Feedback from David K. Cundiff, MD Sent 2-14-07

 

Dr Julia Mortimer
Review Group Co-ordinator
London School of Hygiene & Tropical Medicine
Department of Epidemiology & Population Health
Keppel Street
London
UK
WC1E 7HT

 

19.       GYH Lip, I Chung. Anticoagulation for heart failure in sinus rhythm. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD003336. DOI: 10.1002/14651858.CD003336 (Heart)

 

Dear Dr. Mortimer, 

 

Below are my comments on the above Cochrane review.

 

Thank you for considering this feedback.

 

Sincerely,

 

David K. Cundiff, MD

 

The only modern RCT included in this review is the WASH  trial, comparing

of warfarin, aspirin, and placebo in patients with heart failure.1 In this trial, aspirin was associated with increased admissions for decompensated heart failure (P = 0.044) and no reduction in morbidity or mortality. Based on this and other evidence, Professor John GF Cleland, PI of the WASH trial, wrote, "A series of studies has shown that long-term aspirin therapy is ineffective, or worse, for the primary, secondary or tertiary prevention of cardiovascular events..."2

 

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).3 Similarly, AHA/ACC 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affect the clinical status of patients with current or prior symptoms of HF and reduced LVEF should be avoided or withdrawn whenever possible (e.g., nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and most calcium channel blocking drugs; see text).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).4

 

Consequently, the results of the ongoing WATCH and WARCEF trials are meaningless in defining safety or efficacy of warfarin. These trials should be stopped immediately based on the increased HF hospitalizations with ASA compared with placebo in the WASH trial, the results of the HELAS RCT (catagorized as “ongoing” in the Lip review but now published and showing no benefit with warfarin over ASA5), and other evidence of harm due to ASA in HF patients cited by Cleland,2 the AHA/ACC guidelines, and The European Society of Cardiology guidelines.

 

The bleeding risk of warfarin in these RCTs supervised by anticoagulation researchers may not correspond to the risk of patients in general clinical practice. In nonresearch outpatient settings, the risk of fatal bleeding with vitamin K antagonists is 2%/year,6 1.2%/year,7 and 1%/year.8 By virtue of having an average age of about 72 years old,9 CHF patients are at greater than average risk of major and fatal bleeding from vitamin k antagonists.6, 10 Those CHF patients at greatest risk of thrombosing would also be at greatest risk of major and fatal bleeding.

 

Accordingly, the “implications for practice” and “implications for research” in this review should be revised.

 

Suggested implications for practice: Anticoagulants should not be used in any patients with HF.

 

Suggested implications for research: (1) Since the current consensus based on increasing evidence is that ASA should be avoided in patients with HF, ongoing trials of warfarin versus ASA in HF patients should be stopped immediately. (2) Given the bleeding risk in HF patients, the additional risk of thrombosis on discontinuation of vitamin k antagonists (rebound hypercoagulability),11, 12 and two negative RCTs of warfarin in HF patients thus far (one versus ASA1 and one compared with both ASA and placebo5), further RCTs involving vitamin k antagonists for HF would be hard to justify.

 

 

1.         Cleland JG, Findlay I, Jafri S. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J. 2004;148:157-164.

2.         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.

3.         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.

4.         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.

5.         Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail. 2006;8(4):428-432.

6.         van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Archives of Internal Medicine. 1993;153(13):1557-1562.

7.         Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. American Journal of Medicine. 1993;95(3):315-328.

8.         Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Annals of Internal Medicine. 1993;118(7):511-520.

9.         Go AS, Yang J, Ackerson LM, et al. Hemoglobin Level, Chronic Kidney Disease, and the Risks of Death and Hospitalization in Adults With Chronic Heart Failure: The Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. 10.1161/CIRCULATIONAHA.105.577577. Circulation. June 13, 2006;113(23):2713-2723.

10.       Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. American Journal of Medicine. 1989;87(2):144-152.

11.       Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994;72(2):222-226.

12.       Cundiff DK. Commentary - Insufficient Evidence Supporting Low-Intensity Warfarin for Venous Thromboembolism (VTE) Prophylaxis. Medscape General Medicine™. 07/02/2003;http://www.medscape.com/viewarticle/457570.