Coronary Angiography and Percutaneous Coronary Intervention after Fibrinolytic Therapy:
When and For Whom?
Satyavan Sharma. Department of Cardiology
Bombay Hospital Institute of Medical Sciences, Mumbai

analysis by Collet JP et al (6) included five randomized trials comparing rescue PCI to a conservative approach after failed fibrinolysis were identified, representing a total of 920 patients. Rescue PCI was performed ≤ 12 hours of symptom onset in all trials. Stent and GP IIb/IIIa receptor antagonists were used in the 2 most recent trials, REACT and MERLIN (8, 9). (TABLE 1) Rescue PCI for failed thrombolysis reduced mortality (6.9% vs 10.7%) (OR, 0.63, 95% confidence interval (CI), 0.39 to 0.99; p = 0.055) and the rate of death or reinfarction (10.8% vs 16.8%) (OR, 0.60; 95% CI, 0.41 to 0.89; p = 0.012) compared with a conservative approach. Rescue PCI was associated with major bleeding in 11.9% (44 of 368) of patients as compared with 1.3% (5 of 373) in the group treated conservatively (OR, 9.05, 95% CI, 3.71 to 22.06 ; p < 0.001). In patients treated with rescue PCI, major bleeding was associated with the femoral sheath used, and none was fatal.
The major findings of the Collet’s meta-analysis (6) are that “rescue angioplasty” after failed fibrinolysis improves survival as compared with a conservative approach. The European society of cardiology PCI guidelines (10) formed after publication of results of REACT (8) and MERLIN (9) recommend rescue PCI after failed thrombolysis as class I recommendation (with level of evidence B, I B).

TABLE 2: SYSTEMATIC AND EARLY PCI VS ISCHEMIA GUIDED PCI

ODDS RATIO FOR DEATH AT 30 D       ODDS RATIO FOR DEATH OR REMI AT 6 MO - 1 Y

 

*Collet JP et al: PCI After Fibrinolysis; JACC 2006: 48; 1326 - 35

However the “stent era” coupled with use of ticlopidine, clopidogrel, and glycoprotein IIb/IIIa blocking agents revolutionized the treatment. European society of cardiology PCI guidelines in 2005 (10) recommended routine coronary angiography, and if applicable, PCI in all patients after successful thrombolysis. These recommendations were largely based on the data of SIAM III, GRACIA – 1 and CAPITAL AMI (11-13). (TABLE 2) In the south west German Interventional Study in Acute myocardial infarction (SIAM III) (11), a total of 197 patients with STEMI receiving thrombolysis (full-dose reteplase) < 12 h were randomized either to early coronary angiography / PCI (within 6h from thrombolysis) or to elective coronary angiography 2 weeks after thrombolysis with stenting of the infarct related artery (11). Strategy of early angiography and immediate stenting (3.5 ± 2.3 h after thrombolysis) was associated with significant reduction of the combined end point of death, reinfarction, target lesion revascularization, and other ischemic events after 30 days (8.5 vs 30.9%, p < 0.001) and 6 months (25.6 vs 50.6%, p < 0.001), without significant difference in bleeding risk. Similarly, in the GRACIA-1 study 500 STEMI patients treated with thrombolysis (alteplase) were assigned to angiography and intervention if indicated 6-24 hr of thrombolysis, or to an ischemia-guided conservative approach (12). Patients allocated to interventional strategy received oral ticlopidine (500 mg) or clopidogrel (300 mg). The mean time from thrombolytic infusion to coronary angiography was 16.7 ± 5.6 h. Early angiography / PCI approach was associated with significant risk reduction of the combined end point of death, non-fatal reinfarction and revascularization by 1 year in comparison to conservative group (9 vs 21%, p = 0.0008). Frequency of major bleeding was equal in both groups (12). In the CAPITAL AMI study, 170 patients with high risk STEMI treated with fibrinolysis (full-dose tenecteplase) were randomized either to immediate angiography / PCI or conservative approach (13). Patients received aspirin and clopidogrel dose of 300 mg in the catheterization laboratory and the median of time from randomization to first balloon inflation was 95 min. The incidence of primary endpoint (death, reinfarction, recurrent unstable ischemia or stroke) at 6 months was lower in patients undergoing PCI (11.6 vs 24.4%, p = 0.04). Observed difference was driven mainly by a reduction in the rate of recurrent unstable ischemia (20.7 vs 8.1%, p = 0.03). There was no difference in frequency of major bleedings (13). As already mentioned, the results of these studies were the basis of ESC PCI guidelines (Class IA) recommending routine post thrombolysis coronary angiography and PCI, if applicable up to 24 h after thrombolysis, independent of angina and/or ischemia (10).

In the European Society of Cardiology guidelines, the optimal time from thrombolysis initiation to intervention is not clearly defined. The recommendation has been criticized by some and questions have been raised about the 3-24 h time frame, it would not be optimal to perform angiography too soon after lytic therapy because there is a prothrombotic environment and an increased risk of thrombotic complications, or too long after lytic therapy (i.e. before hospital discharge) because of the increased risk of re-occlusion, re-thrombosis, reinfarction in the first days following the successful thrombolysis. Recent studies indicated that the time from fibrinolysis initiation to angiography can be safely shortened even to 2-3 h, if optimal anti-platelet therapy with early loading dose of clopidogrel and/or abciximab is

administered. The safety and advantages of immediate PCI after combination of reduced dose fibrinolytic and full dose abciximab have been confirmed by the data of CARESS in AMI trial (14). This randomized trial, in fact, has shown that transfer of high risk STEMI patients (with at least one high risk feature : sum of ST-segment elevation or depression > 15 mm in 12-lead ECG or new onset complete left bundle branch block, prior MI, Killip Class 2 or 3, and left ventricular ejection fraction < 35%) for early routine PCI soon after the administration of abciximab and half dose reteplase reduces the risk of recurrent ischemia and all complications (death, repeat MI, recurrent ischemia, immediate PCI vs standard care / rescue PCI group : 4.4 vs 10.7%, P = 0.004) at 30 days in comparison to conservatively treated patients with ischemia guided PCI (rescue PCI), without a significant increase in major bleeding complications (immediate PCI group vs standard care / rescue PCI group : 3.4 vs 2.3%, p = 0.47), as well as stroke (0.7 vs 1.3 %, P = 0.50) (14). Median of the time from fibrinolysis initiation to angiography in immediate PCI group was 135 min. Further data on this subject, results of TRANSFER – AMI trial (routine early angiogplasty after fibrinolysis for acute myocardial infarction) were recently reported (15). In this study, 1059 high-risk patients who had a STEMI and received fibrinolytic therapy at centers that did not have the capability of performing PCI were randomized to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within 6 hours after fibrinolysis. All patients received aspirin, tenecteplase, and heparin or enoxaparin; concomitant clopidogrel was recommended. The primary end point was the composite of death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days. Cardiac catheterization was performed in 88.7% of the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% patients assigned to routine early PCI a median of 2.8 hours after randomization. At 30 days, the primary end point occurred in 11% of the patients who were assigned to routine early PCI and in 17.2 % of the patients assigned to standard treatment (relative risk with early PCI, 0.64 ; 95% confidence interval, 0.47 to 0.87 ; P = 0.004). There were no significant difference between the groups in the incidence of major bleeding. In this study, transfer for PCI within 6 hours after fibrinolysis was associated with significantly fewer ischemic complications than was standard treatment. After the publication of CARESS in AMI (14) and TRANSFER AMI (15) trials, it seems convincing that all patients after lytic or Lytic and GP IIb/IIIa receptor inhibitor administration should be immediately transferred to the center with facilities for angiography and PCI. Immediate angiography after lysis should be a part of patient assessment and this will allow deciding the need and optimal timing of PCI.

Facilitated Percutaneous Coronary Intervention       

Facilitated PCI is defined as a pharmacologic reperfusion treatment administered before primary PCI to bridge the delay between first medical contact and mechanical reperfusion. In the meta-analysis of 17 trials of STEMI patients assigned to facilitated (routine, immediate PCI after fibrinolysis) or primary PCI, increase in mortality (5 vs 3%, P = 0.04), rates of non-fatal reinfarction ( 3 vs 2%, P = 0.006), and urgent target vessel revascularization (4 vs 1 %, P = 0.01) in facilitated PCI group were observed (16). The increased rates of adverse events seen with the facilitated PCI approach were mainly seen with the fibrinolytic therapy based regimens, mainly based on the results of the Assent – 4 trial (17). Mentioned meta-analysis has a number of limitations. One of them is a high heterogeneity of included studies (nine studies with early GP IIb/IIIa inhibitor administration, six studies with full dose fibrinolytic regimen, and two studies with combined fibrinolytic therapy). Also, data concerning time from symptom onset to pharmacological treatment and to PCI were not incorporated into the model. Another meta-analysis by Collet et al (6) included 4 studies PACT, PRAGUE, GRACIA-2 and ASSENT-4 and did not find any benefit of this strategy compared with primary PCI. (TABLE 3) The recent premature interruption of the ASSENT – 4 (Assessment of the safety and efficacy of a New Thrombolytic regime – 4 trial) (17), opposing tenecteplase (TNK) facilitated PCI to primary goes, however, in the same direction (negative trial).

TABLE 3: FACILITATED PCI VS PRIMARY PCI*

ODDS RATIO FOR DEATH WITHIN 90 D                    ODDS RATIO FOR REMI WITHIN 90 D

 Collet JP et al: PCI After Fibrinolysis; JACC 2006: 48; 1326 - 35

The significant excess of reinfarction related to early stent thrombosis in the TNK – facilitated

group suggests a deleterious prothrombotic effect of fibrinolysis given immediately before PCI. This further supports the concept that fibrinolysis is not the ideal facilitating agent for PCI. Data from a recently completed facilitated intervention with enhanced reperfusion speed to stop events (FINESSE) trial have shown no difference at 90 days in all cause mortality and complications of MI, between patients treated and complications of MI, between patient treated with conventional primary PCI, abciximab facilitated PCI, or half-dose reteplase / abciximab facilitated PCI. According to currently available data, if facilities for primary PCI are available and the same has been planned then fibrinolysis should not be given.

The European Society of Cardiology PCI guidelines (10) are summarized in TABLE 4. In addition, the following conclusions can be drawn from the preceding discussion:

1. If primary PCI is available, patients with STEMI should be treated by this modality. All efforts should be made to reduce the delay to PCI center. When primary PCI is planned, fibrinolytic therapy should not be given (facilitated PCI is not recommended).
2. Fibrinolytic therapy should be administered when referral for primary PCI is not a reasonable (or available option). If the delay to primary PCI is likely to be more than 90-120 min, fibrinolysis is recommended.
3. After fibrinolysis, emergency referral for rescue PCI is indicated for fibrinolytic failure.
4. Fibrinolytic therapy should not be the end of the reperfusion therapy in STEMI patients. All patients treated with fibrinolysis should be transferred to primary PCI facilities for reperfusion success assessment, immediate angiography, and PCI, if needed. The transfer to PCI centers should be done as early as possible and certainly within 24 hours. With good antiplatelet coverage with loading dose of clopidogrel and /or glycoprotein IIb/IIIa receptor inhibitor, PCI after fibrinolytic therapy is safe even 2-3 hours after its initiation.

   
There are few limitations and caveats to the post fibrinolytic early angiography data in our country. It is important to remember the following:TABLE 4: RECOMMENDATION FOR PCI IN STE-ACS (STEMI)*

PCI	INDICATION	CLASS OF RECOMMENDATIONS & LEVEL OF EVIDENCE	RANDOMIZED STUDIES
PRIMARY PCI WITH STENTING	< 12 HRS (EXPERIENCED TEAM)	1 A	23 STUDIES
PRIMARY PCI	THROMBOLYSIS CI	1 C	23 STUDIES
PRIMARY PCI	PREFERRED OVER THROMBOLYSIS WITHIN 3 H & < 12 HRS	1 C	23 STUDIES
RESCUE PCI	THROMBOLYSIS FAILED WITHIN 45-60 MTS OF ADMINISTRATION	1 B	REACT
EMERGENCY (MULTIVESSEL) PCI	CARDIOGENIC SHOCK IABP EVEN  > 12 TO < 36 H	1 C	REACT
ROUTINE POST THROMBOLYSIS CAG & PCI	UPTO 24 H AFTER THROMBOLYSIS, INDEPENDENT OF ANGINA AND/ OR ISCHEMIA	1 A	SIAM III, GRACIA – 1, CAPITAL AMI LPLS
ISCHEMIA GUIDED PCI AFTER SUCCESSFUL THROMBOLYSIS	PRE DISCHARGE AND/OR ISCHEMIA AFTER STEMI	1 B	DANAMI – I
*ESC GUIDELINES FOR PCI : 26 ; 804 – 847, 2005 (Ref 10)

1) Fibrinolysis is still the dominant reperfusion therapy in India and streptokinase remains the main agent. Tenecteplase is available in the country; however, its widespread use is limited by high cost.

2) Most of the data pertaining to early angiography (and PCI) following fibrinolytic therapy is with fibrin specific agents like reteplase and tenecteplase. Whether the excellent results of early PCI will hold true in our patients following streptokinase is open to debate? It will be worth remembering that streptokinase is not a cath-lab friendly agent.

3) The early transfer for coronary angiography to equipped centers is still a major issue. Although, the number of cardiac catheterization laboratories have increased in the country (over 500) their distribution remains uneven. The quick and safe transport of the sick patients within a city and across the country continues to be major obstacles for speedy reperfusion.

4) The cost of early angiography and PCI also continue to remain pertinent issues.

Summary
The current data supports rescue PCI for failed fibrinolysis. The data also favors systematic and early PCI in all patients after fibrinolysis. However, the current data do not support fibrinolysis-facilitated PCI in lieu of primary PCI alone.

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