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- 4. High prevalence of AF in heart failure Normal sinus rhythm Atrial fibrillation
- 6. Thromboembolism prevention in patients with HF and AF Recommendation Class Level The CHA2DS2-VASc and HAS-BLED scores are recommended to determine the likely risk–benefit (thrombo-embolism prevention vs. risk of bleeding) of oral anticoagulation. I B An oral anticoagulant is recommended for all patients with paroxysmal or persistent/permanent AF and a CHA2DS2- VASc score ≥1, without contraindications, and irrespective of whether a rate- or rhythm-management strategy is used (including after successful cardioversion). I A In patients with AF of ≥48 h duration, or when the known duration of AF is unknown, an oral anticoagulant is recommended at a therapeutic dose for ≥3 weeks prior to electrical or pharmacological cardioversion. I C
- 13. Pivotal trials of novel oral anticoagulants (NOACs) vs. warfarin Dabigatran/RE-LY Rivaroxaban/ROCKET-AF Apixaban/ARISTOTLE Edoxaban/ENGAGE-AF Study design Randomised, open label Randomised, double blind Randomised, double blind Randomised, double blind Patients recruited 18, 111 14,264 18,201 21,105 Follow-up period (median, years) 2 1.9 1.8 2.8 Randomised groups Dose-adjusted warfarin vs. blinded doses of dabigatran (150 mg b.i.d., 110 mg b.i.d.) Dose-adjusted warfarin vs. rivaroxaban 20 mg o.d. Dose-adjusted warfarin vs. apixaban 5 mg b.i.d. Dose-adjusted warfarin vs Edoxaban (60mg o.d., 30mg o.d.) Inclusion NVAF (non-valvular atrial fibrillation) + 1 risk factor for stroke i.e. CHADS2 ≥1 NVAF + 2 risk factors i.e. moderate to high risk (i.e. CHADS2 ≥2) NVAF + + 1 risk factor for stroke (i.e. CHADS2 ≥1) NVAF + CHADS2 2 Desired INR Range 2.0-3.0 2.0-3.0 2.0-3.0 2.0-3.0 Primary outcome Stoke or systemic embolism Stoke or systemic embolism Stroke or systemic embolism Stoke or systemic embolism Summary of large randomized trials in NVAF comparing NOACs/DOACs vs. warfarin
- 14. NOACs versus warfarin in NVAF: Primary outcome ROCKET-AF2ARISTOTLE1 ENGAGE-AF4* *97.5% confidence intervals (CI). 1. Granger CB et al., NEJM 2011;365:981-992; 2. Patel MR et al., NEJM 2011;365:883-891; 3. Connolly SJ et al., NEJM 2009;361:1139-1151; 4. Giugliano RP et al., NEJM 2013;369:20932-104. HR = hazard ratio; RR = relative ris; NVAF = non-valvular atrial fibrillation RELY-AF3 Patients with event (%) Years Years HR (95% CI): 0.79 (0.66–0.95); P<0.001 for noninferiority; P = 0.01 for superiority
- 15. ARISTOTLE: SSE or death according to LV systolic function and HF status 0.20 0 6 12 18 24 0.00 0.05 0.10 0.15 Event rate Months since randomization LVSD HF-PEF No LVSD/HF Warfarin Apixaban
- 16. ARISTOTLE: SSE, major bleeding or death according to LV systolic function and HF status 0.20 0 6 12 18 24 0.00 0.05 0.10 0.15 Event rate Months since randomization LVSD HF-PEF No LVSD/no HF Warfarin Apixaban
- 17. NOACs/DOACs: Dose adjustment and renal monitoring Apixaban ARISTOTLE Dabigatran RELY Rivaroxaban ROCKET-AF Edoxaban ENGAGE AF Drug class Factor Xa inhibitor (FXa) Direct thrombin inhibitor (DTI) Factor Xa inhibitor (FXa) Factor Xa inhibitor (FXa) Renal excretion 25% renal 80% renal 30-40% renal 50% renal Landmark trial population stratified by eGFR 25-30 n=268 30-50 n=2737 50-80 n=7587 >80 n=7518 30 – 50 n=3374 50 – 80 n=10697 >80 n=3880 30-50 n=1481 50-80 n=3290 >80 n=2278 30-50 n=4074 Recommended eGFR method Cockcroft-Gault (ml/min) Not specified Cockcroft-Gault (ml/min) - Recommended minimum renal monitoring Annually Annually if moderate renal impairment Annually - EU Labelling revised 9/2014 revised 10/2014 revised 10/2014 trial criteria* Dose reduction Dose reduction if 2 of 3: 1) ≥ 80 years 2) ≤ 60 kg 3) sCr ≥ 133µmol/L (1.5 mg/dL) or CrCl 15 – 29 ml/min ≥ 80 years ≥ 75 years with additional bleeding risk factor including moderate impairment CrCl 30 – 50 ml/min CrCl 15 – 49 ml/min CrCl 30 – 50 ml/min or weight ≤60kg Contraindication CrCl < 15 ml/min CrCl < 30 ml/min CrCl < 15 ml/min CrCl < 30 ml/min *awaiting EMA decision
- 19. NOACs/DOACs: Dose adjustment and renal monitoring according to EMA product labelling n=689 (% relative to baseline) Baseline Additional 6 weeks Additional 14 months Additional 26 months Cumulative following baseline Overall including baseline Dose Reduction Apixaban 67 (9.7) 17 (2.5) 20 (2.9) 10 (1.5) 47 (6.8) 114 (16.5) Dabigatran 99 (14.4) 11 (1.6) 24 (3.5) 19 (2.8) 54 (7.8) 153 (22.2) Rivaroxaban 188 (27.3) 50 (7.3) 37 (5.4) 26 (3.8) 113 (16.4) 301 (43.7) Discontinuation Apixaban 0 (0) 2 (0.3) 1(0.1) 0 (0) 3 (0.4) 3 (0.4) Dabigatran 46 (6.7) 16 (2.3) 18 (2.6) 6 (0.9) 40 (5.8) 86 (12.5) Rivaroxaban 0 (0) 2 (0.3) 1(0.1) 0 (0) 3 (0.4) 3 (0.4) Dose-reductions and discontinuations modelled based on serial changes in renal function in CHARM Data analysed by Nat Hawkins
- 23. · Hypothesis: Which of two commonly used treatments warfarin or aspirin is better for preventing death and stroke in patients with low LVEF? · Population: 2305 patients NYHA I-IV with LVEF ≤35% and not in AF. · Intervention: Aspirin 325mg or warfarin (target INR 2.7, range 2.0-3.5) · Primary endpoint: Death, ischaemic stroke or intra- cerebral haemorrhage. · Status: Recruitment started October 2002/ended January 2010. WARCEF Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial
- 25. · Fewer ischaemic strokes on warfarin (55 vs 29, P=0.005) · More serious bleeding on warfarin (72 vs 35, P<0.001) · Trend to more HF hospitalization on warfarin (239 vs 203, P=0.053) WARCEF: Other outcomes
- 27. CORONA and GISSI-HF · CORONA (n=5011): age ≥60 years; NYHA class II–IV; ischemic aetiology; LVEF ≤40% if NYHA class III/IV (LVEF ≤35% in NYHA class II). Rosuvastatin vs. placebo. · GISSI-HF (n=69750: NYHA II–IV; any aetiology; LVEF ≤40% or if >40% had to have HF hospitalization in past year. n-3 PUFA vs. placebo and rosuvastatin vs. placebo. · 9,585 patients suitable for analysis; 3,531 with AF; 6,054 no AF. · Median follow-up 3.10 (IQR: 2.38-3.82) yrs; 371 patients had a fatal or non-fatal stroke (overall rate 13.1 per 1000 patient-years)
- 28. CORONA and GISSI-HF: Fatal or non-fatal stroke 3210 0 1 2 3 4 5 6 7 8 9 10 AF Sinus rhythm Number at risk Without AF 6054 5983 5921 5872 With AF 3531 3472 3432 3388 Time (years) Cumulativehazardsofstroke(%) No AF No AF AF Antiplatelet therapy 5,352 (55.8) 4,094 (67.6) 1,258 (35.6) Anticoagulant therapy 3,146 (32.8) 963 (15.9) 2,183 (61.8) Antiplatelet or anti- coagulant therapy 8,230 (85.9) 4,953 (81.8) 3,277 (92.8) All patients (n=9585) Without AF (n=6054) With AF (n=3531)
- 30. Predictors of stroke in HR-REF patients not in AF: Multivariable risk model Variables HR Lower 95%CI Upper 95%CI Χ2 Co- eff. SE P-value Age (per 1 year increase) 1.03 1.01 1.05 11.4 0.030 0.009 <0.001 NYHA class (NYHA III and IV) 1.54 1.16 2.04 8.8 0.430 0.145 0.003 BMI (per 1kg/m2 increase up to 30) 0.94 0.90 0.98 8.4 -0.063 0.022 0.004 Previous Stroke 1.78 1.17 2.70 7.3 0.576 0.212 0.007 Diabetes treated with insulin 1.75 1.13 2.72 6.3 0.562 0.224 0.012 Coronary heart disease 1.27 0.92 1.76 2.1 0.240 0.165 0.146 Peripheral artery disease 1.31 0.87 1.96 1.7 0.268 0.208 0.198 Creatinine (per 1umol/L increase) 1.00 0.99 1.01 1.4 0.003 0.002 0.242 Model c-statistic 0.75 (95%CI: 0.62-0.86)
- 31. CORONA and GISSI-HF: derivation cohort (n=6054 patients not in AF) 3210 0 1 2 3 4 5 6 7 8 9 10 1 2 3 Tertiles Number at risk Tertile 1 2017 2005 1996 1986 2 2015 1992 1974 1959 3 2022 1986 1951 1927 Cumulativehazardsofstroke(%) Time (years) • Patients in risk tertile 3 had a stroke rate of 19.8 per 1000 pt-yr • Rate of ischaemic stroke in ASA group in WARCEF: 11.4 per 1000 pt-yr • Rate in AF patients not treated with an anticoagulant: 21.7 per 1000 pt-yr
- 33. Predictors of stroke in HR-REF patients not in AF: Multivariable risk model (with NT proBNP) Variables HR Lower 95%CI Upper 95%CI Χ2 Co-eff SE P-value Log NT-ProBNP 1.28 1.07 1.54 7.1 0.248 0.093 0.008 Diabetes treated with insulin 2.12 1.19 3.79 6.4 0.751 0.297 0.011 Previous Stroke 1.87 1.07 3.27 4.8 0.625 0.286 0.029 NYHA class (NYHA III and IV) 1.22 0.80 1.86 0.9 0.200 0.214 0.349 Age (per 1 year increase) 1.01 0.98 1.04 0.4 0.008 0.013 0.536 BMI (per 1kg/m2 increase up to 30) 0.99 0.92 1.05 0.2 -0.016 0.033 0.643 NT pro-BNP measurements were available in 4,381 patients (45.7%) overall (1,749 patients [49.5%] with AF and 2,632 patients [43.5%] without AF)
- 35. ESC guidelines
- 36. Thromboembolism prevention in patients hospitalized with HF Recommendation Class Level An i.v. loop diuretic is recommended to improve breathlessness and relieve congestion. Symptoms, urine output, renal function, and electrolytes should be monitored regularly during use of i.v. diuretic. I B High-flow oxygen is recommended in patients with a capillary oxygen saturation <90% or PaO2 <60 mmHg (8.0 kPa) to correct hypoxaemia. I C Thrombo-embolism prophylaxis (e.g. with LMWH) is recommended in patients not already anticoagulated and with no contraindication to anticoagulation, to reduce the risk of deep venous thrombosis and pulmonary embolism. I A Patients with pulmonary congestion/oedema without shock
- 42. · Hypothesis: Rivaroxaban will reduce morbidity and mortality in pts with HF due to CHD. · Population: 5000 patients; symptomatic HF; CHD; EF ≤40%; BNP ≥200 pg/ml or NT-proBNP ≥ 800 pg/ml; recent exacerbation of HF (up to 30d post-discharge). · Intervention: Rivaroxaban (2.5mg bid) vs placebo. · Primary endpoint: Death, MI or stroke (984 events). · Status: Started 2013. COMMANDER HF: Rivaroxaban following hospitalization for HF in patients with CAD
- 43. Summary and conclusions · There are small discrepancies between the ESC and ACCF/AHA guidelines regarding anticoagulation in chronic and acute heart failure · We are still learning about the monitoring of NOACs/DOACs in patients with chronic heart failure and AF · Even after WARCEF, there may still be a role for anticoagulants in patients with heart failure not in AF · The potential value of rivaroxaban in patients recently hospitalized with heart failure (and CAD) is currently under investigation
- 48. • patients with HF who did not have contraindications to warfarin therapy and were discharged home from hospitals participating in the GWTG-HF Registry between January 1, 2005 and September 30, 2011 • We excluded patients with a history of AF, stroke or transient ischemic attack, valvular heart disease, or in-hospital valve surgery. We also excluded in-hospital deaths and patients with a documented contraindication for anticoagulation, incomplete discharge data, or missing ejection fraction. • final study population of 66,140 patients from 283 hospitals, warfarin was prescribed at discharge in 7404 (11.2%) HF patients without an established indication for anticoagulation documented. • Among these 7404 patients, more than half were new users at discharge.
- 50. CORONA and GISSI-HF · Patients with AF: The rate of stroke in patients treated with an anticoagulant was 14.0 per 1000 patient-years; in those not treated with an anticoagulant it was 21.7 per 1000 patient-years. · Sinus rhythm risk model: Patients in risk-tertile 3 had an overall stroke rate of 19.7 per 1000 patient-years. · Sinus rhythm risk model with NT-pro BNP: Patients in risk-tertile 3 had an overall stroke rate of 22.4 per 1000 patient-years.