Superiority of primary percutaneous coronary intervention (PPCI) over thrombolysis in ST-elevation acute myocardial infarction (AMI) is well established. 1-3  Although thrombolysis is widely available and easily applicable, its effectiveness is limited due to high rates of reopening failures and re-occlusion, as well as bleeding concerns especially with older generation of thrombolytics.
Tenecteplase (TNK) is 14 times more fibrin specific than standard tissue plasminogen activator (tPA) and thus acts specifically on fibrin containing clots, thus limiting the systemic effect. 4 As such bleeding risk may be lower with TNK.5 Tenecteplase is 80–fold more resistant to inhibition from PAI- 1 than tPA.4 It is compatible for combination with a broad range of other medications, such as glycoprotein (GP) IIb/IIIa and low-molecular-weight heparin, while rPA and tPA may precipitate with the administration of heparin.4 Finally, it can be administered in a bolus form, thus saving time during administration unlike tPA which must be administered over a 90 minute period. In addition to speed and ease of use, potential for errors is reduced. 6 As such it is much more effective in opening up infarct related artery. In an animal model of acute arterial occlusion, a bolus of TNK was found to produce a 6 to 12-fold rapid re-canalization and a greater degree of clot lysis as compared with a front-loaded tPA regimen.4-5 TIMI – 10B has also demonstrated superior efficacy of TNK compared with tPA. 5

Primary percutaneous coronary intervention is highly effective and has become the procedure of choice for patients presenting with AMI. Unlike clinical trials with thrombolytics  which have shown a significant correlation between the time of their administration after the symptoms onset and the mortality, first studies with PPCI demonstrated no such correlation, which was attributed to higher efficacy of angioplasty to re-open the infarct related artery (IRA) than what thrombolytic therapy could provide (irrespective of ischemia duration). 7Only ‘door-to-balloon time’ and not ‘symptoms onset-to-balloon time’ have appeared to correlate with patient mortality. 8 A confounding factor contributing to this result may have been the fact that these patients were essentially very low risk.

A subsequent study demonstrated that a relationship between pain onset to PCI and mortality is exists in ‘high risk’ patients. 9 Another study co-related the delay of PPCI in AMI with the presence or absence of left ventricular contractile function recovery in long-term follow-up. 10 De Luca and colleagues recently found a convincing relationship between the ischemia duration and mortality assessed at 1 year. 11 They demonstrated that every additional 30 min delay led to an increase in 1 year mortality by 7.5%.

 Current practice guidelines indeed recommended PPCI as a preferred method of reperfusion in AMI, as long as it can be performed within 90 min from patient’s first medical contact. 12 Unfortunately, in the majority of cases achieving this 90 min time goal remains elusive, mainly because the AMI care is not streamlined enough between different levels and components of health care system. It has been estimated that due to geographic and other constraints, the therapy is available for less than 20% of all patients with AMI, world over, and an even smaller number of patients are treated within the optimal therapeutic window of 2 hours following symptom onset (6% in the PAMI trial). 13 Because of these limitations, there is a need for new pharmacologic alternatives that can be administered early to facilitate the reopening of the occluded artery until a more definitive (mechanical) therapy can be administered. Previous trials (PACT, GRACIA, and SPEED) have shown that early PCI after thrombolysis can be performed safely. 14-16

In patients with full reperfusion after thrombolysis, there is an optimal time window for coronary intervention. The ASSENT-4 trial had planned to enroll 4000 patients with a large MI, who were expected to arrive at the catheterization laboratory (cath lab) between 60 minutes and three hours after first presentation and randomized to TNK or no thrombolytic treatment. All patients received aspirin and unfractionated heparin and were also given clopidogrel at the time of stenting. GP IIb/IIIa blockers were allowed to be used in patients undergoing PCI alone but were contraindicated in the TNK group because of concerns about bleeding. The trial was prematurely stopped after the enrollment of 1667 patients There was a higher in-

hospital mortality in the facilitated (6%) than in the standard PCI (3%) group (p=0.0105).  Manifestation of stroke was increased with facilitated compared to standard PCI, 1.8% and 0% (p<0.0001) respectively. There were more in-hospital cardiac events—such as repeat MI, abrupt vessel closures, and repeat revascularizations—in the TNK group. Bleeding complications were also increased in the TNK group, but major bleeding did not fully explain the difference in mortality rates between the two groups. 17   Subsequently it was hypothesized that there was not a large enough time delay between giving the thrombolytic and performing the PCI (the median delay was just 104 minutes, much shorter than the average delay in the US, which is 170 minutes) to show a benefit of such a strategy, and performing PCI too soon after full-dose thrombolysis may be harmful because thrombolytics might promote a pro-thrombotic milieu in the context of decreased platelet inhibition, which could explain the higher rate of abrupt closures and would put the TNK group at a higher risk of events. Several other limitations to ASSENT 4 trial were also pointed out. A suboptimal dose of heparin may have been used. In the trial, a bolus dose of heparin was given (a slightly lower dose in the TNK group than in the PCI group, 60 vs. 70 U/kg), and no infusion was given because of concerns about bleeding. Gp IIb/IIIa inhibitors were strictly avoided in TNK arm and clopidogrel was loaded only at the time of PCI (and not during first contact with the patient) contributing perhaps to higher incidence of Re MI and abrupt closures. Another negative trial was FINESSE trial. It enrolled 2452 patients randomized in a 1:1:1 fashion to primary PCI with in-lab abciximab, upfront abciximab-facilitated primary PCI, or half-dose reteplase / abciximab-facilitated PCI. Investigators were interested in whether the combination strategy would be better than abciximab alone or whether abciximab facilitation would be better than primary PCI with abciximab given in the cath lab. At 90 days, there were no differences between treatment arms for the primary composite end point of the trial: all-cause mortality, readmission for heart failure, ventricular fibrillation, or cardiogenic shock. There were also no differences in all-cause mortality, complications of MI, or any of the independent components of the primary composite end point. For safety end points, rates of TIMI non-intracranial major bleeding and minor bleeding were significantly higher for the abciximab / thrombolytic facilitated PCI strategy as compared with primary PCI.

Major and minor bleeding combined was statistically more common in the combination strategy as compared with primary PCI and as compared with the abciximab-only group. 18 In FINESSE Trial again estimated time to cath lab was one to four hours (which was blamed for increased bleeding risk in context of abciximab usage). On further analysis it was found that the overall outcomes in FINESSE were better than expected in patients with longer delays, resulting in lower power than originally anticipated. This finding also opened up the possibility that the accepted 90-minute window used as a cutoff to undertake patient for PCI should indeed be widened. The WEST study set out to evaluate whether optimal pharmacologic therapy at the earliest point of care was non-inferior to expeditious primary percutaneous coronary intervention. In the study, 304 STEMI patients within six hours of symptom onset all received aspirin and subcutaneous enoxaparin (1 mg/kg) and were randomized to one of three groups: TNK and usual care; TNK and mandatory invasive study within 24 hours; and primary PCI with 300-mg loading dose of clopidogrel. The protocol emphasized expedited care with ECG, randomization and therapy undertaken pre-hospital where ever possible and direct communication to PCI teams to enhance their state of readiness. The investigators noticed that the efficacy end-points were generally lowest in the pharmaco-invasive arm (although not statistically different from PPCI arm). 19 In the GRACIA – 2 trial a total of 212 patients with STEMI (< 12 hours) were randomized to either immediate primary PCI (n = 108) or facilitated intervention (n = 104). The time between randomization and catheterization was significantly lower in the primary PCI group compared with facilitated PCI (1.08 vs. 5.89 hours, respectively, P = .001). Normal coronary artery blood flow in the infarct-related artery was more frequently achieved in patients randomized to the facilitated arm (14% vs. 59%, P = .005. There was no difference with respect to ST-segment resolution at 1 or 3 hours, but at 6 hours, a higher percentage of patients from the facilitated PCI arm had ST-segment resolution (43% vs. 61%, P = .03). Investigators reported that the rate of death was lower in the facilitated group (3% vs. 6%, respectively). Bleeding and vascular complications were similar in both groups. In GRACIA – 2 trial PCI in pharmaco-invasive arm was carried out 3-12 hour after randomization again retreating the value of optimal delay in PCI after delivery of thrombolysis.

In summary, pharmaco-invasive strategy (immediate, even pre-hospital thrombolysis followed by delayed PCI) has emerged as an alternate to PPCI especially when a lot of delay is anticipated in undertaking PPCI. The patients should receive the full dose TNK administration followed by elective angiography/PCI. However, the PCI procedure should not be performed immediately after full dose of thrombolysis, if there are clear signs of reperfusion. In these cases PCI should be delayed for at least a few hours (3-24hours) after thrombolysis, and is found to be safer than immediate PCI (Facilitated PCI).

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