Feedback by David K. Cundiff, MD

 

Sent 6/28/07    J Dörffler-Melly, HR Büller, MM Koopman, MH Prins. Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD000536. DOI: 10.1002/14651858.CD000536.

 

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 but on clinical endpoints. The clinical endpoints are the last four outcome measures: (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.

 

Types of outcome measures

Comment: The implications for practice focus on benefical therapies for subgroups of patients: (1) patients with venous graphs and (2) patients with artificial graphs. These subgroups were not defined in the protocol, so post hoc statistical analyses of outcomes of these subgroups should not be emphasized in the results or conclusions. In several places, the Cochrane Handbook warns against problems with post hoc analyses:

 

(pg 19) “Changes in the protocol should not be made on the basis of how they affect the results of the review. Post hoc decisions (such as excluding selected studies) that are made when the impact on the results of the review is known are highly susceptible to bias and should be avoided”

 

(pg 63) “Post-hoc questions are more susceptible to bias than those asked a priori, and data-driven questions can generate false conclusions based on spurious results.”

 

(pg 143) “8.8.4.2 Specify characteristics in advance Authors should, whenever possible, pre-specify characteristics in the protocol that later will be subject to subgroup analyses or meta-regression. Pre-specifying characteristics reduces the likelihood of spurious findings, first by limiting the number of subgroups investigated and second by preventing knowledge of the trials’ results influencing which subgroups are analysed.”

 

(pg 147) “Findings for the most important comparisons and/or outcomes should be prominent in the text of the review, even when little relevant data were available. Answers to post hoc analyses and less important questions for which there happen to be plentiful data should not be oveemphasised. Post hoc analyses should always be identified as such.”

 

Results

VKA versus no VKA (Arfvidsson 1990; Johnson 2002; Kretschmer 1992; Sarac 1998)
Limb salvage
Comment: Apparently, the Johnson trial (n = 831) was not included with these other smaller trials (combined n = 268) regarding limb salvage, because limb salvage was not reported. However, given the nonsignificant differences in the occlusion rates in the Johnson trial (OR: 0.92 , 0.95, 0.86 at 12 months, 24 months, and 5 years respectively), limb salvage rates between the groups would not be expected to be significantly different. Consequently, no benefit of coumarin can be inferred in terms of limb salvage. 

 

Survival
For survival, a non-significant trend was observed (OR 0.34; 95% CI fixed 0.08 to 1.39 at six months; OR 0.66; 95% CI fixed 0.38 to 1.15 at 24 months).

Comment: The authors did not specify why the Johnson trial was omitted from this analysis. In that trial with a mean followup of 38 months,”there were 133 deaths in the warfarin + ASA group and 95 deaths in the ASA group (RR 1.41; 95% confidence interval, 1.09 to 1.84; P =.0001).

 

Side effects
Comment: Although side effects were reported in the Johnson trial, they were not included in the analysis: “Major hemorrhagic events occurred more frequently in the warfarin + ASA group (WASA, n = 35; ASA, n = 15; P =.02)…. In the WASA group, an intracranial hemorrhage occurred in six patients, of whom four died; one subdural hemorrhage occurred in the aspirin group.”1, 2 Given that there were no clear benefits in limb salvage, overall mortality, or any other clinical parameter, these are unacceptable rates of serious bleeding.

 

VKA versus aspirin/dipyridamol (BOA 2000; Schneider 1979)
Limb salvage and survival
No statistically significant difference between groups is seen.

Comment: The post hoc subgroup analysis showing apparent benefit with VKA for venous grafts and for ASA/DIP for artifical conduits is meaningless in the absence of benefit for either VKA or ASA/DIP against placebo overall.

 

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 of major and fatal bleeding are also unacceptable.

 

Unfractioned heparin (UH) versus low molecular weight heparin (LMWH) (Samama 1994; Swedenborg 1996)

Comment: No clinical efficacy or safety endpoints were analysed in the comparisons. Neither LMWH nor UH has been shown to be safe and effective in placebo-controlled trials. While bleeding risk did not differ between groups, it was very high with either. (Samama: 12 major hemorrhages [12%] in each group; Swedenborg: Hematoma more than 10 cm and spurious aneurysm by 3 weeks, LMWH: 22/86 [26%] versus UH: 16/86 [19%]). Neither treatment is safe and effective.

 

LMWH versus aspirin/dipyridamol (Edmondson 1994)

Comment: No statistical comparisons of clinical outcomes were reported.

 

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 should receive 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 1.2 – 26.2, my statistical analysis)

Comment: This important clinical endpoint, not included in the figures or tables or mentioned elsewhere in the text, deserves some discussion by the authors.

 

Implications for practice

“The evidence suggests that patients subjected to infrainguinal venous graft surgery might have improved patency rates with VKA. Patients receiving an artificial graft might profit more from platelet inhibitors (aspirin).”

Comment: There is no clinical evidence that either VKA or ASA/DIP improve clinical outcomes compared with placebos or no antithrombotic treatment. Consequently, the post hoc subgroup analysis indicating that VKA works better for venous grafts and ASA/DIP works better for artificial conduits is meaningless.

 

 “Prevention of early occlusion in infrainguinal bypass surgery by perioperative treatment with low molecular weight heparins seems to be more successful than administration of unfractionated heparin.”

Comment: The control group, UH, is not evidence-based to work based on clinical endpoints. 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.

 

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 infrainguinal bypass surgery, any drug trial should have a no treatment or placebo control group.

 

 

Potential conflict of interest

“None known.”

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),3 and research funding from Leo Laboratories for a comparison of tinzaparin and enoxaparin.4 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.5 

 

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.3, 6 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.7 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.5 Sanofi Winthrop provided him with research funding for a study comparing nadroparine (Fraxiparine)  with heparin.8

 

Marianne Koopman, MD has been paid by Sanofi Winthrop (Paris) for being the principle investigator for a trial involving nadroparine (Fraxiparine, a LMWH).8

 

1.         Johnson WC, Williford WO, Corson JD, Padberg FTJ. Hemorrhagic complications during long-term postoperative warfarin administration in patients undergoing lower extremity arterial bypass surgery. Vascular Surgery. 2004;12(6):362-368.

2.         Johnson WC, Williford WO. Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures: A prospective randomized study. Members of the Department of Veterans Affairs Cooperative Study #362. Journal of Vascular Surgery. 2002;35(3):413-421.

3.         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.

4.         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.

5.         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.

6.         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.

7.         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.

8.         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.