Docstoc

The Detrimental Impact of Chronic Renal Insufficiency

Document Sample
The Detrimental Impact of Chronic Renal Insufficiency Powered By Docstoc
					 A Prospective, Randomized Evaluation
of Supersaturated Oxygen Therapy After
 Percutaneous Coronary Intervention in
  Acute Anterior Myocardial Infarction
         Gregg W. Stone MD
   For the AMIHOT II Investigators
                 Disclosures
• Gregg W. Stone MD
    Research support from TherOx Inc.
                  Background
• Despite successful reperfusion in AMI, myocardial
  recovery is often suboptimal, resulting in
  extensive infarction.
• In experimental infarct models, hyperbaric oxygen
  reduces myocardial tissue damage, in part by
  reducing reperfusion injury and improving
  microcirculatory perfusion.
• Regional hyperoxemia in the infarct zone can be
  achieved by infusion of supersaturated blood into
  the infarct artery after successful primary PCI.
• This concept was tested in the AMIHOT I trial.
              The AMIHOT I Trial
 269 pts with anterior or large inferior AMI and TIMI 0-2
flow undergoing primary or rescue PCI within 24 hours
from symptom onset were randomized after successful
  PCI to intracoronary supersaturated oxygen therapy
  (SSO2; PaO2 760-1000 mmHg) for 90’ versus control.
                                           Therox, Inc.
           AMIHOT I Results
    3 Co-Primary Efficacy Endpoints
                                     Control          SSO2       P value
All patients
                                     N=135            N=134      (one sided)

Infarct size (tc-99m-
                                  13 [3, 28.5]      11 [2, 29]     0.30
sestamibi at 14 days; %LV)
ST resolution (Holter; AUC
                                       57%                55%       NS
from 0-3 hrs post PCI)
Improvement in echo RWMSI
                                   0.57±0.48        0.62±0.53      0.24
from baseline to 3 months
Anterior MI, reperfused <6h           N=53                N=52
Infarct size                        23 [5, 37]       9 [0, 30]     0.04
Complete ST resolution                 37%                59%     <0.05
Improvement in RWMSI               0.54±0.49        0.75±0.57      0.03

                O’Neill WW et al. JACC 2007;50:397-405.
                    AMIHOT II Trial Design
              Anterior AMI* with TIMI 0-2 flow
        reperfused by PCI with stenting within 6 hrs
                  TIMI 2-3 flow achieved
                                          Randomize**

        Standard therapy                                   SSO2 for 90 mins

                                 2 Primary Endpoints
                      Efficacy: Infarct size (superiority)
                     (tc=99m sestamibi SPECT @14 days)
                   Safety: 30 day MACE (noninferiority)
*STE ≥1 mm in ≥2 contiguous leads V1-V4 or LBBB with LAD infarct
**Stratified by time to reperfusion (<3 vs. 3-6 hrs) and prox vs. non prox lesion
          Principal Exclusion Criteria
   Cardiogenic shock, CPR for >10’, or IABP
   Hemorrhagic diathesis, thrombocytopenia, or
    hemorrhagic stroke within 6 months
   Severe valvular stenosis or insufficiency, pericardial
    disease, non-ischemic cardiomyopathy, recent CABG
   Unsuccessful or complicated PCI: DS% in infarct lesion
    >50%, or final TIMI 0-1 flow, or major procedural
    complications such as perforation or shock
   Other angiographic: severe calcification or tortuosity,
    SVG infarct artery, LM >60%, proximal stenosis >40%,
    unstented dissection, MVD with likelihood for CABG
   Systemic PO2 <80 mmHg despite supplemental oxygen
                   Study Procedures
•   Consent before cath; randomize after successful PCI
•   ASA 325 mg, clopidogrel 300-600 mg, UFH ± optional GPI
•   24 hour Holter placed in ER or cath lab (ST res; 2 EP)
•   Supplemental oxygen to keep PaO2 >80 mmHg
•   SSO2 procedures
      Begin immediate post successful PCI
      Draw line from sheath sideport (≥8F) or contralateral FA
      SSO2 delivery via a Tracker-38 or INCA-1 infusion catheter
      90' target infusion either in cath lab, holding area or CCU
      Infusion at 75 cc/min; ACT (≥250 secs during SSO2), HR, BP,
      PaO2 checked every 30' during infusion
• CK, CK-MB, troponins at baseline and Q8 x3
Endpoints and Statistical Methodology
• Objective 1 - Efficacy: To demonstrate that compared to
  control, SSO2 results in reduced infarct size as measured by
  tc-99m-sestamibi SPECT imaging at 14 (±7) days in pts with
  anterior MI reperfused within 6 hours

• Objective 2 - Safety: To demonstrate that compared to
  control, SSO2 has noninferior rates of major adverse
  cardiac events (MACE – death, reinfarction, TVR or stroke)
  at 30 days
• Bayesian hierarchical modeling: To allow pooling of data
  from AMIHOT I, with the amount of pooling determined by
  the similarity of the AMIHOT II results to the AMIHOT I data,
  while still preserving type I error to <5% (as per FDA “Draft
  Guidance for the Use of Bayesian Statistics in Medical
  Device Clinical Trials”)*

*http://www.fda.gov/cdrh/osb/guidance/1601.pdf
                          Power Analysis
 Assumed rates:
    - Efficacy (median infarct size): The absolute difference in
      imputed infarct size* between control and SSO2 will be >5%**
    - Safety (30 day MACE): Control and SSO2 = 7%, with a
      noninferiority margin (delta) = 6%
 Randomizing 304 pts in a 2.8:1 ratio between SSO2 and
 control in AMIHOT II, utilizing Bayesian hierarchical
 modeling to pool data from AMIHOT I, provides (with
 type I error <0.05):
    1. 85.4% power to demonstrate superiority (smaller infarct size
       with SSO2 than control) with a posterior probability of >95%
    2. 80.7% power to declare noninferiority between the
       2 groups with a posterior probability of >95%
*Missing values imputed for treatment, study, MI location, time to reperfusion, age
and gender; **Consistent with a 17.6% reduction in 6 month mortality
(Burns RJ et al. JACC 2002;39:30-6)
           Primary Bayesian Analysis
 • AMIHOT II was not powered as a stand alone
   trial, instead relying on Bayesian hierarchical
        modeling to allow partial pooling with
                     AMIHOT I data
                        Trial Power
                                               Bayesian
         Frequentist power Simple pooling
Endpoint                                       posterior
         (AMIHOT II alone) (AMIHOT I + II)
                                                power*
Efficacy          73%                 93%       85.4%
Safety            64%                 86%       80.7%

         *Posterior Probability of >95%  Success
                 Study Organization
   Principal Investigator:      Gregg W. Stone
   Co-Principal Investigator:   Jack L. Martin
   Bayesian Statistician:       W. John Boscardin
   Data Management:             Boston Biomedical Associates
   Site and Data Monitoring:    TherOx, Inc.
   Clinical Events Committee: Bonnie H. Weiner (Chair)
   SPECT Core Lab:              Mayo Clinic, Ray J. Gibbons (Director)
   Angiographic Core Lab:       Cardiovascular Research Foundation,
                                 Alexandra J. Lansky (Director)
   ECG/Holter Core Lab:         Duke Clinical Research Institute,
                                 Mitchell W. Krucoff (Director)
   DSMB:                        David Holmes (Chair), E. Bates,
                                 J. Ferguson, W. Gaasch, K. Freeman
   Sponsor:                     TherOx, Inc.
                Top Enrolling Sites
1. Menko-Jan deBoer, Isala Clinics Weezenlanden, Zwolle, NL

2. Massimo Margheri, Universitaria di Careggi, Florence, Italy

3. Ezio Bramucci, Policlinico San Matteo, Pavia, Italy

4. James Blankenship, Geisinger Clinic, Danville, PA

5. Jack L. Martin, Main Line Health, Bryn Mawr, PA

6. D. Christopher Metzger, Wellmont Holston Med Cntr, Kingsport, TN

7. Michael Chang, Mercy Heart Institute, Sacramento, CA

8. Aaron Kugelmass, Henry Ford Health System, Detroit, MI
            Patient Enrollment
 304 patients randomized at 20 sites in 4 countries
        (US, Canada, Netherlands, Italy) between
          September 13, 2005 and May 26, 2007
                                          3 randomization errors

                  301 ITT patients
                      Randomize 2.8:1

             SSO2                   Control
             N=222                   N=79

  SPECT      N=209                   N=72
endpoint    (94.1%)                 (91.1%)

30 day FU   N=222                        N=79
 complete   (100%)                      (100%)
            Baseline Characteristics
                               Control            SSO2
                               (N=79)            (N=222)
  Age (years)              59.3 [50.1, 69.6] 60.5 [51.7, 71.3]
  Male                          87.3%             77.9%
  Diabetes                      13.9%             16.2%
  Hypertension                  45.6%             46.9%
  Hyperlipidemia                43.0%             45.1%
  Current smoking               43.0%             38.2%
  Prior MI                      8.9%               9.0%
  Prior PCI of TV               10.1%              5.9%
  CrCl <60 ml/min               12.0%             18.8%
P=NS for all comparisons
                   Procedural Results
                                  Control         SSO2
                                  (N=79)         (N=222)
Symptom to ER (mins)            90 [60, 150]   109 [60, 170]
Door to balloon (mins)          75 [45, 117]    77 [47, 116]
Symptom to reperfusion (mins) 171 [143, 290] 194.5 [154, 265]
Infarct lesion
 - Proximal LAD                    46.8%          47.8%
 - Mid LAD                         51.9%          49.1%
 - Distal LAD                       0%             2.3%
 - Diagonal                         1.3%           0.9%
LVEF % (site)                    40 [35, 45]    40 [35, 45]

 P=NS for all comparisons
               Procedural Results
                                          Control    SSO2
                                          (N=79)    (N=222)
 Stent implanted                           97.5%    99.1%
 GP IIb/IIIa used                          64.6%    68.0%
 Rescue PCI (failed lytic)                  8.9%     5.0%
 TIMI flow pre (core lab)
   - 0/1                                   69.9%    75.5%
   -2                                      13.7%    17.1%
   -3                                      16.4%    7.4%*
 TIMI flow post (core lab) – pre randomization
   - 0/1                                    2.8%     1.4%
   -2                                       4.2%    10.2%
   -3                                      93.0%    88.4%

*P=0.02; otherwise P = NS for all comparisons
                         Primary Efficacy Endpoint
  Infarct Size by Tc-99m-sestamibi SPECT
                    70
                                  P=0.07                           P=0.10
                    60               (2-sided)                        (2-sided)
Infarct size, %LV



                    50

                    40

                    30

                    20

                    10

                     0
                           Control               SSO2       Control               SSO2
                              N=52               N=49          N=72               N=209
                           Median [IQR]     Median [IQR]    Median [IQR]    Median [IQR]
                           23 [5, 37]       9 [0, 30]      26.5 [8.5, 44] 20 [6, 37]
                                AMIHOT I                        AMIHOT II
                         Primary Efficacy Endpoint
                    Infarct Size by Tc-99m-sestamibi SPECT
                    70     Pooled, adjusted                 Difference
                    60                N=382                 of medians
                                                            -6.5%
Infarct size, %LV




                    50
                                                          P   =0.023
                                                           Wilcoxon
                    40

                    30
                                                                  
                    20
                                                           Bayesian
                                                           Posterior
                    10
                                                         Probability =
                     0
                           Control            SSO2
                                                            98.0%*
                             N=124            N=258
                           Median [IQR]   Median [IQR]     *Imputed infarct size;
                           25 [7, 42] 18.5 [3.5, 34.5]       95.6% using only
                                                             non imputed data
                  Infarct Size Distribution
Proportion
               Pooled, adjusted                   Pooled, adjusted
                     Control                             SSO2
                      (n=124)                           (n=258)
                    Median [IQR] =                    Median [IQR] =
                    25 [7, 42]                     18.5 [3.5, 34.5]




             Infarct size in 5% increments      Infarct size in 5% increments
  0-5%                                   0-5%
Proportion with “0% LV” infarcts (%)   Immeasurable Infarcts

                                       P = 0.11

                                                              RR [95%CI] =
                                                             1.76 (1.04, 3.00)
                                                                P = 0.03
                                                  P = 0.20
  Primary Safety Endpoint: 30 Day MACE
                           10.0
                            9.0         SSO2     Control
    Cumulative MACE rate



                            8.0
                                                                 Plog rank = 0.58
                            7.0
                            6.0
                                                                                               5.4%
                            5.0
                            4.0                                                                3.8%
                            3.0
                            2.0
                            1.0
                            0.0
                                  0      5       10        15           20          25    30
                                               Time to MACE Events (days)
No. at Risk
SSO2                              222    217     213       211         211          206   195
Control                            79     77      77       77          77            74   63
   Primary Safety Endpoint: 30 Day MACE
 AMIHOT I                     Control               SSO2       Difference [95%CI]   Psup
 MACE, all pts             7/135 (5.2%)         9/134 (6.7%)   1.5% [-4.5, 7.8]     0.62
 MACE, ant <6              2/53 (3.8%)          3/52 (5.8%)   2.0% [-7.8, 12.4] 0.68
 AMIHOT II                      N=79                N=222
 MACE                         3 (3.8%)            12 (5.4%)    1.6% [-5.5, 6.3]     0.77
    - Death                    0 (0%)              4 (1.8%)                         0.58
    - Reinfarction            2 (2.5%)             4 (1.8%)                         0.65
    - TVR                     3 (3.8%)             8 (3.6%)                         1.0
    - Stroke                   0 (0%)               0 (0%)                           -
 MACE pooled1             10/214 (4.7%) 21/356 (5.9%)          1.2% [-3.0, 4.9]     0.57
 MACE pooled2              5/132 (3.8%)        15/274 (5.5%)   1.7% [-3.5, 5.8]     0.48


                     Bayesian Posterior ProbNI = 99.8%
1 = using all pts from AMIHOT I
2 = using only anterior MI reperfused <6 from AMIHOT I
    Other Adverse Events at 30 Days
                                 Control            SSO2            P
                                  N=79              N=222
Stent thrombosis                 2 (2.5%)          9 (4.1%)        0.73
Any access site AE             10 (12.7%)         50 (22.5%)       0.07
 - Hematoma                     8 (10.1%)         39 (17.6%)       0.15
Any bleeding AE                10 (12.7%)         54 (24.3%)       0.04
 - Access site related          9 (11.4%)          41 (18.5)       0.16
 - Non access site related       1 (1.3%)         15 (6.8%)        0.08
 - Hemoglobin baseline       14.7 [13.7, 15.5] 14.3 [13.4, 15.5]   0.27
 - Hemoglobin 24 hours       13.6 [12.6, 14.6] 12.9 [12.0, 13.8] 0.0005
 - Transfusion                   1 (1.3%)         14 (6.3%)        0.13
                 Limitations
• The AMIHOT II trial per se was (intentionally)
  underpowered for a stand alone determination
  of safety or efficacy
• A broad delta for safety was utilized; as such,
  lesser differences in safety measures cannot
  be excluded
• The trial was also underpowered for mortality;
  longer term follow-up (ongoing to 1-year) will
  reveal whether the reduction in infarct size
  with SSO2 results in directionally enhanced
  survival or reduced heart failure
          Conclusion
  Among high risk patients with
  acute anterior MI undergoing
successful PCI within 6 hours of
   symptom onset, infusion of
SSO2 into the myocardial infarct
 territory results in a significant
     reduction in infarct size

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:19
posted:3/29/2012
language:
pages:26