HORIZONS AMI Trial by qwc99136

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									HORIZONS AMI Trial
A Prospective, Randomized Comparison of Bivalirudin
vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During
Primary Angioplasty in Acute Myocardial Infarction
– One Year Results –
Roxana Mehran MD
for the HORIZONS-AMI Investigators, TCT 2008
Background

● Numerous studies have demonstrated a strong association
  between hemorrhagic complications and subsequent mortality in
  pts with ACS and after PCI
● In the HORIZONS-AMI trial, among high risk pts with STEMI
  undergoing primary PCI, randomization to bivalirudin
  monotherapy compared to UFH + GPI resulted in reduced rates
  of bleeding, thrombocytopenia, and blood transfusions; non
  significantly different rates of reinfarction, stent thrombosis and
  TVR; and improved survival at 30 days
● Whether these benefits are maintained at 1-year is unknown




 Mehran R, TCT 2008
 HORIZONS AMI

               3,602 pts with STEMI with symptom onset ≤12 hours
                             Aspirin, thienopyridine
                                                        R
                                                       1:1

         UFH + GP IIb/IIIa inhibitor                          Bivalirudin monotherapy
         (abciximab or eptifibatide)                          (± provisional GP IIb/IIIa)

           Emergent angiography, followed by triage to primary PCI, CABG or medical therapy
                            3006 pts eligible for stent randomization
                                                        R
                                                       1:3

     Paclitaxel-eluting TAXUS stent                          Bare metal EXPRESS stent

                                Clinical FU at 30 days, 6 months,
                             1 year, and then yearly through 5 years
Stone GW. NEJM 2008;358:2218-30.
HORIZONS AMI

          3,602 pts with STEMI with symptom onset ≤12 hours
                     Aspirin, thienopyridine
                                                R
                                               1:1

     UFH + GP IIb/IIIa inhibitor                     Bivalirudin monotherapy
     (abciximab or eptifibatide)                     (± provisional GP IIb/IIIa)


                                Pharmacology Arm
                        Primary and Secondary Endpoints
                                       1-Year
                           Intention to Treat Population

                     Outcomes in the 4 randomized groups




Mehran R, TCT 2008
 Inclusion Criteria

 ● STEMI >20 mins and <12 hours in duration
   – ST-segment elevation of 1 mm in 2 contiguous leads; or
   – Presumably new left bundle branch block; or
   – True posterior MI with ST depression of 1 mm in 2
     contiguous anterior leads
   – Patients with cardiogenic shock, left main disease, etc., were
     not excluded
 ● Age ≥18 years
 ● Written, informed consent




Stone GW. NEJM 2008;358:2218-30.
 Principal Exclusion Criteria
 ● Contraindication to any of the study medications
 ● Prior administration of thrombolytic therapy, bivalirudin, GP
   IIb/IIIa inhibitors, LMWH or fondaparinux for the present
   admission (prior UFH allowed)
 ● Current use of coumadin
 ● History of bleeding diathesis or known coagulopathy (including
   HIT), or will refuse blood transfusions
 ● History of intracerebral mass, aneurysm, AVM, or hemorrhagic
   stroke; stroke or TIA within 6 months or any permanent
   neurologic deficit; GI or GU bleed within 2 months, or major
   surgery within 6 weeks; recent or known platelet count <100,000
   cells/mm3 or hgb <10 g/dL
 ● Planned elective surgical procedure that would necessitate
   interruption of thienopyridines during the first 6 months post
   enrollment
Stone GW. NEJM 2008;358:2218-30.
 Study Medications (i)
 ● Unfractionated heparin
   – 60 U/kg IV*; subsequent boluses titrated by nomogram to
     ACT 200-250 secs; terminated at procedure end unless
     prolonged antithrombin needed
 ● Bivalirudin
   – Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to
      ACT; terminated at procedure end unless prolonged
      antithrombin needed (0.25 mg/kg/hr infusion)
 ● Glycoprotein IIb/IIIa inhibitors
   – Routine use in UFH arm; recommended only for giant
     thrombus or refractory no reflow in bivalirudin arm
   – Abciximab or double bolus eptifibatide as per investigator
     discretion – dosing per FDA label, renal adjusted; continued
     for 12 (abcx) or 12-18 (eptif)
   * If pre randomization UFH administered, ACT is checked first
   ** If pre randomization UFH administered, started 30’ after last bolus
Stone GW. NEJM 2008;358:2218-30.
 Study Medications (ii)

 ● Aspirin
   – 324 mg chewed non enteric coated or 500 mg IV in the ER,
     followed by 300-325 mg/day in-hospital and 75-81 mg/day as
     out patient indefinitely
 ● Thienopyridines
   – Clopidogrel 300 mg or 600 mg loading dose (per investigator
     discretion) in the ER followed by 75 mg PO QD for at least 6
     months (1 year or longer recommended)
      – Ticlopidine load + daily dose permissible if clopidogrel
        is unavailable or patient is allergic
 ● Other
   – Beta blockers: IV pre procedure followed by PO QD in the
     absence of contraindications; ACE inhibitors for HTN, CHF or
     LVEF <40%; Statin if LDL >100 mg/dl

Stone GW. NEJM 2008;358:2218-30.
 2 Primary Endpoints (at 30 Days)
                                   1) Net Adverse Clinical Events
                                               and
                               2) Major Bleeding (non-CABG)
                       •   Intracranial bleeding
                       •   Intraocular bleeding
                       •   Retroperitoneal bleeding
                       •   Access site bleed requiring intervention/surgery
                       •   Hematoma ≥5 cm
                       •   Hgb  ≥3 g/dL with an overt source
                       •   Hgb  ≥4 g/dL w/o overt source
                       •   Reoperation for bleeding
                       •   Blood product transfusion




Stone GW. NEJM 2008;358:2218-30.
 2 Primary Endpoints (at 30 Days)
                                   1) Net Adverse Clinical Events

                                                    =
                               2) Major Bleeding (non-CABG)

                                                   or

                                           Major adverse
                                       cardiovascular events
                                         (major secondary
                                              endpoint)
                                         •   All-cause death
                                         •   Reinfarction
                                         •   Ischemic TVR
                                         •   Stroke
Stone GW. NEJM 2008;358:2218-30.
 HORIZONS AMI

                                                               3602 pts with STEMI

                                                                                  R
                                                                                 1:1
                                        UFH + GP IIb/IIIa                                       Bivalirudin
       Randomized                          N=1802                                                N=1800


            30 Day FU                    N=1791 (99.4%)                                     N=1787 (99.3%)
                                                               28 • • • Not true MI* • • • 29

1-Year FU Eligible                               N=1774                                          N=1771
                                                               26       • • • Withdrew • • •    22
                                                               46      • • • Lost to FU • • •   53

             1-Year FU                   N=1702 (95.9%)                                     N=1696 (95.8%)

   * Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only

  Mehran R, TCT 2008
Baseline Characteristics (i)

                                        UFH + GP IIb/IIIa         Bivalirudin
                                           (N=1802)                (N=1800)
Age (years)                             60.7 [52.9, 70.1]       59.8 [51.9, 69.5]
Male                                         76.1%                   77.1%
Diabetes                                     17.3%                   15.6%
Hypertension                                 55.2%                   51.8%
                                                            *
Hyperlipidemia                               42.7%                   43.4%
Current smoking                              45.0%                   47.2%
Prior MI                                     11.4%                   10.4%
Prior PCI                                    11.0%                   10.5%
Prior CABG                                    2.6%                   3.3%


*P=0.04
Stone GW et al. NEJM 2008;358:2218-30
Baseline Characteristics (ii)

                                        UFH + GP IIb/IIIa   Bivalirudin
                                           (N=1802)          (N=1800)

Weight (kg)                                80 [71, 90]       80 [71, 90]
Chest pain – ER, hrs                      2.1 [1.3, 3.9]    2.2 [1.3, 4.0]
Killip class 2-4                              8.5%              8.5%
Anterior MI                                  43.9%             41.2%
LVEF                                       50 [41, 59]       50 [45, 60]
Femoral a. access                            93.6%             93.9%
Venous access                                 8.4%              9.3%
Closure device                               27.7%             28.3%
Aspiration catheter                          11.1%             11.9%



Stone GW et al. NEJM 2008;358:2218-30
Study Drugs

                                                           UFH + GP IIb/IIIa    Bivalirudin
                                                              (N=1802)           (N=1800)
UFH pre randomization                                           65.6%             65.6%
Antithrombin in CCL
  - UFH                                                         98.9%              2.6%
  - Bivalirudin                                                  0.2%             96.9%
  - Peak ACT                                                264 [228, 320]     357 [300, 402]
GP IIb/IIIa in CCL                                             94.5%*              7.2%*
  - Bail-out per protocol**                                       —                4.4%
  - Abciximab                                                   49.9%              4.0%
  - Eptifibatide                                                44.4%              3.1%
  - Tirofiban                                                    0.2%              0.1%
*97.7% and 7.5% during PCI.
** For giant thrombus or refractory no reflow after PCI.
CCL = cardiac catheterization laboratory
Stone GW. NEJM 2008;358:2218-30.
 Primary Management Strategy*

        UFH + GP IIb/IIIa Inhibitor                                        Bivalirudin Monotherapy
               N=1802                                                               N=1800

             Primary PCI                             Deferred PCI             CABG            Medical Rx


                      0% 2.1% 5.4%                                             0.1%    1.3% 5.3%




                             92.5%                                                    93.4%




          *Primary ITT analysis includes all pts regardless of treatment


Stone GW. NEJM 2008;358:2218-30.
               Primary Endpoints at 30 Days
                                  Heparin + GPIIb/IIIa inhibitor (N=1802)    Bivalirudin monotherapy (N=1800)



                                    Diff = -2.9% [-4.9, -0.8]    Diff = -3.3% [-5.0, -1.6]   Diff = 0.0% [-1.6, 1.5]
30 day event rates (%)




                                    RR = 0.76 [0.63, 0.92]       RR = 0.60 [0.46, 0.77]      RR = 0.99 [0.76, 1.30]
                           20
                                          PNI ≤ 0.0001                 PNI ≤ 0.0001                Psup = 0.95
                                          Psup = 0.005                Psup ≤ 0.0001
                           15
                                           12.1

                           10                            9.2
                                                                      8.3

                                                                                               5.5      5.4
                                                                               4.9
                             5


                             0
                                      Net adverse clinical       Major bleeding (non              MACE
                                            events                     CABG)

                                            1 endpoint               1 endpoint            Major 2 endpoint

                         Stone GW et al. NEJM 2008;358:2218-30
                 Aspirin and Thienopyridine Use

                                           Regular* aspirin use (%)                                 Regular* thieno. use (%)

                                       UFH + GPI                         Bivalirudin             UFH + GPI               Bivalirudin
                                            98.1          97.3               97    96.1
                               100                                                         100      93.7       93.3
Antiplatelet agent use (%)




                                                                                                                         87.8
                                            97.1          96.7           96.3      95.7
                                                                                                    92.7       92.9
                                 80                                                         80                           87.2
                                                                                                                                    68


                                 60                                                         60                                     65.8

                                                           All P=NS                                            All P=NS
                                 40                                                         40

                                 20                                                         20

                                  0                                                          0
                                       Discharge       30 Days       6 Months     1 Year         Discharge   30 Days   6 Months   1 Year


                                      *Taken >50% of days since last visit

                             Mehran R, TCT 2008
1-Year Net Adverse Clinical Events*
                                          Bivalirudin alone (n=1800)
                          20              Heparin + GPIIb/IIIa (n=1802)
                          18
                                                                                                 18.3%
                          16                                                                     15.7%
                          14
               NACE (%)




                          12                                                     Diff [95%CI] =
                          10                                                    -2.6% [-5.1, -0.1]
                           8                                                     HR [95%CI] =
                                                                                0.84 [0.71, 0.98]
                           6
                                                                                       P=0.03
                           4
                           2
                           0
                               0      1    2     3      4    5   6      7   8   9   10    11    12
                                                            Time in Months
Number at risk
Bivalirudin alone              1800              1559            1514           1483            1343
Heparin+GPIIb/IIIa             1802              1499            1459           1427            1281
          *MACE or major bleeding (non CABG)

Mehran R, TCT 2008
   1-Year Major Bleeding (non-CABG)
                                                       Bivalirudin alone (n=1800)
                                          12           Heparin + GPIIb/IIIa (n=1802)
                                          11
                                          10
                     Major Bleeding (%)

                                           9                                                                         9.2%
                                           8
                                           7
                                           6                                                                         5.8%
                                           5                                                 Diff [95%CI] =
                                           4                                                -3.4% [-5.2, -1.7]   2




                                           3                                                  HR [95%CI] =
                                           2                                                 0.61 [0.48, 0.78]
                                           1
                                                                                                 P<0.0001
                                           0
                                               0   1     2    3     4   5     6     7   8    9     10   11   12

                                                                    Time in Months
      Number at risk
      Bivalirudin alone                    1800              1621           1601            1586             1448
      Heparin+GPIIb/IIIa                   1802              1544           1532            1515             1368

Mehran R, TCT 2008
1-Year Bleeding Endpoints*
                                                        UFH + GP IIb/IIIa   Bivalirudin
                                                                                          P Value
                                                           (N=1802)          (N=1800)
Protocol Major, non CABG**                                         9.2%        5.8%       <0.0001
Protocol Major, All                                               11.8%        7.7%       <0.0001
Protocol Minor                                                   16.5%         9.1%       <0.0001
Blood transfusion                                                  4.0%        2.7%        0.02
TIMI Major                                                         5.5%        3.6%        0.005
TIMI Minor                                                         4.8%        3.0%        0.008
TIMI Major or Minor                                              10.2%         6.5%       <0.0001
GUSTO LT*** or Severe                                              0.7%        0.8%        0.70
GUSTO Moderate                                                     5.4%        3.7%        0.01
GUSTO LT or Sev or Mod                                             6.0%        4.4%        0.02

 *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor;
 **Primary endpoint; ***Life threatening

 Mehran R, TCT 2008
1-Year Major Adverse CV Events*
                            15              Bivalirudin alone (n=1800)
                            14              Heparin + GPIIb/IIIa (n=1802)
                            13
                            12
                                                                                                            11.9%
                            11
                                                                                                            11.9%
                 MACE (%)


                            10
                             9
                             8                                                            Diff [95%CI] =
                             7                                                            0.0% [-2.1, 2.2]
                             6
                                                                                        HR [95%CI] =
                             5
                             4                                                         1.00 [0.83, 1.21]
                             3                                                               P=0.98
                             2
                             1
                             0
                                 0      1     2     3      4       5   6      7   8   9      10   11   12
                                                                 Time in Months
Number at risk
Bivalirudin alone                1800              1627                1579           1544             1394
Heparin+GPIIb/IIIa               1802              1619                1573           1540             1380

 *MACE = All cause death, reinfarction, ischemic TVR or stroke

Mehran R, TCT 2008
 1-Year All-Cause Mortality
                                              Bivalirudin alone (n=1800)
                               5              Heparin + GPIIb/IIIa (n=1802)
                                                                                                       4.8%

                               4                                                                          Δ = 1.4%
               Mortality (%)


                                                                                                       3.4%
                               3              3.1%

                                                                                                 Diff [95%CI] =
                               2              2.1%                                              -1.5% [-2.8,-0.1]
                                                                                                 HR [95%CI] =
                                              Δ = 1.0%
                               1                                                                0.69 [0.50, 0.97]
                                              P=0.049
                                                                                                     P=0.029
                               0
                                   0      1     2    3      4    5   6      7   8   9      10   11   12

                                                                Time in Months
Number at risk
Bivalirudin alone                  1800              1705            1684           1669             1520
Heparin+GPIIb/IIIa                 1802              1678            1663           1646             1486

Mehran R, TCT 2008
   1-Year Mortality: Cardiac and Non
   Cardiac
                                                     Bivalirudin alone (n=1800)
                                     5               Heparin + GPIIb/IIIa (n=1802)         HR [95%CI] =
                                                                                          0.57 [0.38, 0.84]
                                                                                                P=0.005
                                     4
                                                                                                              3.8%
                     Mortality (%)




                                     3                                                                            Δ = 1.7%
                                                    2.9%                                    Cardiac

                                     2
                                                                                                              2.1%
                                                1.8%
                                     1            Δ = 1.1%
                                                  P=0.03
                                                                                          Non Cardiac         1.3%
                                     0                                                                        1.1%
                                         0      1     2    3      4    5   6      7   8     9    10   11   12

                                                                      Time in Months
 Number at risk
 Bivalirudin alone                       1800              1705            1684             1669           1520
 Heparin+GPIIb/IIIa                      1802              1678            1663             1646           1486

Mehran R, TCT 2008
 1-Year Death or Reinfarction
                                               Bivalirudin alone (n=1800)
                                 10            Heparin + GPIIb/IIIa (n=1802)
                                  9
                                                                                                           8.5%
                                  8                                                                          Δ = 1.9%
               Death or MI (%)



                                  7                                                                        6.6%
                                  6           4.5%
                                  5
                                  4                                                       HR [95%CI] =
                                              3.8%
                                  3                                                   0.77 [0.61, 0.98]
                                  2           Δ = 0.7%                                      P=0.04
                                  1           P=0.30
                                  0
                                      0   1     2      3    4     5    6     7   8    9     10   11   12

                                                                Time in Months
Number at risk
Bivalirudin alone                 1800               1670             1638           1617             1469
Heparin+GPIIb/IIIa                1802               1648             1617           1593             1431

Mehran R, TCT 2008
 1-Year MACE Components*
                                              UFH + GPI    Bivalirudin                        P
                                                                          HR [95%CI]
                                              (N=1802)      (N=1800)                        Value
Death                                               4.8%      3.4%       0.69 [0.50,0.97]   0.029
 - Cardiac                                          3.8%      2.1%       0.57 [0.38,0.84]   0.005
 - Non cardiac                                      1.1%      1.3%       1.14 [0.62,2.11]   0.67
Reinfarction                                        4.4%      3.6%       0.81 [0.58,1.14]   0.22
 - Q-wave                                           2.1%      2.2%       1.06 [0.67,1.67]   0.81
 - Non Q-wave                                       2.7%      1.4%       0.53 [0.32,0.86]   0.01
Death or reinfarction                               8.5%      6.6%       0.77 [0.61,0.98]   0.04
Ischemic TVR                                        5.9%      7.2%       1.23 [0.94,1.60]   0.12
 - Ischemic TLR                                     4.5%      6.0%       1.34 [1.00,1.80]   0.051
 - Ischemic remote TVR                              2.0%      2.3%       1.13 [0.71,1.79]   0.60
Stroke                                              1.2%      1.1%       1.00 [0.54,1.85]   0.99

     *All Kaplan-Meier estimates, CEC adjudicated



Mehran R, TCT 2008
Adverse Events Between 30 Days
and 1-Year
                                                                 UFH + GPI   Bivalirudin
                                                                                           P Value
                                                                  (N=1802)    (N=1800)
Death                                                              1.8%         1.4%        0.31
  - Cardiac                                                        0.9%         0.4%        0.046
  - Non cardiac                                                    0.9%         1.0%        0.75
Reinfarction                                                       2.8%         1.7%        0.04
Death or reinfarction                                              4.4%         3.0%        0.02
Ischemic TVR                                                       4.3%         4.7%        0.57
Stroke                                                             0.5%         0.4%        0.77
MACE                                                               7.3%         6.8%        0.52
Major bleeding (non CABG)                                          0.7%         0.8%        0.71
NACE                                                               7.8%         7.3%        0.52
   *Kaplan-Meier estimates, landmark analysis, CEC adjudicated


Mehran R, TCT 2008
  1-Year Stent Thrombosis
  (ARC Definite/Probable)
                                                    Bivalirudin alone (n=1611)
                                        5           Heparin + GPIIb/IIIa (n=1591)


                                                                                                           Δ = 0.3%
                 Stent Thrombosis (%)


                                        4
                                                                                                             3.5%
                                                                                                             3.2%
                                        3       2.7%


                                        2       2.2%                                       HR [95%CI] =
                                                                                          1.11 [0.76, 1.63]
                                                Δ = 0.5%
                                        1       P=0.31                                          P=0.59

                                        0
                                            0   1    2    3     4    5    6      7   8    9     10   11    12

                                                                Time in Months
   Number at risk
   Bivalirudin alone                    1611             1525            1504            1486             1356
   Heparin+GPIIb/IIIa                   1591             1495            1475            1457             1315

Mehran R, TCT 2008
 1-Year Stent Thrombosis* (N=3,202)
                                                                      UFH + GPI   Bivalirudin     P
                                                                       (N=1591)    (N=1611)     Value
ARC definite or probable, ≤24 hrs                                       0.3%         1.5%       0.0002
 - definite, ≤24 hours                                                  0.2%         1.4%       <0.0001
 - probable, ≤24 hours                                                  0.1%         0.1%         1.0
ARC definite or probable, >1 - ≤30d                                     1.9%         1.3%        0.14
 - definite, >1 day - ≤30 days                                          1.3%         1.1%        0.60
 - probable, >1 day - ≤30 days                                          0.6%         0.2%        0.049
ARC definite or probable, >30d – 1y                                     1.1%         0.9%        0.53
 - definite, >30 days – 1-year                                          1.0%         0.9%        0.65
 - probable, >30 days – 1-year                                          0.1%         0.1%        0.55
ARC definite or probable, ≤1-year                                       3.2%         3.5%        0.59
 - definite, ≤1-year                                                    2.4%         3.2%        0.15
 - probable, ≤1-year                                                    0.8%         0.3%        0.06
  *All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated
Mehran R, TCT 2008
HORIZONS AMI

                             3,602 pts with STEMI

                                         R
                                        1:1

           UFH + GP IIb/IIIa                             Bivalirudin
              N=1802                                      N=1800


                    N=1479        Stent rand.             N=1527
                                    eligible
                      R                                        R
                     3:1       Stratified by 1st rand.        3:1


       TAXUS          EXPRESS                        TAXUS          EXPRESS
       N=1111          N=368                         N=1146          N=381




Stone G, TCT 2008
 Interaction Between Drug and Stent Randomization
 30 Day Pharmacology Endpoints (N=3006)
                                                UFH + GPI                 Bivalirudin
Kaplan-Meier estimates                                                                     HR [95%CI]        Pint
                                                 (N=1479)                  (N=1527)
NACE, all*                                           11.3%                         8.7%   0.76 [0.60,0.95]   —
 - TAXUS subgroup                                    11.5%                         9.1%   0.78 [0.60,1.01]
                                                                                                             0.95
 - EXPRESS subgroup                                 10.6%                          7.4%   0.69 [0.42,1.11]
Major bleeding, all**                                 8.4%                         5.1%   0.59 [0.44,0.78]   —
 - TAXUS subgroup                                     8.9%                         5.4%   0.59 [0.43,0.81]
                                                                                                             1.0
 - EXPRESS subgroup                                   7.1%                         4.2%   0.58 [0.31,1.09]
MACE, all***                                          4.7%                         4.9%   1.05 [0.75,1.45]   —
 - TAXUS subgroup                                     4.6%                         5.1%   1.11 [0.76,1.62]
                                                                                                             0.89
 - EXPRESS subgroup                                   4.9%                         4.2%   0.86 [0.44,1.69]

 *MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction,
 stroke or ischemic TVR

 Mehran R, TCT 2008
 Interaction Between Drug and Stent Randomization
 1-Year Stent Endpoints (N=3006)
                                                TAXUS         EXPRESS
Kaplan-Meier estimates                                                    HR [95%CI]        Pint
                                               (N=2257)        (N=749)
Ischemic TLR, all                                  4.5%         7.5%     0.59 [0.43,0.83]   —
  - UFH + GPI subgroup                             3.3%         7.9%     0.42 [0.25,0.68]
                                                                                            0.17
  - Bivalirudin subgroup                           5.6%         7.1%     0.78 [0.50,1.24]
Safety MACE, all*                                  8.1%         8.0%     1.02 [0.76,1.36]   —
  - UFH + GPI subgroup                             8.2%         8.8%     0.92 [0.66,1.27]
                                                                                            0.89
  - Bivalirudin subgroup                           8.0%         7.2%     1.17 [0.83,1.64]
Binary restenosis, all**                          10.0%        22.9%     0.44 [0.33,0.57]   —
  - UFH + GPI subgroup                            10.9%        19.2%     0.57 [0.38,0.84]
                                                                                            0.18
  - Bivalirudin subgroup                           9.2%        26.7%     0.34 [0.24,0.49]

*Death, reinfarction, stroke or stent thrombosis
**1081 lesions in the TAXUS group, 332 in the EXPRESS group
 Mehran R, TCT 2008
  1-Year Mortality (All-Cause)

                                 Heparin + GPI / TAXUS (n=1111)
                     5           Heparin + GPI / EXPRESS (n=368)
                                 Bivalirudin / TAXUS (n=1146)
                                 Bivalirudin / EXPRESS (n=381)                             4.6%
                     4                                                                     4.0%
     Mortality (%)




                     3                                                                     3.0%
                                                                                           2.6%
                     2


                                                                                Pint=0.75
                     1



                     0
                         0   1    2     3    4     5     6    7    8   9   10   11    12

                                                 Time in Months
Mehran R, TCT 2008
 Limitations

 ● Open label design
      – Potential bias was mitigated by high protocol procedure
        compliance and use of blinded clinical event adjudication
        committees and core laboratories

 ● Underpowered for low frequency safety endpoints and subgroup
   interactions
      – All such observations should be considered hypothesis-
        generating




Mehran R, TCT 2008
Conclusions

● In this large scale, prospective, randomized trial of pts with
  STEMI undergoing a primary PCI management strategy,
  bivalirudin monotherapy compared to UFH plus the routine
  use of GP IIb/IIIa inhibitors resulted in:

     – A significant 16% reduction in the 1-year rate of
       composite net adverse clinical events

     – A significant 39% reduction in the 1-year rate of major
       bleeding




Mehran R, TCT 2008
 Conclusions

 ● In this large scale, prospective, randomized trial of pts with
   STEMI undergoing a primary PCI management strategy,
   bivalirudin monotherapy compared to UFH plus the routine
   use of GP IIb/IIIa inhibitors resulted in:

      – Significant 31% and 43% reductions in the 1-year rates
        of all-cause and cardiac mortality (absolute 1.4% and
        1.7% reductions), with non significantly different rates of
        reinfarction, stent thrombosis, stroke and TVR at 1-year




Mehran R, TCT 2008
Clinical Implications

● HORIZONS has demonstrated that the prevention of
  hemorrhagic complications after primary PCI in STEMI
  results in improved early and late survival

      – Optimal drug selection and technique to minimize
        bleeding are essential to enhance outcomes for pts
        undergoing interventional therapies




Mehran R, TCT 2008

								
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