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JM ten Berg, St Antonius Hospital

Elderly ACS patients: a special case?. JM ten Berg, St Antonius Hospital. Disclosures. JM ten Berg reported Speakers fee and consultancy: AstraZenica, Eli Lilly / Daiichi Sankyo, MSD Accumetrics. Background. 35% of patients presenting with ACS ≥ 75 yrs. 

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JM ten Berg, St Antonius Hospital

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  1. Elderly ACS patients: a special case? JM ten Berg, St Antonius Hospital

  2. Disclosures JM ten Berg reported Speakers fee and consultancy: AstraZenica, Eli Lilly / Daiichi Sankyo, MSD Accumetrics |

  3. Background • 35% of patients presenting with ACS ≥ 75 yrs.  • 60% of MI-related death in patients ≥ 75 yrs. • Risk of in hospital death for ACS increases with age: 70%/10 yrs. • The elderly population is increasing |

  4. The evidence is not coming from randomized trials Number of patients over 75 years of age is very low in RCT. In contrast, this age group represents 30-40% of those presenting in community hospitals Alexander et al. Circulation 2007 |

  5. Alexander et al Circ 2007: ACS in Elderly >75 yrs (VIGOUR vs GRACE) Patients in RCT: lower risk, less co-morbidities, less CKD than their community counterparts ESC guideline: Thus the applicability of findings from clinical trials to elderly patients encountered in routine clinical practice may be questionable. |

  6. Elderly an other animal? Yes: Higher Bleeding Risk • Elevated anticoagulant and fibrinolytic system protein levels • More CKD, decreased clearance of medications • More interactions among medications, and concurrent use of agents that increase bleeding risk Higher Thrombotic Risk • Higher platelet activation • Higher on treatment platelet reactivity • Age-related changes to vascular endothelium, and impaired synthesis of and response to NO.  |

  7. Elderly an other animal? Yes: • They more often have CKD • They bleed more often |

  8. They more often have CKDFox et al 2010: CKD is Bad

  9. They more often bleedPredictors of Major Bleeding Variable OR p value Patient factors Age (per 10 yrs) 1.28 <0.0001 Female sex 1.43 <0.0001 History of bleeding 2.83 <0.0001 History of renal insufficiency 1.48 0.0004 Medications Diuretics 1.69 <0.0001 GPI 1.93 <0.0001 Lytics and GPI 2.38 <0.0001 IV inotropes 2.05 <0.0001 Procedures PCI 1.63 <0.0001 Right heart cath 2.48 <0.0001 -- Moscucci Eur Heart J 2003;24:1815–1823

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  11. How Might Bleeding Increase Long-Term Mortality? • Hemodynamic compromise • Hyperadrenergic state • Transfusion-induced microcirculatory disorder, NO depletion, immunologic effects • Inflammatory response • Discontinuation of antithrombotics |

  12. Bleeding (Day 1) and Subsequent Antithrombotic Use Use of Meds After Bleed Med Bleed No bleed ASA 69% 86% thien 50% 51% UFH 30% 36% LMWH 26% 50% GPIIb/IIIa 8% 14% Spencer Circ 2007

  13. What can be done to reduce bleeding? • When invasive use radial • Avoid overdose |

  14. Avoid Excessive Dosing of Anticoagulants 42% of patients got excess <65 >65 >75 -- Alexander JAMA 2005;294:3108-3116

  15. Case A 78-year-old woman presents with non-ST elevation MI. Physical examination and lab tests reveal the following: hematocrit, 35%; creatinine clearance, 55 mL/min; heart rate, 90 beats per minute; blood pressure 100/60 mm Hg, 74 kg. She has type 2 diabetes but no vascular history or previous heart failure. Q1: how do you estimate her bleeding risk according to ESC guidelines? a. GRACE risk score b. TIMI bleeding risk c. CRUSADE score

  16. Q2: which of her characteristics define the bleeding risk? a. Age, Hct, GFR, blood pressure, pulse, DM b. Hct, GFR, blood pressure, pulse, DM c. GFR, blood pressure, pulse, DM |

  17. Q3: what is her estimated bleeding risk in %? a. 2% b. 30% c. 15% |

  18. CRUSADE case |

  19. In the CRUSADE bleeding risk score, age is no independent predictor after covariate adjustment • It highlights the importance of anemia and renal failure, which are more common in elderly • On a scale from 1-100, Hct 35% adds 8 points to the score, while creatine clearance 55 ml/min is associated with 28 points |

  20. Case II An 80-year-old diabetic woman presents with NONSTEMI; blood pressure 130/70, pulse 80/min, weight 55 kilo’s, her calculated glomerular filtration rate is 40 mL/min. How should the antithrombotic therapy be managed in this patient (assuming no other contraindications)? Q. Aspirin leads to bleeding thus in elderly: a. No aspirin, only thienopyridine b. No loading dose, start 75 mg per day c. Loading dose of 300 mg, followed by low dose |

  21. ASPIRIN • Recent registry data demonstrate that a loading dose of ≥ 300 mg was safe and not associated with an increase in bleeding or transfusion among 791 patients with acute MI ≥ 75 years old, some of whom received fibrinolytics • Large databases (Medicare) demonstrate a similar reduction in mortality following MI in patients over 65 yrs of age • ACC/AHA and ESC guidelines support initial use of loading dose followed by low dose aspirin • Several studies have demonstrated in increase in bleeding risk (most GI, intracranial uncommon); however this risk, although minimal, increases in the elderly |

  22. Case II An 80-year-old diabetic woman presents with NONSTEMI; blood pressure 130/70, pulse 80/min, weight 55 kilo’s, her calculated glomerular filtration rate is 40 mL/min. How should the antithrombotic therapy be managed in this patient (assuming no other contraindications and an invasive approach) ? Q. Clopidogrel, Prasugrel, Ticagrelor added? • If treated with clopidogrel 150 mg/day 1 yr • If treated with Ticagrelor half dose/d 1 yr • If treated with Prasugrel 5 mg/d 1 yr |

  23. CKD and use of Prasugrel or Ticagrelor • In TRITON the reduction in the primary endpoint ( CV death, non-fatal MI, or non fatal stroke) with prasugrel compared to clopidogrel was independent of the presence of CKD. • In PLATO, in 3237 patients with CKD (creatinine clearance <60 ml/L) ticagrelor reduced the primary endpoint (cardiovascular death, myocardial infarction, stroke) to 17.3% from 22.0% (HR 0.77, 95% CI0.65-0.90). This reduction was greater than that observed in patients with normal renal function (7.9% versus 8.9%, HR 0.90, 95% CI: 0.79-1.02).

  24. Bleeding EventsSafety Cohort(N=13,457) ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel Prasugrel Clop 0 (0) %Pras 6 (2.3)% (P=0.02) % Events ARD 0.6%HR 1.32P=0.03NNH=167 ARD 0.5%HR 1.52P=0.01 ARD 0.2%P=0.23 ARD 0.3%P=0.002 ARD 0%P=0.74

  25. Net Clinical BenefitBleeding Risk Subgroups Post-hoc analysis Risk (%) + 54 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR

  26. Prasugrel in this case? • ESC guideline "in patients over 75 years of age, prasugrel is generally not recommended because of the increased risk for fatal and intracranial bleeding and uncertain benefit except in high-risk situations (DM a history of MI), in which its effect appears to be greater”. • Similarly, “body weight < 60 kg is a relative CI and prior stroke is an absolute CI for prasugrel”. • Currently the FDA label provides the option of a 5-mg dose in patients over 75 although there is limited data on this dose.

  27. Ticagrelor in this patient? • In PLATO patients < 75 years demonstrated a significant reduction in the composite endpoint (8.6% vs 10.4%) favoring ticagrelor. • For patients ≥ 75 years old, there was no significant difference in composite endpoint between ticagrelor (17.2%) and clopidogrel (18.3%). However, an interaction analysis for age was not significant and it is unclear whether the lack of clear benefit reflects the small size elderly subgroup (n = 2878, [15%]) or a potential decreased efficacy in older patients. • While the rate of bleeding was numerically increased within the elderly subgroup, it did not reach statistical significance (11.2% vs 10.8%).

  28. Case II Answer An 80-year-old diabetic woman presents with NONSTEMI; blood pressure 130/70, pulse 80/min, weight 55 kilo’s, her calculated glomerular filtration rate is 40 mL/min. How should the antithrombotic therapy be managed in this patient (assuming no other contraindications) and an invasive approach? Q. Clopidogrel, Prasugrel, Ticagrelor added? • If treated with clopidogrel 150 mg: NO • If treated with Ticagrelor half dose; No • If treated with Prasugrel 5 mg Yes |

  29. Case II An 80-year-old diabetic woman presents with NONSTEMI; blood pressure 130/70, pulse 80/min, weight 55 kilo’s, her calculated glomerular filtration rate is 40 mL/min. Q. What anticoagulant to use in this patient? • UFH • Enoxaparin • Fondaparinux |

  30. Mortality at 30 days Major Bleeding at 9 days 0.04 3.5 % 17 % Enoxaparin RRR 4.1 % Enoxaparin 0.04 0.03 2.9 % 48% HR: 0.52 relative 95% CI: 0.44 - 0.61 risk Fondaparinux 0.03 p<0.0001 0.02 reduction 2.2 % 0.02 HR: 0.83 0.01 95% CI: 0.71 - 0.97 Fondaparinux p=0.02 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 0.0 Days 7 8 9 5 6 0 1 2 3 4 Fondaparinux: 295 deaths Days Enoxaparin: 352 deaths - - Background: OASIS 5 Randomized trial of Fondaparinux vs. Enoxaparin in NSTEACS (n=20,078) demonstrated non-inferiority for CV death, MI, Refractory Ischemia Fondapa vs. Enox reduced major bleeding by 48% and mortality by 17% In patients over 75: similar efficacy and bleeding advantage OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

  31. Acuity – Primary Endpoint Measures NEJM 2006;355:2203 A subgroup 2441 patients ≥ 75 years : bivalirudin monotherapy yielded similar ischemic outcomes but significantly lower rates of bleeding compared with heparin plus IIb/IIIa inhibitor

  32. Invasive Treatment in Elderly? • TACTICS-TIMI 18 trial subgroup analysis of 962 ≥ 65 years old found that an early invasive strategy resulted in a more pronounced absolute (4.8% vs 1%) and relative reduction (39%) in death or MI at 6 months. • Similarly, both absolute and relative reduction were also observed in the 278 patients ≥ 75 years old. • However, the invasive strategy was associated with a 3-fold increased risk of in-hospital major bleeding in subjects ≥ 75 years old (16.6% vs 6.5%, P = .009). • Radial excess reduces bleedings (OCTOPLUS trial) • PPIs reduce bleedings |

  33. POPular AGE • Aim: to study the effect of ticagrelor and prasugrel versus clopidogrel in NONSTEMI patients over 75 years of age • Design: Multicenter RCT (Antonius, UMCU, Zwolle, Woerden, UMC Nijmegen • Study population: 1,000 pt NSTEMI, > 75 jaar, CRUSADE >31, • Hypothesis: clopidogrel superior in bleeding risk without increasing the net clinical benefit |

  34. Conclusions: Treating ACS in Elderly • More often CKD and bleeding • Be aware of overdosing • Use aspirin as in younger patients • Prasugrel and Ticagrelor no benefit over clopidogrel in TRITON and PLATO • Use fonda or bival for high-risk patients • Use Proton pump inhibitors liberally • Consider radial access • After bleeding, readdress risk/benefit and resume antithrombotics (carefully) |

  35. Take Care ! |

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