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Sumario Vol. 43 - Nº 1 Enero - Marzo 2014


Heart Failure with Sinus Rhythm: Anticoagulation? Why?
Héctor L. Luciardi

Hospital Centro de Salud "Zenón J Santillán"
Facultad de Medicina, UNT
(4000) Tucumán, Argentina
E mail

Recibido el 15-ENE-14 – ACEPTADO el 31-ENERO-2014.

The author declares not having a conflict of interest.

Rev Fed Arg Cardiol. 2013; 43(1): 3-5
 

Opinion articles reflect the views of the authors,
not necessarily those of the Editorial Committee FAC.


Print version Imprimir sólo la columna central

 

Heart failure has been acknowledged as a prothrombotic or hypercoagulable state. Frequently, thrombotic events occur in patients with heart failure, events that may be precipitated by different mechanisms that involve the components of the classical Virchow’s triad: anomalies in vascular walls, vulnerable blood and anomalies in blood flow [1].

An increase in the risk of stroke and thromboembolism is acknowledged in patients with heart failure (HF) and atrial fibrillation (AF). The level of thromboembolic risk in patients with systolic HF in sinus rhythm is less clear.

There is enough evidence on the reduction of stroke in patients with HF in treatment with warfarin; however, in patients with HF in sinus rhythm, the data available suggest that the risk of greater bleeding overshadows the benefit of antithrombotic therapy [2].

Venous thromboembolism (VTE), cardioembolic ictus and sudden cardiac death occur in up to 30% of the patients with HF and significantly contribute to a high overall morbi-mortality observed [3].

In an analysis of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), with an average follow-up of 45.5 months, the rate of thromboembolism was 3.4%, with a fourfold greater increase in the presence of severe ventricular function (VF) impairment [4].

In the light of the evidence of the randomized clinical studies available to this date, why anticoagulate? [5].

Although platelet activation is present in heart failure, currently there is no randomized clinical trial available that would answer whether it is convenient to administer an antiplatelet treatment in patients with HF. Its indication was conditioned by the presence of concomitant vascular disease.

The information that springs from the main HF studies (SOLVD, CONSENSUS-II) on the relevance of antithrombotic therapy is limited in patients with reduced ejection fraction and sinus rhythm, a condition prevalent in the current practice.

In the pilot study WASH (Warfarin/Aspirin Study in Heart Failure), the general results of the study argued against the benefit of antiplatelet therapy in patients with HF to prevent thromboembolic events. No differences were observed in the rate of events between the treatment arms when analyzing the primary endpoint made up of death, nonfatal myocardial infarction (MI) or nonfatal ictus [6].

The HELAS study (HEart failure Long-term Antithrombotic Study), prematurely ended due to the slow rhythm of inclusion of patients, had similar results to the WASH study [7].

The WATCH study (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) was also ended early by the slow enrollment. Just as with previous studies, there was no difference in the primary endpoint made up of death, nonfatal stroke and nonfatal MI [8].

In the WARCEF study (Warfarin versus Aspirin in patients with Reduced Cardiac Ejection Fraction), the largest one made to this date, there were no significant differences in the primary endpoint made up of death, ischemic stroke or intracerebral hemorrhage, between the treatment arms. With the implementation of the Cox model, there was a marginal trend in favor of a benefit with warfarin therapy [9].

In one of the secondary endpoints of the WARCEF study, as in the WATCH study, there was a significant reduction in ischemic stroke with the therapy with warfarin in comparison to aspirin (0.72% vs. 1.36%/year; HR: 0.52, 95% CI: 0.33-0.82, p=0.005), but with a significantly greater frequency of major hemorrhagic events (5.8% vs. 2.7%; OR: 2.2, 95% CI: 1.42-2.47, p<0.001). The enrollment was interrupted after 2305 patients instead of the planned 2860, which reduced the power of the study from 89% to 69% to test the primary hypothesis of it.

In a recently published analysis of the WARCEF study subgroups, a 37% reduction was reported in the incidence of the primary endpoint (HR: 0.63, 95% CI: 0.48 to 0.84, p=0.001) in patients <60 years of age, in comparison with the absence of benefits observed in people older than 60 years of age [10].

Anticoagulation therapy offers a clear evidence of preventing stroke, probably embolic in patients with heart failure and severe systolic function impairment; but the rate of stroke is too low to justify a routine clinical use of warfarin in most of the patients with heart failure, in the light of the increased risk of bleeding [11].

The 4 abovementioned randomized clinical trials presented significant limitations: 1) the expected enrollment was not completed, so the power of all these studies was not enough to test the hypothesis proposed; 2) there was a heterogeneous administration of drugs, manifest variability in the etiology of the underlying HF and the definitions of a composite primary endpoint were varied; and 3) the WATCH and WARCEF studies lacked a placebo/control arm to evaluate the real efficacy of antithrombotic therapy [12].

A recent meta-analysis of the 4 mentioned randomized clinical studies [12], which included 4378 patients with chronic HF and ventricular function impairment in sinus rhythm, reported that the general benefit by the use of warfarin in this population would be compensated by an increase in the risk of bleeding (major hemorrhage doubled, but intracranial hemorrhage was rare), with a 41% reduction of the different types of stroke (HR: 0.59, 95% CI: 0.41-0.85, p=0.004), with no differences in mortality by any cause, admittance by HF and nonfatal MI.

In another meta-analysis [13] that included the same population of patients, the necessary number to reduce 1 stroke with warfarin was 61, and the necessary number to cause damage (major hemorrhage) with this antagonist of vitamin K was 34.

In the REDINSCOR study (Red de Investigación Clínica y Básica en Insuficiencia cardíaca), there were no significant differences in total mortality or in stroke, but there was a reduction of the composite primary endpoint (cardiac death, heart transplant, coronary revascularization and cardiovascular hospitalization) in multivariate analysis (HR: 0.74, 95% CI: 0.56 to 0.97, p=0.03) [14].

There are only 2 ongoing clinical trials in patients with HF (NCT01877915 –COMMANDER HF with Rivaroxaban 2.5 mg twice a day, and NCT01765400 with prasugrel vs. clopidogrel) that include the new platelet antiaggregation agents and oral anticoagulation.

Taking into account the absence of the overall benefit of the treatment with warfarin on the rates of death and stroke, with increase in major bleeding; in spite of the possible reduction of ischemic stroke, currently there is no significant reason to use warfarin as a routine in all the patients with HF in sinus rhythm [15].

Until we have more proofs, the clinical choice for the treatment with oral anticoagulation of the patients with HF in sinus rhythm, should be made on the basis of the individual analysis of each patient, with a proper risk/benefit balance of the anticoagulation treatment, especially in the group of patients in high risk [15].

Anticoagulation is a therapeutic possibility to be considered in given groups of patients with HF: with severely depressed ejection fraction, with previous thromboembolism (stroke, transient ischemic attack, VTE), with recently diagnosed intracardiac thrombus, and in right heart failure with pulmonary hypertension; taking into account that the evidence that supports its use is limited. More conclusive data, which may determine the risk/benefit ratio in the long run, are required [15].

The CHADS2 and HAS-BLED risk scores may be useful to select patients in future studies on antithrombotic therapy in a scenario of HF with sinus rhythm.

 

BIBLIOGRAPHY

  1. Zannad F, Stough WG, Regnault V, et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol2013; 167 (5): 1772–82.
  2. Gurbel PA, Tantry US. Antiplatelet and anticoagulant agents in heart failure. Current status and future perspectives. J Am Coll Cardiol HF 2014; 2: 1-14.
  3. Witt BJ, Gami AS, Ballman KV, et al. The incidence of ischemic stroke in chronic heart failure: a meta-analysis. J Card Fail 2007; 13: 489-96.
  4. Freudenberger RS, Hellkamp AS, Halperin JL, et al. SCD-HeFTInvestigators. Risk of thromboembolism in heart failure: an analysisfrom the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).Circulation2007; 115: 2637-41.
  5. Luciardi H, Berman S, Lobo Márquez L, et al. Terapéutica Antitrombótica en la falla cardíaca con ritmo sinusal. Arch CardiolMex2014, in press.
  6. Cleland JGF, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study inHeart Failure (WASH): a randomized trial comparing antithrombotictherapies for patients with heart failure. Am Heart J 2004;148: 157-64.
  7. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK. Efficacyof antithrombotic therapy in chronic heart failure: the HELAS study.Eur J Heart Fail 2006; 8: 428-32.
  8. MassieBM,CollinsJF,AmmonSE, et al.,WATCHTrial Investigators.Randomized trial of warfarin, aspirin, and clopidogrel in patients withchronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic
    Heart Failure (WATCH) trial. Circulation 2009;119: 1616-24.
  9. Homma S, Thompson JLP, Pullicino PM, et al, WARCEF Investigators.Warfarin and aspirin in patients with heart failure and sinusrhythm. N Engl J Med 2012;366: 1859-69.
  10. Homma S.Warfarin versus aspirin in patients with reduced cardiac ejectionfraction (WARCEF) trial. Paper presented at: Heart Failure Societyof America 2012 ScientificMeeting; September 10, 2012; Seattle, WA, USA.
  11. Eikelboom JW, Connolly SJ. Warfarin in heart failure.N Engl J Med 2012; 366: 1936-8.
  12. Hopper I, Skiba M, Krum H. Updated meta-analysis on antithrombotictherapy in patients with heart failure and sinus rhythm. Eur J Heart Fail 2013; 15: 69-78.
  13. Kumar G, Goyal MK. Warfarin versus aspirin for prevention of strokein heart failure: a meta-analysis of randomized controlled clinical trials. J StrokeCerebrovascDis2013; 22: 1279-87.
  14. Avellana P, Segovia J, Ferrero A, et al. Anticoagulationtherapy in patients with heart failure due to systolic dysfunction andsinus rhythm: analysis of REDINSCOR registry. Rev EspCardiol2012;65:705-12.
  15. McMurray JJ, Adamopoulos S, Anker SD, et al, ESC Committee forPractice Guidelines. ESC guidelines for the diagnosis and treatment ofacute and chronic heart failure 2012: the Task Force for the Diagnosisand Treatment of Acute and Chronic Heart Failure 2012 of theEuropean Society of Cardiology. Developed in collaboration with theHeart Failure Association (HFA) of the ESC.Eur J Heart Fail 2012;14: 803-69.

Publication: March  2014

 
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