Importance: Intravenous recombinant tissue plasminogen activator (alteplase) was approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Nearly 20 years later, it remains the only approved treatment, despite limitations in both efficacy and safety. With a growing capacity for stroke treatment worldwide, physicians need to understand where we have come from and what the future of stroke treatment might be.
Objective: To present a historical prospective as well as current trends in thrombolytic therapy, focusing on characteristics of drugs that have worked and clinical trials that are moving the field forward.
Evidence review: Sources are published pivotal clinical trials; seminal articles on physiology, pharmacology, and neuroimanging; and listings from clinical trial registries.
Findings: The slow progress in thrombolysis for acute stroke has been multifactorial. A focus on extending the time window for alteplase beyond 4.5 hours has encumbered substantial resources in the field for many years, yet these efforts have been largely unsuccessful. New drug development has also been slow. Several drugs have failed in clinical trials and currently only tenecteplase remains to be tested as a potential alternative to alteplase. The parallel pursuit for catheter-based interventional revascularization in acute stroke, which appears to be successful, has shifted emphasis away from pharmacologically based studies.
Conclusions and relevance: Although the field of acute thrombolysis has been making progress slowly for many years, advances in neuroimaging and new clinical trials that combine thrombolytics with other pharmacological and interventional techniques are beginning to gain momentum once again. The emergence of new approaches based largely on combination therapy strategies has reset a course to advance thrombolytic treatment for acute stroke and promises to improve outcomes in acute stroke in the near future.