1. Effect of Postconditioning on Myocardial Reperfusion during Primary Percutaneous Coronary Intervention
Joo-Yong Hahn / Hyeon-Cheol Gwon
On behalf of the POST Trial Investigators
Samsung Medical Center, Sungkyunkwan University School of Medicine
Thank you chairman. I’m very honored to present the results of POST trial.

2. Ischemic Postconditioning
Repetitive reversible ischemia during early reperfusion after the prolonged ischemic insult
Comparable protective effects to preconditioning in animal studies
Zhao ZQ et al. Am J Physiol Heart Circ Physiol 2003
Ischemic postconditioning is repetitive reversible ischemia during early reperfusion after the prolonged ischemic insult. Animal studies have demonstrated that postconditioning has cardioprotective effects that are comparable to preconditioning.

3. Ischemic Postconditioning
Postconditioning reduced enzymatic infarct size in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
Staat P et al. Circulation 2005, the first report in human
Inconsistent results of studies using CE-MRI for infarct size
Lonborg J et al. Circ Cardiovasc Interv 2010
Thuny F et al. J Am Coll Cardiol 2012
Sorensson P et al. Heart 2010
Freixa X et al. Eur Heart J 2012
Tarantini G et al. Int J Cardiol 2012
No large scale trials
PostC is Protective!
Enzymatic infarct size was significantly reduced in the postconditioning group compared with the control group in patients undergoing primary PCI. However, the results of studies using magnetic resonance imaging to evaluate the effects of postconditioning on infarct size are inconsistent. While 2 studies have reported that postconditioning reduces infarct size or increases myocardial salvage, infarct size did not differ significantly between the 2 treatment groups in 1 study. Notably, postconditioning showed harmful effects in other 2 studies. Until now, the efficacy and safety of postconditioning have not been demonstrated in a large-scale trial.
PostC is harmful!

4. Objective of Study Hypothesis
To evaluate the safety and efficacy of ischemic postconditioning in patients with STEMI undergoing primary PCI.
Hypothesis
Ischemic postconditioning can improve myocardial reperfusion after primary PCI.
The objective of study was to test the safety and efficacy of postconditioning in patients with ST-segment elevation myocardial infarction undergoing primary PCI. Our hypothesis was that ischemic postconditioning can improve myocardial perfusion after primary PCI.

5. Trial Design
A multicenter, prospective, randomized, open-label, blinded endpoint (PROBE) trial
STEMI patients undergoing primary PCI
Randomization after diagnostic coronary angiogram (n=700)
Web-based
P:C = 1:1
Stratification by infarct-related artery
Postconditioning with primary PCI (n=350)
Conventional primary PCI (n=350)
This study was a multicenter, prospective, randomized, open-label, blinded endpoint (PROBE) trial. Patients were randomly assigned to either the postconditioning group or the conventional primary PCI group in a 1:1 ratio after diagnostic angiography. Randomization was performed using a web-based response system  and was stratified by the site of enrollment and infarct-related artery (left anterior descending artery versus non-left anterior descending artery). Myocardial reperfusion was assessed by ECG and angiogram. Patients were clinically followed-up.
Assessment of myocardial reperfusion
ST-segment resolution
Myocardial blush grade
Clinical follow-up
ClinicalTrials.gov identifier: NCT

6. Eligible patients Patients with STEMI undergoing primary PCI
Inclusion criteria
ST-segment elevation more than 1 mm in 2 or more contiguous leads
The presence of chest pain for less than 12 hours after symptom onset
Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 in the infarct-related artery
Target lesion in a native coronary vessel with reference diameter of 2.25 to 4.25 mm.
Patients were eligible for the trial if they had acute ST-segment elevation myocardial infarction and primary PCI was planned. Inclusion criteria were as follows: 1) the presence of chest pain for less than 12 hours after symptom onset; 2) ST-segment elevation more than 1 mm in 2 or more contiguous leads; 3) Thrombolysis in Myocardial Infarction (TIMI) flow grade of 0 or 1 in the infarct-related artery; and 4) target lesion in a native coronary vessel with reference diameter of 2.25 to 4.25mm.

7. Exclusion Criteria Hemodynamic instability or cardiogenic shock
Left bundle branch block on electrocardiogram (ECG)
Left main lesion
Rescue PCI after thrombolysis or facilitated PCI
Non-cardiac co-morbid conditions with life expectancy <1 year or that may result in protocol non-compliance (per site investigator's medical judgment)
Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plan to become pregnant any time after enrollment into this study.
Exclusion criteria were as follows: 1) hemodynamic instability or cardiogenic shock; 2) left bundle branch block on electrocardiogram (ECG); 3) left main lesion; 4) rescue PCI after thrombolysis or facilitated PCI; 5) non-cardiac co-morbid conditions with life expectancy <1 year or that may result in protocol non-compliance (per site investigator's medical judgment); or 6) female of childbearing potential, unless a recent pregnancy test was negative, who possibly plans to become pregnant any time after enrollment in this study.

8. *Staat P et al. Circulation 2005;112:2143-2148
Study Protocol
Postconditioning
Four episodes of 1-minute balloon occlusion and 1-minute deflation*
Immediately (within 1 minute) after restoration (TIMI grade ≥2) of coronary flow (without regard to method of achieving reflow)
Aspirin 300 mg and clopidogrel 600 mg
Thrombus aspiration, predilation before stenting, or use of glycoprotein IIb/IIIa inhibitors were left to the operators’ discretion.
PCI was performed according to standard techniques. Before the index procedure, all patients received 300 mg of aspirin and 600 mg of clopidogrel as loading doses. In the postconditioning group, immediately after restoration (TIMI grade ≥2) of coronary flow (without regard to method of restoration), an angioplasty balloon was positioned at the culprit lesion or stented segment and inflated 4 times for 1 minute with low-pressure (<6 atm) inflations, each instance of inflation separated by 1 minute of reflow. Thrombus aspiration, predilation before stenting, or use of glycoprotein IIb/IIIa inhibitors were left to the operators’ discretion.
Ischemia
Reperfusion
Conventional PCI
Postconditioning
Ballooning for 1 min X 4
*Staat P et al. Circulation 2005;112:

9. Endpoints Primary End point
Complete ST-segment resolution (STR >70%) at 30 minutes after the procedure
Secondary End Points
TIMI flow grade after PCI
Myocardial blush grade
Major adverse cardiac events (MACE: a composite of death, reinfarction, severe heart failure*, or stent thrombosis†) at 30 days
Each component of MACE at 30 days
Target vessel revascularization at 30 days
The primary end point was the rate of complete ST-segment resolution on ECG obtained at 30 minutes after the procedure. Complete ST-segment resolution was defined as the percentage resolution of ST-segment elevation >70%. Secondary end points included TIMI flow after PCI, myocardial blush grade, and major adverse cardiac events (a composite of death, reinfarction, severe heart failure, or stent thrombosis) at 30 days.
* Heart failure with documented arterial partial pressure of oxygen less than 60 mmHg or with pulmonary edema documented radiographically or requiring intubation, 100% oxygen, or insertion of a mechanical support device.
†Definite or probable stent thrombosis by the ARC definition

10. Sample Size Calculation
Primary Endpoint
The rate of complete STR
The rate of complete STR in the conventional PCI group: 50%
The expected rate of complete STR in the postconditioning group: 62.5% (relative increase 25%)
Type I error 0.05
Sampling ratio of postconditioning : conventional PCI = 1:1
We assumed that the rate of complete ST-segment resolution in the conventional primary PCI group would be 50%. We expected that postconditioning would increase the rate of complete ST-segment resolution by 12.5% (relative increase of 25%), leading to a final percentage of 62.5%. Based on the estimated improvement in the primary endpoint, we selected a target sample size of 700 subjects, which would provide 91.7% power at the .05 significance level to detect anticipated differences and offer some protection against the inability of measuring the ECG, losses to follow-up, or smaller effect size than anticipated.
A target sample size of 700 subjects would provide 91.7% power.

11. Independence in Trial Coordination
Steering Committee
17 study investigators
DSMB
Data Safety
Monitoring Board
CTC-SMC
Trial
Coordinating Center
CEAC
Clinical Event Adjudication Committee
Core Laboratory
ECG and angiographic data analyses
The steering committee was comprised of 17 study investigators. This study was coordinated by the Clinical Trial Center of Samsung Medical Center. ECG and angiographic data were analyzed at the core laboratory (Samsung Medical Center, Seoul, Korea) by independent observers, who were blinded to the study randomization. The independent clinical event adjudication committee, whose members were unaware of the study-group assignments, assessed all of the clinical end points. An independent data safety monitoring board reviewed data once per year.
The sponsors were not involved with the protocol development or the study process, including site selection, management, and data collection and analysis.
Grant Support
1) The Korean Society of Interventional Cardiology
2) The Sungkyunkwan University Foundation for Corporate Collaboration
3) Medtronic Korea

12. Participating Centers
17 Hospitals in Republic of Korea
Samsung Medical Center
Samsung Changwon Hospital
Kyungpook National University Hospital
Hanil General Hospital
Konyang University Hospital
Korea University Anam Hospital
Gyeongsang National University Hospital
Eulji University School of Medicine
Kangbuk Samsung Hospital
Chungbuk National University Hospital
Sejong General Hospital
Daegu Catholic University Hospital
Chung-Ang University Hospital
Boramae Medical Center
Yeungnam University Hospital
Dankook University Hospital
Kyung Hee Medical Center
Seventeen hospitals in Republic of Korea participated in our trial.

13. 3916 Patients were assessed
3216 Were not enrolled
478 Declined to participate
1053 Had TIMI flow grade of 2 or 3
412 Had hemodynamic instability or cardiogenic shock
47 Had left main lesions
36 Underwent rescue PCI or facilitated PCI
94 Non-cardiac co-morbid conditions with life expectancy <1 year
401 Participated in other studies
695 Had other reasons
Between July 2009 and June 2012
700 Underwent randomization
350 Were assigned to postconditioning
350 Were assigned to conventional PCI
27 Did not undergo postconditioning per protocol
1 underwent coronary artery bypass grafting surgery
Between July 2009 and June 2012, we screened 3916 patients with ST-segment elevation myocardial infarction undergoing primary PCI at 17 centers (Fig. 1). Of the screened patients, a total of 700 (17.9%) were enrolled and randomly assigned to either the postconditioning group (n=350) or to the conventional PCI group (n=350). One patient in the conventional PCI group underwent emergent coronary artery bypass grafting surgery due to failure of guidewire passage. Among the patients assigned to the postconditioning group, balloon occlusion immediately after reflow was performed for 4 cycles per protocol in 323 patients (92.3%). Baseline and follow-up ECG data were available for analysis in 341 patients (97.4%) of the postconditioning group and 335 patients (95.7%) of the conventional PCI group (P=0.21).
323 Underwent postconditioning per protocol
349 Underwent conventional primary PCI
341 Were included in analysis of STR
335 Were included in analysis of STR
350 Had clinical follow-up
350 Had clinical follow-up

14. Baseline Clinical Characteristics
Postconditioning
(n=350)
Conventional PCI
P Value
Age ― yr
60±12
0.96
Male sex
276/350 (78.9%)
261/350 (74.6%)
0.18
Body mass index*
24.1±3.2
24.4±3.0
0.34
Diabetes mellitus
84/346 (24.3%)
87/346 (25.1%)
0.79
Hypertension
161/341 (46.4%)
159/349 (45.6%)
0.82
Dyslipidemia
139/345 (40.3%)
0.16
Current smoking
184/349 (52.7%)
182/348 (52.3%)
0.91
Previous myocardial infarction
10/344 (2.9%)
9/348 (2.6%)
0.80
Previous revascularization
20/346 (5.8%)
16/349 (4.6%)
0.48
Cerebrovascular disease
10/346 (2.9%)
16/348 (4.6%)
0.24
Chronic renal failure
4/345 (1.2%)
2/348 (0.6%)
0.45
Ejection fraction (%)
50·0 (10.9)
50·2 (11.6)
0.88
Baseline clinical characteristics were well-balanced between the 2 groups. Mean age was 60 and most patients were male.

15. Angiographic Findings
Postconditioning
(n=350)
Conventional PCI
P Value
Number of diseased vessels
0.19 1
189/350 (54.0%)
165/350 (47.1%) 2
99/350 (28.3%)
115/350 (32.9%) 3
62/350 (17.7%)
70/350 (20.0%)
Infarct-related artery
0.90
Left anterior descending
163/350 (46.6%)
157/350 (44.9%)
Left circumflex
38/350 (10.9%)
40/350 (11.4%)
Right coronary artery
149/350 (42.6%)
153/350 (43.7%)
TIMI flow before PCI
328/350 (93.7%)
324/347 (93.4%)
8/350 (2.3%)
7/347 (2.0%)
2/3
14/350 (4.0%)
16/347 (4.6%)
Angiographic findings were also similar. Although patients had to have TIMI flow grade of 0 or 1 in the infarct-related artery, preprocedural TIMI flow was graded as 2 or 3 after core laboratory analysis in a minor portion of patients.
TIMI = thrombolysis in myocardial infarction.

16. Procedural Findings Postconditioning (n=350) Conventional PCI P Value
Symptom onset-to-reperfusion time ― min
196 ( )
195 ( )
0.91
Door-to-reperfusion time ― min
54 (43-73)
56 (44-74)
0.14
Thrombus aspiration
158/350 (45.1)
178/350 (50.9)
0.13
Direct stenting
43/350 (12.3)
51/350 (14.6)
0.38
Obtaining method of reflow
0.69
Wire passage
36/350 (10.3%)
45/349 (12.9%)
111/350 (31.7%)
114/349 (32.7%)
Predilation ballooning
202/350 (57.7%)
189/349 (54.2%)
1/350 (0.3%)
1/349 (0.3%)
Use of glycoprotein IIb/IIIa inhibitor
81/350 (23.1)
80/350 (22.9)
0.93
Stent implantation
337/350 (96.3)
342/350 (97.7)
0.28
Drug-eluting stent
291/337 (86.4)
295/342 (86.3)
0.97
Total stent length, mm
28.2±11.8
28.7±12.6
0.60
Stent diameter, mm
3.3±0.5
0.31
Symptom onset-to-balloon time and door-to-balloon time were not significantly different between the two groups. Predilation before stenting was performed in most patients and thrombus aspiration was performed in about half of the patients. Obtaining reflow (TIMI flow grade ≥2) in the infarct-related artery was achieved in a similar way in the postconditioning and conventional PCI groups, mostly by ballooning or thrombus aspiration.

17. Complete ST-segment Resolution
1˚ Endpoint
Complete ST-segment Resolution
(%)
100
Intention-to-treat analysis
PostC
Conv 20 40 60 80
100
(%)
Per-protocol analysis 80
P=0.79
P=0.80 60
40.5%
41.5%
40.6%
41.6% 40 20
The primary end point of complete ST-segment resolution occurred in 138 of the 341 patients (40.5%) in the postconditioning group and 139 of the 335 patients (41.5%) in the postconditioning group. The rates were very similar and difference was not significantly different (P=0.79). Among the 323 patients who completed 4 cycles of occlusion immediately after reflow per-protocol, baseline and follow-up ECG data were available for analysis in 315 patients (97.5%) and the rate of complete ST-segment resolution was 40.6%, a rate which was similar to that of the conventional PCI group (P=0.75).
PostC
Conv
Postconditioning
Conventional PCI
P Value
ECG analysis
341/350 (97.4%)
335/350 (95.7%)
0.21
Time to ECG ― min
31 (29-38)
31 (29-37)
0.77
Per-protocol analysis
315/323 (97.5%)
334/349 (95.7%)
0.19

18. Difference (95% Confidence Interval)
Postconditioning
Conventional PCI
Difference (95% Confidence Interval)
P value
n / total n (%)
Age
<65
87/211 (41.2%)
88/205 (42.9%)
-1.7 (-11.1 to 7.7)
0.73
65
51/130 (39.2%)
0.0 (-11.7 to 11.7)
0.99
Sex
Male
105/269 (39.0%)
98/249 (39.4%)
-0.3 (-8.7 to 8.0)
0.94
Female
33/72 (45.8%)
41/86 (47.7%)
-1.8 (-17.0 to 13.5)
0.82
Infarct-related artery
LAD
32/158 (20.3%)
28/151 (18.5%)
1.7 (-7.2 to 10.5)
0.70
Non-LAD
106/183 (57.9%)
111/184 (60.3%)
-2.4 (-12.3 to 7.6)
0.64
Symptom onset-to-reperfusion time
<3 hours
71/154 (46.1%)
75/153 (49.0%)
-2.9 (-13.9 to 8.2)
0.61
3 hours
67/187 (35.8%)
64/181 (35.4%)
0.5 (-9.3 to 10.2)
0.93
Thrombus aspiration
Yes
60/154 (39.0%)
67/170 (39.4%)
-0.5 (-11.0 to 10.1) No
78/187 (41.7%)
72/165 (43.6%)
-1.9 (-12.2 to 8.3)
0.72
Direct stenting
17/41 (41.5%)
19/45 (42.2%)
-0.7 (-20.7 to 19.4)
0.97
121/300 (40.3$)
120/290 (41.4%)
-1.1 (-8.9 to 6.9)
0.80
Glycoprotein IIb/IIIa inhibitors
35/79 (44.3%)
36/78 (46.2%)
-1.9 (-17.0 to 13.4)
103/262 (39.3%)
103/257 (40.1%)
-0.8 (-9.1 to 7.6)
0.86
According to the pre-specified subgroup analyses, results between the 2 groups were consistent across various subgroups. A significant or strong trend suggesting that postconditioning leads to improved ST-segment resolution was not found in any of the subgroups.
-20
-15
-10 -5 5 10 15 20
Conventional PCI Better
Postconditioning Better
CP Rihal,CS CW

19. Angiographic Outcomes
Postconditioning
(n=350)
Conventional PCI
P Value
TIMI flow after PCI
0.08
0/1
8/349 (2.3%)
19/348 (5.5%) 2
20/349 (5.7%)
23/348 (6.6%) 3
321/349 (92.0%)
306/348 (87.9%)
Myocardial blush grade after PCI
0.20
60/349 (17.2%)
78/348 (22.4%)
108/349 (30.9%)
106/348 (30.5%)
181/349 (51.9)
(47.1)
The postprocedural myocardial blush grade and TIMI flow grade could be assessed in 349 patients (99.7%) in the postconditioning group and 348 patients (99.4%) in the conventional PCI group. Patients in the postconditioning group tended to have a higher rate of postprocedural TIMI flow grade of 3 than those in the conventional PCI group, but statistical significance was not achieved (92.0% versus 87.9%, P=0.08). There was no significant difference in the postprocedural myocardial blush grade of 0 or 1 between the 2 groups (17.2% versus 22.4%, P=0.20).
TIMI = thrombolysis in myocardial infarction.

20. Clinical Outcomes at 1-month
Postconditioning
(n=350)
Conventional PCI
Relative risk (95% CI)*
P Value
Death
13 (3.7%)
10 (2.9%)
1.30 ( )
0.53
Cardiac death
9 (2.6%)
1.11 ( )
0.82
Reinfarction
2 (0.6%)
1 (0.3%)
2.00 ( )
0.99†
Severe heart failure
5 (1.4%)
0.40 ( )
0.29†
Stent thrombosis
7 (2.0%)
6 (1.7%)
1.17 ( )
0.78
Target-vessel revascularization
3 (0.9%)
1.00 ( )
MACE‡
15 (4.3%)
1.15 ( )
0.70
Complete clinical follow-up 1-month data were obtained in all patients. No significant differences were observed between the 2 groups with regard to 1-month clinical outcomes (Table 3). Major adverse cardiac events occurred in 15 patients (4.3%) of the postconditioning group and 13 patients (3.7%) of the conventional PCI group (P=0.70).
* Relative risk is for the postconditioning group as compared with the conventional PCI group.
† The P value was calculated with the use of Fisher’s exact test.
‡ Major adverse cardiac event was a composite of death, reinfarction, severe heart failure, or stent thrombosis.

21. Outcomes according to STR, postprocedural MBG and TIMI flow grade
Figure 2
Outcomes according to STR, postprocedural MBG and TIMI flow grade
P<0.001
P<0.001 20
18.5% 20
18.5%
Major Adverse Cardiac Events (%) 18
16.3% 18
16.3%
P<0.001 16
P<0.001 16
Death (%) 14 14
10.9% 12
10.1% 12
P=0.02 10
P=0.04 10 8 8
5.3% 6
4.3% 6
2.8% 4
2.3% 4
2.4%
1.4%
1.6%
1.8%
1.7% 2
0.9% 2
ST-segment resolution, myocardial blush grade, and postprocedural TIMI flow grade were significantly associated with clinical outcomes at 1-month. Patients with complete ST-segment resolution had significantly lower rates of death and major adverse cardiac events while those with myocardial blush grades of 0 or 1 had significantly higher rates of major adverse cardiac events and death.
>70
≤70 3 2
0/1 3 2
0/1
>70
≤70 3 2
0/1 3 2
0/1
Resolution of ST-Segment Elevation (%)
Myocardial Blush Grade
Postprocedural TIMI flow grade
Resolution of ST-Segment Elevation (%)
Myocardial Blush Grade
Postprocedural TIMI flow grade

22. Study Limitations
The sample size was inadequate to make definite conclusion on clinical outcomes.
This study was not a double-blinded study.
Postconditioning was not performed per protocol (4 cycles of ballooning) in about 8% of patients in the postconditioning group.
ECGs before and 30 minutes after the procedure were not available in 3.5% of all patients.
We excluded patients with hemodynamic instability, cardiogenic shock, or left main lesion who might have lethal reperfusion injury and receive potential benefits from postconditioning.

23. Conclusions
In this multicenter, prospective, randomized, open-label, blinded endpoint trial,
Ischemic postconditioning with primary PCI did not improve myocardial reperfusion compared with conventional primary PCI.
Clinical outcomes at 1-month were not significantly different between the randomized groups.
Cardioprotective effect of ischemic postconditioning was not found in any of prespecified subgroups.