Insufficienza renale e DOAC

Transcription

1 Insufficienza renale e DOAC Domenico Prisco DMSC, Università di Firenze SOD Patologia Medica, AOU Careggi Bologna 14 ottobre 2014 Ha ricevuto onorari per relazioni e partecipazione ad advisory board e supporto alla ricerca da Bayer e Daichi Sankyo

2 An Epidemic of Kidney Disease Prevalence CKD stages % % Coresh, JAMA 298:2038, 2007 Stage 5: GFR <15 Stage 4: GFR Stage 3: GFR n=300,000 n=400,000 n=7,600,000 Stage 2: GFR 60 89* n=5,300,000 n=5,900,000 Stage 1: GFR 90* Total=23 million USA Clinical Practice Guidelines for CKD Am J Kidney Dis. 2002;39(suppl 1):S17 S31. GFR = glomerular filtration rate (ml/min/1.73 m2); *with kidney damage

3 Filtrato Glomerulare (ml/min) lieve moderata severa Terapia sostitutiva milioni 2.1 milioni

4 Chronic Kidney Disease is common among AF patients Leiden anticoagulation clinic (n=5039; ) 1 AURICULA registry, Malmö (n=2603; ) % of patients % 30.9% 34.2% % of patients Using different egfr cut-off values 40.4% % 0.8% % 4.3% > <60 <45 <30 egfr, ml/min/1.73 m 2 (MDRD formula) egfr, ml/min/1.73 m 2 (MDRD formula) egfr: estimated glomerular filtration rate; MDRD: modification of diet in renal disease 1. Kooiman et al. J Thromb Haemost 2011;9: Jönsson et al. Thromb Res 2011;128:341-5.

5 Frequency of CKD in Atrial Fibrillation patients Hart R, Can J of Cardiol 2013

6 Chronic Kidney Disease increases the risk of thromboembolism in AF patients not receiving warfarin Crude rate of thromboembolism (% person-year)* - ATRIA cohort (n=10,908 NVAF patients off warfarin ) 6 Thromboembolism rate (per 100 person-years) P<0.001 for trend <45 egfr (ml/min/1.73 m 2 ) ATRIA: Assembly of the Anticoagulation and Risk Factors in Atrial Fibrillation egfr: estimated glomerular filtration rate MDRD: modification of diet in renal disease *676 validated thromboembolic events (637 ischaemic strokes, 39 other thromboembolism) Go AS et al. Circulation. 2009;119:

7 Cumulative incidence of stroke or non-cns systemic embolism according to R2CHADS2 scores* *Additional 2 points for CrCl < 60 ml/min Piccini 2012

8 Chronic Kidney Disease increases the risk of bleeding and all-cause death in AF patients Risk of events in NVAF patients with non-end-stage CKD (n=3587) or with CKD requiring renal replacement therapy (n=901) compared with NVAF patients with no renal disease (n=127,884) - Danish registry ( ) Reference: patients with no renal disease HR (95% CI)* Stroke or systemic thromboembolism Non-end-stage CKD 1.49 (1.38; 1.59) CKD requiring renal replacement therapy 1.83 (1.57; 2.14) Bleeding Non-end-stage CKD 2.24 (2.10; 2.38) CKD requiring renal replacement therapy 2.70 (2.38; 3.07) Myocardial infarction Non-end-stage CKD 2.00 (1.86; 2.16) CKD requiring renal replacement therapy 3.00 (2.58; 3.50) Death from any cause Non-end-stage CKD 2.37 (2.30; 2.44) CKD requiring renal replacement therapy 3.35 (3.13; 3.58) *Adjusted for baseline characteristics Adapted from Olesen et al. N Engl J Med 2012;367:

9 CKD and risk of bleeding ESC guidelines European Heart Journal. doi: /eurheartj/ehq278

10 Anticoagulation is effective in AF patients with CKD Warfarin anticoagulation markedly reduces the incidence of stroke in stage 3 CKD patients with atrial fibrillation. In a subgroup analysis of 516 atrial fibrillation participants with stage 3 CKD in the randomized SPAF III trial, ischaemic stroke or systemic embolism was reduced by 76% (95% CI 42 90, p <0.001) by adjusted-dose warfarin compared with aspirin plus low, ineffective doses of warfarin 1. Prostaglandin induced vasodilatation is important in maintaining renal blood flow in subjects with CKD 2. By inhibiting the synthesis of renal prostaglandins, aspirin makes CKD patients vulnerable to further deterioration in renal function. 1. Marinigh R et al. J Am Coll Cardiol 2011;57: Circulation. 2012;125:

11 Patients With Renal Dysfunction Require Lower Doses of Warfarin Warfarin dose (mg/d) P < P = 0.02 > 60 ml/min ml/min < 30 ml/min Limdi NA, et al. J Am Soc Nephrol. 2009;20:

12 Warfarin is not effective in AF pts on haemodyalisis Shah 2014

13 Warfarin use and the risk for stroke (a) and bleeding (b) in patients with AF undergoing dialysis (a) (b) Shah 2014

14 Warfarin-related nephropathy An acute increase in INR over 3 in patients with CKD is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. This was termed warfarin-related nephropathy (WRN), and previous cases of WRN were reported only in patients with CKD

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16 INR and changes in serum creatinine (SC) levels associated with INR >3.0 in patients with and without WRN Brodsky 2011

17 Survival analysis in patients with and without WRN according to CKD Brodsky 2011

18 CKD Classification used in NOAC studies Mild renal impairment: 50ml/min CrCl 79 ml/min Moderate renal impairment : 30ml/min CrCl 49 ml/min Severe renal impairment : 15ml/min CrCl 29 ml/min

19 Pharmacokinetic Parameters Affected by Chronic Kidney Disease Capodanno D, Circulation 2013

20 * not approved yet Absorption and metabolism of NOAC

21 Patients with chronic kidney disease

22 Plasma concentration profiles of NOACs in AF patients Canadian Journal of Cardiology 29 (2013) S24eS33

23 Mean dabigatran plasma concentration time curves in subjects with normal and impaired renal function Harder S, Clin Pharmacol 2012

24 Mean rivaroxaban plasma concentration time curves in subjects with normal and impaired renal function Harder S, Clin Pharmacol 2012

25 Dose adjustment for patient characteristics in NOAC studies RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 ENGAGE-AF 4 None mg QD for: Creatinine clearance ml/min mg BID for ANY TWO of: Age 80 years body weight 60 kg Serum creatinine 1.5 mg/dl mg QD or mg QD for: Creatinine clearance ml/min body weight 60 kg Use of quinidine, verapamil or dronedarone BID=twice daily; QD=once daily 1. Connolly et al. New Engl j Med 2009;361: Patel et al. N Engl J Med 2011;365: Granger et al. N Engl J Med 2011;365: Giugliano et al. N Engl J Med 2013; e-pub ahead of print

26 CAVEATS Limited evidence for optimal anticoagulant strategies in CKD, as most randomized controlled trials (RCT) of anticoagulants have excluded CKD (especially stage 4-5, i.e. GFR<30ml/min) To date, no RCT of anticoagulant therapy targeted to CKD patients (unmet need, given the high prevalence of disease and narrow therapeutic range of anticoagulant drugs)

27 Dabigatran vs warfarin in patients with renal impairment 1. Adapted from Connolly SJ et al. N Engl J Med 2009;361: Adapted from Eikelboom JW et al. Circulation 2011;123:

28 Rivaroxaban vs warfarin in patients with renal impairment Adapted from Fox KAA et al. Eur Heart J 2011; 32:

29 ARISTOTLE: Efficacy and safety according to creatinine clearance (Cockcroft-Gault) Apixaban Warfarin Hazard Ratio (95% CI) P value %/yr (No. of events) Stroke / SE Interaction: egfr >80 ml/min % (70) 1.12% (79) egfr >50-80 ml/min % (87) 1.69% (116) egfr 50 ml/min % (54) 2.67% (69) Major Bleeding Interaction: 0.03 egfr >80 ml/min % (96) 1.84% (119) egfr >50-80 ml/min % (157) 3.21% (199) egfr 50 ml/min % (73) 6.44% (142) All-cause death Interaction: egfr >80 ml/min % (169) 2.71% (195) egfr >50-80 ml/min % (244) 3.56% (251) egfr 50 ml/min % (188) 8.30% (221) 1 n=7518 (41%); 2 n=7587 (42%); 3 n=3017 (17%) Results were consistent regardless of methods for GFR estimation Apixaban better Warfarin better Adapted from Hohnloser et al. Eur Heart J 2012; 2012;e-published August 29, doi: /eurheartj/ehs274.

30 Hazard ratios for stroke and systemic embolism in subgroups of patients with stage III CKD estimated creatinine clearances ml/min for dabigatran and rivaroxaban; ml/min for apixaban Hart R, Can J of Cardiol 2013

31 Hazard ratios for major bleeding in subgroups of patients with stage III CKD estimated creatinine clearances ml/min for dabigatran and rivaroxaban; ml/min for apixaban Hart R, Can J of Cardiol 2013

32 Meta-analysis of the effect of new oral anticoagulants on thrombotic events in patients with estimated glomerular filtration rate <50 ml Lega JC, JTH 2014

33 Metaregression of relative risk of thrombotic events with NOACS vs VKAs in patients with moderate or severe renal impairment according to percentage renal excretion (pts with moderate or severe RI) The results of venous thromboembolism trials are in dotted line Lega JC, JTH 2014

34 Meta-analysis of the effect of new oral anticoagulants on major bleeding in patients with estimated glomerular filtration rate <50 ml Lega JC, JTH 2014

35 Metaregression of relative risk of major bleeding with NOACS vs VKAs in patients with moderate or severe renal impairment according to percentage renal excretion (pts with moderate or severe RI) Major and clinically relevant non-major hemorrhage for edoxaban The results of venous thromboembolism trials are in dotted line Lega JC, JTH 2014

36 Conclusion The benefit-risk balance seemed to be favorable for this new pharmacologic class in the case of egfr < 50 ml min -1, with a significant global reduction of thrombosis. The renal excretion of drugs might modify the safety profile, contrary to the efficacy of these new drugs Halvorsen S, Eur Heart J 2014

37 Major bleeding event rate according to renal function in the phase III AF studies Schulman TH 2014

38 Sardar P, Can J Cardiol 2014

39 Stroke or systemic embolism patients with mild renal insufficiency Sardar P, Can J Cardiol 2014

40 VTE or VTE related death patients with mild renal insufficiency Sardar P, Can J Cardiol 2014

41 Major or clinically relevant bleeding patients with mild renal insufficiency Sardar P, Can J Cardiol 2014

42 Stroke or systemic embolism patients with moderate renal insufficiency Sardar P, Can J Cardiol 2014

43 VTE or VTE related death patients with moderate renal insufficiency Sardar P, Can J Cardiol 2014

44 Major or clinically relevant bleeding patients with moderate renal insufficiency Sardar P, Can J Cardiol 2014

45 Conclusion NOACs might have a more acceptable efficacy and safety profile than the comparators used in these trials, when evaluated in patients with mild renal insufficiency. For patients with moderate renal insufficiency, these agents were equally safe as conventional agents (warfarin, LMWH). No clinical efficacy and safety data are available for patients with severe (stage IV) renal insufficiency, and the NOACs should be avoided in these patients. Similarly, the efficacy and safety of NOACs for patients using renal replacement therapy (dialysis) has not been evaluated. Sardar P, Can J Cardiol 2014

46 AVERROES: The beneficial effect of apixaban vs ASA was maintained in stage III CKD patients Apixaban ASA Hazard Ratio (95% CI) P value %/yr (No. of events / No. of patients) Stroke / SE Interaction: 0.10 egfr 60 ml/min/1.73 m 2 1.7% (34/1917) 2.8% (60/1911) egfr ml/min/1.73 m 2* 1.8% (17/857) 5.6% (51/840) <0.001 Major Bleeding Interaction: 0.82 egfr 60 ml/min/1.73 m 2 0.9% (19/1917) 0.8% (18/1911) 0.85 egfr ml/min/1.73 m 2* 2.5% (24/857) 2.2% (20/840) 0.58 All-cause death Interaction: 0.39 egfr 60 ml/min/1.73 m 2 2.3% (49/1917) 3.3% (71/1911) 0.05 egfr ml/min/1.73 m 2* 6.2% (59/857) 7.1% (66/840) *egfr ml/min/1.73 m 2 : stage III CKD patients Adapted from Eikelboom et al. J Stroke Cerebrovasc Dis 2012;21: Apixaban better ASA better

47 ENGAGE AF: Characteristics requiring edoxaban dose reduction Edoxaban dose was 60 mg or 30 mg QD with or without food Edoxaban dose was halved from 60 to 30 mg or from 30 to 15 mg QD, respectively, with or without food At randomization: CrCl ml/min Body weight 60 kg Concomitant use of specific P-gp inhibitor (quinidine, verapamil, dronedarone) * During study: CrCl ml/min and >20% drop from baseline Body weight 60 kg and >10% drop from baseline Concomitant use of specific P-gp inhibitors (quinidine, verapamil, dronedarone) * * if concomitant medications were discontinued dosages were adjusted accordingly CrCl=creatinine clearance; P-gp=P-glycoprotein; QD=once daily DU176b-C-U301 Protocol ver 8.0_07 Nov Daiichi Sankyo Inc Giugliano et al. N Engl J Med 2013; e-pub ahead of print

48 Characteristic CHADS 2, mean±sd, n (%) Dose reduction at randomization*, n (%) Creatinine clearance ml/min Weight 60 kg Verapamil or quinidine ENGAGE AF: Overall patient characteristics Warfarin (n=7,036) 2.8±1.0 5,445 (77.4) 1,591 (22.6) 1,787 (25.4) 1,361 (19.3) 701 (10.0) 243 (3.5) Edoxaban 60 mg (n=7,035) 2.8±1.0 5,422 (77.1) 1,613 (22.9) 1,784 (25.4) 1,379 (19.6) 684 (9.7) 258 (3.7) Edoxaban 30 mg (n=7,034) 2.8±1.0 5,470 (77.8) 1,564 (22.2) 1,785 (25.4) 1,334 (19.0) 698 (9.9) 260 (3.7) Previous vitamin K antagonist for 60 days, n (%) 4138 (58.8) 4140 (58.8) 4163 (59.2) Medications at time of randomization, n (%) Aspirin Thienopyridine Amiodarone Digoxin or digitalis preparations 2,092 (29.7) 164 (2.3) 827 (11.8) 2,176 (30.9) 2,070 (29.4) 174 (2.5) 866 (12.3) 2,078 (29.5) 2,018 (28.7) 149 (2.1) 799 (11.4) 2,073 (29.5) Patients could appear in more than one category, therefore percentages may not total 100% *Patients with CrCl ml/min, body weight 60 kg or those receiving concomitant strong P-gp inhibitors (verapamil, quinidine or dronedarone) at randomization received a 50% reduction in the dose of edoxaban to maintain similar exposure to the patient with out these factors SD=standard deviation Giugliano et al. N Engl J Med 2013; e-pub ahead of print

49 ENGAGE AF: Subgroup efficacy Subgroup Edoxaban Hazard Ratio with High (95% CI) Interaction p-value Hazard Ratio with Low (95% CI) Interaction p-value Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin All Patients Dose Adjusted Yes No VKA Naive Yes No * Aspirin Use at Baseline Yes No Amiodarone Use at Baseline Yes No <0.01 Centre Level TTR >66.4% 66.4% * i Edoxaban better Warfarin better Edoxaban better Warfarin better Giugliano et al. N Engl J Med 2013; e-pub ahead of print

50 ENGAGE AF: Subgroups safety Subgroup Edoxaban Hazard Ratio with High (95% CI) Interaction p-value Hazard Ratio with Low (95% CI) Interaction p-value Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin All Patients Dose Adjusted Yes No VKA Naive Yes No Aspirin Use at Baseline Yes No Amiodarone Use at Baseline Yes No Centre Level TTR >66.4% 66.4% * 0.02 < * i Edoxaban better Warfarin better Edoxaban better Giugliano et al. N Engl J Med 2013; e-pub ahead of print

51 NOAC dosing recommendations according to renal function 1. Apixaban SPC February Available at: 2. Dabigatran SPC April Available at: 3. Rivaroxaban SPC June Available at:

52 BMJ Open 2013

53 Treatment decisions made about dabigatran using the egfr from the MDRD method assuming the ecrcl from the Cockcroft-Gault (CG) method is the gold standard MacCallum P, BMJ Open 2013

54 Treatment decisions made about rivaroxaban using the egfr from the MDRD method assuming the ecrcl from the Cockcroft-Gault (CG) method is the gold standard MacCallum P, BMJ Open 2013

55 OR for likelihood of being over treated due to a contraindication being missed by MDRD adjusted for age, sex and weight MacCallum P, BMJ Open 2013

56 Conclusion Were the MDRD-derived egfr to be used instead of Cockcroft-Gault in prescribing these new agents, many elderly patients with AF would either incorrectly become eligible for them or would receive too high a dose. Safety has not been established using the MDRD equation, a concern since the risk of major bleeding would be increased in patients with unsuspected renal impairment. Given the potentially widespread use of these agents, particularly in primary care, regulatory authorities and drug companies should alert UK doctors of the need to use the Cockcroft-Gault formula to calculate eligibility for and dosing of the new oral anticoagulants in elderly patients with AF and not rely on the MDRD-derived egfr. MacCallum P, BMJ Open 2013

57 Changes in egfr from baseline to 2-year follow-up measurement Roldan V, JACC 2013

58 When to stop NOACs before a planned surgical intervention Last intake of drug before elective surgical intervention *no EMA approval yet.; Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding many of these patients may be on the lower dose of dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d)..

59 Quale NAO? Considerare: La clearance renale L efficacia sugli end-point primari sulla riduzione della mortalità sulla riduzione dello stroke non emorragico e delle embolie sistemiche La safety meno EIC meno emorragie maggiori non aumento emorragie GI non aumento IM

60 1 Gong 2013

61 Conclusions New oral anticoagulants all have some restrictions in the use in patients with impaired renal function. In general, lower doses are recommended in those with moderate renal impairment. In patients with a severe decrease in renal function and individuals requiring hemodialysis, treatment with vitamin K antagonists remains the better option for balancing risk of stroke and risk of bleeding. Mod from Camm J, Circulation 2013