Episode 109. STREAM-2 Study Journal Club with Nick Servati and Alex Cruz Pabon


Title: STREAM-2: Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Segment–Elevation Myocardial Infarction: A Randomized, Open-Label Trial

Background/Purpose: STEMI guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. In the STREAM-1 study (Strategic Reperfusion Early After Myocardial Infarction), a pharmaco-invasive strategy resulted in similar rates of death, shock, heart failure, or reinfarction, compared with primary PCI but an excess of ICH in patients ≥75 years of age prompted a protocol amendment that halved the dose of weight-adjusted bolus tenecteplase. After the adjustment, there was no subsequent ICH. STREAM-2 sought to investigate if half-dose tenecteplase is effective and safe in older patients with STEMI.

Patient Population: (N=604)

  • Included:
    • Age ≥60 years*
    • Onset of symptoms < 3 hours prior to randomisation
    • 12-lead ECG indicative of an acute STEMI (ST-elevation will be measured from the J point; scale: 1 mm per 0.1 mV):
      • ≥2 mm ST-elevation across 2 contiguous precordial leads (V1-V6) or leads I and aVL for a minimum combined total of  4 mm ST-elevation
      • ≥2 mm ST-elevation in 2 contiguous inferior leads (II, III, aVF) for a minimum combined total of  4 mm ST-elevation
    • Informed consent received
      • *Original protocol included patients ≥70 years of age but slow recruitment (+analysis of bleed starting ~60) prompted an amendment to include patients ≥60 years of age.
    • 2020 Armstrong et al, trial design amendment
      • Performed an internal systematic review of the ASSENT trial series and their initial STREAM-1 trial à risk of major bleeding and/or ICH begins to increase around the age of 60 years
      • Amendment made in 2018, ~1 year into enrollment that lasted thru 2022
  • Exclusion criteria:
    • Expected PCI < 60 min from diagnosis (qualifying ECG) or inability to arrive at the catheterisation laboratory within 3 hours
    • Previous CABG
    • LBBB or ventricular pacing
    • Cardiogenic shock – Killip Class 4
    • Wt < 55 kg (known or estimated)
    • Uncontrolled HTN (sustained SBP >180 mmHg and/or DBP >110 mmHg) prior to randomisation
    • Known prior stroke or TIA
    • AC within 12 hours (UFH, enoxaparin, and/or bivalirudin or current use of OAC (i.e. warfarin or a NOACs)
    • Active bleeding or known bleeding disorder/diathesis
    • Known Hx of CNS damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) or recent trauma to the head or cranium (i.e. < 3 months)
    • Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (includes any trauma associated with the current MI)
    • Clinical Dx associated with increased risk of bleeding including known active peptic ulceration and/or neoplasm with increased bleeding risk
    • Known severe renal insufficiency
    • Prolonged CPR(> 2 minutes) 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 enrollment in this study or Tx with an investigational drug/device under another study protocol in the past 7 days
    • Known allergic reactions to tenecteplase, clopidogrel, enoxaparin and aspirin
    • Inability to follow the protocol and comply with follow-up requirements or any other reason that the investigator feels would place the patient at increased risk if the investigational therapy is initiated.

Treatment Regimen: 

  • Intervention (Pharmacoinvasive): half-dose Tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization (n=401)
    TNKase Dosing

* 50 or 40 mg of drug reconstituted in 10 or 8 ml SWFI given as single weight-adapted IV bolus over 5 to 10 seconds

  • Control: Primary PCI (n=203)
    • *median time Sx to randomization
      • → TNKase: 97 min
      • → PCI: 92 min
    • *median times from randomization to Tx
      • → TNKase: 10 min (could be pre-hospital) – so in total: 107 min or just shy of 2 h from sx to lytic
      • → Sheath insertion: 81 minutes

Adjunctive therapy (in addition to intervention Tx): 

  • Pharmacoinvasive Group
  • ASA: 150 to 325 mg
    • 75-100 mg/d thereafter
  • Clopidogrel: 300 mg
    • Current guidelines rec NO LOAD for 75 years or older, however in this trial roughly 1/4th were 75 or older and would have received the 300 mg load
    • 75 mg/d thereafter
  • SQ enoxaparin 0.75 mg/ kg + additional IV dose of 30 mg in patients ≤75 years (after amendment)
    • Was continued q12h until discharge or MAX 4 days
    • CrCl <30 = q24h dosing
  • Meds in the Primary PCI group (according to local guidelines)
    • Aspirin
    • P2Y12 antagonist
    • anticoagulants

Therapy considerations: If unsuccessful reperfusion 60-90 min after TNKase (≥50% ST resolution in the ECG lead with maximum ST-segment elevation and clinical stability): coronary angiography was undertaken 6 to 24 hours after randomization → rescue PCi if failed reperfusion based on ST resolution/instability


  • Design:
    • Investigator-initiated, open-label, randomized, multicenter study
    • N=604
    • 49 centres in 10 countries (Canada, France, Spain, Mexico, Brazil, Chile, Australia, Russia, Serbia, Montenegro)
    • From August 1, 2017 to September 12, 2022
    • Goal for power = 600 pts (400 pharm/200 PCI) → after 50% recruitment
      • Original protocol included patients ≥70 years of age but slow recruitment (+analysis of bleed starting ~60 yrs) prompted an amendment to include patients ≥60 years of age
  • Efficacy Endpoints: 
    • PRIMARY: ST resolution (≥50%)
    • 30-day composite of death, shock, HF, or reinfarction (not powered)
      • Shock: SBP<90min, req VP or interventions to maintain BP, HR>60 + Sx of end organ damage (UO<30 ml/hr, confusion, cold ext) OR CI<2.2 + PCWP>15
      • HF: requiring diuretics + pulmonary oedema/congestion, rales KC≥2,, PCWP >25 mmHg, dyspnea with pO2 < 80 mmHg or O2 sat < 90%  in the absence of known lung disease
      • Reinfarction related to PCI or surgery
        • ≤48 hrs after PCI: trops>5x 99th percentile; >20% trop rise if previously stable/falling; new ischemic changes ECG/angiography
        • >48hrs after PCI/CABG: Rise/fall of trops & ≥99th percentile URL % ≥1 of the following: • Sx of ischemia; • New significant ST-T changes or new LBBB; • Pathological Q waves in the ECG; • Imaging New loss of viable myocardium or new regional WMA; • Identification of an intracoronary thrombus eg stent thrombosis by angiography or autopsy
        • ≤48 hrs after CABG: trops>10x 99th percentile; >20% trop rise if previously stable/falling +  new Q waves/LBBB OR angiographic documented new graft or new native coronary artery occlusion or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
  • Safety Endpoints (ITT)
    • Stroke
    • Non-intracranial bleeding

Follow Up: 

Results  Avg. patient: 71 y/o male (two-thirds) with HTN (55%), DM. P/w inferior STEMI (~60%), mostly Killip class I (no signs of congestion) & great BP (SBP 130s), TIMI Risk score 4 (corresponds to a ~20% risk of 14-day death, new MI, recurrent MI, or ischemia req’ing repeat intervention; max score is 7 = 41% risk)


  • ST resolution
    • → Pharmaco-invasive: 85.2%
    • → median declined from  3.0 to 1.0 mm
    • → pPCI: 78.4%
    • *residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively
    • * TIMI flow grade 3 at last angiography ≈87% in both groups. / 53.8% after TNKase versus 18.9% before PCI
  • Rescue PCI:168 (42.2%) patients randomly assigned to a pharmaco-invasive strategy at median 142 min from randomization
  • Of 401 pts given TNK, 345 (86%) went for angiography within 24 h (rescue or not), and most of them received stents (335 or 84% of total)
  • Composite Clinical endpoint
    • → Pharmaco-invasive: 12.8% (51/400)
    • → pPCI:  13.3% (27/203)
    • (RR,, 0.96 [95% CI, 0.62–1.48])

→ 3/37 non-cardaic deaths in pharmaco-invasive group related to ICH


  • ICH
    • → Pharmaco-invasive: 6 (1.5%)
    • 3 protocol violations (excess AC 2/6 and uncontrolled HTN [174/117] in 1/6)
    • Therapeutic IV UFH during rescue PCI despite full-dose IV/SC LMWH
    • This underscores the value of pharmacist involvement – authors commented “underscores the hazard…also reinforces the need for clear and timely communication regarding given treatments between various members of the health care team when rapid transitions in STEMI care unfold.”
    • → 1ry PCI: 0
    • RR 6.61 (0.81-53.84)
  • Non-ICH bleeding
    • → Pharmaco-invasive: 5/400 (1.3%)
    • → 1ry PCI: 2/203 (1.0%)
    • RR 1.27, 95% CI 0.25-6.48 → no difference
  • Stroke
    • → Pharmaco-invasive: 9/400 (2.3%)
      •   → 3 fatal (0.75%), none in pts>75 y
    • → 1ry PCI: 1/203 (0.5%)

Pre-specified subgroup analysis

  • Only found 1 significant difference in favor of pharmaco-invasive strategy, which was when pts were randomized to TNK within 60 minutes
    • Aligns with the idea of a “golden hour” where lytic therapy is most efficacious within the 1st 60 minutes


  • Not powered to show a difference in clinical events
  • Possibility of heterogeneity between meds for pPCI in local guidelines
  • Protocol violations could have influenced increased bleeding risk
  • Unblinded intervention (for obvious reasons), but could have contributed to bias


  • TNKase ½ dose led to comparable ECG changes as 1ry PCI in early presenting, older pts w/ STEMI
  • Nick – One of my personal takeaways – this trial and the continued adoption of pharmaco-invasive strategies even in the most recent ACS guidelines (2023 Europeans) highlights the continued challenge in accessing timely PCI even in developed STEMI networks
    • Based on 2010 census data and 2011 AHA data, ~85% of the US is within 1 hour of a PCI Center.
    • However that leaves 50 million Americans (a decade ago) farther out
    • Sadly, even when holding rural & urban locations as a constant, low-income areas and highly Hispanic communities had the largest delays to PCI
    • Growth of PCI capable centers continues around resource-risk areas leading to a worsening imbalance despite continued growth in health-care infrastructure
  • Higher ICH risk w/ TNKase
    • Although that risk remained the same as the original STREAM-1 trial from a decade ago (1.5%), and 0 events have occurred in those 75 or older since the original protocol amendment in STREAM-1 for ½ dose TNK
  • PCI is preferred but if unavailable, ½ dose pharmaco-invasive strategy is a reasonable alternative, provided that CI to fibrinolysis are observed and excess anticoagulation is avoided
    • Do we feel comfortable broadening this rec to alteplase?
      • Only trial for alteplase was the EARLY-MYO rial which was ½ dose tPA for a pharmaco-invasive strategy in China that excluded those >75 years


Jimmy L. Pruitt III, PharmD, BCPS, BCCCP

The Pharm So Hard Podcast is a show focused primarily on emergency medicine and hospital pharmacy related topics. To empower healthcare providers with the knowledge and skills they need to provide evidence-based, safe care for critically ill patients.

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