Congestive heart failure anticoagulants
Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. Kashish Goel, M.D.
Chronic heart failure is associated with a hypercoagulable state secondary to increased blood viscosity and stasis, endothelial dysfunction and increased levels of biomarkers such as D-dimer, fibrinopeptide A and von-Willebrand factor. This hypercoagulable state places heart failure patients at an elevated risk for development of thromboembolic events such as pulmonary embolism, acute MI, and stroke). Atrial fibrillation is present in 10-30% of the patients with heart failure, and this may require anticoagulation. This chapter will discuss the role of anti-coagulation in heart failure patients with atrial fibrillation and those in sinus rhythm, respectively.
Indications for Anti-coagulation
Patients with congestive heart failure should be anticoagulated if they have a history of:
- Documented paroxysmal, persistent or long-standing Atrial fibrillation.
- Systemic or pulmonary emboli including stroke or transient ischemic attack.
- While hospitalized, patients should receive DVT prophylaxis.
Patients with Heart Failure and Atrial Fibrillation
A patient with congestive heart failure and atrial fibrillation should be anticoagulated with:
1. Warfarin or dabigatran if the CHADS2 Score is > 2.
2. Aspirin if the CHADS2 Score is 1 (Heart failure gives 1 point).
- Recently, the CHA2DS2-VASc score has been shown to better predict the incidence of stroke in patients with atrial fibrillation. European society of cardiology guidelines recommended further risk stratification using this score in those with a CHADS2 score of 1. However, it has still not been adopted in American guidelines.
- In the RELY Trial dabigatran at a dose 150mg BID was shown to be superior to warfarin in stroke prevention and can be used for patient in whom the INR is difficult to monitor, however it is currently brand-name only so discussion of cost should be undertaken with the patient.
- In patients at relatively low risk for stroke (CHADS2 score 0 or 1), aspirin is a reasonable alternative to warfarin, given its more benign side effect profile and relative convenience to use, although warfarin or dabigatran reduce stroke risk more than does aspirin at all CHADS2 scores.
Patients with Heart Failure and Sinus Rhythm
- Anticoagulation is not recommended for the treatment of patients with heart failure based upon current evidence.
- Randomized controlled trials with anticoagulation in this group of patients have failed to demonstrate a mortality benefit, however, there were reductions in the incidence of ischemic stroke. There are conflicting results with respect to a reduction in the risk of rehospitalization for aspirin versus warfarin among patients with heart failure. The WASH and WATCH trials report lower rates of hospitalization among those treated with aspirin while the WARCEF trial reported a trend towards higher rate of hospitalization among patients treated with warfarin. The following trials have been conducted in chronological order:
Warfarin/Aspirin Study in Heart failure (WASH) trial (2004)
- To investigate the effect of anticoagulation in heart failure patients.
Study design and population
- Randomized open-label controlled trial enrolling 279 patients with a mean follow-up of 2.3 years.
- No significant difference in the primary outcome (composite of death/nonfatal myocardial infarction, and nonfatal stroke) was observed among the 3 groups of aspirin (32%), warfarin (26%) or no anti-thrombotic therapy (26%), respectively.
- Patients in the aspirin group had the highest risk of all-cause hospitalization. Results were similar after excluding patients with atrial fibrillation (4-7%).
- This trial highlighted the lack of evidence for anticoagulation in heart failure patients and provided the basis for designing future larger trials evaluating the effect of anticoagulation in heart failure.
Heart Failure Long-term Antithrombotic Study (HELAS) trial (2006)
- To assess the impact of antithrombotic therapy on incidence of thromboembolic events in patients with heart failure and sinus rhythm.
Study design and population
- Multicenter, randomized, double-blind, placebo controlled trial enrolling 197 patients with heart failure (systolic dysfunction) with a mean follow-up of 1.8 years.
- Patient with ischemic heart disease were randomized to receive either aspirin 325 mg or warfarin, and patients with dilated cardiomyopathy were randomized to either warfarin or placebo.
- A very low incidence of 2.2 embolic events per 100 patient years was noted in the whole study group, without any significant differences between the groups.
- There was no difference in the composite end-point of myocardial infarction, hospitalization, heart failure exacerbation, death and hemorrhage between the study groups.
- The investigators concluded that there is no evidence for the role of anticoagulant or antiplatelet therapy in patients with heart failure in sinus rhythm.
Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial (2009)
- To determine the optimal antithrombotic agent in patients with heart failure and sinus rhythm.
Study design and population
- WATCH was a multinational prospective, randomized clinical trial that enrolled a total 1587 patients with symptomatic heart failure (for at least 3 months) who had systolic dysfunction (ejection fraction ≤ 35%) and were in sinus rhythm.
- Patient were randomized to receive 1 of the 3 possible treatments: aspirin 162 mg or clopidogrel 75 mg daily in a double-blind, double dummy manner or open-label warfarin with a target INR of 2.5-3.0.
- During a mean follow-up of 1.9 years, no signficant difference was observed in the primary composite outcome of all-cause mortality/nonfatal myocardial infarction and nonfatal stroke.
- The hazard ratios for warfarin versus aspirin comparison was 0.98 (95% CI 0.86-1.12), for clopidogrel versus aspirin comparison was 1.08 (95% CI 0.83-1.40) and for warfarin versus clopidogrel comparison was 0.89 (95% CI 0.68-1.16).
- Patients in the warfarin treatment arm had a 40% relative reduction in heart failure admission compared with the aspirin arm.
- A total of 21 nonfatal strokes were noted in the study during follow-up, with a significant reduction in warfarin group, as compared to aspirin or clopidogrel groups (p<0.01 in both).
- The incidence of major hemorrhage was also more frequent in warfarin patients as compared with clopidogrel patients (p=0.007).
- This was an important study reporting that aspirin was neither effective or contraindicated in patients with heart failure and sinus rhythm.
- Additionally, this large clinical trial did not show any benefit of anticoagulation with warfarin or antithrombotic therapy with clopidogrel in heart failure patients who are in sinus rhythm.
- The minimal benefit in reduction of strokes with warfarin was offset by higher number of major bleeds.
- The trial had to be stopped prematurely because of slow enrollment.
Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial (2012)
- To compare the efficacy and safety of warfarin with aspirin in patients with heart failure (reduced left ventricular ejection fraction) who are in sinus rhythm.
Study design and population
- Double-blind, multicenter randomized controlled trial enrolling 2305 patients who were randomized to receive warfarin (with a target INR of 2.0 to 3.5) or aspirin (325 mg per day).
- Inclusion criteria were age ≥ 18 years, no contraindication to warfarin therapy an LVEF ≤ 35%. Patient in NYHA class I could not account for more than 20% of the total number of patients undergoing randomization.
- Exclusion criteria were clear indication of warfarin or aspirin, condition that conferred a high risk of cardiac embolism, such as atrial fibrillation, mechanical heart valves, endocarditis or an intracardiac mobile/pedunculated thrombus.
- During a mean follow-up of 3.5 years, there was no significant difference in the rates of primary outcome (ischemic stroke, intracerebral hemorrhage, and all-cause mortality) among the patients randomized to warfarin (7.47 events/100 patient years; HR 0.93, 95% CI 0.79-1.10, p=0.04) or aspirin (7.93 events/100 patient years).
- A small benefit of borderline significance was noted for warfarin as compared to aspirin in those with at least 4 years of follow-up (p=0.046).
- Warfarin use significantly reduced the rate of ischemic stroke (HR 0.52, 95% CI 0.33-0.82, p = 0.005) compared with aspirin, however the rate of major hemorrhage was significantly higher with warfarin (HR 2.05, 95% CI 1.36-3.12, p<0.001).
- There was no difference in the rate of intracerebral hemorrhage between the two treatments.
- A trend towards higher rate of hospitalization was observed with warfarin (HR 1.2, 95% CI 0.998-1.47, p = 0.053) compared with aspirin.
- This is the largest trial to-date evaluating the role of warfarin or aspirin in patients with heart failure who are in sinus rhythm.
- The most important result of this trial is that there is no difference in the primary outcomes with either of these therapies.
- A small benefit noticed among patients who were followed for more than 4 years, is of uncertain clinical significance.
- The reduction in ischemic strokes with warfarin was offset by an increased risk of bleeding.
- In contrast to previous trials, aspirin was not associated with increased risk of hospitalizations.
2009 ACC/AHA Focused Update and 2005 Guidelines for the Diagnosis and Management of Chronic Heart Failure in the Adult (DO NOT EDIT) 
Anticoagulants in Patients Presenting With Heart Failure (DO NOT EDIT) 
|"1. Physicians should prescribe anticoagulants in patients with HF who have paroxysmal or persistent atrial fibrillation or a previous thromboembolic event. (Level of Evidence: A) "|
|"1. The usefulness of anticoagulation is not well established in patients with HF who do not have atrial fibrillation or a previous thromboembolic event. (Level of Evidence: B) "|
Heart Failure Society of America Guidelines- Recommendations for Anticoagulation and Antiplatelet Drugs
1. Treatment with warfarin (goal international normalized ratio [INR] 2.0-3.0) is recommended for all patients with HF and chronic or documented paroxysmal, persistent, or long-standing atrial fibrillation (Level of Evidence: A) or a history of systemic or pulmonary emboli, including stroke or transient ischemic attack (Level of Evidence: C), unless contraindicated.
2. It is recommended that patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documented LV thrombus be treated with warfarin (goal INR 2.0-3.0) for the initial 3 months post-MI (Level of Evidence: B) unless contraindicated. Other patients with ischemic or nonischemic cardiomyopathy and LV thrombus should be considered for chronic anticoagulation, depending on the characteristics of the thrombus, such as its size, mobility, and degree of calcification. (Level of Evidence: C)
3.Long-term treatment with an antiplatelet agent, generally aspirin in doses of 75 to 81 mg, is recommended for patients with HF due to ischemic cardiomyopathy, whether or not they are receiving ACE inhibitors. (Level of Evidence: B) Warfarin (goal INR 2.0-3.0) and clopidogrel (75 mg) also have prevented vascular events in post-MI patients and may be considered as alternatives to aspirin. (Level of Evidence: B)
4. Routine use of aspirin is not recommended in patients with HF without atherosclerotic vascular disease. (Level of Evidence: C)
Vote on and Suggest Revisions to the Current Guidelines
- The ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult 
- 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation 
- ↑ Stevenson WG, Stevenson LW (1999). "Atrial fibrillation in heart failure". N. Engl. J. Med. 341 (12): 910–1. doi:10.1056/NEJM199909163411209. PMID 10486424. Unknown parameter
- ↑ Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L (2009). "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 361 (12): 1139–51. doi:10.1056/NEJMoa0905561. PMID 19717844. Retrieved 2012-04-03. Unknown parameter
- ↑ Cleland JG, Findlay I, Jafri S; et al. (2004). "The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure". Am. Heart J. 148 (1): 157–64. doi:10.1016/j.ahj.2004.03.010. PMID 15215806. Unknown parameter
- ↑ Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK (2006). "Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study". Eur. J. Heart Fail. 8 (4): 428–32. doi:10.1016/j.ejheart.2006.02.012. PMID 16737850. Unknown parameter
- ↑ Massie BM, Collins JF, Ammon SE; et al. (2009). "Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial". Circulation. 119 (12): 1616–24. doi:10.1161/CIRCULATIONAHA.108.801753. PMID 19289640. Unknown parameter
- ↑ Homma S, Thompson JL, Pullicino PM; et al. (2012). "Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm". N Engl J Med. doi:10.1056/NEJMoa1202299. PMID 22551105. Unknown parameter
- ↑ 7.0 7.1 7.2 Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. 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. Circulation. 2005 Sep 20; 112(12): e154-235. Epub 2005 Sep 13. PMID 16160202
- ↑ 8.0 8.1 8.2 Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG et al. (2009) 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119 (14):1977-2016. DOI:10.1161/CIRCULATIONAHA.109.192064 PMID: 19324967
- ↑ Lindenfeld J, Albert NM, Boehmer JP; et al. (2010). "HFSA 2010 Comprehensive Heart Failure Practice Guideline". J. Card. Fail. 16 (6): e1–194. doi:10.1016/j.cardfail.2010.04.004. PMID 20610207. Unknown parameter