Terapia anticoagulante ed antiaggregante nel paziente con insufficienza cardiaca: tra linee guida ed indicazioni individ

1. Terapia anticoagulante ed antiaggregante nel paziente coninsufficienza cardiaca: tra linee guida ed indicazioni individualizzate Nadia Aspromonte MD, FESC, FACC Heart Failure Unit S.Spirito Hospital Rome, Italy

2. Epidemiological sketch of thromboembolism in CHF • Increased risk of thromboembolic events, 1.6-4.5% per year • Chronic systolic dysfunction independent risk factor for thromboembolic stroke in patients with non-valvular atrial fibrillation • Brain magnetic resonance imaging studies revealed that more than 30% of patients with ischemic and non-ischemic CHF/systolic dysfunction had developed asymptomatic thromboembolic strokes • The overall risk of vascular thrombotic events in patients with CHF, particularly in those with sinus rhythm, has not been studied in a homogeneous population group.

3. Incidence of stroke in large studies in CHF pts Thatai et al Am J Cardiov Drugs 2006

4. Mechanism of Stroke in Left Ventricular Dysfunction : the Virchow’s Triad • The etiology of stroke in left ventricular dysfunction is multifactorial (embolization from intracardiac thrombi, systemic arterial or venous thrombosis and/or embolization, as well as acute coronary or cerebral thrombogenesis in situ) • A hypercoagulable state is often evident in cardiac failure of all etiologies

5. Pathobiological background of thromboembolism in CHF • ↑ in circulating platelet aggregates in patients with CHF • platelet laboratory abnormalities • impaired vascular endothelial function • role of of proinflammatory cytokines • activation of the sympathetic and renin–angiotensin–aldosterone systems • ↑ plasma viscosity and elevated concentrations of the proteins involved in thrombinofibrinogenesis and fibrinolysis

6. Degree of Left Ventricular Dysfunction • The degree of left ventricular dysfunction is a strong correlate to the occurrence of stroke, as reported by the SAVE trial. LVEF ~ 28% predicted nearly 2-fold the relative risk of stroke than a LVEF >28%. • 18% increase in risk of stroke for every 5% decrease in LVEF. • The reported incidence of stroke in patients with mild-to-moderate left ventricular dysfunction is 1,5% per year, and 4% per year for severe left ventricular systolic dysfunction. • Certain parameters on echocardiography can raise suspicion of the presence of left ventricular thrombus and a subsequent higher incidence of stroke.

7. Is antithrombotic therapy beneficial in heart failure?

8. Antithrombotic therapy in CHF: evidence from clinical studies • Data from non-randomized studies (post hoc analyses of CHF trials) • Randomized prospective clinical studies

12. CHF ESC guidelines 2005Antiplatelet Therapy and Anticoagulation • There is little evidence to show that anti-thrombotic therapy modifies the risk of death or vascular events in patients with heart failure. • In general, the rates of thromboembolic complications in heart failure are sufficiently low to limit the evaluation of any potential beneficial effect of anti-coagulation/ anti-thrombotic therapy in these patients.

13. AHF ESC guidelines 2005Anticoagulation • There is less evidence for unfractioned heparin or LMWH in AHF • A large placebo controlled trial of enoxaparine 40 mg in acutely ill and hospitalized pts showed no clinical improvement but less venous thrombosis (controindicated if creatinine clearance <30/mL/min) (Samama, NEJM1999)

14. Anticoagulant Therapy Guidelines: WHICH PATIENTS WITH HEART FAILURE SHOULD BE TREATED?

15. Warfarin Recommendations (CHF GUIDELINES ESC 2005) In CHF associated with atrial fibrillation, a previous thromboembolic event or a mobile left ventricular thrombus, anti-coagulation is firmly indicated.

16. Warfarin Recommendations Prevention of Cardiovascular Disease 2006 ACC/AHA Prevention Guidelines Warfarin (INR 2.0-3.0) in those with HF or LVSD with indication for anticoagulation*. HF=Heart failure, LVSD=Left ventricular systolic dysfunction *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities.

17. Background: Patients with atrial fibrillation (AF) who also have heart failure have a worse outcome but the diagnosis of heart failure is often missed. Aim: To compare the effects of warfarin and ximelagatran on morbidity and mortality in patients with AF with and without markers of heart failure. Methods and results: Data for 7329 patients from two randomised controlled trials were merged. Treatment with loop diuretics or the presence of left ventricular dysfunction, were used as markers of possible heart failure. The 3555 (49%) patients with markers of heart failure had higher composite event rates on warfarin (10.81% per year [py] [95% CI 9.59 to 12.13]) compared to the 3774 (51%) patients without markers of heart failure (4.18% py [95% CI 3.44 to 5.01]). The composite event rate was lower on ximelagatran overall (6.18% py [95% CI 5.51 to 6.89] versus 7.34% py [95% CI 6.63 to 8.10] on warfarin; P=0.0219 for the difference) with similar effects in each trial and in patients with and without markers of heart failure, mainly due to fewer heart-failure events (hazard ratio 0.69 [95% CI 0.54 to 0.87]; Pb0.001). Conclusions: Patients with markers of heart failure, even if the diagnosis is not well established, are at increased risk of thromboembolic events and might be targeted for more effective antithrombotic therapy. This might include patients in sinus rhythm as well as AF.

18. CHF patients in sinus rhythm: • In patients with sinus rhythm, the only situations in which to consider VKA anticoagulation are severely depressed left ventricular systolic function, previous vascular thrombotic events (and underlying disorders associated with increased vascular thrombotic event risk, e.g. amyloidosis), and cases when the presence of intracardiac thrombi cannot be excluded

19. Warfarin Recommendations (Continued) Secondary Prevention Warfarin (INR 2.0-3.0) in those with HF or LVSD, but without indication for anticoagulation*. Close monitoring of anticoagulation in those receiving warfarin along with aspirin and/or clopidogrel because of increased risk of bleeding. HF=Heart failure, LVSD=Left ventricular systolic dysfunction *Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities.

20. Special Considerations in the Elderly—Bleeding • Increased age associated with increased sensitivity at usual doses • Comorbidity • Increased drug interactions • ? Increased bleeding risk independent of the above Because of the potential for increased bleeding complications in CHF pts, anti-coagulant therapy should be administered under the most controlled conditions, planning monitoring in properly managed anti-coagulation clinics.

21. This is a multicentre double-blind clinical trial, the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study, recruiting 2860 patients with left ventricular EF < 30% who do not have established indications for warfarin (such as atrial fibrillation) . Randomizations are to aspirin (325 mg day) and warfarin [target International Normalized Ratio (INR) 2.75] arms, and the primary endpoint is a composite outcome of death or ischemic or hemorrhagic stroke occurring during a 3–5-year period after randomization.

22. Antiplatelet Therapy: Benefits and Risks

23. Platelet activation in CHF • Several markers of platelet activity have been found increased in CHF patients, including b-thromboglobulin, platelet factor 4 and cellular adhesion molecules such as P-selectin, platelet/endothelial cell adhesion molecule, and osteonectin • The origin of platelet activation in CHF remains to be established, and is obviously multifactorial, and it might be related to calcium imbalance, sympathoadrenal activation, catecholamine release, and reduced kidney and liver blood flow resulting in decreased clearance of platelet-activating substances.

24. IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I C Anti- thrombotic agents Recommendations (CHF GUIDELINES ESC 2005) After a prior myocardial infarction, either aspirin or oral anti-coagulants are recommended as secondary prophylaxis (Class of recommendation IIa, level of evidence C). Aspirin should be avoided in patients with recurrent hospitalization with worsening heart failure (Class of recommendation IIb, level of evidence B). .

25. Is aspirin bad in heart failure? Membrane Phospholipids Arachadonic Acid Aspirin COX-1 A likely source of interaction between ACE inhibitors and aspirin is a derangement of prostaglandin action. Prostaglandin H2 Thromboxane A2  Platelet Aggregation Vasoconstriction Prostacyclin  Platelet Aggregation Vasodilation

26. ACE-I, antiplatelet agents and CHF • Despite being plausible, the adverse clinical interactions between aspirin and ACE inhibitors have not been demonstrated so far in a robust clinical study. • The most recent guidelines of the European Society of Cardiology on CHF management state that there is” little evidence to support the concomitant treatment with an ACE inhibitor and aspirin in heart failure” • In the meantime, the wider use of clopidogrel (an antiplatelet agent with a different mechanism of action from aspirin) may circumvent the anticipated problems with aspirin for CHF patients receiving ACE inhibitors.

27. ADP / ATP P2Y1 P2X1 P2T12 Gq coupled Calcium mobilization Gi2 coupled Cation influx Ca2+ Ca2+ cAMP No effect on fibrinogen receptor Platelet shape change Transient aggregation Fibrinogen receptor activation Thromboxane A2 generation Thienopyridine: Mechanism of Action Clopidogrel or Ticlopidine Sustained Aggregation Response Savi P et al. Biochem Biophys Res Commun 2001; 283:379–83 and Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35.

28. We retrospectively analyzed platelet characteristics with respect to CHF etiology, class, and ejection fraction in patients enrolled in the PLUTO-CHF study. Patients with LVEF less than 40% or CHF symptoms in the setting of preserved systolic function and NYHA class were screened for platelet activation condition The CHF population was randomly divided into two groups receiving 75mg clopidogrel in combination with 325mg aspirin, or receiving 325mg aspirin alone every day for 30 days. In our analysis, 25 patients from the clopidogrelþaspirin group were divided by CHF etiology (ischemic, nonischemic), severity (NYHA class II, NYHA class III–IV, ), and ejection fraction (LVEF <30%,; LVEF 30–40%, ) Platelet function studies were performed at baseline and after 30 days of therapy. There were no differences in platelet parameters dependent on clinical characteristics of CHF, except for a significant decrease in platelet/ endothelial cell adhesion molecule 1 (PECAM-1) Therapy with clopidogrel resulted in a significant inhibition of platelet activity in the broad spectrum of patients with CHF independently of its etiology, severity, or myocardial contractility. This uniform platelet inhibition with clopidogrel may be an important consideration in designing future large-scale clinical trials.

29. Journal of Cardiac Failure Vol. 12 No. 6 2006

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