Government and Regulations

Recommendations for Antithrombotic and Thrombolytic Therapy



Each year, 1 million people are hospitalized with a diagnosis of stroke; it was the fourth-leading cause of death in the U.S. in 2009 and 2010.1 The majority of strokes (80%) are caused by focal cerebral ischemia, and the remainder are caused by hemorrhage.1 In 2008, the direct medical costs of stroke were approximately $18.8 billion, with almost half of this amount directed toward hospitalization.1 Although stroke inpatients make up only 3% of total hospitalizations, the mortality rate is more than twice that of other patients’.1

Over the past several decades, much has been learned about the pathophysiology and treatment for ischemic stroke. The mainstays of therapies include restoring perfusion in a timely manner and targeting both clot formation and hemostasis. These therapies improve patient outcomes and reduce the risk of recurrence in appropriately selected populations.

Guideline Update

In February, the American College of Chest Physicians (ACCP) published new practice guidelines for medical patients regarding antithrombotic and thrombolytic therapy in acute ischemic stroke.2 These evidence-based guidelines are the result of new clinical trial data and a review of previous studies. They address three aspects of management decisions for stroke, including acute treatment, VTE prevention, and secondary prevention, as well as specifically address the treatment of cerebral venous sinus thrombosis.

In the management of acute ischemic stroke, several recommendations were made. In terms of IV recombinant tissue plasminogen activator (r-tPA) administration, the guidelines were expanded and allow for a less restrictive time threshold for administration. Previous recommendations limited the usage of IV r-tPA to within three hours of symptom onset in acute ischemic stroke. A science advisory from the American Heart Association/American Stroke Association (AHA/ASA) from 2009 extended that window to 4.5 hours. The 2012 ACCP guidelines have followed suit to extend this time to 4.5 hours from symptom onset as well.

In addition, intrarterial r-tPA can be given in patients not eligible for IV r-tPA within six hours of presentation of acute ischemic stroke due to proximal cerebral artery occlusion.

These updated acute stroke guidelines recommend against the use of mechanical thrombectomy based mostly on lack of data rather than lack of benefit.2

The new guidelines continue to recommend early aspirin therapy at a dosage of 160 mg to 325 mg within the first 48 hours of acute ischemic stroke. Therapeutic parenteral anticoagulation with heparin or related drugs was not recommended in patients with noncardioembolic stroke due to atrial fibrillation (afib) or in patients with stroke due to large artery stenosis or arterial dissection. In this updated analysis, there was no benefit of anticoagulation compared with antiplatelet therapy, and the risk for extracranial hemorrhage was increased. No specific recommendation regarding anticoagulation was made in patients with mechanical heart valves or intracardiac thrombus.

Updates have been made for VTE prophylaxis in patients hospitalized for acute stroke. In stroke patients with restricted mobility, prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and/or intermittent pneumatic compression devices should be initiated as early as possible. The panel is no longer recommending elastic compression stockings as VTE prevention given the risk of skin damage and no clear benefit in symptomatic VTE prevention. For patients with hemorrhagic stroke and restricted mobility, similar recommendations were made for VTE prevention, except to start pharmacologic treatment between days 2 and 4 of the hospital stay. However, if there is a bleeding concern, intermittent pneumatic compression devices are favored over pharmacologic prophylaxis. In all patients for whom pharmacologic prevention is utilized, prophylactic LMWH is preferred over UFH.

Secondary stroke prevention is addressed, with 2012 guidelines outlining a preference for clopidogrel or aspirin/extended-release dipyridamole rather than aspirin or cilostazol in patients with a history of noncardioembolic ischemic stroke or TIA. Oral anticoagulation is preferred in patients with a history of stroke or TIA with afib over aspirin alone, aspirin plus clopidogrel, or no antithrombotic therapy. Of the available anticoagulants, the panel recommended dabigatran 150 mg twice daily over adjusted-dose warfarin.2 This recommendation is based on results from the RE-LY trial, which showed dabigatran as noninferior to warfarin in patients with nonvalvular afib without severe renal failure or advanced liver disease.3

For patients who have contraindications or choose not to initiate anticoagulation, the combination of aspirin (ASA) and clopidogrel is a reasonable alternative. Timing of the initiation of oral anticoagulation should be between one and two weeks after the stroke. Patients with extensive infarction or hemorrhagic transformation should delay starting oral anticoagulation, with no exact timeline. Long-term antithrombotic therapy is contraindicated in patients with history of a symptomatic primary intracerebral hemorrhage.2 New guidelines also recommend full anticoagulation for patients with symptomatic cerebral venous sinus thrombosis.

The panel did not make any recommendations regarding statin usage. In several studies, findings showed that statins reduced infarct size and had improved outcome in all stroke types.4


Prior to the 2012 update, the last guideline for antithrombotic and thrombolytic therapy for ischemic stroke was published by the ACCP in the June 2008 issue of Chest.5 Dating back to 2001, medications included r-tPA administration within three hours of stroke symptom onset, and aspirin, clopidogrel, or a com bination of aspirin and extended-release dipyridamole for stroke prophylaxis.

The management of stroke continues to focus on early intervention and secondary prevention. Thrombolytic therapy is an effective treatment of acute ischemic stroke if given within the narrow window from onset of stroke symptoms up to 4.5 hours, with the goal of treatment within a three-hour window. Beyond this time constraint, the risk outweighs the benefit of using r-tPA except in the case of intra-arterial r-tPA administration for proximal cerebral artery occlusion.

In 2010, a meta-analysis supported this by showing that the risk of death increased significantly in patients receiving r-tPA beyond 4.5 hours. Therefore, antiplatelet therapy is the best alternative for patients ineligible for thrombolytic therapy.6 Even so, that study offered little data for patients with mechanical heart valves or intracardiac thrombi. Thus, the choice for acute anticoagulation therapy is variable and uncertain. If the hemorrhagic risk is low, anticoagulation can be considered in this subgroup, but no specific guideline endorsement was made.

In 2011, the AHA/ASA published an updated treatment guideline for patients with stroke or TIA. This was an update to 2007 guidelines that outlined the early management of ischemic stroke and affirmed the benefit of IV r-tPA at 4.5 hours for the treatment of stroke.7 Of note, IV r-tPA is only FDA-approved for treatment of acute ischemic stroke within the previously recommended three-hour period from symptom onset.

Aspirin has been found to be effective in both early treatment of acute ischemic stroke and secondary prevention. The CAST trial showed a statistically significant rate of reduction of nonfatal strokes with the use of aspirin. Other antiplatelet agents, including clopidogrel and dipyridamole, can be used. The FASTER trial compared aspirin alone versus aspirin plus clopidogrel, with no difference in outcome measures, although the MATCH trial found a larger risk of hemorrhagic and bleeding complications in the acetylsalicylic acid (ASA)-plus-clopidogrel group.6,7

In TIA or stroke patients, clopidogrel is not superior to ASA in preventing recurrent stroke. However, patients who have peripheral artery disease (PAD), previous coronary artery bypass grafting (CABG), insulin dependent diabetes mellitus (IDDM), or recurrent vascular events show a benefit of transitioning from ASA to clopidogrel for secondary long-term prevention. Clopidogrel or aspirin/extended-release dipyridamole is preferred over aspirin alone or cilostazol for long-term treatment in patients with a history of noncardioembolic ischemic stroke or TIA based on the PROFESS trial.2,7

HM Takeaways

The 2012 guidelines are a resource available to hospitalists for treating acute ischemic stroke either alone or with neurology consultation. These guidelines further define the timing of r-tPA and the use of both anticoagulation and antiplatelet therapy in the proper clinical settings.

In terms of VTE prevention, the guidelines recommend using LMWH preferentially over UH, except in patients at risk for rebleeding. The clinician should be aware of the treatment considerations for secondary prevention, noting the primary role of aspirin therapy in ischemic stroke with consideration of other agents (i.e. clopidogrel) in select populations.

Drs. Barr and Schumacher are hospitalists and assistant professors in the division of hospital medicine at The Ohio State University College of Medicine in Columbus.


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