La bivalirudina ed il suo annus horribilis: un update scientifico Bernardo Cortese Intv’ Cardiology, A.O. Fatebenefratelli

HORIZONS AMI 30 Day and 1-Year All-Cause Mortality Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Mortality (%) Time in Months Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% 3.4% HR [95%CI] = 0.69 [0.50, 0.97] P= % 2.1% Δ = 1.0% Δ = 1.4% Stone GW et al. NEJM 2008;358: Mehran R et al. Lancet 2009;374: HR [95%CI] = 0.66 [0.44, 1.00] P=0.048

cardiac mortality 30 days to 3 years* Stone GW NEJM. 2008;358: Mehran R Lancet. 2009;374: Stone GW Lancet. 2011;377: ' Bivalirudin (n=1,800)Heparin + GP IIb/IIIa (n=1,802) 30-d † HR [95% CI]= 0.62; [0.40,0.96] P = % 2.9% * 3-year all cause mortality was also lower with bivalirudin (5·9% vs 7·7%), HR 0·75 [0·58–0·97]; p=0·03 † These time points were prespecified analyses. NNT=number needed to treat 1-yr † HR [95%CI]= 0.57 [0.38, 0.84] P = yr † HR [95%CI]= 0.56 [0.40, 0.80] P = NNT=45

Bivalirudin [0.65, 1.23] Three-Year Stent Thrombosis (ARC Definite/Probable) p=0.49 HR [95%CI]= 4.5% 4.5% 5.1% 5.1% Stent Thrombosis (%) Months 369 Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) Number at risk Heparin+GPIIb/IIIa [0.79, 1.71] p=0.45 HR [95%CI]= % 3.0%

HEAT PPCI: Design and enrollment 29 (1.5%) already randomized in the trial 59 (3.0%) met one or more other exclusion criteria Exclusion Criteria Exclusion Criteria Active bleeding at presentationActive bleeding at presentation Factors precluding oral DAPTFactors precluding oral DAPT Intolerance or contraindication to trial medicationsIntolerance or contraindication to trial medications Previous enrolment in this trialPrevious enrolment in this trial 1917 STEMI pts scheduled for emergency angiography at a single center between Feb 2012–Nov 2013* Heparin 70 IU/Kg (n=914) Bivalirudin (n=915) 17 (1%) refused post procedure consent and were withdrawn Heparin* (n=907) Assigned to Bivalirudin (n=905) 1829 eligible for recruitment were randomized 1:1 Shahzad A et al. Lancet 2014

HEAT PPCI: MACE Outcomes Bivalirudin (n=905) Heparin (n=907) Any MACE Any MACE 79 (8.7%) 52 (5.7%) - Death - Death 46 (5.1%) 39 (4.3%) - CVA - CVA 15 (1.6%) 11 (1.2%) - Reinfarction - Reinfarction 24 (2.7%) 8 (0.9%) - TLR - TLR 24 (2.7%) 6 (0.7%) -Acute ST 20 (2.9%) 6 (0.9%) Shahzad A et al. Lancet pts

HEAT PPCI: Safety Outcomes Bivalirudin (n=905) Heparin (n=907) P BARC (12.7%)126 (13.9%) BARC (3.5%)28 (3.1%) BARC 283 (9.2%)98 (10.8%) 0.25 Thrombocytopenia (moderate/severe) 6 (0.8%) 0.99 Shahzad A et al. Lancet 2014

HEAT PPCI: ACT* and GPI bailout Bivalirudin arm (n=915) NMeasure ACT 5-15 mins after bolus806 (88%)251 [229, 285] sec ACT end-procedure771 (84%)246 [229, 270] sec Bivalirudin rebolus anytime** 12.7% GPI bailout13.5% **By protocol, rebolus for ACT <225 seconds ~25% <229 seconds; rebolus rate should have been ~25% Shahzad A et al. Lancet 2014

Bivalirudin alone N=735 Biv 0.75 mg/kg bolus mg /kg/h (0.3 mg/kg bolus if ACT< 225s). Biv infusion (0.2 mg/kg/h) continued for at least 30 min post PCI (mean 4h). Biv infusion (0.2 mg/kg/h) continued for at least 30 min post PCI (mean 4h). 4.4% bailout tirofiban. UFH alone N=729 Heparin 100 U/kg bolus + additional dose if ACT <200 s. ACT goal = % bailout tirofiban. UFH + Tirofiban N=730 Heparin 60U/kg bolus. Tirofiban 10μg/kg bolus μg/kg/min infusion for h. ACT goal = BRIGHT: Study flow Follow-up at 30 days, 6 months and 1 year Randomization (1:1:1) Primary endpoint: NACE, including MACCE (all-cause death, reMI, TVR or stroke) and bleeding events at 30 days. Han Y. TCT % STEMI 13.8% NSTEMI 79% radial Aspirin and clopidogrel 2,194 pts with AMI randomized at 82 centers in China

BRIGHT: events at 30 Days P<0.001 P=0.74 Biv vs. Hep, p=0.009 RR (95%CI) 0.67 ( ), NNT=23.1 Biv vs. Hep+Tiro, p<0.001 RR (95%CI) 0.52 ( ), NNT=12.3 Hep vs. Hep+Tiro, p=0.04 RR (95%CI) 0.78 ( ), NNT=26.2 (%) Primary endpoint NACE MACCEAny Bleeding Bivalirudin (n=735) Heparin (n=729) Heparin + Tirofiban (n=730) Han Y. TCT 2014

BRIGHT: 30-day ST STEMI Only P=0.59 P=0.49 P=1.00 P=0.81 P=0.71 (%) Bivalirudin (N=629) Heparin (N=620) Heparin+Tirofiban (N=609) Definite Probable 0.2 Acute Subacute Def/prob Han Y. TCT 2014

StudyNComparatorSetting Ischemic Events Bleeding REPLACE-26002UFH + GPIElective PCI-  ISAR REACT 34570UFH (140 u/kg)Elective PCI-  ACUITY13800UFH/LMWH + GPINSTEACS-  ISAR REACT 41721UFH + GPINSTEACS-  BRIGHT2100UFH or UFH + GPISTEMI & NSTEMI-  HORIZONS3602UFH + GPISTEMI (-) MACE  Death  Stent thromb  EUROMAX2218UFH ± GPISTEMI (-) MACE  Stent thromb  HEAT PPCI1829UFHSTEMI  MACE- “Contemporary” Bivalirudin Trials courtesy of A Kirtane, 2014

Question n° 1: Bleedings the deck was stacked against heparin! (routine GPI use explains bleeding advantage) vascular Closure Devices could mitigate the bleeding advantage of bivalirudin! transradial access could mitigate the bleeding advantage of bivalirudin!

16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI: Bivalirudin vs UFH Monotherapy Meta-analysis Major Bleeding Bertrand OF et al. Am J Cardiol 2012;110:599–606 Study or subgroupEvents Odds Ratio M-H, Random, 95% CI Total Bivalirudin Events Heparin 0.01 Favors Bivalirudin Favors Heparin Total Events Test for heterogeneity: Tau 2 =0.08, Chi 2 =21.99, df=13 (P=0.06),I 2 =41% Test for overall effect: Z=4.38 (P<0.0001) Test for subgroup differences: Chi 2 =0.47, df=1 (P=0.49),I 2 =0% Total (95% CI) Observational Randomized Kastrati 2008 Parodi 2010 Patti 2011 Subtotal (95% CI) 0.55 [0.43, 0.72] Total Events Test for heterogeneity: Tau 2 =0.00, Chi 2 =0.37, df=2 (P=0.83),I 2 =0% Test for overall effect: Z=2.60 (P=0.009) [0.25, 0.99] 0.31 [0.08, 1.19] 0.51 [0.05, 5.67] 0.45 [0.25, 0.82] Total Events Test for heterogeneity: Tau 2 =0.11, Chi 2 =20.84, df=10 (P=0.02),I 2 =52% Test for overall effect: Z=3.55 (P=0.0004) [0.18, 1.47] 0.55 [0.05, 6.12] 0.30 [0.07, 1.31] 0.97 [0.49, 1.90] 0.52 [0.21, 3.17] 0.32 [0.21, 0.49] 1.21 [0.23, 6.33] 0.39 [0.16, 0.95] 0.87 [0.65, 1.16] 0.82 [0.39, 1.74] 0.47 [0.32, 0.70] 0.57 [0.42, 0.78] Wolfram 2003 Rha 2005 Chu 2006 Bonello 2009 Lemesle 2009 Lemesle 2009-b Delhaye 2010 Lindsey 2010 Lopes 2010 Schultz 2010 Bangalore 2011 Subtotal (95% CI) Total %↓

N = 458,448 PCI pts at 299 hosps (Premier Perspective Database, ~1/5 th of all US hosp discharges; bival in 41%) Wise GR et al. J Interv Cardiol 2012;25:278–88 Bleeding + Transfusion In-hospital events, propensity adjusted Mortality Comparator Better Heparin + GPI Better (n=182,948) (0.66, 0.76) Heparin alone (n=85,870) < (0.87, 1.06) Bivalirudin + GPI (n=33,566) (0.48, 0.55) Bivalirudin monotherapy (n=156,064) < OR (95% CI)Comparator P Value Comparator Better Heparin + GPI Better (n=182,948) (0.82, 0.96) Heparin alone (n=85,870) (0.72, 0.94) Bivalirudin + GPI (n=33,566) (0.54, 0.65) Bivalirudin monotherapy (n=156,064) < OR (95% CI)Comparator P Value Anticoagulation Regimens During PCI OR (95% CI) OR (95% CI)

NCDR CathPCI Registry : PCI in 1,522,935 pts Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively. Propensity-adjusted bleeding Impact of Bleeding Avoidance Strategies Marso SP et al. JAMA. 2010;303: %↓ Adj OR (95%CI) = 0.77 (0.73 – 0.80) NNT = 148 Adj OR (95%CI) = 0.67 (0.63 – 0.70) NNT = 118 Adj OR (95%CI) = 0.38 (0.35 – 0.42) NNT = 70 33%↓ 62%↓

Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 568(61.4%) non access site related 925 pts (5.3%) had TIMI major or minor bleeding within 30 days Source of bleeding (absolute rate) Indeterminate – most likely intraprocedural (catheter exchanges) or baseline anemia with lower transfusion threshold Verheugt FWA et al. JACC Int 2011;4;

Impact of Access and Non-Access Site Bleeding after PCI 17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS 925 pts (5.3%) had TIMI major or minor bleeding within 30 days Time-updated multivariable risk of death within 1-year Adjusted risk of 1-year mortality TIMI Bleed - All TIMI Bleed – Non Access Site TIMI Bleed – Access Site Only HR [95%CI]P 3.17 [2.51, 4.00]< [3.07, 5.15]< [1.17, 2.83]0.008 Verheugt FWA et al. JACC Int 2011;4;

StudyNComparatorSetting Ischemic Events Bleeding REPLACE-26002UFH + GPIElective PCI-  ISAR REACT 34570UFH (140 u/kg)Elective PCI-  ACUITY13800UFH/LMWH + GPINSTEACS-  ISAR REACT 41721UFH + GPINSTEACS-  BRIGHT2100UFH or UFH + GPISTEMI & NSTEMI-  HORIZONS3602UFH + GPISTEMI (-) MACE  Death  Stent thromb  EUROMAX2218UFH ± GPISTEMI (-) MACE  Stent thromb  HEAT PPCI1829UFHSTEMI  MACE- “Contemporary” Bivalirudin Trials courtesy of A Kirtane, 2014

Question n° 2: does bivalirudin increase early thrombotic events???

acute stent thrombosis with bivalirudin in STEMI NO prolonged infusion prolonged infusion 0.2 mg/Kg/min prolonged infusion

Landmark Analysis: Stent Thrombosis to 30 days* Estimated event rate (%) Time from Randomization (days) 0.48% 0.37% Bivalirudin (n=1089) UFH ± GPI (n=1109) 1.11% 0.18% Stent thrombosis adjudicated according to Academic Research Consortium (ARC) CEC blindly adjudicated ST after review of angiograms (CEC chair : K.Thygesen) AST = 0 deaths at 30 days. Sub-acute ST = 1 death at 30 days (UFH) *Based on the ITT population. Data on file, The Medicines Company. Log rank p=0.007 Log rank p=0.71 The median time to AST was 2.3 hours (IQR )

Different drug regimens

antithrombotics halflife minutes

In CKMB negative pts (80%) eptifibatide protected from procedural-related MIs better than bivalirudin (any CK MB increase, 16.6 vs. 25.2%, p=0.01). Protect TIMI 30 study CM Gibson, J Am Coll Cardiol 2006

“Antithrombotic protection” TIME PCI end of PCI 4 hrs12 hrs24 hrs GPI B stop B stop end of PCI Prolonged B -Plt activation -Distal embolization -Small vess closure -Stent thrombosis antithrombotics “protection” B Cortese 2008 & 2011

PROBI VIRI study design 178 pts with SA or UA, complex PCI Randomization (post angio) Primary endpoint Cath lab Biv bolus and infusion (1.75 mg/Kg/h) 4-hrs infusion at 0.25 mg/Kg/h (n=88)Stop infusion (n=90) B Cortese et al., AJC 2009

PROBI VIRI Results 16,7% 6,8% p=0.041 In-hospital Major Bleedings, % 1, In-hospital Minor Bleedings, % 3,33,40.96 CONTROL GROUP (n=90) PROL BIV (n=88) p value B Cortese et al., AJC 2009

PATIENT POPULATION AND TREATMENT ASA i.v mg in ambulance/first aid clopidogrel 600 mg cath lab Cath lab UFH (60 IU/Kg bolus and subseq boluses with target ACT sec) and abciximab (0.25 mg/Kg bolus and µg/Kg/min) Cath lab bivalirudin (0.75 mg/Kg bolus and 1.75 mg/Kg/h infusion) Cath lab bivalirudin (0.75 mg/Kg bolus, 1.75 mg/Kg/h infusion) abciximab infusion (12 hours after PCI) bivalirudin infusion at 0.25 mg/Kg/h (4 hours after PCI) Primary PCI 92 pts. 86 pts. PROBI VIRI II study design B Cortese et al., AJC 2011

RESULTS primary endpoint STR >70% 90 min GPI Prol B B 69,669,848,8 P between GPI and B = P between B and PB = P between GPI and PB = 0.98 B Cortese et al., AJC 2011

Treatment Breakdown and Outcomes by Bivalirudin Post-PCI Infusion Dose BIVALIRUDIN 1.75 mg/kg/hour infusion BIVALIRUDIN 1.75 mg/kg/hour infusion 0.25 mg/kg/hr (n=670) ‡ 0.25 mg/kg/hr (n=670) ‡ 1.75 mg/kg/hr (n=244) § 1.75 mg/kg/hr (n=244) § Pre-PCI PCI Post-PCI † BIVALIRUDIN Bolus 0.75 mg/kg mg/kg/hour infusion BIVALIRUDIN Bolus 0.75 mg/kg mg/kg/hour infusion P2Y 12 Load ASA + Heparins ± GPI BIV-LOWBIV-HIGH AST2 (0.2%) 11 (1.6%) * 1 (0.4%) Major Bleeding57 (6.0%)16 (2.4%)*7 (2.9%) *p < 0.05 vs. heparins ± GPI

1:1 1:1 NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker Trans-Femoral Access Heparin ±GPI Bivalirudin Mono-Tx Stop Infusion Prolong≥ 6 hs infusion 1:1 Trans-Radial Access MATRIX Trial NCT

conclusions bivalirudin decreases bleeds independently from its antagonist; this might be associated with improved long term outcome; there is an increased very early thrombotic risk; this risk might be attenuated or eliminated by a prolonged bivalirudin infusion.

La bivalirudina ed il suo annus horribilis: un update scientifico Bernardo Cortese Intv’ Cardiology, A.O. Fatebenefratelli