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Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment
J Dörffler-Melly, MMW Koopman, MH Prins, HR Büller
DOI:10.1002/14651858.CD002071.pub2
J Dörffler-Melly, MMW Koopman, MH Prins, HR Büller
DOI:10.1002/14651858.CD002071.pub2
Date received: February 22, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9609#9609
I will comment on aspects of this review according to section.
Background
“……….Current peri-interventional treatment strategies mostly include aspirin intake before and after percutaneous transluminal angioplasty (PTA), initial administration of either unfractionated heparin (UH) (Ellis 1989) followed mostly by antiplatelet drugs or anticoagulants on a long-term basis (Do 1994; Hess 1985; Shammas 2003b; Watson 2000)….”
Comment: The implication that antiplatelet drugs and anticoagulants are evidence-based to safely reduce adverse clinical events after PTA is not borne out by a perusal of the references:
1. (Ellis) RCT of UH versus dextrose (no untreated control): No clinical or surrogate outcome differences in efficacy.1
2. (Do) RCT of ASA versus oral anticoagulants (no untreated control): No clinical or surrogate outcome differences2
3. (Hess) RCT of ASA 330 mg; dipyridamole 75 mg and ASA 330 mg; or placebo 3 times daily: No clinical outcome differences.3
4. (Shammas) Retrospective chart survey of complications of unfractionated heparin in 213 patients: 4.6% of patients had major bleeding while in hospital.4
5. (Watson)5 A review of RCTs of antithrombotic agents to reduce restenosis and clinical endpoints after angioplasty for peripheral vascular disease (PVD): “CONCLUSIONS: evidence for a reduction in the likelihood of re-occlusion or restenosis after peripheral transluminal angioplasty with platelet inhibitors remains equivocal. Evidence for the efficacy of any other agent in this indication is also lacking.”
Types of outcome measures
Primary endpoints
• occlusion or restenosis > 50%, shown by duplex sonography or angiography, according to previously described diagnostic criteria (Moneta 1987; Ranke 1992)
Secondary endpoints
• amputation
• death
• myocardial infarction
• stroke
• major bleeding (i.e. requiring blood replacement therapy or intensive care)
• side-effects
Comment: The primary endpoint, which determines the main conclusions of the review, is a surrogate endpoint while the secondary endpoints are the important clinical ones. The order should be reversed. If interventions do nothing for clinical endpoints, they are not evidence-based to be effective.
Results
Comment: Considering only clinical endpoints, the comparisons showed the following:
ASA versus placebo- no statistically significant effects
ASA/DIP versus ASA- no significant difference demonstrated in efficacy
ASA high dose versus ASA low dose- no statistically significant benefits of high dose ASA, but significantly more side effects
ASA/DIP versus VKA- No significant difference demonstrated in efficacy
Suloctidil versus VKA- No significant difference demonstrated in efficacy
Ticlopidine versus VKA- No significant difference demonstrated in efficacy
ASA/DIP versus taprostene- No significant difference demonstrated in efficacy
Urokinase plus abciximab versus urokinase alone- The control treatment, urokinase, is not standard therapy or evidence-based to work. Major bleeds occurred in 4/50 (8%) and “minor complications” in 9/50 (18%) of patients receiving urokinase plus abciximab.
Comment: These drugs should be avoided because the high bleeding risk.
Abciximab versus placebo- No significant difference demonstrated in efficacy. “Minor bleeding” occurred in 17/47 (36%) of subjects receiving abciximab
LMWH versus UH- The control group, UH, is not evidence-based to work based on clinical endpoints.1 Between LMWH and UH, there was no significant difference demonstrated in clinical efficacy. While bleeding risk did not differ between groups, it was very high with either drug (Hematoma more than 10 cm and spurious aneurysm by 3 weeks, LMWH: 22/86 (26%) versus UH: 16/86 (19%)).
Implications for practice
“Evidence suggests that patients treated by peripheral angioplasty would benefit from receiving aspirin at a dose of 50 mg to 300 mg daily, started prior to PTA and continued for at least two years or life-long.”
Comment: This is based on the surrogate end-point, vessel patency. The clinical endpoints (amputation, death, and bleeding at puncture sites) had no significantly different outcomes in the comparison of ASA with placebo. Data on myocardial infarctions, strokes, and congestive failure hospitalizations, and other side effects were not reported. Aspirin causes significant side effects but is not evidence-based to provide a net benefit to PAD patient after peripheral endovascular treatments.
“Thienopyridines, e.g. clopidogrel, might represent a useful alternative in cases where aspirin is not tolerated, or as a combination therapy with aspirin where increased risk factors for reocclusion are detected, although specific data is lacking.”
Comment: In an Cochrane review of RCTs and other relevant studies, the implications for practice should not use the implications for practice section to plug a patented, expensive treatment that is not evidence-based to work as an alternative to ASA, which is also not evidence-based to provide net clinical benefit.
“The use of low molecular weight heparins might be superior to unfractionated heparin to prevent early and mid-term reocclusion/restenosis after femoropopliteal angioplasty.”
Comment: UH increases bleeding, but does not reduce adverse clinical events compared with dextrose.1 LMWH is statistically more effective that UH regarding radiographically detected restenosis (a surrogate endpoint) but not with regard to preventing amputation, the only clinical endpoint reported (LMWH: 3/86, UH: 3/86). Since both LMWH and UH cause high rates of bleeding, they should not be used.
“Abciximab might be a useful drug for extended femoropopliteal interventions in patients with high risks for reocclusion.”
Comment: Since no clinical outcomes other than “minor bleeding” were reported from the abciximab trial (headed by this review’s lead author),6 this recommendation should be omitted from the implications for practice.
Implications for research
Comment: The implications for research should indicate that, since no drug thus far tested is evidence-based to reduce adverse clinical events after PTA, any drug trial should have a no treatment or placebo control group.
Potential conflict of interest
Comment: One of the comparisons in this review was UH versus LMWH. LMWHs were deemed possibly superior to UH despite the lack of demonstrated clinical efficacy of either and the significant bleeding risk of both. Some of the authors have received funding for research with LMWHs.
Harry Buller, MD received honoraria and grants from Sanofi-Synthe´labo, NV Organon (fondaparinux and enoxaparin),7 and research funding from Leo Laboratories for a comparison of tinzaparin and enoxaparin.8 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.9
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.7, 10 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.11 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.9 Sanofi Winthrop provided him with research funding for a study comparing nadroparine (Fraxiparine) with heparin.12
Marianne Koopman, MD has been paid by Sanofi Winthrop (Paris) for a trial involving nadroparine (Fraxiparine, a LMWH).
1. Ellis SG, Roubin GS, Wilentz J, Douglas JSJ, King SBI. Effect of 18 to 24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. American Heart Journal. 1989;117(4):777-782.
2. Do DD, Mahler F. Low-dose aspirin combined with dipyridamole versus anticoagulants after femoropopliteal percutaneous transluminal angioplasty. Radiology. 1994;193(2):567-571.
3. Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral arterial occlusive disease. Lancet. 1995;1(8426):415-419.
4. Shammas NW, Lemke JH, Dippel EJ, McKinney DE, Takes VS, Youngblut M. In-hospital complications of peripheral vascular interventions using unfractionated heparin as the primary anticoagulant. Journal of Invasive Cardiology. 2003;15(5):242-246.
5. Watson HR, Bergqvist D. Antithrombotic agents after peripheral transluminal angioplasty: a review of the studies, methods and evidence for their use. European Journal of Vascular & Endovascular Surgery. 2000;19(5):445-450.
6. Dörffler-Melly J, Mahler F, Do D, Triller J, Voegele J, Baumgartner I. Adjunctive abciximab improves patency and functional outcome in patients undergoing endovascular treatment of femoropopliteal occlusions. submitted. Radiology. 2005;237(3):1103-1109.
7. 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.
8. 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.
9. 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.
10. 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.
11. Sanofi-Synthelabo to Sell to GlaxoSmithKline Arixtra, Fraxiparine and Notre Dame de Bondeville Plant. PRNewswire-FirstCall. April 13, 2004. Accessed July 29, 2006.
12. 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.