Contemporary outcomes of rescue percutaneous coronary intervention for acute myocardial infarction: Comparison with primary angioplasty and the role of distal protection devices (EMERALD trial)

Contemporary outcomes of rescue percutaneous coronary intervention for acute myocardial infarction: Comparison with primary angioplasty and the role of distal protection devices (EMERALD trial) George Dangas, MD,a Gregg W. Stone, MD,a Mitchell D. Weinberg, MD,a John Webb, MD,b David A. Cox, MD,c Bruce R. Brodie, MD,d Mitchell W. Krucoff, MD,e Raymond J. Gibbons, MD,f Alexandra J. Lansky, MD,a and Roxana Mehran, MDa for the EMERALD Investigators New York, NY; Vancouver, British Columbia, Canada; Indianapolis, IN; Greensboro and Durham, NC; and Rochester, MN

Background The value of distal protection devices during rescue PCI has not been studied. Methods The population enrolled in a prospective, randomized multicenter trial of distal microcirculatory protection in ST-elevation MI, was stratified for those undergoing rescue (n = 93) or primary (n = 408) PCI; we performed the prespecified comparisons of distal protection in rescue and primary PCI.

Results Compared to primary PCI, rescue patients had higher baseline rates of TIMI-3 flow, but lower rates of post PCI TIMI-3 flow. However, no differences in the primary endpoints of complete ST-segment resolution (STR) at 30 minutes or infarct size, or 6 month mortality were present. In rescue PCI patients, randomization to distal protection did not significantly affect infarct size, STR, mortality or other clinical events. Conclusion

Despite reduced rates of post-procedural TIMI-3 flow, patients undergoing rescue PCI compared to primary PCI have similar myocardial perfusion, infarct size and clinical outcomes. Distal protection did not offer any detectable benefit in this patient population. (Am Heart J 2008;155:1090-6.)

Primary PCI for acute myocardial infarction (MI) results in greater survival and freedom from reinfarction, recurrent ischemia and stroke than thrombolytic therapy. 1 As thrombolytic therapy restores epicardial TIMI-3 flow in only 60% of patients in the best of circumstances, 2,3 rescue PCI may be considered for patients failing pharmacologic reperfusion. Though prior studies were unable to demonstrate a clear cut benefit of this approach, 4-9 a recent, large randomized trial demonstrated that rescue PCI in patients failing thrombolytic therapy significantly reduced a composite endpoint of reinfarction, death, cerebrovascular event and severe

From the aColumbia University Medical Center, Cardiovascular Research Foundation, New York, NY, bSt. Paul's Hospital, Vancouver, British Columbia, Canada, cMethodist Hospital, Indianapolis, IN, dMoses Cone Hospital, Greensboro, NC, eDuke University Medical Center, Durham, NC, and fMayo Clinic Foundation, Rochester, MN. The EMERALD study was funded by Medtronic Corp, Santa Rosa, California, US. Submitted October 21, 2006; accepted December 5, 2007. Reprint requests: George Dangas, MD, 111 East 59th Street, 6th Floor, New York, NY 10022. E-mail: [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.12.003

heart failure rates compared to conservative treatment or repeat lytic administration. 10 The majority of early studies found PCI after failed thrombolytic therapy to be associated with lower success (i.e. less restoration of TIMI-3 flow). However, these studies were limited by small sample size,4,11 outdated angioplasty techniques and technologies, 3,4,6 and high complication rates due to the excessive anticoagulation used at that time. 12,13 Although recent studies comparing rescue and primary PCI have yielded more favorable results, 14-16 in general most investigators believe that procedural success rates after rescue angioplasty are inferior to primary PCI, possibly a function of lytic induced platelet activation with more refractory thrombosis, greater time delay and/or subselection of a mechanistically more refractory population within STEMI patients. While it is commonly assumed that lytics are failing at the epicardial level, it is also possible that inadequate reperfusion at the microvascular level might be a contributing factor to worse outcomes in rescue PCI. 9,17,18 We analyzed the outcomes of patients undergoing rescue versus primary PCI in the recently completed Enhanced Myocardial Efficacy and Removal by Aspiration

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Table I. Baseline clinical and angiographic characteristics Primary PCI

Age (years) Male Diabetes mellitus Current smoker Prior hypertension Prior hypercholesterolemia Prior myocardial infarction Killip class ≥ 2 Symptom onset to hospital arrival (minutes) Peak ST-segment elevation (mm) Angiographic characteristics – Single-vessel Disease InLfarct vessel – left anterior descending – left circumflex – right coronary artery Left ventricular ejection fraction

Table II. Procedural results and angiographic outcomes

N = 408 58.5 (51.6, 69.3) 78.2% 12.7% 42.2% 36.4% 23.3%

N = 93 60.8 (53.5, 69.4) 79.6% 10.8% 44.1% 39.8% 29%

9.6%

17.2%

.04

12.5% 80 (47, 120)

12% 80 (50, 115)

1.00 .76

4.0 (2.5, 6.0) 3.5 (2.4, 5.2)

.16

.48 .89 .73 .73 .55 .28

50.9%

46.2%

.49

40.4% 10.3% 49.3% 48.0 (40.0, 55.0)

35.5% 11.8% 52.7% 45.5 (40.0, 55.0)

.42 .71 .57 .86

70.9% 13.2% 15.9%

43.8% 18.0% 38.2%

b.0001 .24 b.0001

86.4% 9.5% 4.1%

60.9% 21.8% 17.2%

b.0001 .003 b.0001

Angiographic vessel characteristics Baseline TIMI flow – zero/one – two – three Baseline myocardial blush grade – zero/one – two – three

Primary PCI

Rescue PCI

N = 408

N = 93

P-value

91.4%

48.4%

b.0001

113.0 (89.0, 142.0)

165.0 (91.0, 197.0)

.0001

11.2%

.0011

Rescue PCI P-value

Angiographic lesion characteristics Reference vessel 3.0 (2.7, 3.3) 3.0 (2.7, 3.4) diameter (mm) Lesion length (mm) 14.4 (10.8, 13.1 (9.3, 19.1) 20.0)

.36 .29

Values are percentages or median (interquartile range). PCI, Percutaneous coronary intervention; RR, respiratory rate; TIMI, thrombolysis in

of Liberated Debris (EMERALD) trial 19 in order to examine the contemporary results of rescue PCI, and to evaluate whether the use of distal protection devices during rescue PCI may be beneficial.

Methods The EMERALD trial was a prospective, randomized, multicenter trial of distal microcirculatory (embolic) protection as an adjunct to mechanical reperfusion therapy in acute MI with ongoing chest pain. The study methodology has been published in detail elsewhere. 19 Of note, both patients undergoing primary and rescue PCI were eligible for enrollment, as long as the electrocardiographic and 6 hour

Glycoprotein IIb/IIIa inhibitor administered Hospital arrival to first balloon inflation (mins)

Angiographic vessel characteristics Final TIMI flow – zero/one 2.6%

(continued on next page)

time window criteria were met. Failed thrombolysis was defined as the persistence of cardiac symptoms and ST elevations or left bundle branch block despite the administration of thrombolytics. Patients were randomized to angioplasty with stent implantation, either preceded or not by distal protection using the GuardWire Plus balloon occlusion and aspiration system (Medtronic, Santa Rosa, CA). Randomization was stratified by primary versus rescue PCI and by intention to use IIb/IIIa inhibitors. Post procedural medications consisted of aspirin 325mg daily indefinitely, clopidogrel 75mg daily for 4 weeks in patients receiving a stent (of note, only bare metal stents were available during the study period), oral beta-blockers in the absence of contraindications and angiotensin converting enzyme inhibitors for patients with hypertension or left ventricular dysfunction. Clinical follow-up was performed at 1 and 6 months.

Endpoints As described previously, 19 EMERALD primary endpoints included reperfusion success as evidenced by the rate of complete (defined as N70%) ST-segment resolution (STR) measured by continuous digital 12 lead ECG monitor 30 minutes after the last contrast injection, and infarct size measured by tc99m-sestamibi imaging on day 5–14 (both parameters assessed by blinded core lab analysis). The composite major adverse cardiac events (MACE) rate related to left ventricular dysfunction [MACE-1 = death, new onset sustained hypotension (defined as systolic blood pressure less than 90 mmHg lasting for more than 30 minutes and requiring either pressor support or insertion of an intra-aortic balloon pump), new onset severe heart failure and hospital readmission for left ventricular dysfunction] and the more usual composite MACE rate related to ischemia (MACE-2 = death, reinfarction, ischemic target vessel revascularization and disabling stroke) were determined. All the clinical endpoints were adjudicated by an independent clinical events committee blinded to treatment allocations after review of original source documentation.

Statistical analysis The EMERALD analysis plan has been previously published in detail. 19 Categorical data were compared using Fisher's

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Table III. Procedural results and angiographic outcomes in the primary and rescue groups according to randomization Primary PCI

Rescue PCI

Distal Protection No Distal Protection

Distal Protection No Distal Protection

N = 206 Two or more lesions treated Glycoprotein IIb/IIIa inhibitors used ER arrival to first balloon inflation (mins) Stents implanted Thrombectomy performed (bail-out) Temporary pacemaker used Intraaortic balloon pump used Total procedure time (mins) Total fluoroscopy time (mins) Total amount of contrast used (cc)

11.2% 90.3% 125 (91, 156)

P

N = 202 19.8% 92.6% 106 (84, 133)

.02 .48 .001

198 (96.1%) 0 12.9% 10.0% 54.0 (43.0, 70.0) 15.6 (11.1, 20.8) 240 (196, 305)

195 (96.5%) 3.5% 13.5% 4.5% 39.0 (29.0, 51.0) 10.9 (7.5, 16.3) 225 (176, 300)

1.00 .007 .88 .052 b.0001 b.0001 .064

N = 206 1.0% 1.9% 1.9%

N = 202 4.5% 1.5% 3.5%

.03 1.00 .38

Angiographic vessel characteristics Final TIMI flow – zero/one – two – three Final corrected TIMI frame count Final blush grade – zero/one – two – three

1.5% 5.6% 92.8% 18.0 (13.0, 26.0) N = 183 14.8% 23.5% 61.7%

3.6% 4.1% 92.3% 20.0 (15.0, 28.0) N = 185 20.0% 25.4% 54.6%

Angiographic lesion characteristics Reference vessel diameter (mm) Minimal luminal diameter (mm)

N = 203 3.1 (2.7, 3.5) 2.5 (2.1, 2.9)

N = 215 3.1 (2.8, 3.4) 2.5 (2.2, 2.8)

Angiographic complications No reflow Side branch closure Distal embolism

exact test, and are expressed as n (%). Continuous variables are presented as medians with interquartile ranges (except for infarct size, which was also expressed as mean ± 1 S.D. as per standard convention), and were compared by the Kruskal-Wallis non-parametric test. Time-to-event data are summarized as Kaplan-Meier estimates, and compared with the log-rank test. All comparisons are 2-sided, and a p-value of b0.05 was defined as significant. Infarct size for patients who did not undergo sestamibi scan because of death before the end of the imaging acquisition period was imputed as the largest infarct measured for any patient in the study (72% of the left ventricle).

Results A total of 501 acute MI patients were enrolled in EMERALD; 93 who had received thrombolytic therapy (rescue PCI group) and 408 who had not (primary PCI group) were randomized to either distal protection (n = 46 rescue and n = 206 primary) or no protection (n = 47 rescue and n = 202 primary).

.34 .49 1.00 .061

N = 46

N = 47

P

17.4% 52.2% 165 (91, 204)

12.8% 44.7% 166 (95, 192)

.57 .54 .60

46 (100.0%) 0 (0.0%) 3 (6.7% ) 2 (4.4%) 47.5 (40.0, 61.0) 16.6 (8.4, 21.4) 230 (180, 325) N = 46 2.2% 0 2.2%

46 (97.9% ) 0 (0.0%) 3 (6.5%) 4 (8.7%) 40.0 (27.0, 50.0) 10.0 (7.0, 14.4) 205 (156, 270) N = 47 4.3% 0 2.1%

.22 .72 .17

9.1% 4.5% 86.4% 20.5 (13.5, 30.0) N = 43 16.3% 25.6% 58.1%

13.3% 11.1% 75.6% 20.0 (15.0, 30.0) N = 42 26.2% 28.6% 45.2%

.75 .86

N = 48 3.2 (2.9, 3.6) 2.7 (2.4, 3.1)

N = 51 3.1 (2.6, 3.4) 2.4 (2.0, 2.8)

1.00 1.00 .68 .0008 .001 .064

1.00 1.00

.74 .43 .28 .90 .30 .81 .28

.04 .01

Patient characteristics The baseline demographic features were similar between patients undergoing primary and rescue PCI (Table I). However, the rescue PCI group had a higher incidence of prior myocardial infarction and higher risk hemodynamic measures on presentation compared to the primary PCI group, as indicated by higher mean heart rate and respiratory rate, with lower systolic and diastolic arterial pressure, in spite of similar time from MI symptom onset to hospital arrival. Similarly, the angiographic characteristics were generally similar between primary and rescue PCI patients (Table I). The rescue group, however, was less likely to have an occluded infarct vessel, and more likely to have TIMI 3 flow and myocardial blush grade 3 on the initial angiogram, compared to the primary PCI group. Among the primary PCI patients, baseline characteristics were well matched between the randomized groups (data not shown), except for a higher percentage of diabetes (17.8% vs. 7.8%, P = .003) and

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Table IV. Primary endpoint measures of ST-resolution and infarct size Primary PCI

Rescue PCI

Extent of ST segment resolution at 30 minutes STR data 95% (388/ 98% (91/93) performed/available 408) None (b30%) 9.8% (38) 14.3% (13) Partial (30% – 70%) 26.5% (103) 27.5% (25) Complete (N70%) 63.7% (247) 58.2% (53) Tc-99m infarct size (day 5–14) Sestamibi scan 87% (354/ 87.% (81/93) performed 408) Sestamibi Scan of 85% (348/ 85% (79/93) Acceptable Quality 408) Imputed median 11.0 (0.0, 13.0 (3.0, infarct size 24.0) 25.0)

P-Value

.25 .89 .34

.73

.21

Figure 1

Comparison of percent ST Segment Resolution (STR) and Median Imputed Infarct Size in rescue and primary PCI patients randomized to distal protection. Randomization to distal protection did not affect STR or infarct size within either the primary or the rescue groups.

hypercholesterolemia (28.2% vs. 18.4%, P = .03) among those randomized to no distal protection. Among the rescue PCI patients, baseline features were also similar among the randomized groups, except that those randomized to no distal protection had a greater percentage of triple vessel disease (27.7% vs. 6.5%, P = .01) and smaller reference vessel diameter (median 3.0 vs. 3.2, P = .0495) than patients randomized to distal protection.

Procedural results and angiographic outcomes Comparing patients undergoing rescue PCI vs. primary PCI, the time from hospital arrival to balloon inflation was significantly longer in the rescue group, glycoprotein IIb/IIIa inhibitors were used much less frequently (Table II) and they were not associated with

Table V. Clinical outcomes (6-months) in the primary and rescue PCI groups according to randomization Primary PCI

Rescue PCI

Death – 6-months 3.7% 2.2% New onset severe heart failure – 6-months 2.0% 1.1% New onset severe sustained hypotension – 6-months 13.1% 5.4% Readmission for left ventricular failure – 6-months 1.3% 1.2% Reinfarction – 6-months 2.8% 4.7% Ischemic target vessel revascularization – 6-months 5.7% 7.5% Disabling stroke – 6-months 1.5% 0.0% Composite MACE-1 related to left ventricular dysfunction – 6-months 16.9% 7.6% Composite MACE-2 related to ischemic complications – 6-months 10.5% 10.8%

P-value

.56 .58

.04

.94 .38

.61 .25 .03 .99

post-PCI anemia. TIMI-3 flow, determined by the angiographer, was also less likely to be achieved in the rescue PCI compared to the primary PCI group, though no significant differences were present in the final myocardial blush grade. Among primary PCI patients randomized to distal protection, 83% (172/206) had all angioplasty and stent balloon inflations fully protected with occlusion balloon inflation, 14% (29/206) had some but not all inflations protected, and 5 had no protected inflations. Among rescue patients randomized to distal protection, 85% (39/46) were fully protected during all inflations, 11% (5/46) were protected during some inflations, and 2 had no protected inflations. The primary PCI group had increased incidence and size of pre-PCI thrombus compared to the rescue group (presence of thrombus: 74.6% vs 61.6% P = .01). Within the primary PCI group, several procedural differences were noted according to the use of distal protection (Table III). Patients assigned to no protection were more likely to have multiple lesions treated than those randomized to distal protection, shorter time intervals from hospital arrival to balloon inflation, more no reflow and bailout use of thrombectomy, but less intraaortic balloon pump usage and shorter procedure time; nonetheless, final angiographic outcomes (TIMI flow and myocardial blush) were similar in the 2 groups (Table III). Within the rescue PCI group, procedure and fluoroscopy times were again shorter without use of distal protection, and both reference vessel and final minimal lumen diameters were smaller compared to patients assigned to distal protection use (Table III). Patients

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Table VI. Clinical outcomes in the primary and rescue PCI groups according to randomization Primary PCI Distal Protection

Rescue PCI

No Distal Protection

PValue

Distal Protection

No Distal Protection

PValue

3.6%

.93

2.2%

2.2%

.99

1.6%

.52

2.2%

0

.31

12.6%

.74

4.3%

6.4%

.67

0.0%

.03

0

2.4%

.32

3.6%

.32

4.4%

4.9%

.98

4.8%

.47

4.4%

10.5%

.43

2.1%

.37

0

0

–

15.6%

.55

6.5%

8.7%

Death – 6-months 3.7% New onset severe heart failure – 6-months 2.5% New onset severe sustained hypotension – 6-months 13.7% Readmission for left ventricular failure – 6-months 2.5% Reinfarction – 6-months 2.0% Ischemic target vessel revascularization – 6-months 6.6% Disabling stroke – 6-months 1.0% Composite MACE-1 related to left ventricular dysfunction – 6-months 18.1% Composite MACE-2 related to ischemic complications

undergoing rescue PCI randomized to distal protection had arithmetically higher TIMI-3 flow (86.4% vs. 75.6%) and grade 3 blush (58.1% vs. 45.2%) rates than patients assigned to no protection (P = .28 for both).

ST-segment resolution and infarct size As seen in Table IV, there were no significant differences in either of the co-primary endpoints of STR (Primary N = 388, Rescue N = 91) or tc-99 m-assessed infarct size (Primary N = 348, Rescue N = 79) between patients undergoing primary or rescue PCI. Six tc-99 m scans in the primary group and 2 in the rescue group were of very poor quality and therefore not included in infarct size imputation. Randomization to distal protection also did not affect the STR or infarct size co-primary endpoints within either the primary or the rescue PCI groups (Figure 1). Clinical outcomes There was a significantly lower incidence of new onset sustained hypotension at 30-day follow-up among patients undergoing rescue PCI compared to primary PCI, a difference which persisted at 6 months, resulting in a lower rate of MACE related to left ventricular dysfunction in the rescue PCI group (Table V). The rates of ischemicrelated MACE were similar among patients undergoing primary and rescue PCI. MACE rates among patients undergoing rescue or primary PCI were essentially unaffected by application of distal protection (Table VI). In subset analysis of rescue PCI patients according to pre-procedure TIMI flow, distal protection did not improve primary or secondary outcomes; this lack of

.70

benefit was noted within both subgroups of baseline TIMI flow (0-1 and 2-3).

Discussion Contemporary outcomes of rescue PCI Whether rescue PCI is of clinical utility has been investigated in a number of studies 5-8,20 with the largest randomized trial demonstrating clear benefit compared to more conservative approaches.10 Nonetheless, PCI in patients with exposure to thrombolytics has traditionally been associated with greater angiographic complications, compared to primary PCI,21 possibly a reflection of systemic platelet activation by thrombolytics.22-24 The results of the present study offer insight into the contemporary outcomes of rescue PCI, in which the full complement of adjunct pharmacologic and device based therapies are available for use, including glycoprotein IIb/ IIIa inhibitors and distal protection devices. We found that in contrast to prior studies, patients undergoing rescue PCI (persistent chest pain and ST elevation after lytics) mostly with stents and judiciously with IIb/IIIa inhibitors had similar infarct size, STR, mortality and ischemic MACE as primary PCI, and slightly lower MACE rates related to left ventricular dysfunction.(MACE 1). While the rescue PCI group had increased TIMI-3 flow rates at baseline after receiving thrombolysis compared to primary PCI, the reverse was evident post procedure. Although post procedure TIMI-3 flow is a surrogate of myocardial recovery and survival,25-28 the primary and rescue PCI groups in the present study had comparable mortality and infarct size. This may be due to the fact that

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the groups had comparable post-procedure myocardial blush grade and ST-segment resolution. Previous analyses have shown both the post procedural myocardial blush grade and extent of ST-segment resolution to be a predictor of long-term-mortality, independent of TIMI flow and other variables.29-32 These data thus again emphasize the greater prognostic utility of assessing myocardial reperfusion (e.g. blush or STR) compared to epicardial blood flow (TIMI flow or frame counts). Another possibility is that early administration of thrombolytic agents rapidly restores flow in certain patients (as indicated by the rescue group's superior baseline TIMI-3 flow rate), thereby providing some degree of early myocardial salvage. Distal embolic protection in primary and rescue PCI. Distal embolization of atheromatous and thrombotic material is quite common after primary angioplasty.33,34 This led to the hypothesis that prevention of distal embolization would enhance myocardial perfusion, reduce infarct size and improve event-free survival after primary PCI, as supported by small observational studies.35,36 However, this was not evident in the prospective, randomized EMERALD trial, and in a randomized trial using filter-based distal protection.37 The utility of distal protection devices in patients undergoing rescue PCI, in which refractory thrombus and no reflow are more common and final TIMI-3 flow rates are decreased compared to primary PCI, has not been previously reported. As numerous studies have indicated that myocardial perfusion post PCI, as assessed either by myocardial blush or by STR, may be sub-optimal in a significant proportion of patients despite TIMI-3 flow, a finding which correlates strongly with increased infarct size and reduced survival,38,39 distal protection offers the potential to further improve the prognosis of patients undergoing rescue PCI. In the MERLIN study, the unexpected increase in mortality in the rescue PCI group was possibly due to failure to restore adequate perfusion at the microvascular level, as indicated by reduced STR.9 In TIMI 10B, rescue PCI patients who achieved a higher myocardial perfusion grade score had lower mortality rates at follow-up.18 Thus, protecting the capillary bed using distal protection devices may be particularly advantageous in this population. The potential benefits of distal protection in patients undergoing rescue PCI could not be verified in the present study. Randomization of rescue PCI patients to distal protection resulted in similar rates of STR, infarct size and clinical outcomes compared to no protection. However, only 93 patients undergoing rescue PCI were randomized in EMERALD. Furthermore, when we examined rescue PCI patients with baseline TIMI 0–1 flow we found that distal protection device usage conferred no benefit. As this analysis was limited by sample size, further investigation is warranted.

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Limitations While patients were randomized to distal protection device use, the person deploying the device could not be blinded for obvious reasons. Additionally, the present report is a subgroup analysis of the EMERALD trial and is thus subject to all limitations relevant to this type of study. However, randomization in EMERALD was stratified by the performance of primary versus rescue PCI, and rescue PCI was pre-specified as an important subset for analysis. Conclusions and clinical implications The present study, consistent with the recent REACT trial,10 supports current understanding that rescue PCI is a safe and acceptable therapy in patients failing thrombolysis. Despite reduced post procedure TIMI-3 flow rates associated with rescue PCI, contemporary devices and adjunct pharmacologic agents may result in similar myocardial perfusion, infarct size and clinical outcomes compared to primary PCI. Further investigation of microcirculatory protection is warranted, especially in those with large thrombotic burden, a patent infarctrelated vessel and preserved left ventricular function in whom distal embolization is likely to be hazardous.

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