Prevalence AFHF ATRIA study prevalence of AF in

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Prevalence AF+HF ATRIA study → prevalence of AF in US < 55 and ≥

Prevalence AF+HF ATRIA study → prevalence of AF in US < 55 and ≥ 80 years → 0. 1 and 9%, respectively 1 With the onset of HF, the prevalence of AF increased from < 10% in NYHA I to approximately 50% in NYHA IV + 37% of new AF patients were found to have HF 2 Although it has been demonstrated that the risk of developing AF is higher in HFp. EF than HFr. EF, no differences in the risk of stroke and thromboembolism between two groups were observed History of HF is an independent risk factor for thromboembolic events 1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the An. Ticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285: 2370– 2375 2. Maisel WH, Stevenson LW (2003) Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 91: 2 D– 8 D

Shared mechanisms in heart failure and atrial fibrillation contributing to a vicious pathophysiologic cycle

Shared mechanisms in heart failure and atrial fibrillation contributing to a vicious pathophysiologic cycle Lei Zhao & William Y. S. Wang & Xinchun Yang Anticoagulation in atrial fibrillation with heart failure. Heart Failure Reviews (2018) 23: 563– 571

Central role of LA disease D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M.

Central role of LA disease D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M. Hamilos, K. Naka, S. Tzeis, S. Xydonas, A. Karavidas and J. Parissis. The management of atrial fibrillation in heart failure: an expert panel consensus. Heart Failure Reviews. https: //doi. org/10. 1007/s 10741 -020 -09978 -0

AF Management Requires a Multifaceted, Holistic and Multidisciplinary Approach, with Patients’ Active Involvement Hindricks

AF Management Requires a Multifaceted, Holistic and Multidisciplinary Approach, with Patients’ Active Involvement Hindricks G et al. Eur Heart J 2020; doi: 10. 1093/eurheartj/ehaa 612.

ESC 2020 Recommendations for the Prevention of Thromboembolic Events in AF For stroke prevention

ESC 2020 Recommendations for the Prevention of Thromboembolic Events in AF For stroke prevention in AF patients NOACs are recommended in preference to VKAs as a Class IA recommendation Recommendation Class Level For stroke prevention in AF patients who are eligible for OAC, NOACs are recommended in preference to VKAs* I A For stroke risk assessment, a risk-factor-based approach is recommended, using the CHA 2 DS 2 -VASc clinical stroke risk score to initially identify patients at ‘low stroke risk’ (CHA 2 DS 2 -VASc score=0 in men, or 1 in women) who should not be offered antithrombotic therapy I A OAC is recommended for stroke prevention in AF patients with CHA 2 DS 2 VASc score ≥ 2 in men or ≥ 3 in women I A IIa B OAC should be considered for stroke prevention in AF patients with a CHA 2 DS 2 -VASc score of 1 in men or 2 in women. Treatment should be individualized based on net clinical benefit and consideration of patient values and preferences *Excluding patients with mechanical heart valves or moderate-to-severe mitral stenosis. Hindricks G et al. Eur Heart J 2020; doi: 10. 1093/eurheartj/ehaa 612

High Bleeding Risk Alone Is not a Reason to Withhold Anticoagulation Non-modifiable and partially

High Bleeding Risk Alone Is not a Reason to Withhold Anticoagulation Non-modifiable and partially modifiable bleeding risks are important drivers of bleeding events in synergy with modifiable factors Recommendation For bleeding risk assessment, a formal structured risk-score-based bleeding risk assessment is recommended to help identify non-modifiable and address modifiable bleeding risk factors in all AF patients, and to identify patients potentially at high risk of bleeding who should be scheduled for early and more frequent clinical review and follow-up For a formal risk-score-based assessment of bleeding risk, the HASBLED score should be considered to help address modifiable bleeding risk factors, and to identify patients at high risk of bleeding (HAS-BLED score ≥ 3) for early and more frequent clinical review and follow-up Stroke and bleeding risk reassessment at periodic intervals is recommended to inform treatment decisions and address potentially modifiable bleeding risk factors Estimated bleeding risk, in the absence of absolute contraindications to OAC, should not in itself guide treatment decisions to use OAC for stroke prevention *Excluding patients with mechanical heart valves or moderate-to-severe mitral stenosis. Hindricks G et al. Eur Heart J 2020; doi: 10. 1093/eurheartj/ehaa 612. Class Level I B IIa B III B

Risk Factors for Bleeding with OAC and Antiplatelet Therapy Non-modifiable Age >65 years Previous

Risk Factors for Bleeding with OAC and Antiplatelet Therapy Non-modifiable Age >65 years Previous major bleeding Severe renal impairment Severe hepatic dysfunction Malignancy Genetic factors Previous stroke, small vessel disease, etc. Diabetes mellitus Cognitive impairment/demen tia Potentially modifiable Extreme frailty ± excessive risk of falls Anaemia Reduced platelet count or function Renal impairment (Cr. Cl <60 ml/min) VKA management strategy *For patients receiving VKA treatment. Hindricks G et al. Eur Heart J 2020; doi: 10. 1093/eurheartj/ehaa 612. Modifiable Hypertension/elev ated SBP Concomitant antiplatelet/NSAID Excessive alcohol intake Non-adherence to OAC Hazardous hobbies/occupatio ns Bridging therapy with heparin INR control (target 2. 0– 3. 0), target TTR >70%* Appropriate choice of OAC and correct dosing Biomarkers GDF-15 Cystatin C/CKDEPI c. Tn. T-hs von Willebrand factor (+ other coagulation markers)

1 Warfarin and VKAs • Until recently, warfarin and other VKAs have been the

1 Warfarin and VKAs • Until recently, warfarin and other VKAs have been the most frequently prescribed agents for the prevention of thromboembolism • In NVAF, warfarin has been shown to ↓ stroke by 62% and ischemic stroke by 65%, with absolute risk reductions of 2. 7% and 8. 4 % /yr for primary and secondary stroke prevention, respectively 1 • Polypharmacy, drug interactions - AFFIRM trial showed that HF was associated with less time in therapeutic range 2 → NOACs 1. Cleland JG, Mumtaz S, Cecchini L (2012) Role of antithrombotic agents in heart failure. Curr Cardiol Rep 14: 314– 3252. 2. Apostolakis S, Sullivan RM, Olshansky B, Lip G (2013) Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe. TT(2)R(2) score. Chest 144: 1555– 1563

NOACs Potential advantages • fixed dosing regimens, • wide therapeutic windows • more sustained

NOACs Potential advantages • fixed dosing regimens, • wide therapeutic windows • more sustained and stable anticoagulant responses • with fewer drug and food interactions

NOACs Trials

NOACs Trials

A: Anticoagulation/Avoid stroke Considering that inappropriate dose reductions are frequent in clinical practice, thus

A: Anticoagulation/Avoid stroke Considering that inappropriate dose reductions are frequent in clinical practice, thus increasing the risks of stroke/systemic embolism, hospitalization, and death, but without decreasing bleeding risk, NOAC therapy should be optimized based on the efficacy and safety profile of each NOAC in different patient subgroups Hindricks G et al. Eur Heart J 2020; ehaa 612. doi: 10. 1093/eurheartj/ehaa 612

Dabigatran • RE-LY trial → 4904 of 18113 pts (27. 1%) had HF the

Dabigatran • RE-LY trial → 4904 of 18113 pts (27. 1%) had HF the annual rate of stroke or systemic embolism was 1. 92% for warfarin compared with 1. 90% for dabigatran at 110 mg and 1. 44% for dabigatran at 150 mg. • The annual rate of major bleeding was 3. 9% for warfarin compared with 3. 26% for dabigatran at 110 mg and 3. 1% for dabigatran at 150 mg. • Contraindicated in patients with severe renal impairment with a (Cr. Cl) < 30 ml/min, which is especially important in patients with decompensated HF

Apixaban • In the ARISTOTLE trial 35% of the trial population had HF. In

Apixaban • In the ARISTOTLE trial 35% of the trial population had HF. In this subgroup of HF, apixaban was better than warfarin for preventing stroke and systemic embolism (1. 4 vs. 1. 6% per year), and apixaban markedly reduced the incidence of major bleeding (1. 9 vs. 3. 1% per year), which was consistent with the overall population. • Patients with LVSD (with/without HF) had a higher risk of SSE or death (but similar rate of SSE) compared with patients with HF but preserved LV systolic function; both had a greater risk than patients without either HF or LVSD. Apixaban reduced the risk of both outcomes more than warfarin in all 3 patient groups Mc. Murray JJV, et. al (2013) Left ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: insights from the ARISTOTLE trial. Circ Heart Fail 6: 451– 460

Rivaroxaban • ROCKET-AF →This trial included 9033 (63. 7%) patients with HF → the

Rivaroxaban • ROCKET-AF →This trial included 9033 (63. 7%) patients with HF → the rate of stroke and systemic embolism was consistent with the main trend (1. 90 vs. 2. 09 per 100 patient-year • The risk of major or non major clinically relevant bleeding was similar in HF patients (14. 22 vs. 14. 02 per 100 patient-years), and there was a reduction in hemorrhagic stroke (adjusted hazard ratio [HR], 0. 38) • Patel MR, et. al (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 365: 883– 891

ROCKET AF: Rivaroxaban in AF Patients With Heart Failure 9, 033 (63. 7%) patients

ROCKET AF: Rivaroxaban in AF Patients With Heart Failure 9, 033 (63. 7%) patients had HF or reduced LVEF Similar rates of stroke/SE in AF patients with or without HF Similar efficacy and safety of rivaroxaban compared with warfarin in AF patients with and without HF; results consistent with overall trial results Cumulative event rate (%) Primary endpoint: Stroke/SE (ITT) Results 0. 0 5 0. 04 0. 0 3 0. 0 2 0. 0 1 0 Warf. without Riva. without HF Warf. with HF Riva. with HF HF 0 HR (95% CI) riva. vs. warf. : Without HF: 0. 84 (0. 65– 1. 09) 120 240 36 48 With 600 HF: 720. 91 84(0. 74– 0 randomization Days from 0 1. 13) 0 0 Conclusion With HF (%/year) Without HF p(%/year) value (int. ) Riva. Warf. Results support use of rivaroxaban as an effective alternative to warfarin for stroke prevention in patients with AF and HF 2. 54%/yr 2. 09%/yr 2. 10%/yr 1. 90%/yr Major/NMCR bleeding 14. 22 14. 02 16. 12 15. 35 0. 99 Haemorrhagic stroke 0. 16 0. 43 0. 47 0. 067 Intracranial haemorrhage 0. 40 0. 65 0. 64 0. 89 0. 71 Van Diepen S et al. Circ Heart Fail. 2013; 6(4): 740 -747

 • 42, 411 participants received a new oral anticoagulant and 29, 272 participants

• 42, 411 participants received a new oral anticoagulant and 29, 272 participants received warfarin • NOACs significantly ↓ embolic events by 19% compared with warfarin (RR 0· 81, 95% CI 0· 73 -0· 91; p<0· 0001), mainly driven by a reduction in haemorrhagic stroke (0· 49, 0· 380· 64; p<0· 0001). NOACs also significantly ↓ all-cause mortality (0· 90, 0· 85 -0· 95; p=0· 0003) and intracranial haemorrhage (0· 48, 0· 39 -0· 59; p<0· 0001), but increased gastrointestinal bleeding (1· 25, 1· 01 -1· 55; p=0· 04). Ruff CT, Giugliano RP, Braunwald E, et al. . Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet. 2014 Mar 15; 383(9921): 955 -62.

Among AF patients with HF, single-/high-dose NOAC regimens have a better efficacy and safety

Among AF patients with HF, single-/high-dose NOAC regimens have a better efficacy and safety profile, but low-dose regimens had similar efficacy and safety to warfarin. NOACs were similarly effective or even safer (less intracranial hemorrhage) in AF patients with HF compared with those without HF. Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials Xiong Qinmei , Yee Cheng Lau, Senoo Keitaro , Deirdre A Lane, Hong Kui , Gregory Y H Lip Eur J Heart Fail. 2015 Nov; 17(11): 1192 -200

Yao X, Abraham NS, et. al. (2016) Effectiveness and safety of , rivaroxaban, and

Yao X, Abraham NS, et. al. (2016) Effectiveness and safety of , rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 5: e 3725

Hazard Ratios of Stroke/SE in NOAC– Warfarin Propensity Score-Matched Subgroups

Hazard Ratios of Stroke/SE in NOAC– Warfarin Propensity Score-Matched Subgroups

Hazard Ratios of Major Bleeding in NOAC–Warfarin Propensity Score-Matched Subgroups

Hazard Ratios of Major Bleeding in NOAC–Warfarin Propensity Score-Matched Subgroups

Hazard Ratios of Stroke/SE in NOAC–NOAC Propensity Score-Matched Subgroups

Hazard Ratios of Stroke/SE in NOAC–NOAC Propensity Score-Matched Subgroups

Hazard Ratios of Stroke/SE in NOAC– Warfarin Propensity Score-Matched Subgroups

Hazard Ratios of Stroke/SE in NOAC– Warfarin Propensity Score-Matched Subgroups

Aristophanes Trial • 162, 707 patients followed for a mean of 6 months •

Aristophanes Trial • 162, 707 patients followed for a mean of 6 months • Apixaban was associated with a lower risk of S/SE, MB, and net clinical outcome compared to dabigatran and rivaroxaban; dabigatran was associated with a lower risk of MB and net clinical outcome compared to rivaroxaban

What about low doses ? With the exception of dabigatran 110 mg twice daily

What about low doses ? With the exception of dabigatran 110 mg twice daily that was studied in a significant number of patients (n = 6015, 49. 7% of the total study population in RE-LY), low doses of DOAC have not been adequately studied in the seminal studies in AF; rivaroxaban 15 mg once daily was studied in 1474 patients (20. 7% of the total population in ROCKET-AF), edoxaban 30 mg once daily in 1784 patients (25. 4% of the total population in ENGAGE-AF), while apixaban 2, 5 mg twice daily only in 428 patients (4. 7% of the total population in ARISTOTLE) D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M. Hamilos, K. Naka, S. Tzeis, S. Xydonas, A. Karavidas and J. Parissis. The management of atrial fibrillation in heart failure: an expert panel consensus. Heart Failure Reviews. https: //doi. org/10. 1007/s 10741 -020 -09978 -0

Impact of HF co-morbidities on anticoagulation strategies • Chronic kidney disease • Coronary artery

Impact of HF co-morbidities on anticoagulation strategies • Chronic kidney disease • Coronary artery disease and acute coronary syndromes • Structural heart disease • Cancer

The use of NOACs in patients with renal insufficiency • • No prospective randomized

The use of NOACs in patients with renal insufficiency • • No prospective randomized trials on the efficacy and safety of NOACs in end stage renal diseases are available. FDA has approved apixaban for hemodialysis patients, warfarin remains the favored anticoagulant for these patients Apixaban at 2. 5 mg → higher rates of ischemic stroke/systemic embolism vs warfarin Rivaroxaban 15 mg, dabigatran 110 mg→ lower thromboembolic trend vs warfarin (not significantly different results). The rates of bleeding were significantly lower for dabigatran, but not for apixaban and rivaroxaban Nielsen PB, Skjøth F, Søgaard M, Kjældgaard JN, Lip GYH, Larsen TB (2017) Effectiveness and safety of reduced dose non vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 356: j 510

D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M. Hamilos, K. Naka, S. Tzeis,

D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M. Hamilos, K. Naka, S. Tzeis, S. Xydonas, A. Karavidas and J. Parissis. The management of atrial fibrillation in heart failure: an expert panel consensus. Heart Failure Reviews. https: //doi. org/10. 1007/s 10741 -020 -09978 -0

Open issues in the anticoagulation management of AF in patients with HF • Optimal

Open issues in the anticoagulation management of AF in patients with HF • Optimal anticoagulation strategies in patients with comorbidities such as cancer or CKD • Anticoagulation in left atrial disease/cardiomyopathy • Anticoagulation in HF patients without AF • Correct dosing of DOAC in patient with AF and HF D. Farmakis, C. Chrysohoou, G. Giamouzis, G. Giannakoulas, M. Hamilos, K. Naka, S. Tzeis, S. Xydonas, A. Karavidas and J. Parissis. The management of atrial fibrillation in heart failure: an expert panel consensus. Heart Failure Reviews. https: //doi. org/10. 1007/s 10741 -020 -09978 -0

Conclusions • The management of HF in the presence of AF should generally follow

Conclusions • The management of HF in the presence of AF should generally follow the corresponding guideline recommendations that apply to the general HF population • However, the efficacy of some disease-modifying therapies may be altered in the presence of AF. • Issue to be solved is the lower than expected prescription rates of DOAC over the VKAs and the inappropriate dose reductions of DOAC, despite the higher thromboembolic risk associated with the syndrome

Thank you for your attention !

Thank you for your attention !