The second strategic reperfusion early after myocardial infarction (STREAM-2) study

Primary PCI when performed in a timely fashion is the reperfusion treatment of choice for patients presenting with ST-elevation myocardial infarction (STEMI).1,2 Unlike PCI, the efficacy of fibrinolysis in establishing Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct-related artery (IRA) is highly time-dependent and most effective in the early time period (0–3 h) after STEMI onset.3 Although randomized clinical trials have proven the benefit of optimally performed primary PCI over initial fibrinolysis in transfer subjects,4 this process is often significantly delayed in the real world.5,6,7 A pharmaco-invasive strategy holds the promise of limiting infarct size with early fibrinolytic administration, with the security of downstream emergent/urgent angiographic definition with adjunctive revascularization that ensures long-term patency of the IRA, thus diminishing the likelihood of recurrent ischaemia and infarction. When tested in the STREAM trial, which enrolled STEMI patients who presented within 3 h after symptom onset and who were unable to undergo primary PCI within 1 h, the 30-day primary composite outcome of death, shock, heart failure, or reinfarction were similar between the pharmaco-invasive and primary PCI arms.8 Also, recent observational trials have supported the findings that in patients with long transfer delays to primary PCI, a pharmaco-invasive strategy might be a better choice.9 A major downside of exposure to fibrinolysis is the risk of major bleeding including intracranial haemorrhage (ICH). In STREAM, the dosage of tenecteplase in patients >75 years of age was modified during the study in response to increased ICH rates. The current trial was then designed to further explore the role of a pharmaco-invasive approach utilizing this new dosage combined with a 300 mg loading dosage of clopidogrel.10 The second strategic reperfusion early after myocardial infarction (STREAM-2) is a clinical study that compares outcomes in patients presenting within 3 h of STEMI, receiving reperfusion therapy with either primary PCI, or a pharmaco-invasive approach consisting of half-dose tenecteplase, loading dose of 300 mg clopidogrel as a bolus, then 75 mg daily, and aspirin along with enoxaparin; with subsequent transfer to a PCI centre for catheterization within 6–24 h or rescue coronary intervention as required. Randomized (allocation 2:1 to pharmaco-invasive reperfusion strategy vs. primary PCI) Open-label Parallel arm Multi-centre Total number = 604 Mean age = 71 years Female sex = 32.7% White/black/other race = not available Anterior MI = 42% Median TIMI risk score = 4 Median time from Symptom onset-randomization = 100 min Median time to half-dose tenecteplase post randomization = 10 min Time to PCI post randomization = 81 min Age ≥60 years Onset of symptoms <3 h before randomization EKG meeting STEMI criteria Expected performance of PCI < 60 min from diagnosis [qualifying electrocardiogram (ECG)] or inability to arrive at the catheterization laboratory within 3 h Previous coronary artery bypass graft surgery Left bundle branch block or ventricular pacing Patients with cardiogenic shock—Killip Class 4 Patients with a body weight <55 kg (known or estimated) Uncontrolled hypertension, defined as sustained blood pressure (BP) ≥180/110 mm Hg (systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg) before randomization Known prior stroke or transient ischemic attack Recent administration of any IV or subcutaneous anticoagulation within 12 h, including unfractionated heparin, enoxaparin, and/or bivalirudin or current use of oral anticoagulation (i.e. warfarin or a novel oral anticoagulant) Active bleeding or known bleeding disorder/diathesis Known history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial, or spinal surgery) or recent trauma to the head or cranium (i.e. <3 months) Major surgery, a biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with the current myocardial infarction) Clinical diagnosis associated with increased risk of bleeding including known active peptic ulceration and/or neoplasm with increased bleeding risk Known severe renal insufficiency Prolonged cardiopulmonary resuscitation (>2 min) within the past 2 weeks Known acute pericarditis and/or subacute bacterial endocarditis Known acute pancreatitis or known severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices), and active hepatitis Dementia Previous enrolment in this study or treatment with an investigational drug or device under another study protocol in the past 7 days Known allergic reactions to tenecteplase, clopidogrel, enoxaparin, and aspirin Inability to follow the protocol, comply with follow-up requirements, or other reasons leading to increased risk of the investigational therapy Resolution of ST elevation/deviation after percutaneous intervention (PCI)/last angiography Composite of all-cause death, shock, heart failure, and recurrent MI at 30 days Stroke Major non-intracranial bleeding The time from MI onset to receiving initial reperfusion therapy with half-dose tenecteplase was 80 min sooner in the pharmaco-invasive group. Consequently, TIMI 3 flow rate pre-PCI in the pharmaco-invasive arm was 53% compared to 19% in the PCI arm, This early exposure to a fibrinolytic agent led to improved post-angiography ECG parameters of sum ST-deviation resolution (71 vs. 62%; P = 0.03) and worst lead ST-segment resolution (85 vs. 78%; P = 0.05) in the pharmaco-invasive arm. The 30-day composite event rates were similar; 12.8% with pharmaco-invasive compared to 13.3% with primary PCI [relative risk (RR) 0.96; 95% CI 0.62, 1.48]. Despite the use of half-dose tenecteplase, a 1.5% ICH rate was noted in the pharmaco-invasive arm [RR 6.61; 95% confidence interval (CI) 0.81, 53.89]. The rates of major non-intracerebral bleeding were 1.3% with pharmaco-invasive compared to 1.0% with primary PCI (RR 1.27, 95% CI 0.25, 6.48). Similar to the data observed in large registries, randomization to a pharmaco-invasive strategy translated into improved pre-PCI TIMI 3 flow rates and improvement in ST-segment parameters on ECG.11 Unlike the Canadian registry, however, no meaningful clinical benefit compared to primary PCI was noted in this trial which was underpowered to assess clinical effectiveness.5 Of major concern, a significant, unexpected 1.5% ICH rate in the pharmaco-invasive arm was observed despite the half-dose of tenecteplase that was universally utilized (restricted to age > 75 years in STREAM). All ICH events were noted in subjects < 75 years of age (range 60–74 years). In contrast, the ICH rate in STREAM was 0.5% with this modified dosage. While this may be a chance finding, individual patient characteristics, protocol violations, or factors related to the loading dosage of clopidogrel/anticoagulation may have contributed to this observation. In the setting of a relative absence of delay for primary PCI as observed in the trial, these unexpected ICH findings should temper the utilization of the protocol-mandated regimen, especially in subjects with increased risk of ICH. There was a 34% utilization of rescue angioplasty/urgent angiography in the pharmaco-invasive arm. This highlights the critical importance of having reliable transfer systems and receiving PCI hubs when adopting and effectively implementing the pharmaco-invasive approach. Morbidity and mortality following STEMI are most effectively addressed by increasing access to primary PCI that is performed in a timely fashion. However, worldwide, a significant proportion of patients presenting with STEMI will continue to have delayed access to primary PCI. The overall median time from presentation to primary PCI in STREAM 2 was within the 120 min recommended by current STEMI guidelines. In patients with longer time delays to primary PCI,12 especially in early presenters, the pharmaco-invasive approach may be the preferred strategy to limit infarct size and save lives.13 The risk of ICH remains the chink in the armour with the pharmaco-invasive approach. Despite years of prior research, the experience in STREAM 2 emphasizes the need for ongoing efforts to better understand and mitigate the risk of ICH with this approach. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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