(ClinicalTrials.gov ID: NCT ) Title: The Italian Elderly ACS Study Author: Stefano Savonitto. Date: 29 August 2011 Meeting: ESC congress, Paris

Transcription

1 Early aggressive versus initially conservative strategy in elderly patients with non-st- elevation acute coronary syndrome: the Italian randomised trial (ClinicalTrials.gov ID: NCT ) Stefano Savonitto, Ernesto Murena, Roberto Antonicelli, Claudio Cavallini, Anna Sonia Petronio, Alice Sacco, Giuseppe Steffenino, Nuccia Morici, Maria Cristina Jori and Stefano De Servi On behalf of the Italian Investigators

2 Dr Savonitto has no conflict of interest to declare with regard to this presentation

3 At least part of the worse outcome in elderly patients with NSTE seems to be attributable to a conservative approach 30-days Outcomes Treatments ,7 75 y >75 y 6,4 5 7,1 7 13, aa >75 aa death MI MACE angiography PCI 2b/3a RB Conservative Strategy: OR 2.31 ( ) events at 30 days De Servi S, et al. Am Heart J 2004; 147:

4 patients are under-represented in RCTs of early invasive treatment in NSTE Trial Average age % pts >75y Outcome TIMI IIIB 59 3 Benefit only >65 y VANQWISH 61 8 No difference FRISC II (mean 76y) Benefit only >65 y RITA Not reported by age TACTICS % RR >65 56% RR >75 ICTUS (max 80y) Trend towards > benefit >65y

5 PCI/angiography ratio stratified by age and region < >74 EHJ 2006;27:393 % corox North % PTCA ratio Center South

6 Seventy is old enough. After that there is too much risk Mark Twain Following the Equator Hartford, Connecticut: American Publishing Inc 1897

7 RCT Patients >75 years with NSTE Registry Registry of excluded pts with simplified CRF web random Early invasive (angio within 72 hours) Initially conservative (angio for refractory ischemia) 12-month follow-up 12-month follow-up 12-month follow-up Primary endpoint the composite of all-cause mortality, myocardial (re)mi, disabling stroke and re-hospitalization for cardiovascular causes or severe bleeding within 12 months Savonitto S, J Cardiovasc Med 2008;9:217

8 Inclusion criteria Age >75 years Symptoms suggestive of acute myocardial ischemia at rest within 48 h prior to randomization, together with a) ischemic ECG changes and/or b) elevated CKMB or Tn. Written informed consent before inclusion.

9 Main exclusion criteria Secondary causes of myocardial ischemia Ongoing ischemia despite maximal anti-ischemic rx Ongoing signs of heart failure despite treatment PCI or surgery within 30 days prior to randomization Serum creatinine level >2.5 mg/dl History of severe bleeding Cerebrovascular accident within the previous month Known platelet count of <90,000 cells/ml Ongoing OAT or INR>1.5

10 Randomised treatment strategies Patients >74 years With NSTE Web random Early invasive (angio within 72 hours) Initially conservative (angio for refractory ischemia) Angio During index admission Angio After index discharge Recurrent ischemia: recurrent symptoms and ECG changes >12 hrs after admission despite maximal therapy Post-admission (re)mi Refractory heart failure Malignant ventricular arrhythmia Recurrent ischemic symptoms (CCS III-IV) after index discharge despite optimal antianginal therapy, particularly if ischemia is documented on provocative testing Savonitto S, J Cardiovasc Med 2008;9:217

11 Recommendations about antithrombotic treatments Aspirin, 325 mg p.o on admission, then mg throughout follow-up Clopidogrel, 300 mg on admission, then 75 mg throughout follow-up GPIIb/IIIa RB: invasive arm (and conservative arm in case of angio) - either upstream eptifibatide-tirofiban if delay to angio >4 hrs - or post-angio abciximab, particularly if delay to angio <4hrs UFH: 2500 i.v. bolus, then start infusion of 7U/kg/hr nomogram-adjusted to a target aptt of seconds up to 30 minutes prior to angiography Enoxaparin: i.v. bolus of 3000 U, followed by sq administration of 75U/kg (max 6000 U) b.i.d. for 3-5 days. Latest dose >8 hrs prior to angio No further UFH/enoxa post-angio, except for patients laying in bed (50 U o.d.) Bivalirudin as anticoagulant during PCI, according to REPLACE-2 dosing: - i.v. bolus 0.75 mg/kg mk/kg/hour infusion during PCI Fondaparinux, 2.5 mg subq o.d., during the whole hospital stay, particularly in patients treated conservatively

12 Centers declaring participation: august 2007 Active Centers N=59 N=

13 Enrolment completed May y follow-up completed May 2011 Year/month Protocol amendment for PE and sample size

14 Sample size and power calculations (original and amended) Original sample size based on the PE rates at 6 months in pts >75y in the retrospective analysis of the TACTICS-TIMI 18 trial (death + MI + rehospitalization 30% in the conservative arm vs 20% in the invasive arm). Two-tailed alpha Power 1 b N per group N total 502 Amended sample size with PE rates at 12 months extrapolated from original: 40% in the conservative arm: we aimed at detecting a PE reduction to 25%. Two-tailed alpha Power 1 b N per group N total 312

15 Average enrolment / center / month Years patients / 23 centres / 29 months = patients / centre / month Years Lancet 2002 TIME study pts with Symptomatic Stable CAD 302 patients / 14 centres / 59 months = patients / centre / month Years NEJM patients / 196 centres / 24 months = patients / centre / month

16 Inclusion criteria & signed consent N= 645 Randomised N= 313 Excluded (n=322) Secondary causes of ischemia (n=20) Ongoing ischemia despite treatment (n=47) Ongoing HF despite treatment (n=18) PCI or CABG <30 days (n=5) Serum creatinine >2.5 mg/dl (n=32) Active or recent bleeding (n=26) Known platelet count <90,000 cells/ml (n=11) Cerebrovascular accident <1 month (n=4) Ongoing OAT or INR >1.5 (n=17) Severe COPD, neurologic deficit or malignancy (n=38) Participation in other trials (n=7) Inability to perform angio within 48 hours (n=27) Other or mixed reasons (n=80) Early aggressive (n=154) Angiography during index admission (n=136) No angiography during index admission (n=18) Initially conservative (n=159) No angiography during index admission (n=113) Angiography during index admission (n=46) Recurrent ischemia (n=37) Heart failure (n=6) Reinfarction (n=1) Ventricular tachycardia (n=2) Withdrawn consent (n=1) Lost to follow-up (n=2) Withdrawn consent (n=1) Lost to follow-up (n=2) Analysed (n=154) Analysed (n=159)

17 Baseline characteristics (1) Early aggressive (n=154) Initially conservative (n=159) Age (yrs) Female (%) Hypertension (%) Diabetes (%) Prior stroke (%) egfr (ml/min/1.73 sqm) >moderate mitral valve insuff (%) Prior MI (%) Prior HF (%) 10 9

18 Baseline characteristics (2) Early aggressive (n=154) Initially conservative (n=159) Prior CABG (%) Prior PCI (%) Chronic angina (%) Mean Ejection fraction (%) Mean TRS Sinus rhythm (%) A fibrillation (%) Ischemic ECG (%) Elevated Tn (%) 62 60

19 Cardiac procedures during index admission and at follow-up Early Aggressive (n=154) Initially Conservative (n=159) Index admission Within one year Index admission Within one year Angio (%) PCI (%) CABG (%) Any revasc (%)

20 Coronary angiography performed Revascularization procedures during index admission Early Aggressive (n=154) Initially Conservative (n=159) 136 (88) 46 (29) Time from random (hrs) 24 (IQR 15-46) 67 (IQR ) PCI immediate PCI delayed 65 (48) 13 (9.6) 32 (71) 4 (8.9) Radial access 55 (70) 28 (78) Coronary stenting BMS/DES (%) 73 (96) 46/54 34 (97) 44/56 Procedural success 74 (97) 35 (100) CABG 9 (5.8) 1 (0.6) Surgical success 9 (100) 1 (100)

21 Antithrombotic treatments during index admission Early Aggressive (n=154) Initially Conservative (n=159) Aspirin Ticlopidine Clopidogrel Unfractionated heparin Enoxaparin GPIIb/IIIa inhibitor 17 6 Bivalirudin Fondaparinux

22 Adverse clinical events during index hospitalization Early Aggressive (n=154) Initially Conservative (n=159) p Death N (%) 8 (5.2) 5 (3.1) Myocardial (re)infarction 3 (1.9) 5 (3.1) Severe recurrent ischemia 1 (0.6) 15 (9.4) Heart failure 11 (7.1) 4 (2.5) Cardiac arrhythmia 3 (1.9) 3 (1.9) Any stroke / Disabling stroke 2 / 0 1 / 0 TIMI major bleeding 0 1 (0.6) CABG-related bleeding/transfusion N 4 (2.6) 0 Infection/sepsis 2 (1.3) 1 (0.6)

23 Cumulative rate of the primary endpoint and its components Outcome Early Aggressive Initially Conservative HR (95% CI) Logrank P (n=154) (n=159) Primary EP 43 (27.9) 55 (34.6) 0.80 ( ) 0.26 Death CV non CV Myocardial Infarction 19 (12.3) 16 (10.4) 3 (2.0) 22 (13.8) 18 (11.3) 4 (2.5) 0.87 ( ) (7.1) 17 (10.7) 0.67 ( ) 0.27 Rehosp for CV causes of severe bleeding 18 (11.7) 22 (13.8) 0.81 ( ) 0.49

24 Primary endpoint KM survival to primary endpoint and its components Early aggressive Initially conserv All cause death HR 0.80; 95% CI Logrank P= 0.26 HR 0.87; 95% CI Logrank P= 0.65 Myocardial Infarction Rehosp CV causes or severe bleeding HR 0.67; 95% CI Logrank P= 0.27 HR 0.81; 95% CI Logrank P= 0.49

25 Primary endpoint rate in subgroups Baseline Characteristics N HR (95% CI) Cumulative event rate Nominal (%) P value Early initially aggressive conservative Overall ( ) Age <median (81.6y) ( ) > median ( ) Sex women ( ) men ( ) Diabetes no ( ) yes ( ) Ischemic ECG no ( ) yes ( ) Baseline troponin levels within normal limit ( ) above normal limit ( ) Early aggressive better 2 Initially conservative better

26 Effect of treatment strategy according to troponin status at trial entry HR 1.67; 95% CI Logrank P=0.24 Normal troponin (N=113) EA IC Primary Endpoint Mortality Myocardial Infarction Rehospitalization For CV causes HR 0.43; 95% CI Logrank P=0.015 Elevated troponin (N=190) Primary Endpoint Mortality Myocardial Infarction Rehospitalization For CV causes

27 Kaplan Meier survival without primary endpoint according to troponin status at trial entry Elevated troponin (N= 190) Normal troponin (N= 113) Early aggressive Initially conserv HR 0.43; 95% CI Logrank P=0.015 HR 1.67; 95% CI Logrank P=0.24

28

29 Conclusions (with the caveat of subgroup analysis of a trial which did not meet its primary endpoint) In elderly patients with NSTE and no emergency indication for coronary angiography, a systematic early aggressive approach confers significant benefits only in those with elevated troponin levels on admission. An early aggressive strategy with extensive use of the radial approach and a moderate use of i.v. antithrombotic agents is extremely safe in patients who don t have severe renal dysfunction or recent bleeding.