STATINS EVALUATION IN CORONARY PROCEDURES AND REVASCULARIZATION

Transcription

1 STATINS EVALUATION IN CORONARY PROCEDURES AND REVASCULARIZATION Otávio Berwanger, MD, FACS - On behalf of the SECURE Steering Committee and Investigators

2 Trial Organization Trial Steering Committee Dr. Otávio Berwanger (Co-Chair) Dr Renato Delascio Lopes (Co-Chair) Dr Luiz Alberto Mattos Dr. Alexandre Biasi Cavalcanti Dr. Pedro G. M. de Barros e Silva Dr. Hélio Penna Guimarães Dr. Amanda Sousa Dr. José Eduardo Sousa Dr. Roberto Giraldez Dr. Christopher B. Granger Dr. John H. Alexander Study Coordinating Offices Research Institute Heart Hospital (HCor) Brazilian Clinical Research Institute (BCRI)

3 BACKGROUND IMPORTANCE The effect of loading dose of statins in patients with acute coronary syndrome (ACS) is uncertain since the evidence is limited to studies with low numbers of events, and different statin doses and regimens. OBJECTIVE To determine if periprocedural loading doses of atorvastatin decreases 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management.

4 SECURE PCI TRIAL Design: pragmatic, multicenter, double-blind, placebo controlled, randomized clinical trial Prevention of Bias: Concealed allocation (central web-based randomization) and Intention-to-treat analysis Blinding of patients, physicians and adjudicator assessors Quality control: on-site monitoring + central statistical checking + e-crf + central adjudication of outcomes Sample Size: 4,192 patients from 58 hospitals in Brazil, considering incidence of MACE = 12.3%, 25% relative risk reduction (RRR), with 90% statistical power, and two-tailed alpha of 5%

5 ELIGIBILITY Inclusion criteria Both genders, Aged 18 years Acute Coronary Syndrome intended to be treated with PCI (including those with ST segment elevation MI treated with primary angioplasty) Exclusion criteria Pregnant and breastfeeding women or women aged <45 not using effective contraceptive methods; Previous inclusion in the study; Refusal to sign the informed consent form (ICF); Concurrent participation in other RCTs with hypolipemiant agents; Drug hypersensitivity; History of advanced liver disease; Use of any statin at a maximum dose in the last 24 hours before PCI; Use of any fibrate in the last 24 hours before the loading dose of the study.

6 FLOWCHART Patients with age 18 years and with Acute Coronary Syndrome intended to be treated with PCI 80mg pre-procedure, followed by 80mg 24 hours after PCI RANDOMIZATION Conventional management pre-procedure, followed by placebo 24 hours after PCI 40mg/day for 30 days 40mg/day for 30 days Primary outcome: MACE at 30 days (all-cause mortality, nonfatal acute myocardial infarction, stroke or recurrent ischemia leading to urgent revascularization)

7 OUTCOMES Primary Outcome Major adverse cardiac events (MACE) at 30 days defined as a composite of all-cause mortality, nonfatal acute myocardial infarction, non-fatal stroke, and unplanned coronary revascularization Secondary Outcomes Individual components of primary outcome over 30 days Cardiovascular mortality at 30 days Stent thrombosis at 30 days Target vessel revascularization at 30 days Coronary revascularization * All outcomes were adjudicated by standardized criteria

8 BASELINE Characteristic (n=2087) (n=2104) Age, mean (SD), years 61.7 (11.3) 61.9 (11.7) Male sex, No.(%) 1581 (75.8) 1525 (72.5) Initial Diagnosis, No.(%) STEMI 495 (24.4) 517 (25.2) NSTEMI 1241 (61.1) 1236 (60.3) Unstable angina 295 (14.5) 296 (14.4) Previous use of chronic statin therapy (6 months before randomization), No.(%) 608 (29.2) 600 (28.5) Medical history, No.(%) Hypertension 1475 (70.7) 1499/(71.3) Hypercholesterolemia 755 (36.2) 764 (36.3) Diabetes mellitus 653 (31.3) 673 (32.0) Tobacco use 564 (27.1) 618 (29.4) Previous MI 342 (16.4) 320 (15.2) Previous Stroke 74 (3.5) 76 (3.6) Renal Impairment 60 (2.9) 73 (3.5) Obesity 324 (15.5) 339 (16.1)

9 Characteristic BASELINE (n=2087) (n=2104) Initial Treatment strategy, No.(%) PCI 1351 (64.8) 1359 (64.7) CABG 162 (7.8) 171 (8.1) Medical Management 572 (27.4) 572 (27.2) Reason why PCI was not performed, No.(%) Clinical treatment 450 (61.3) 472 (63.5) CABG 162 (22.1) 171 (23.0) Not a final diagnosis of ACS 109 (14.9) 88 (11.8) Unknown 13 (1.8) 12 (1.6) Other medical therapy, No.(%) Aspirin 1880 (90.2) 1883 (89.6) Clopidogrel/Ticagrelor/Prasugrel 1775 (85.1) 1766 (84.0) Beta-blockers 1606 (77.0) 1599 (76.1) ACE inhibitors or ARA 1484 (71.2) 1444 (68.7) Time from hospital admission to PCI (hours) Mean (SD) 47.8 (66.6) 45.3 (63.8) Median (Interquartile range) 20 (3 72) 19 (3 64) Time from randomization to PCI (hours) Mean (SD) 7.2 (88.8) 9.1 (59.2) Median (Interquartile range) 3 (1 6) 3 (1 6)

10 STUDY-DRUG ADMINISTRATION Characteristic (n=2087) (n=2104) First loading dose, No. (%) 2039 (97.8) 2054 (97.7) Second loading dose, No. (%) 1594 (76.5) 1622 (77.2) 40mg at 30-days, mean (SD) (34.1) 87 (32.1) Time of study-drug administration in patients that underwent PCI, No.(%) (n=1349) (n=1357) More than 12h before PCI 50 (3.7) 76 (5.6) 2h to 12h before PCI 699 (51.7) 685 (50.5) Until 2h before PCI 577 (42.8) 569 (41.9) Until 2h after PCI 8 (0.6) 4 (0.3) 2h to 4h after PCI 1 (0.1) 1 (0.1)

11 STUDY-DRUG ADMINISTRATION Characteristic Time from randomization to study drug (hours) (n=2087) (n=2104) Mean (SD) 6.1 (31.2) 5.2 (24.3) Median (Interquartile range) 0.1 (0-0.5) 0.2 (0-0.6) In patients that underwent PCI (n=1349) (n=1357) First loading dose, No. (%) 1337 (99) 1337 (98.4) Second loading dose, No. (%) 1292 (95.6) 1297 (95.4) 40mg at 30-days, mean (SD) (20.2) 94.8 (19.7) Time of study-drug administration in patients that underwent PCI, No.(%) (n=1349) (n=1357) More than 12h before PCI 50 (3.7) 76 (5.6) 2h to 12h before PCI 699 (51.7) 685 (50.5) Until 2h before PCI 577 (42.8) 569 (41.9) Until 2h after PCI 8 (0.6) 4 (0.3) 2h to 4h after PCI 1 (0.1) 1 (0.1)

12 Cumulative MACE incidence (%) CUMULATIVE INCIDENCE OF PRIMARY OUTCOME (ALL PATIENTS) Hazard ratio 0.88 (95% CI, ); p=.27 No. at risk Time (days) Event rates of the combined primary outcome (all-cause mortality, acute myocardial infarction, stroke, and unplanned coronary revascularization) occurrence in all patients.

13 OUTCOMES AT 30 DAYS ALL PATIENTS Outcomes (n=2087) (n=2104) Hazard ratio (95% CI) P value Death, No.(%) 67 (3.2) 70 (3.3) 0.97 (0.69 to 1.35) 0.84 Cardiovascular Death 59 (2.8) 61 (2.9) 0.98 (0.68 to 1.40) 0.90 Myocardial Infarction, No.(%) 61 (2.9) 77 (3.7) 0.80 (0.57 to 1.11) 0.18 Peri-PCI MI 42 (2.0) 54 (2.6) 0.78 (0.52 to 1.17) 0.23 Non-PCI related MI 20 (1.0) 26 (1.2) 0.77 (0.43 to 1.39) 0.39 Coronary Revascularization, No.(%) 11 (0.5) 14 (0.7) 0.79 (0.36 to 1.75) 0.57 Urgent/Target Vessel 5 (0.2) 9 (0.4) 0.56 (0.19 to 1.67) 0.30 Stroke, No.(%) 10 (0.5) 11 (0.5) 0.92 (0.39 to 2.16) 0.85 Stent Thrombosis, No.(%) 7 (0.3) 15 (0.7) 0.47 (0.19 to 1.15) 0.10

14 Cumulative MACE incidence (%) CUMULATIVE INCIDENCE OF PRIMARY OUTCOME (PCI PATIENTS) , PCI, PCI Hazard ratio 0.72 (95% CI, ); p=.02 No. at risk Time (days) The primary outcome occurrence in patients undergoing percutaneous coronary intervention (PCI) group and in patients who did not undergo percuateneous coronary intervention.

15 OUTCOMES AT 30 DAYS PCI PATIENTS Outcomes (n=1351) (n=1359) Hazard ratio (95% CI) P value MACE, No.(%) 81 (6.0) 112 (8.2) 0.72 (0.54 to 0.96) 0.02 Death, No.(%) 31 (2.3) 43 (3.2) 0.72 (0.46 to 1.15) 0.17 Cardiovascular Death 28 (2.1) 37 (2.7) 0.76 (0.46 to 1.24) 0.27 Myocardial Infarction, No.(%) 48 (3.6) 70 (5.2) 0.68 (0.47 to 0.99) 0.04 Peri-PCI MI 41 (3) 54 (4) 0.76 (0.51 to 1.14) 0.18 Non-PCI related MI 8 (0.6) 19 (1.4) 0.42 (0.18 to 0.96) 0.04 Coronary Revascularization, No.(%) 8 (0.6) 12 (0.9) 0.67 (0.27 to 1.63) 0.38 Urgent/Target Vessel 3 (0.2) 7 (0.5) 0.43 (0.11 to 1.66) 0.22 Stroke, No.(%) 4 (0.3) 8 (0.6) 0.50 (0.15 to 1.66) 0.26 Stent Thrombosis, No.(%) 7 (0.5) 15 (1.1) 0.47 (0.19 to 1.14) 0.10

16 Cumulative MACE incidence (%) CUMULATIVE INCIDENCE OF PRIMARY OUTCOME (PCI AND NON-PCI PATIENTS), Non-PCI, Non-PCI, PCI, PCI PCI: Hazard ratio 0.72 (95% CI, ); p=.02 Non-PCI: Hazard ratio 1.36 (95% CI, ); p=.15 No. at risk, Non-PCI Non-PCI, PCI, PCI Time (days) The primary outcome occurrence in patients undergoing percutaneous coronary intervention (PCI) group and in patients who did not undergo percutaneous coronary intervention.

17 SUBGROUP ANALYSIS OF THE PRIMARY OUTCOME (n=2087) (n=2104) Hazard Ratio (95% CI) Favors Favors P Value for interaction Sex Male 95/1581 (6%) 104/1525 (6.8%) 0.88 ( ) 0.96 Female 35/506 (6.9%) 45/579 (7.8%) 0.89 ( ) Age (years) 65 62/1320 (4.7%) 77/1314 (5.9%) 0.80 ( ) 0.41 > 65 68/767 (8.9%) 72/790 (9.1%) 0.97 ( ) Type of ACS PCI STEMI 42/495 (8.5%) 65/517 (12.6%) 0.66 ( ) 0.21 NSTEMI 73/1241 (5.9%) 69/1236 (5.6%) 1.05 ( ) UA 10/295 (3.4%) 12/296 (4.1%) 0.83 ( ) No 49/734 (6.7%) 37/743 (5%) 1.36 ( ) 0.02 Yes 81/1351 (6%) 112/1359 (8.2%) 0.72 ( ) Previous use of statin No 98/1477 (6.6%) 109/1502 (7.3%) 0.91 ( ) 0.58 Yes 32/608 (5.3%) 40/600 (6.7%) 0.78 ( ) Type of stents (patients who underwent PCI) At least one Drugeluting stent 56/1013 (5.5%) 82/1020 (8%) 0.68 ( ) 0.18 Bare metal only 21/298 (7%) 26/312 (8.3%) 0.83 ( )

18 CONCLUSION Among patients with ACS and planned invasive management, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. However, among patients undergoing PCI, loading doses of atorvastatin seems to improve clinical periprocedural outcomes and might be an attractive treatment strategy for patients with acute coronary syndromes.

19 O Berwanger and coauthors Effect of Loading Dose of Prior to Planned Percutaneous Coronary Intervention on Major Adverse Cardiovascular Events in Acute Coronary Syndrome: The SECURE-PCI Randomized Clinical Trial Published online March 11, 2018 Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com jamanetwork.com