Δημήτριος Αγγοσράς, FETCS

Transcription

1 ΣΕΜΙΝΑΡΙΟ ΟΜΑΔΩΝ ΕΡΓΑΣΙΑΣ Δημήτριος Αγγοσράς, FETCS Επίκοσρος Καθηγηηής Καρδιοτειροσργικής Ιαηρική Πανεπιζηημίοσ Αθηνών Πανεπιζηημιακό Γενικό Νοζοκομείο Αηηικόν

2 Randomized Controlled Trials (RCTs) Why are they so important anyway? RCTs provide level I evidence which is often incorporated into the formulation of clinical practice guidelines. RCTs are important to the cardiac surgeon because they produce data which justifies the utilization of open heart surgery for the treatment of cardiac diseases in an era in which patients and referring physicians demand less invasive, non-surgical therapies.

3 The SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) is the most important trial ever conducted of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with multivessel (MVD) and left main stem (LMS) coronary artery disease (CAD).

4 SYNTAX is unique for two reasons. First, and in contrast to all the previous trials of PCI vs. CABG, which enrolled highly select patients, SYNTAX was a relative all comer trial that recruited 1800 real life patients with multivessel and LMS CAD.

5 Many of the large CABG vs. PCI RCTs conducted over the past two decades were plagued by selective enrollment (entry bias). The BARI trial was the largest CABG vs. PCI RCT trial when it was conducted from 1988 to A total of patients with multivessel coronary artery disease (MVD) were screened, patients met the eligibility requirements, and only 1829 patients were enrolled into the trial, resulting in a 7.3% randomized/screened patient ratio. Selective enrollment was also present in many other major CABG vs. PCI RCTs - German Angioplasty vs. Bypass Investigation, Emory Angioplasty Surgery Trial, Randomized Intervention Treatment of Angina, Argentine Randomized Trial of Percutaneous Transluminal Coronary Angioplasty versus Coronary Artery Bypass Surgery in Multi-Vessel Disease, Coronary Angioplasty versus Bypass Revascularization Investigation, Medicine, Angioplasty, or Surgery Study, Angina With Extremely Serious Operative Mortality Evaluation, Stent or Surgery (SoS), Arterial Revascularization Therapies Study (ARTS) - in which the cumulative randomized/screened patient ratio was approximately 5%.

6 The most common reason for trial exclusion in all of these RCTs was anatomic inappropriateness in the PCI arm. Given this significant element of selective enrollment/entry bias, it is inappropriate to extrapolate the results of these trials to a generalized patient population with MVD, and therefore these trials are not considered to be externally valid. In contrast, the all-comers design of SYNTAX trial resulted in a 58.5% randomized/screened patient ratio. Additionally, those patients who were only deemed eligible for one treatment or the other were placed into a parallel CABG or PCI registry. This highly inclusive design makes the results of the SYNTAX trial more externally valid to the general population.

7 SYNTAX is unique for two reasons. First, and in contrast to all the previous trials of PCI vs. CABG, which enrolled highly select patients, SYNTAX was a relative all comer trial that recruited 1800 real life patients with multivessel and LMS CAD. Second, SYNTAX also had a parallel nested registry to examine outcomes in 1275 patients who were, for whatever reason, deemed ineligible for randomization. In fact, most of these patients (1077; 84%) underwent CABG because their CAD was of such severity that it was considered that PCI, even with drug-eluting stents (DES), could not achieve equivalent revascularization to that possible with CABG. Even prior to examining the results of the randomized component of SYNTAX over onethird of all patients were referred for CABG.

8 Comments on the Syntax trial: The Primary endpoint: the magnitude of Δ The larger is Δ the less patients are needed for the study however, a generous Δ should raise concerns about permitting treatments with more modest but important extents of inferiority to be falsely accepted as non-inferior. In Syntax trial, PCI was intended to be accepted as being noninferior to CABG if the rate of MACCE with the former came 6.6 % behind that encountered with the latter. Although 6.6% appears to be a small percentage, yet it represents more than 50% of the over all 12% rate of MACCE reported in previous RCTs comparing CABG and PCI using bare metal stents. In other words, PCI was intended to be accepted as being non-inferior to CABG with as much as 50% higher rate of MACCE.

9 Comments on the Syntax trial: The Primary endpoint: MACCE - Major Adverse Cardiac and Cerebrovascular Event Was it a good choice? Previous RCTs comparing CABG to bare metal stents showed lower % of freedom from MACCE that was attributed to a higher need for revascularization. The power of the study As in most of RCTs, power calculations were only made for the main analysis (freedom of MACCE) and not for subgroups.

10 Comments on the Syntax trial: The primary end point and post-hoc analysis Since the pre-defined endpoint is not achieved, post-hoc stratification is not permissible. Therefore, further stratified comparisons as LM and 3VD, outcome per syntax score stratum and evaluation of individual components of MACCE are only observational and hypothesis generating. It was known from the start that Syntax trial will not have sufficient power for analyzing LM disease only. As superiority was proved, subgroup analysis is no longer a question of inferiority and hence, non significant findings should never be interpreted as a sign of similarity both: by definition and by the main result of the trial.

11 Although the primary end point was not reached, deeper analysis shows that PCI was associated with significantly lower MACCE rates in patients with low syntax score and comparable rates in those with intermediate scores. Also exclusion of need for revascularization from MACCE results in a significant non-inferiority.

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52 EXCEL trial In view of the fact that SYNTAX suggested that patients with LMS scores below 33 did at least as well with PCI as CABG, if indeed not better, this is the subject of the new EXCEL trial sponsored by Abbott Vascular. This worldwide trial plans to randomize around 3100 patients with SYNTAX scores below 33 to PCI or CABG. Unlike all previous trials, revascularization will be a secondary rather than a primary end point. Like SYNTAX, EXCEL will also have a parallel registry of 1000 patients to understand why potentially eligible patients were not randomized. EXCEL recruited its first patient in Oxford in 2010.

53

54

55

56 Conclusion A. The SYNTAX trial is the most important trial of surgery and stents in severe CAD because it reflects real clinical practice.

57 Conclusion A. The SYNTAX trial is the most important trial of surgery and stents in severe CAD because it reflects real clinical practice. B. SYNTAX clearly indicates that for most patients with more severe CAD there is still a survival benefit and marked reduction in repeat revascularization with CABG in comparison to stents. This conclusion is entirely consistent with the findings of large propensity-matched registries.

58 Conclusion A. The SYNTAX trial is the most important trial of surgery and stents in severe CAD because it reflects real clinical practice. B. SYNTAX clearly indicates that for most patients with more severe CAD there is still a survival benefit and marked reduction in repeat revascularization with CABG in comparison to stents. This conclusion is entirely consistent with the findings of large propensity-matched registries. C. The results of SYNTAX will have a profound effect on practice recommendations for the foreseeable future and already has had a major influence on the new ESC/EACTS guidelines for myocardial revascularization.

59

60 Inclusion Criteria: Three-vessel disease, left main disease or LM equivalent with or without 1, 2 or 3VD (left anterior descending [LAD], left circumflex [LCX], right coronary artery [RCA] territory) De novo lesions with at least 50% stenosis Myocardial ischemia (stable, unstable, silent) Exclusion Criteria: Prior PCI or CABG Acute myocardial infarction (with creatinine kinase >2x upper limit of normal) Concomitant cardiac valve disease requiring surgical therapy (reconstruction or replacement) Participation or planned participation in another cardiovascular clinical study before 1 year follow-up is completed Inability to give informed consent due to mental condition, mental retardation, or language barrier

61

62