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					   Long-Term Comparison of Medical
 Treatment With Percutaneous Closure
 of Patent Foramen Ovale for Secondary
  Prevention of Paradoxical Embolism:
A Propensity-Score Matched Comparison

   Andreas Wahl*, Fabien Praz*, Bindu Kalesan†, Marie-Luise Mono#,
           Laura Geister#, Krassen Nedeltchev#, Lorenz Räber*,
  Heinrich P. Mattle#, Peter Jüni†, Stephan Windecker*, Bernhard Meier*


Departments of Cardiology* and Neurology# and Clinical Trials Unit†
              Bern University Hospital, Switzerland
     Conflicts of Interest

• Research grants
• Lecture and consultation fees
  – AGA Medical, Plymouth, MN, USA
            PFO as Predictor of Adverse Outcome
         in Patients With Major Pulmonary Embolism
                 Konstantinides S et al. Circulation 1998;97:1946




- PFO: independent predictor of mortality
- Suggested mechanism: paradoxical embolism


• 139 patients with major pulmonary embolism
   undergoing TEE
  • 35% with PFO
  • 59 ± 17 (17 - 89) years

• Clinical endpoints
  • death
  • cerebral embolism
  • arterial thrombo-embolism
  • major bleeding
Silent Cerebral Infarctions (by MR)
     2,040 Framingham Offsprings
          (53% female; mean age, 62±9 years)




       Das RR, Stroke. 2008;39:2929-2935
        Prevalence of PFO According to Age
                                      PFO in 263/965 autopsies (mean 27%)

                                                Y=35-0.12x
                                                 2
                                                R =0.6, p=0.008

   %




                                            Age (years)
Hagen PT, Mayo Clin Proc 1984; 59: 17-20
          Percutaneous PFO Closure
• Percutaneous PFO closure has been shown to be
  safe and efficacious using several devices
   - Small procedural risk
   - Minimal long-term risk
   - Satisfactory closure rate
   - Acceptable cost (outpatient procedure)

• Observational, non-randomized data suggest a
  lower risk of recurrence as compared to medical
  treatment alone

• No randomized trial published to date
• Limitations of ongoing randomized trials
   - High risk patients closed with device, not randomized
   - Follow-up too short
                 Patient Population

Inclusion Criteria
All patients with ischemic stroke or TIA, confirmed clinically
or radiologically at the University Hospital of Bern Stroke
Center between January 1994 and August 2000 were
prospectively entered into the stroke/PFO registry if they had
        - PFO ± atrial septal aneurysm (contrast TEE)
Exclusion Criteria
Obvious other cardiac, aortic, or cerebrovascular cause
Treatment decision
Based on consensus among neurologist and patient
       Patient Flow – Intention to Treat Analysis
(Windecker S, JACC 44: 750-8, 2004)
                                            308 Patients
                                       Jan. 1994 – Aug. 2000

Percutaneous PFO closure                                            Medical treatment alone
                150 patients                                                       158 patients
- 6 brands used                                                 - 50% antiplatelet therapy
- 42% Amplatzer occluders                                       - 50% warfarin
- 6% acute complications (no sequelae), no late complications
- 87% complete closure, 4% after 2nd intervention


                            After Propensity Score Matching
                                      206 Patients
Percutaneous PFO closure                                                     Medical treatment alone
              103 Patients                                                               103 Patients
                                                                          - 27% PFO closure during follow-up



1,011 patient-years                           Clinical Follow-up                         1,170 patient-years
                                              Median 10.3 years
                     All neurovascular events adjudicated by neurologist
                       Patient Characteristics
           Before Propensity Score Matching (N=308)
                                 PFO Closure Medical Treatment    P
                                 150 Patients  158 Patients
Age                                 50±12          51±13         0.55
Male , %                             54              58          0.39
Diabetes mellitus, %                  4              9           0.08
Hypertension, %                      28              32          0.49
Hypercholesterolemia, %              45              29          0.003
Smoking, %                           33              32          0.94
Cerebrovascular index event, %                                   0.022
 - Ischemic stroke                   65              77
 - TIA                               35              23
Mean number of CV events           1.8±1.1         1.5±1.0       0.025
More than 1 CV event, %              39              28          0.033
                       Patient Characteristics
             After Propensity Score Matching (N=206)
                                 PFO Closure Medical Treatment    P
                                 103 Patients  103 Patients
Age                                 49±12          50±13         0.65
Male , %                             52              55          0.68
Diabetes mellitus, %                  5              3           0.47
Hypertension, %                      26              30          0.54
Hypercholesterolemia, %              29              35          0.37
Smoking, %                           30              31          0.88
Cerebrovascular index event, %                                   0.44
 - Ischemic stroke                   75              70
 - TIA                               25              30
Mean number of CV events           1.5±1.0         1.5±0.9       0.88
More than 1 CV event, %              25              28          0.64
                     Patient Characteristics
             Before Propensity Score Matching (N=308)

                                   PFO Closure Medical Treatment    P
                                   150 Patients  158 Patients
Atrial septal anatomy, %                                            0.6
- PFO only                             75             78
- PFO and atrial septal aneurysm       25             22
Interatrial shunt grade, %                                         0.001
- Small                                 3             11
- Moderate                             17             28
- Large                                79             61
                     Patient Characteristics
              After Propensity Score Matching (N=206)

                                    PFO Closure Medical Treatment    P
                                    103 Patients  103 Patients
Atrial septal anatomy, %                                            0.41
 - PFO only                             74             79
 - PFO and atrial septal aneurysm       26             21
Interatrial shunt grade, %                                          0.40
 - Small                                 4              9
 - Moderate                             11             21
 - Large                                74             70
Primary Endpoint – Propensity Score Matched Cohort
              Stroke, or or Peripheral Embolism at 10 Years
        Stroke, TIA, TIA PeripheralEmbolism
                                                                       __ PFO Closure
                                                                           - - - Medical
                                                                                p=0.033
             30

             25                                      Medical Treatment 21.4%

             20
                                                               Hazard Ratio = 0.43
             15                                                 95% CI 0.20 – 0.94
                                                                    P=0.033
             10

              5
                                                      PFO Closure 10.7%
              0
                  0    1     2     3     4     5      6    7       8        9       10
                                        Follow-up, years
     No. at risk
   PFO closure 103     103   100   98   98    98    98     97     96       60       29
   Medical       103   96    94    89   87    85    84     82     82       54       28
      Propensity Score Matched Cohort
                  Death
         All Cause Mortality at 10 Years                                 __ PFO Closure
                                                                             - - - Medical
                                                                                   p=1.00
          25

          20            Hazard Ratio = 1.00, 95% CI 0.32 – 3.10 P=1.00

          15

          10                                            Medical Treatment 5.8%

              5

              0                                                  PFO Closure 5.8%
                  0       1   2     3      4     5     6     7      8         9       10
                                          Follow-up, years
No. at risk
PFO closure       103   102   102   102   101   101   101    101    99        64      32
Medical           103   101   101   101   101   101   101    99     98        64      30
        Propensity Score Matched Cohort
               Stroke
               Ischemic Stroke at 10 Years                         __ PFO Closure
                                                                       - - - Medical
                                                                             p=0.59
          25

          20        Hazard Ratio = 0.75, 95% CI 0.26 – 2.16, P=0.59
          15

          10                                             Medical Treatment 7.8%

           5

           0                                               PFO Closure 5.8%
               0     1    2     3      4     5      6     7    8        9       10
                                      Follow-up, years
  No. at risk
PFO closure 103     103   102   102   102   102   102    101   100     65       31
Medical       103   101   100   98    97    97    97     96    96      65       31
        Propensity Score Matched Cohort
               TIA
     Transient Ischemic Attack at 10 Years                         __ PFO Closure
                                                                       - - - Medical
                                                                            p=0.039
          25

          20
                                                 Medical Treatment 13.6%
          15
                                                         Hazard Ratio = 0.31
          10
                                                         95% CI 0.10 – 0.94
                                                              P=0.039
           5
                                                         PFO Closure 4.9%
           0
               0     1     2     3     4     5      6     7    8        9       10
                                      Follow-up, years
  No. at risk
PFO closure 103      103   101   99   99    99    99     99   99       63       31
Medical       103    98    97    94   93    91    90     89   89       57       30
Propensity-Matched Cohort                              Stroke/TIA/Periph. Embol.
                      HR (95% CI)     P
Overall             0.43 (0.20-0.94) 0.033
PFO only            0.42 (0.15-1.18) 0.54
PFO and ASA         0.61 (0.20-1.86)
Age <55 yrs         0.33 (0.09-1.23)
                                     0.69
Age ≥55 yrs         0.50 (0.09-2.73)

Female              0.14 (0.03-0.76)
Male                1.00 (0.29-3.45) 0.07
No severe shunt     0.25 (0.03-2.24)
                                     0.21
Severe shunt        0.70 (0.27-1.84)

≤1 event            1.00 (0.35-2.85)
                                     0.074
>1 event            0.22 (0.06-0.80)

Index event TIA    0.04 (0.00-0.63)
                                    0.039
Index event stroke 0.86 (0.29-2.55)
                                             .1    .15 .2 .25   .5   1    2     4   6

                                                  PFO closure better Medical tr. better
Primary Endpoint – Intention to Treat Population
               Stroke, TIA or Peripheral Embolism
                                                 10 Years
Ischemic Stroke, TIA, or Peripheral Embolism at __ PFO Closure
                                                                     - - - Medical
                                                                          p=0.004
          30

          25                                        Medical Treatment 21.5%
          20
                                                         Hazard Ratio = 0.40
          15                                             95% CI 0.22 – 0.75
                                                              P=0.004
          10

           5
                                                          PFO Closure 9.3%
           0
               0     1    2     3      4     5      6    7     8      9       10
                                      Follow-up, years
  No. at risk
PFO closure 150     148   144   142   142   142   142    141   140   136     136
Medical       158   149   144   137   135   131   130    128   127   126     124
   Intention to Treat Population (N=308)
                  Death
         All Cause Mortality at 10 Years                                  __ PFO Closure
                                                                              - - - Medical
                                                                                    p=0.21
          15

                      Hazard Ratio = 0.55, 95% CI 0.22 - 1.38, P=0.21
          10                                                 Medical Treatment 8.2%


              5


                                                                   PFO Closure 4.7%
              0
                  0       1   2     3      4     5      6      7      8        9       10
                                          Follow-up, years
No. at risk
PFO closure       150   149   149   149   147   147   147     147    145      144     143
Medical           158   155   154   153   153   153   152     149    146      145     145
    Intention to Treat Population (N=308)
               TIA
                           TIA at 10 Years                          __ PFO Closure
                                                                        - - - Medical
                                                                              p=0.04
          15
                                                   Medical Treatment 11.4%

          10                                              Hazard Ratio = 0.40
                                                          95% CI 0.17 – 0.96
                                                               P=0.04
           5

                                                          PFO Closure 4.7%
           0
               0     1     2     3      4     5      6     7    8        9       10
                                       Follow-up, years
  No. at risk
PFO closure 150      149   146   144   144   144    144   144   144     143     143
Medical       158    153   151   146   145   142    141   140   140     140     140
             Event Rates per Year (%)
                                                                                           P<0.001
                                                                                                  3.0
       Device                     No Device                             P<0.001
(1,796 patient-years)         (1,323 patient-years)                            2.4




                 P<0.001             P<0.001
 P<0.001                                    1.1
                        1.1                                                                 1.1
       0.9
                                                                         0.8

 0.4              0.4                 0.4               NS
                                                             0.1
                                                        0
   Death           Stroke               TIA       Peripheral Embolism   Stroke/TIA/PE   Death/Stroke/TIA/PE
               Conclusions
• PFO closure appears more effective
  than medical treatment for secondary
  prevention of recurrent cerebrovascular
  events among patients with stroke or
  TIA presumably related to PFO.

• Less death, stroke, or TIA with a PFO
  closure device than without.

• Results require confirmation in
  randomized clinical trials.

				
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posted:10/17/2012
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