)
No clinical endpoint data reported.
Aspirin/dipyridamol (ASA/DIP) versus indobufen (IND)
No clinical endpoint data reported.
Aspirin/dipyridamol (ASA/DIP) versus vitamin K antagonists (VKA)
Limb salvage and survival
No statistically significant difference between groups
Side effects
VKA treatment significantly increased the bleeding complications (9% (119/1326) versus 4.5% (59/1324) had haemorrhage requiring hospital admission). Both ASA/DIP and VKA were associated with fatal bleeding (coumarin: 16(1.2%), ASA/DIP: 12 (0.9%)).
Comment: These rates are unacceptably high given the absence of proven clinical benefit.
Death
No statistically significant difference between groups
Aspirin/dipyridamol (ASA/DIP) versus low molecular weight heparin (LMWH)
Side effects
No major bleedings or adverse events occurred.
Comment: According to the Cochrane Handbook, “The analysis of zero events in either arm (for example, “the drug was safe”, and “no serious adverse effects were seen”) needs careful consideration. Data of this type need to be evaluated in the following contexts: How thorough were the methods used to detect adverse effects? How many patients were studied and for how long?” The absence of side effects in these 200 patients is probably an anomaly and warrants some discussion by the authors.
Death
Nine patients in the LMWH group (four with patent grafts) and two in the aspirin group died during follow-up. (OR: 5.51, 95% CI 1.16 – 26.16)
Comment: This important clinical endpoint was not included in the figures or tables or mentioned in the discussion.
Ticlopidine (TIC) versus nothing
No clinical endpoint data reported.
Aspirin versus prostaglandin E1 (PGE1)
No clinical endpoint data reported.
Authors’ conclusions
Implications for practice
“In conclusion, there is evidence to suggest that the administration of platelet-inhibitors such as ASA, ASA/DIP, TIC or PTX, will result in improved venous and artificial graft patency compared to no treatment.”
Comment: This finding is based on surrogate not clinical endpoints. Given the absence of demonstrated clinical benefit and the risk of major side effects (gastrointestinal, haemorrhagic, and cardiovascular), platelet inhibitors should not be used.
“However, patients receiving a prosthetic graft may profit more from ASA or ASA/DIP administration than those treated with a venous graft.”
Comment: Again, “profit” is only based on surrogate endpoints.
“Patients receiving venous femoropopliteal, infragenicular bypasses seem to benefit more from VKA than from ASA.”
Comment: No differences in clinical endpoints were seen while both drugs were associated with fatal bleeding (coumarin: 16(1.2%), ASA/DIP: 12 (0.9%)). Rebound hypercoagulability was not assessed by collecting study data for two month after VKA withdrawal in all patients.8 Neither drug should be recommended to practicing clinicians.
“A combination of ASA and a thienopyridine, e.g. Clopidogrel, might be as effective for primary patency rates as VKA.”
Comment: This non evidence-based plug for a patented, expensive drug is inappropriate.
Implications for research
Comment: Since no drugs are evidence-based to provide any net clinical benefit, any future drug treatment RCT should have a placebo or untreated control group.
Potential conflict of interest
“There was no potential conflict of interest recognised.”
Comment: One of the comparisons in this review was antiplatelet agents versus LMWH. The statistically significant increase in deaths in the LMWH group was not included in the figures or tables or mentioned in the discussion. Some of the authors have received funding for research involving LMWHs.
Harry Buller, MD received honoraria and grants from Sanofi-Synthe´labo, NV Organon (fondaparinux and enoxaparin),9 and research funding from Leo Laboratories for a comparison of tinzaparin and enoxaparin.10 AstraZeneca LP; Aventis Pharmaceuticals; Bristol-Myers Squibb/Sanofi-Syntholabo Partnership; GlaxoSmithKline; Organon Sanofi-Synthelabo LLC supported his review of Antithrombotic Therapy for Venous Thromboembolic Disease for the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.11
Martin Prins, MD participated on the steering committees and in obtaining funding from Santofi-Synthelabo and NV Organon drug companies for trials of a LMWH versus fondaparinux (Aristra) in treatment of DVT and PE.9, 12 Based on the results of these two studies, the FDA approved fondaparinux for the treatment of DVT and PE on May 28, 2004. Anticipating this approval, Sanofi-Synthelabo announced the sale of Arixtra and nadroparine (Fraxiparine) on April 13, 2004 to GlaxoSmithKline for about $360 million.13 AstraZeneca LP; Aventis Pharmaceuticals; Bristol-Myers Squibb/Sanofi-Syntholabo Partnership; GlaxoSmithKline; Organon Sanofi-Synthelabo LLC supported his review of Antithrombotic Therapy for Venous Thromboembolic Disease for the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.11 Sanofi Winthrop provided him with research funding for a study comparing Fraxiparine with heparin.14
Marianne Koopman, MD has been paid by Sanofi Winthrop (Paris) for a trial involving nadroparine (Fraxiparine, a LMWH).
1. Green RM, Roedersheimer RL, DeWeese J. Effects of aspirin and dipyridamole on expanded polytetrafluoethylene graft patency. Surgery. 1982;92(6):1016-1026.
2. Donaldson DR, Salter MCP, Kester RC, Rajah SM, Hall TJ, Sreeharan N. The influence of platelet inhibition on the patency of femoro-popliteal Dacron bypass grafts. Vascular Surgery. 1985;19(4):224-230.
3. Clyne CA, Archer TJ, Atuhaire LK, Chant ADB, Webster JHH. Random control trial of a short course of aspirin and dipyridamole (Persantin) for femorodistal grafts. British Journal of Surgery. 1987;74(4):246-248.
4. McCollum C, Alexander C, Kenchington G, Franks PJ, Greenhalgh R. Antiplatelet drugs in femoropopliteal vein bypasses: A multicenter trial. Journal of Vascular Surgery. 1991;13(1):150-162.
5. Cleland JG. Chronic Aspirin Therapy for the Prevention of Cardiovascular Events: A Waste of Time, or Worse? Nature Clinical Practice Cardiovascular Medicine. May 30, 2006;3(5):234-235.
6. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. 10.1093 /eurheartj /ehi204. Eur Heart J. June 1, 2005;26(11):1115-1140.
7. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. 10.1161/CIRCULATIONAHA.105.167586. Circulation. September 20, 2005;112(12):e154-235.
8. Cundiff DK. Reply to Letters re Anticoagulation Therapy for Venous Thromboembolism. Medscape General Medicine. January 3, 2005;6(4):http://www.medscape.com/viewarticle/496149.
9. Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial. Ann Intern Med. June 1, 2004;140(11):867-873 http://www.annals.org/cgi/reprint/140/811/867.pdf.
10. Planes A, Samama MM, Lensing AW, et al. Prevention of deep vein thrombosis after hip replacement--comparison between two low-molecular heparins, tinzaparin and enoxaparin. Thromb Haemost. 1999;81(1):22-25.
11. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic Therapy for Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. September 1, 2004 2004;126(3_suppl):401S-428.
12. The Matisse Investigators. Subcutaneous Fondaparinux versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism. 0.1056/NEJMoa035451. N Engl J Med. October 30, 2003;349(18):1695-1702.
13. Sanofi-Synthelabo to Sell to GlaxoSmithKline Arixtra(R), Fraxiparine(R) and Notre Dame de Bondeville Plant. PRNewswire-FirstCall. April 13, 2004. Accessed July 29, 2006.
14. Koopman MM, Prandoni P, Prins MH, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. New England Journal of Medicine. 1996;334(11):682-687.