Riskhantering hos patienter som ska genomgå akut kranskärlskirurgi

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1 Riskhantering hos patienter som ska genomgå akut kranskärlskirurgi Claes Held, MD, PhD Uppsala Clinical Research Center Kardiologkliniken Uppsala

2 Claes Held, Uppsala Riskhantering hos patienter som ska genomgå akut kranskärlskirurgi Intressekonflikt: Konsult/föreläsaruppdrag för AstraZeneca, Pfizer Forskningsanslag från AstraZeneca, Merck, Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline

3 Disclaimer AstraZeneca is dedicated to promote products according to high ethical standards. Hence AstraZeneca will adhere to all legislations and trade association regulations applicable. Since this meeting is judged to be, or might be, promotional in kind AstraZeneca cannot, and will not, promote any product not having received market authorization or products outside its approved indications. AstraZeneca takes no responsibility for any statement or comment regarding the use of products which have not received market authorization or the use outside approved indications made by any persons present at the meeting (incl. AstraZeneca s and non-astrazeneca s speakers, AstraZeneca s and non-astrazeneca s meeting participants). AstraZeneca neither endorse nor recommend such use.

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6 Riskstratifiering vid hjärtkirurgi Trots att CABG är ett rutiningrepp, så finns risk för peri-operativa komplikationer, såsom blödning, reoperation, hjärtinfarkt, stroke eller död Preoperativ bedömning av risk vs nytta nödvändig Risk score har funnits i över 20 år Omkring ca 20 olika risk score algoritmer tillgängliga Prediktion av 30-d och 1-årsmortalitet Morbiditetsrisk: stroke, njursvikt, reoperation, förlängd respiratorvård Prediktion av post-operativ kostnad och IVAvårdtid CABG = coronary artery bypass graft., MI = myocardial infarction.

7 EuroScore Interactive Calculator 17 kliniska parametrar 0 angiografisk

8 Online STS Risk Calculator 40 kliniska parametrar 2 angiografiska STS = Society of Thoracic Surgeons

9 Betydelse av Perioperativ Blödning Ökad risk för postoperativa komplikationer: Re-operation Blodtransfusion Infektion Njursvikt Mortalitet Postoperativ behandlingstid Kostnad Karthik S, et al. Ann Thorac Surg. 2004;78: Christensen MC, et al J Thorac Cardiovasc Surg. 2009;138:

10 Antitrombotisk behandling inför CABG Varför är det viktigt? Antitrombotisk behandling före, under och efter CABG kan vara en av de viktigaste faktorerna för klinisk outcome Risken för blödning Påverkar Graft Patency Risk för ischemiska händelser (Död, Stroke, hjärtinfarkt och instabil angina) Optimering av behandlingsrutinerna för antitrombotisk behandling, kan leda till bättre effektivitet och säkerhet vid CABG

11 Antitrombotisk behandling av ACS patienter som skall genomgå CABG Vid NSTEMI och STEMI ACS, rekommenderar guidelines 12 månaders behandling med dubbel trombocythämning 1 4 Clopidogrel är standardbehandling men problem finns: Långsam och variabel omvandling till den aktiva metaboliten Måttlig och variabel trombocythämning Risk för stent trombos och hjärtinfarkt bland poor responders Irreversibel läkemedelseffekt ökad risk för blödning vid akut CABG Clopidogrel rekommenderas att sättas ut inom 5 dagar före CABG på grund av ökad blödningsrisk 1 4 Klinisk verklighet kräver ofta tidigare kirurgiska ingrepp <5 d ACS = acute coronary syndromes, NSTEMI = non-st-segment elevation myocardial infarction, STEMI = ST-segment elevation myocardial infarction. 1. Bassand JP, et al. Eur Heart J. 2007;28: ; 2. Van der Werf F, et al. Eur Heart J. 2008;29: ; 3. Anderson JL, et al. J Am Coll Cardiol. 2007;50: ; 4. Kushner FG, et al. J Am Coll Cardiol. 2009;54:

12 Net Clinical Benefit Antiplatelet / Anticoagulant Ischemic events CV death MI Stroke Unstable Angina Bleeding Fatal Life-threatening Major Minor What ischemic event is equivalent to what bleed? CV = cardiovascular, UA = unstable angina.

13 CURE: CV Death/MI/Stroke in Various Intervention Groups RR (95% Cl) CURE overall Medical therapy (no CABG/PCI any time) Medical therapy (no CABG/PCI in index hospitalization) Revasc (PCI or CABG) (any time) Revasc (PCI or CABG) (index hospitalization) CABG (any time) CABG (index hospitalization) PCI (any time) PCI (index hospitalization) Clopidogrel better Placebo better CI = confidence interval, CURE = Clopidogrel in Unstable angina to prevent Recurrent ischemic Events trial, PCI = percutaneous coronary intervention, Revasc = revascularization, RR = relative risk. Fox KA, et al. Circulation. 2004;110:

14 CURE Major Bleeding CURE overall N=12,562 RR (95% Cl) Medical therapy (no CABG/PCI any time) Medical therapy (no CABG/PCI in index hospitalization) Revasc (PCI or CABG) (any time) Revasc (PCI or CABG) (index hospitalization) CABG (any time) N=2072 Clopidogrel withdrawn >5 days prior to CABG Reoperation for bleed12/454 (plac) vs 7/456 (clop), RR % CI Life-threatening bleed 2 fewer (clop) deaths CABG (index hospitalization) PCI (any time) PCI (index hospitalization) Clopidogrel withdrawn 5 days prior to CABG Reoperation 11/476 (plac) vs 18/436 (clop) RR % CI Life-threatening bleed excess death (clop) 10 (2.8%) Placebo higher Clopidogrel higher Fox KA, et al. Circulation. 2004;110:

15 Study Design, Flow and Compliance 25,087 ACS Patients (UA / NSTEMI 70.8%, STEMI 29.2%) ü Planned early (<24 h) invasive management with intended PCI ü Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) PCI 17,232 (70%) Randomized to receive (2 X 2 factorial): Clopidogrel: Double dose (600 mg then 150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Angio 24,769 (99%) No PCI 7,855 (30%) Compliance: No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Clop in 1 st 7d (median) 7 d 7 d 2 d 7 d Efficacy Outcomes: CV Death, MI, or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major / Severe and TIMI Major) Key subgroup: PCI vs No PCI Angio = angiography, CABG = coronary artery bypass graft, CAD = coronary artery disease, Clop = clopidogrel Mehta SR, et al. Presented at: European Society of Cardiology Congress Aug-2 Sept 2009; Barcelona, Spain.

16 Clopidogrel Double vs Standard Dose: Bleeding in Overall Population Clopidogrel Standard N=12579 Double N=12508 Hazard Ratio 95% CI P value TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion 2U CABG-related Major ICH = intracerebral hemorrhage, RBC = red blood cells. 1 ICH, Hb drop 5 g/dl (each unit of RBC transfusion counts as 1 g/dl drop) or fatal. 2 Severe bleed + disabling or intraocular or requiring transfusion of 2 3 units. 3 Fatal or Hb 5g/dL, sig hypotension + inotropes/surgery, ICH or txn of 4 units. Mehta SR, et al. Presented at: European Society of Cardiology Congress Aug-2 Sept 2009; Barcelona, Spain. Abstract 177.

17 TRITON Study: Efficacy and Efficacy Endpoint, n (%) a Safety in CABG Patients Prasugrel N=234 [K-M%] b Clopidogrel N=250 [K-M%] b HR (95% CI) P value CV death, MI or stroke 20 (8.5) [9.5] 30 (12.0) [13.6] 0.69 ( ) CV death 8 (3.4) 17 (6.8) Nonfatal MI 9 (3.8) 13 (5.2) Nonfatal stroke 4 (1.7) 3 (1.2) Safety Endpoint, n (%) CABG-related TIMI major bleed Prasugrel N=213 Clopidogrel N=224 P value 24 (11.3) 8 (3.6) Efficacy analyses conducted on all randomized patients who underwent CABG (n=484). Safety analyses conducted on subgroup of patients treated with study drug (n=437). a Observed rate, b Kaplan-Meier estimate at 450 days. HR = hazard ratio, K-M = Kaplan-Meier. TRITON-TIMI 38 = Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38. Wiviott SD, et al. New Engl J Med. 2007;357: ; Prasugrel Advisory Committee Briefing Document available at: DrugsAdvisoryCommittee/ucm pdf

18 PLATO CABG Patient Disposition 18,624 patients randomized CABG in 1899 patients during the course of the study CABG in 1261 patients with last intake of study drug 7 days prior to surgery: 632 patients treated with ticagrelor 629 patients treated with clopidogrel Held C, et al. JACC 2011; 57:672-84

19 Time From CABG to Any Death (CABG Population) 10 Clopidogrel K-M estimated rate (%) Ticagrelor HR: 0.49 (95% CI ), p< No. at risk Ticagrelor Clopidogrel Months Held C, et al. JACC 2011; 57:672-84

20 Characteristic Primary and Secondary Efficacy Primary endpoint Endpoints From Time of CABG Secondary endpoints Ticagrelor (n=629)* Clopidogrel (n=629) 0.52 ( ) 0.49 ( ) 0.35 ( ) HR (95% CI) 0.84 ( ) 1.06 ( ) 1.17 ( ) P value CV death + MI + stroke MI CV death Stroke** All-cause mortality Non-CV death Ticagrelor better Clopidogrel better Patients could have had more than one type of endpoint. Values are incidences=number of events divided by n, not rates. *Three patients had missing values for the efficacy endpoints due to CABG after the censoring date at 12 months. **Results for hemorrhagic stroke: 0.0% (ticagrelor) and 0.2% (clopidogrel); non-hemorrhagic stroke: 2.1% and 1.6%. Held C, et al. JACC 2011; 57:672-84

21 Bleeding From Time of CABG (1) Characteristic Ticagrelor (n=632) Clopidogrel (n=629) Odds ratio (95% CI) P value CABG-related bleeding Major bleeding ( ) 0.67 Life-threatening/ fatal bleeding ( ) ( ) Fatal bleeding All intracranial bleeding post-cabg* 1.01 ( ) TIMI major bleeding ( ) 0.53 TIMI minor bleeding ( ) 0.84 GUSTO severe bleeding ( ) Ticagrelor better Clopidogrel better Values are incidences = number of events divided by n, not rates. *Hazard ratio. Both CABG-related and non-related. Held C, et al. JACC 2011; 57:672-84

22 Bleeding From Time of CABG (2) Characteristic Ticagrelor (n=632) Clopidogrel (n=629) Hazard/odds ratio (95% CI) P value Hemoglobin decrease* 1.08 ( ) >50 g/l ( ) >30 g/l Major/life-threatening CABG-related bleeding resulting in death within 7 days of CABG ( ) 0.05 Re-operation due to bleeding* ( ) Ticagrelor better Clopidogrel better Event rate is number of events divided by n. *Odds ratio and P value from Fisher s exact test. Hazard ratio. Held C, et al. JACC 2011; 57:672-84

23 Transfusions From Time of CABG Characteristic Any transfusion Ticagrelor (n=632) Transfusions within 7 days post-cabg Clopidogrel (n=629) Hazard/odds ratio (95% CI) 0.98 ( ) P value 0.83 PRBC or whole blood* ( ) 0.69 Platelets ( ) 0.37 Fresh frozen plasma ( ) 0.67 Transfusions post CABG-related bleeding >4 units blood >5 units whole blood/ PRBC (2 days) ( ) 1.25 ( ) Chest tube output >2L 1.24 ( ) (24 hours) Ticagrelor better Event rate is number of events divided by n. *Median (range) units transfused within 7 days post-cabg: tic 3.0 ( ) vs clop 3.0 ( ); P=0.86. Odds ratio and P value from Fisher s exact test. Held C, et al. JACC 2011; 57: Clopidogrel better

24 Toward Standardization of Bleeding Definitions Recommended standardized data elements to collect in trials and registries of acute coronary syndromes Rao SV, et al. Am Heart J. 2009;158:881 6.

25 Sammanfattning Preoperativ risk stratifiering är nödvändig i kliniken Flertal risk score tillgängliga för att utvärdera patienter CABG-relaterad blödning är kliniskt viktig, särskilt i relation till antitrombotisk behandling. Net clinical benefit -koncept Optimera utsättningstiden av den antitrombotiska behandlingen innan CABG Glöm ej att återinsätta behandlingen postop! Stor skillnad i blödningsrisk mellan studier Behov av standardiserade definitioner Nya, mer effektiva antitrombotiska läkemedel med gynnsam blödningsprofil och farmakokinetik behövs

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