Kori S. Zachrison, MD, MSc, and Lee Schwamm, MD, are the co-authors of a new commentary in Med, The promise of tenectplase in acute stroke: within reach or beyond approval?
Dr. Zachrison is a physician investigator in the Department of Emergency Medicine at Massachusetts General Hospital and an Associate Professor of Emergency Medticine at Harvard Medical School.
Dr Schwamm is Director of the MGH Center for Telehealth and the C. Miller Fisher Chair in Vascular Neurology at Mass General, and a Professor of Neurology at Harvard Medical School.
What was the question you set out to answer with this study?
Reperfusion, or the restoration of blood flow to the brain, is critical for improving outcomes of patients experiencing ischemic stroke.
A growing body of literature supports the use of tenecteplase (TNK) for intravenous thrombolysis to restore perfusion for patients with acute ischemic stroke.
Using TNK in place of alteplase is appealing mechanistically, as TNK is delivered as a single bolus rather than an infusion, has more fibrin-specificity, longer free plasma half-life, greater resistance to inactivation, and less procoagulant effects than alteplase. But is it better clinically?
What Were Your Findings?
- A number of Phase 2 and 3 clinical trials comparing TNK and alteplase have supported claims of efficacy for TNK in acute ischemic stroke
- TNK has additionally demonstrated early evidence of superiority in recanalization of large arteries in patients with strokes due to large vessel occlusion (LVO)
- The first Phase 3 pragmatic, randomized trial in ischemic stroke comparing TNK at a dose of .025 mg/kg to alteplase 0.9 mg/kg found that 36.9% of patients in the TNK group had favorable functional outcomes at 90-120 days versus 34.8% in the alteplase group
- These results bring further clinical evidence to support a strategy of shifting to TNK from alteplase throughout the 0-4.5-hour window from stroke onset.
In addition to the increasingly well-established clinical evidence supporting TNK, elements related to stroke systems of care and human factors further compel the change.
- In contrast to alteplase, which requires a bolus followed by an hour-long infusion, TNK is administered as a single bolus over 5-10 seconds. Delays between bolus and start of infusion can lead to failure to achieve therapeutic drug concentrations.
- As more communities adopt mobile stroke units (MSU), equipped with CT scanners and multidisciplinary neurologist-led teams, patients will increasingly have the opportunity to receive thrombolytic medication in the prehospital setting.
- Where alteplase requires additional equipment such as infusion pumps, the single bolus administration of TNK does not.
Finally, both in the US and internationally, TNK is consistently less expensive than alteplase (one online source notes manufacturer's retail cost of about USD $6,000 per dose of TNK versus about $9,000 per dose of alteplase).
Recent action by the Centers for Medicare and Medicaid Services provides additional flexibility for negotiating drug prices, which could eventually lead to further savings on intravenous reperfusion medications.
Unfortunately, lack of FDA approval for alteplase–to say nothing of TNK –in the 3-4.5-hour window leads to undertreatment of patients. In turn, undertreatment of patients leads to significant post-stroke morbidity and mortality.
An FDA-approved label extension could eliminate yet another barrier to expanded thrombolysis use, reinforce the efficacy claims of thrombolysis in the 3-4.5-hour window and avoid placing physicians in any perceived or actual increased risk or being held liable for malpractice. Ideally, efficacy-related label updates would be made (1) for alteplase: to extend the eligibility window to include the 3-4.5 hours among eligible patients, and (2) for TNK: to expand its indications from acute myocardial infarction to also include ischemic stroke from 0-4.5 hr.
What are your conclusions?
In summary, there are many stakeholders with the common goal of expanding access to acute ischemic stroke treatment. To address the low rates of thrombolytic receipt among potentially eligible patients and the subsequent morbidity and mortality that result, these stakeholders must come together and coordinate their approaches to achieve this goal.
Strategies to enhance FDA consideration of internationally generated evidence, facilitate efficacy-based label expansions, and incorporate real-world evidence into regulatory considerations may be of great value and are avenues worth exploring.
Zachrison, K. S., & Schwamm, L. H. (2022). The promise of tenecteplase in acute stroke: Within reach or beyond approval?. Med (New York, N.Y.), 3(10), 651–655. https://doi-org.treadwell.idm.oclc.org/10.1016/j.medj.2022.09.005
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.