Elderly Patients with renal insufficiency: Which anti-platelet/ Anti thrombin/minimizing Major bleeds

Transcription

1 Elderly Patients with renal insufficiency: Which anti-platelet/ Anti thrombin/minimizing Major bleeds Blair J O Neill MD FRCPC FACC Text Professor of Medicine, University of Alberta Clinical Co-Director CV Health and Stroke Strategic Clinical Network for Alberta Health Services President, Canadian Cardiovascular Society

2 Routine Invasive VS Selective Invasive Procedure for Elderly Patients with ACS I am an interventional cardiologist No other pertinent disclosures related to this presentation

3 Case Study 83 year old female creatinine 230 (Cr Cl < 20 ml/min), normal CPK /+ troponin (Tn I = 3.4) ECG: Dynamic- Up to 1 mm ST segment depression with C/P HR 88/min; BP 106/70 Hb 100 WBC 11

4 2011 ESC Guidelines for Risk Stratification

5 Bleeding in ACS

6 Possible Relationship Between Bleeding and Mortality Major Bleeding Hypotension Cessation of ASA/Clopidogrel Transfusion Ischemia Stent Thrombosis Inflammation Mortality Bhatt DL et al. In Braunwald: Harrison s Online 2005.

7 A delicate balance: Potent Therapies / Patient Fragility Ischemic events: MI/CKMB Stent Thrombosis Bleeding

8 Mortality (%) ACUITY (N=13,819) Impact of MI and Major Bleeding in the First 30 Days on Risk of Death Over 1 Year 25 1 year Estimate 20 Patients with Major Bleed (N=645) 14.9% Patients with MI (N=705) 11.4% Patients w/o Major Bleed (N=13,168) 3.6% 15 Patients w/o MI (N=13,108) 3.8% 14.9% % % 3.6% Days from Randomization

9 Bleeding Risk:

10 Bleeding Risk Gender Male 0 Female +8 Age (yr) < > scr (mg/dl) < > WBC < > Anemia No 0 Yes +6 Presentation STEMI +6 NSTEMI - +biomarkers +2 NSTEACS - N biomarkers 0 Antithrombotic Medications Heparin + a GPI 0 Bivalirudin monotherapy -5 Mehran R, et al. J Am Coll Cardiol. 2010; 55:

11 Death / MI Evolution of Care in Non ST Elevation ACS Anti-Ischemic Therapy Nitrates, Beta blockers, Ca Channel antagonists Anti-thrombotic Therapy 16-20% 1988 ASA 12-15% 1992 ASA+ Heparin 8-12% 1998 ASA+ Heparin+ GP2B3A 2001 ASA+ LMWH + Clopidogrel+ Intervention 2007 ASA + Clopidogrel + Fondaparinux +/- GP2B/3a Intervention 6-10% 4-8% 3-6% RRR 25% 20% 20% 25% 20% Revascularization PCI (DES Stents), CABG

12 Representation of the Elderly in Clinical Trials Circulation 2007; 115:

13 Anti Platelet Therapy in the Elderly Trial Agent Key Age Parameters Outcomes in the Elderly Antiplatelet Trialists Collaboration ASA >65; 30% Greater benefit in the Elderly (13.3 vs 15.3%) CURE Clopidogrel + ASA vs ASA alone Mean Age: 64y Significant benefit in the elderly TRITON-TIMI 38 Prasugrel vs Clopidogrel > 65: 50% > 75: 13% No Benefit > 75yo; increase in bleeding PLATO Ticagrelor vs Clopidogrel Mean Age: 61y > 65y no significant benefit but no significant interaction between age & Rx effect GP IIb-IIIa metaanalysis Tirofiban, Eptifibitide, Abciximab, vs placebo > 60: 65% > 70: 35% > 60y no significant benefit but trend towards Rx effect decreasing with age Annual Bleeding Risk: 3.2% for ASA & 6.8% for aspirin + clopidogrel/ticlopidine Predictors of bleeding: age, cerebrovascular disease, DM, CRD, peptic ulcer disease, and bleeding during the index acute MI Arch Intern Med 2005, 165:

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16 CREDO: Clopidogrel Loading Dose Timing and Risk of MACE - 2 Placebo P=0.020 for treatment/timing interaction Clopidogrel Hours Prior to PCI of Study Drug Loading Dose Steinhubl, et al

17 Considerable interpatient differences in bioavailability 17

18 Limitations of Current Thienopyridines Slow onset: requires prolonged pretreatment for PCI efficacy Bleeding (especially related to CABG) Modest levels of platelet inhibition Variability of response

19 Choices in P2Y12 inhibitors

20 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic

21 Endpoint (%) Balance of Efficacy and Safety CV Death / MI / Stroke Clopidogrel Prasugrel events HR 0.81 ( ) P= NNT = TIMI Major NonCABG Bleeds Prasugrel Clopidogrel Days events HR 1.32 ( ) P=0.03 NNH = 167

22 Prior Stroke / TIA Yes No Net Clinical Benefit Bleeding Risk Subgroups Post-hoc analysis P int = Risk (%) Age >=75 < 75 P int = Wgt < 60 kg +3 >=60 kg P int = OVERALL Prasugrel Better HR Clopidogrel Better

23 Moderate- to high-risk ACS patients (UA/NSTEMI/STEMI, PCI, medically managed, or CABG) (N=18,000) ASA + Clopidogrel 300 mg ld/75 mg qd 600 mg ld allowed in PCI ASA + Ticagrelor 180 mg ld/90 mg bid 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) Primary endpoint: Secondary endpoint: CVD/MI/stroke CVD/MI/stroke/revascularization with PCI; CVD/MI/stroke, severe recurrent ischemia ASA = acetylsalicylic acid; bid = twice daily; CVD = cardiovascular disease; ld = loading dose; MI = myocardial infarction; NSTEMI = non- ST-segment elevation MI; qd = once daily; STEMI = ST-segment elevation MI; UA = unstable angina. ClinicalTrials.gov Identifier: NCT

24 Cumulative incidence (%) Time to First Primary Efficacy Event (Composite of CV Death, MI or Stroke) P<0.001 Clopidogrel Ticagrelor HR 0.84 (95% CI ) RRR = 16%, ARR = 1.87%, NNT = No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L, et al.new Engl J Med. 2009;361.

25 K-M estimated rate (% per year) PLATO Non-CABG and CABG-related Major Bleeding NS 7.9 Ticagrelor Clopidogrel p= NS p= Non-CABG PLATO major bleeding NS = not significant; K-M=Kaplan-Meier; CABG=coronary-artery bypass grafting Wallentin L, et al.new Engl J Med. 2009; Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

26 2011 ESC Guidelines for the Management of ACS in patients presenting without persistent ST-segment elevation Recommendations Class Level Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all moderate-to-high risk patients for ischemic events, regardless of initial treatment strategy and including those pre-treated with clopidogrel (which should be discontinued when ticagrelor is commenced). Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications. Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel. A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at PCI following an initial 300-mg loading dose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option. (CURRENT Study) A higher maintenance dose of clopidogrel 150 mg daily should be considered for the first 7 days in patients managed with PCI and without increased risk of bleeding. (CURRENT Study) I I I I IIa European Heart Journal doi: /eurheartj/ehr236 B B A B B

27 Evidence for efficacy of PPI s with Clopidogrel 51 GI Bleeds 1.1% with PPI vs 2.9% without A total of 3873 (out of a planned 5000) were randomly assigned A total of 109 patients had a CV event, with event rates of 4.9% with omeprazole and 5.7% with placebo (0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. N Engl J Med 363;20: 1909

28 Anti-Thrombin Agents in the Elderly

29 TIMI 11B-ESSENCE Meta-Analysis: Enox vs UFH - Death/MI Day TIMI 11B N 3910 UFH (%) Enox (%) B OR % p 8 ESSENCE 3171 OVERALL B 0.77 ( ) TIMI 11B ESSENCE B B OVERALL ( ) TIMI 11B 43 ESSENCE OVERALL B B 0.82 ( ) Enox Better Odds Ratio UFH Better

30 Synergy Trial --Enoxaparin: Is it as safe or effective in the elderly? European Heart Journal (2008) 29,

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32 2.5 mg OASIS 5

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35 OASIS-5

36 OASIS-5: Fondaparinux was safer than reduced dose Enoxaparin in Renal Failure Time Point Fondaparinux, n (%) Enoxaparin, n (%) Hazard Ratio (95% Confidence Interval) P value Day 9 76 (3.0) 93 (3.6) 0.82 ( ) 0.19 Day (4.8) 176 (6.8) 0.69 ( ) <0.002 Day (10.4) 303 (12.0) 0.85 ( ) 0.56 Mortality in the 5141 randomized patients with NSTEMI and renal impairment < 60 ml/min in the OASIS-5 trial Fox KA et al. Ann Intern Med 2007;147:

37 Mehta S R et al. Circulation 2008;118: OASIS 5: Clinical Outcome (death, MI, stroke, or major bleed) at 30 days according to management strategy

38 2011ESC Recommendations for AntiThrombin Rx in ACS Recommendation Class Level Anticoagulation is recommended for all patients in addition to antiplatelet therapy. I A The anticoagulation should be selected according to both ischaemic and bleeding risks, and according to the efficacy safety profile of the chosen agent. I C Fondaparinux (2.5 mg subcutaneously daily) is recommended as having the most favourable efficacy safety profile with respect to anticoagulation. I C If the initial anticoagulant is fondaparinux, a single bolus of UFH (85 IU/kg adapted to ACT, or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI. Enoxaparin (1 mg/kg twice daily) is recommended when fondaparinux is not available. I B If fondaparinux or enoxaparin are not available, UFH with a target aptt of s or other LMWHs at the specific recommended doses are indicated. I C Bivalirudin plus provisional GP IIb/IIIa receptor inhibitors are recommended as an alternative to UFH plus GP IIb/IIIa receptor inhibitors in patients with an intended urgent or early invasive strategy, particularly in patients with a high risk of bleeding. In a purely conservative strategy, anticoagulation should be maintained up to hospital discharge. I A Discontinuation of anticoagulation should be considered after an invasive procedure unless otherwise indicated. IIa C Crossover of heparins (UFH and LMWH) is not recommended. III B I I 38 B B

39 Recommendations for patients with CKD-ESC 2011 Recommendation Class Level Kidney function should be assessed by CrCl or egfr in patients with NSTEACS, with special attention to elderly people, women, and patients with low body weight, as near normal serum creatinine levels may be associated with lower than expected CrCl and egfr levels. I C Patients with NSTEACS and CKD should receive the same first-line anti-thrombotic treatment as patients without CKD, with appropriate dose adjustments according to the severity of renal dysfunction. I B Depending on the degree of renal dysfunction, use fondaparinux (to CrCl < 20 ml/min), adjust the dose of enoxaparin, bivalirudin, or small molecule GP IIb/IIIa receptor inhibitors or switch to UFH. I B UFH infusion adjusted to aptt is recommended when CrCl is <30 ml/min or egfr is <30 ml/min/1.73 m 2 with most anticoagulants (fondaparinux <20 ml/min). I C In patients with NSTEACS and CKD considered for invasive strategy, hydration and low- or isoosmolar contrast medium at low volume (<4 ml/kg) are recommended. I B CABG or PCI is recommended in patients with CKD amenable to revascularization after careful assessment of the risk benefit ratio in relation to the severity of renal dysfunction. I B 39

40 Recommendations for the use of antithrombotic drugs in CKD: ESC 2011 Guidelines Clopidogrel Prasugrel Ticagralor No information in patients with renal dysfunction. No dose adjustment necessary, including in patients with end-stage disease No dose reduction required; no information in dialysis patients. Enoxaparin Dose reduction to 1 mg/kg once daily in the case of severe renal failure (CrCl <30 ml/min). Consider monitoring of anti-xa activity. Fondaparinux Bivalirudin Contraindicated in severe renal failure (CrCl <20 ml/min). Drug of choice in patients with moderately reduced renal function (CrCl ml/min). Patients with moderate renal impairment (30 59 ml/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is <30 ml/min, reduction of the infusion rate to 1 mg/kg/h should be considered. No reduction in the bolus dose is needed. If a patient is on haemodialysis, the infusion rate should be reduced to 0.25 mg/kg/hr Abciximab No specific recommendations for the use of abciximab, or for dose adjustment in the case of renal failure. Careful evaluation of hemorrhagic risk is needed before using the drug in the case of renal failure. Eptifibatide The infusion dose should be reduced to 1 μg/kg/min in patients with CrCl <50 ml/min. The dose of the bolus remains unchanged at 180 μg/kg. Eptifibatide is contraindicated in patients with CrCl <30 ml/min. Tirofiban Dose adaptation is required in patients with renal failure; 50% of the 40 bolus dose and infusion if CrCl is <30 ml/min.

41 Case Study 83 year old female creatinine 230 (Cr Cl < 20 ml/min), normal CPK /+ troponin (Tn I = 3.4) ECG: Dynamic- Up to 1 mm ST segment depression with C/P HR 88/min; BP 106/70 Hb 100 WBC 11

42 What would I do? ECASA 81 mg daily Clopidogrel 300 mg / 75 mg daily Pantaloc (Pantoprazole) 40 mg daily Fondaparanux 2.5 mg SQ daily Radial Approach/Bivalrudin for coronary interventions

43 Questions? 43