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PLATO: Study Population Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605.

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Presentation on theme: "PLATO: Study Population Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605."— Presentation transcript:

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2 PLATO: Study Population Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605.

3 180-mg loading dose BRILIQUE (n=9,333) *STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI. † A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. ‡ The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event. 90 mg bid + ASA maintenance dose 300-mg loading dose † 75 mg qd + ASA maintenance dose Clopidogrel (n=9,291) Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Primary safety endpoint: Total PLATO major bleeding ‡ N=18,624 Patients with ACS (UA, NSTEMI, or STEMI*) <24hMonth 1Month 3Month 6Month 9Month 12Screening Visit 2Visit 3Visit 4Visit 5Visit 6 Initial Treatment approaches Medically managed (n=5,216 — 28.0%) Invasively managed (n=13,408 — 72.0%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. James S, et al. Am Heart J. 2009;157:599–605. Randomisation All patients were hospitalised with symptom onset <24 hours Patients could be taking clopidogrel at time of randomisation PLATO: Study Design

4 PLATO Main: Inclusion Criteria Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours With STEMI, the following 2 inclusion criteria were required –Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB –Primary PCI planned With NSTEMI, at least 2 of the following 3 were required –ST changes on ECG indicating ischaemia –Positive biomarker indicating myocardial necrosis –One of the following risk indicators ≥60 years of age Previous MI or CABG CAD with ≥50% stenosis in ≥2 vessels Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral revascularisation Diabetes mellitus Peripheral artery disease Chronic renal dysfunction (creatinine clearance <60 mL/min) James S, et al. Am Heart J. 2009;157:599–605.

5 PLATO Main: Key Exclusion Criteria Contraindication to clopidogrel Fibrinolytic therapy within 24 hours Oral anticoagulation therapy that cannot be stopped ACS event was a complication of previous PCI PCI after index event (initial clinical signs and symptoms) and before first study dose Increased risk for bradycardic events Concomitant therapy with strong CYP3A inhibitors/inducers Patients requiring dialysis James S, et al. Am Heart J. 2009;157:599–605.

6 PLATO Study Summary PLATO (N Engl J Med. 2009;361:1045–1057) was a pivotal clinical study, comparing BRILIQUE to clopidogrel A total of 18,624 patients with ACS were randomised early after admission to the hospital─within 24 hours of symptom onset and generally prior to angiography The study was designed to reflect clinical practice –Allowed prior clopidogrel use –Included both intent for invasive management (72%) and intent for medical management (28%) –PLATO allowed up to 600-mg clopidogrel loading dose pre-PCI PLATO enrolled a broad spectrum of patients with ACS (UA, NSTEMI, or STEMI) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. James S, et al. Am Heart J. 2009;157:599–605. Cannon CP, et al. Lancet. 2010;375:283–293.

7 Efficacy Results

8 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Both groups included aspirin. *NNT at one year. PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) No. at risk Clopidogrel BRILIQUE 9,291 9,333 Months After Randomization 8,521 8,628 8,362 8,460 8,1246,650 6,743 5,096 5,161 4,047 4,1478, Cumulative Incidence (%) 11.7 Clopidogrel 9.8 BRILIQUE ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) 0–30 Days Clopidogrel BRILIQUE ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 0–12 Months

9 PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All Patients* BRILIQUE (n=9,333) Clopidogrel (n=9,291) HR for BRILIQUE (95% CI) P Value ** Primary endpoint, n (%/year) Death from vascular cause + MI † + stroke 864 (9.8)1,014 (11.7)0.84 (0.77–0.92)<0.001 Secondary endpoints, n (%/yr) Death from any cause + MI † + stroke 901 (10.2)1,065 (12.3)0.84 (0.77–0.92)<0.001 Death from vascular causes + MI † + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus 1,290 (14.6)1,456 (16.7)0.88 (0.81–0.95)<0.001 MI † 504 (5.8)593 (6.9)0.84 (0.75–0.95)0.005 Death from vascular causes 353 (4.0)442 (5.1)0.79 (0.69–0.91)0.001 Stroke 125 (1.5)106 (1.3)1.17 (0.91–1.52)0.22 Death from any cause 399 (4.5)506 (5.9)0.78 (0.69–0.89) <0.001 ‡ Nominal Significance Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. * Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; † Excluding silent MI; ‡ Death from any cause was tested after stroke, which was non-significant, so the results should be considered nominally significant.

10 Months After Randomisation Cumulative Incidence (%) Clopidogrel BRILIQUE Clopidogrel BRILIQUE Months After Randomisation Myocardial Infarction Cardiovascular Death Cumulative Incidence (%) PLATO: Secondary Efficacy Endpoints Rate of stroke for BRILIQUE was not different from clopidogrel (1.3% vs 1.1% ), P= Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement. BRILIQUE: Summary of Product Characteristics, ARR=1.1% RRR=16% Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, 0.75–0.95) ARR=1.1% RRR=21% NNT=91 P=0.001 HR: 0.79 (95% CI, 0.69–0.91) Both groups included aspirin.

11 PLATO Efficacy Results Summary In PLATO, BRILIQUE significantly reduced the composite of CV death, MI or stroke vs clopidogrel at 1 year (1.9% ARR, 16% RRR, P<0.001, NNT=54) BRILIQUE significantly reduced CV mortality vs clopidogrel (1.1% ARR, 21% RRR, P=0.001) –Risk of CV death and MI were both significantly reduced –Risk of stroke was not significantly different The absolute risk reduction with BRILIQUE vs clopidogrel starts early and continues to build over the full 1 year treatment period In PLATO, for every 91 ACS patients treated with BRILIQUE for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91) The effect of BRILIQUE over clopidogrel appears consistent across many subgroups Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

12 Safety Results

13 P=0.43 HR: 1.04 (95% CI, 0.95–1.13) PLATO: Primary Safety Endpoint PLATO-defined Total Major Bleeding (%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Days From First Dose Clopidogrel BRILIQUE 11.2% 11.6% P=NS No. at risk Clopidogrel BRILIQUE 9,186 9,235 7,305 7,246 6,930 6,826 6,6705,209 5,129 3,841 3,783 3,479 3,4336,545 Both groups included aspirin.

14 PLATO: Bleeding Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All values presented by PLATO criteria. Both groups included aspirin. Major Bleeding Non-CABG- Major Bleeding Major and Minor Bleeding Life-threatening/ Fatal Bleeding Fatal Bleeding CABG-Major Bleeding K-M Estimated Rate (% Per Year) NS P = 0.03 P = NS

15 PLATO: Dyspnoea BRILIQUE-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy Most events were reported as single episode occurring early after starting treatment Not associated with new or worsening heart or lung disease In 2.2% of patients, investigators considered dyspnoea causally related to treatment with BRILIQUE Label precautions and warnings: use with caution in patients with history of asthma and COPD BRILIQUE: Summary of Product Characteristics, Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007. Dyspnoea in the PLATO trialBRILIQUEClopidogrelP Value Incidence of dyspnoea adverse events (%) <0.001 Patients who discontinued treatment due to dyspnoea (%) <0.001

16 PLATO: Bradycardia-related Events All Patients BRILIQUE (n=9,235) Clopidogrel (n=9,186)P Value Bradycardia-related event, n (%) Pacemaker insertion 82 (0.9)79 (0.9)0.87 Syncope 100 (1.1)76 (0.8)0.08 Bradycardia 409 (4.4)372 (4.0)0.21 Heart Block 67 (0.7)66 (0.7)1.00 Ventricular pauses ≥3 seconds occurred in 5.8% of BRILIQUE-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block) Label precautions and warnings: BRILIQUE should be used with caution in patients at risk of bradycardic events Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, 2010.

17 PLATO: Laboratory Parameters All Patients BRILIQUE (n=9,235) Clopidogrel (n=9,186)P Value Mean % increase (± SD) in serum creatinine from baseline At 1 month10 ± 228 ± 21<0.001 At 12 months11 ± 229 ± 22< month after end of treatment10 ± Mean % increase (± SD) in serum uric acid from baseline At 1 month14 ± 467 ± 44<0.001 At 12 months15 ± 527 ± 31< month after end of treatment7 ± 438 ± Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, Creatinine levels may increase during treatment with BRILIQUE; renal function should be checked after 1 month and thereafter according to medical practice Label precautions and warnings: as a precautionary measure, the use of BRILIQUE in patients with uric acid nephropathy is discouraged

18 PLATO Safety Results Summary No increase in overall major bleeding with BRILIQUE vs clopidogrel Non-CABG major bleeding and major + minor bleeding were more frequent with BRILIQUE vs clopidogrel No increase in overall fatal/life-threatening bleeding with BRILIQUE vs clopidogrel There are more dyspnoea-related events associated with BRILIQUE vs clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment BRILIQUE should be used with caution in patients at risk of bradycardic events Creatinine levels may increase during treatment with BRILIQUE; renal function should be checked after 1 month and thereafter according to routine medical practice Please reference the label for all precautions and warnings Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, 2010.

19 Appropriate Use of BRILIQUE

20 BRILIQUE Indication BRILIQUE, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (unstable angina, non–ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) BRILIQUE: Summary of Product Characteristics, By DiagnosisBy Treatment UA/NSTEMISTEMIMedical management PCICABG   If clinically indicated, BRILIQUE should be used with caution in the following patient groups: Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of BRILIQUE dosing

21 Contraindications Contraindications specific to BRILIQUE –Hypersensitivity to the active substance (BRILIQUE) or to any of the excipients –Active pathological bleeding –History of intracranial haemorrhage –Moderate-to-severe hepatic impairment –Combination with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir is contraindicated, as co-administration may lead to substantial increases in exposure to BRILIQUE BRILIQUE: Summary of Product Characteristics, 2010.

22 Special Warnings and Precautions Precautions specific to BRILIQUE –The use of BRILIQUE in patients at known increased risk for bleeding should be balanced against the benefits –BRILIQUE should be discontinued 7 days prior to elective surgery –BRILIQUE should be used with caution in patients with a history of asthma and/or COPD –BRILIQUE should be used with caution in patients at risk of bradycardic events –BRILIQUE should be used with caution in the following patient groups: patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of BRILIQUE dosing –As a precautionary measure, the use of BRILIQUE in patients with uric acid nephropathy is discouraged –Creatinine levels may increase during treatment with BRILIQUE –Renal function should be checked after 1 month and thereafter according to routine medical practice –High maintenance dose of ASA (>300 mg) is not recommended –The concomitant use of BRILIQUE with doses of simvastatin >40 mg is not recommended BRILIQUE: Summary of Product Characteristics, 2010.

23 Dosing and Administration BRILIQUE treatment should be initiated with a single 180-mg loading dose (two 90-mg tablets) and then continued at 90 mg twice daily with concomitant low dose ASA Treatment with BRILIQUE is recommended for up to 12 months unless discontinuation is clinically indicated BRILIQUE can be administered with or without food Initial treatment: 180 mg Morning – Take one LOADING Continue treatment: 90 mg twice daily + Aspirin: 75–150 mg once daily MAINTENANCE Two 90-mg tablets Initiate BRILIQUE with a loading dose of aspirin. BRILIQUE tablet in the morning (AM) Night – Take one BRILIQUE tablet in the evening (PM) Take aspirin (either in the morning or night) BRILIQUE: Summary of Product Characteristics, 2010.

24 Clinical Summary of BRILIQUE Based on PLATO BRILIQUE significantly reduces the combined risk of CV death, MI, or stroke vs clopidogrel in patients with ACS BRILIQUE significantly reduces CV mortality vs clopidogrel The absolute risk reduction with BRILIQUE vs clopidogrel starts early and continues to build over the full 1 year of treatment BRILIQUE is effective in a broad spectrum of ACS patients There is no increase of overall major bleeding with BRILIQUE vs clopidogrel –No increase in life-threatening/fatal bleeding with BRILIQUE vs clopidogrel –Major and minor bleeding was more common with BRILIQUE vs clopidogrel –Non-CABG-Major bleeding was more common with BRILIQUE vs clopidogrel There are more dyspnoea-related events associated with BRILIQUE vs clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment BRILIQUE: Summary of Product Characteristics, 2010.


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