Optimizing medical therapy after stroke

Stroke survivors often leave the hospital with new prescriptions and substantial confusion about how, or even whether, to take them. This leaves internists with the sometimes formidable job of evaluating, prescribing, or tweaking these regimens, identifying and managing adverse effects, and reinforcing education about treatment risks, benefits, and adherence.

Stroke survivors often leave the hospital with new prescriptions, and substantial confusion about how, or even whether, to take them. This leaves internists with the sometimes formidable job of evaluating, prescribing, or tweaking these regimens, identifying and managing adverse effects, and reinforcing education about treatment risks, benefits, and adherence.

Knowing the underlying cause of stroke is vital when choosing prophylaxis for future events, said Kelly Flemming, MD, a neurologist who specializes in stroke at the Mayo Clinic in Rochester, Minn. “Not every stroke is atherosclerotic and should be treated the same way, so I think joint efforts between neurologists and internists are most successful.”

Internists should start by reviewing hospital records and following up with the neurologist, if necessary, to find out whether a carotid study was done and if other tests are needed to determine the stroke mechanism, Dr. Flemming said.

Deciding among post-stroke antiplatelet or anticoagulant therapies “is a critical issue that often requires close communication between prescribers,” agreed Christopher Smith, MD, FACP, an internist who is director of medical education and medical director of quality at Pacific Medical Centers in Seattle.

After reviewing hospital records, Dr. Smith often calls the hospital neurologist with questions, such as whether atrial fibrillation was documented or only suspected. For each patient, he asks, “Which agent is likely to be the safest and most effective? Does the patient have the support and knowledge to take the medication appropriately?”

Antiplatelet agents

Antiplatelet agents, which include aspirin, aspirin/dipyridamole, clopidogrel, and ticlopidine, are recommended over oral anticoagulation for preventing recurrent noncardioembolic ischemic stroke, according to the 2014 guidelines on stroke prevention from the American Heart Association/ American Stroke Association, available online .

Some evidence supports switching to a nonaspirin antiplatelet agent if a patient has a stroke while taking aspirin monotherapy. In a large registry study, such patients had a significantly lower risk of recurrent stroke, myocardial infarction, or vascular death up to a year after switching or adding a second antiplatelet agent. The findings were published in the January 2016 Stroke.

Anticoagulation is now usually reserved for patients with certain rare coagulation disorders or atrial fibrillation. Most internists know that but may not know how best to look for atrial fibrillation in the 20% to 30% of patients whose strokes were not linked to large- or small-vessel disease, a cardioembolic source, or a coagulation disorder, Dr. Flemming said.

Paroxysmal atrial fibrillation underlies about 15% to 25% of these so-called “cryptogenic” strokes and is undertreated by antiplatelet monotherapy, Dr. Flemming emphasized. Longer-term cardiac monitoring successfully detected paroxysmal atrial fibrillation in recent studies, and AHA/ASA guidelines now recommend approximately 30 days of rhythm monitoring after cryptogenic stroke, she noted.

Options for longer-term monitoring include electrode-based devices or an implantable device, according to Dr. Flemming. Factors that predict paroxysmal atrial fibrillation include advanced age, cortical rather than subcortical stroke, stroke involving multiple arterial territories, a large left atrium on echocardiography, a history of obstructive sleep apnea, or symptoms of stroke upon awakening, she added.


Warfarin is still prescribed for post-stroke anticoagulation, but many patients receive a newer anticoagulant instead, said Margaret Fang, MD, FACP, medical director of the anticoagulation clinic at the University of California, San Francisco.

Examples include dabigatran, a direct thrombin inhibitor, and the factor Xa inhibitors apixaban and rivaroxaban. In randomized trials reported in The New England Journal of Medicine and a subtrial analysis in Lancet Neurology, dabigatran and rivaroxaban were at least as safe and effective as warfarin for preventing recurrent stroke and systemic embolism, and apixaban outperformed both aspirin and warfarin.

“There are pros and cons to using each of these agents, and the best choice for an individual patient depends on their medical conditions, preferences, life situation, and the cost of therapy,” said Dr. Fang. Since anticoagulation creates a small but real risk of hemorrhagic transformation and intracranial hemorrhage, patients need counseling on therapeutic risks and benefits, signs and symptoms of bleeding, and the importance of watching for new neurologic symptoms, she added.

Warfarin requires routine international normalized ratio (INR) monitoring, particularly during the initiation phase. Ideally, the first follow-up visit for INR monitoring should occur within 4 to 7 days of hospital discharge and often can be done with the help of an anticoagulation management service or anticoagulation clinic, Dr. Fang said.

Although the newer oral anticoagulants do not require INR monitoring, patients also benefit from close follow-up to assess adherence and tolerability. They especially need to understand that missing doses could precipitate a recurrent stroke, said Larry Goldstein, MD, chairman of the department of neurology and co-director of the Kentucky Neuroscience Institute at the University of Kentucky in Lexington.

Patients on a newer anticoagulant also should wear a medical alert bracelet or carry a medication list, he said. “If they have a stroke and cannot communicate or are otherwise incapacitated, providers need to know they are taking one of these drugs. It may not be evident on standard laboratory clotting tests and could affect how they are treated.”

Dual or monotherapy?

“In general, aside from the combination of aspirin and sustained-release dipyridamole, combination antiplatelet therapy is not indicated for secondary stroke prophylaxis after ischemic stroke,” Dr. Goldstein said. “The use of such combination therapy does not reduce the risk of ischemic stroke but does increase the risk of bleeding complications.”

In a meta-analysis of 7 trials, aspirin plus clopidogrel failed to prevent more strokes than treatment with either drug alone and increased the risk of intracranial hemorrhage compared with clopidogrel alone, researchers reported in the Oct. 1, 2013, Annals of Internal Medicine.

There are early indications that short-term dual-antiplatelet therapy might be appropriate in some cases, however. In a randomized trial in China, starting clopidogrel-aspirin within 24 hours of minor ischemic stroke or transient ischemic attack and continuing for 21 days was associated with an 8.6% rate of subsequent ischemic or hemorrhagic stroke, compared with 11.7% for aspirin monotherapy. Furthermore, dual therapy did not increase the risk of moderate or severe bleeding, researchers reported in the July 4, 2013, New England Journal of Medicine.

A similar randomized trial is ongoing in North America, but results are not yet available, Dr. Goldstein noted.

Due to higher bleeding risk, combined antiplatelet-anticoagulant therapy is usually not recommended for stroke patients with atrial fibrillation. Exceptions include patients with a high-risk source, such as mechanical valves, or clinically apparent comorbid coronary artery disease, particularly a drug-eluting stent or acute coronary syndrome, according to the 2014 AHA/ASA guidelines.

About 20% of ischemic stroke patients with atrial fibrillation have symptomatic coronary artery disease, while others are at risk for it, the guidelines note. For these patients, a stroke specialist might consider combining oral anticoagulation and aspirin or an adenosine diphosphate (ADP) receptor antagonist, because antiplatelet therapy helps prevent coronary artery disease.

Triple therapy with aspirin, an ADP receptor antagonist, and an anticoagulant is also sometimes considered for atrial fibrillation patients with acute coronary syndrome or a drug-eluting stent. But it can be difficult to balance increased bleeding risk with any benefits of either dual or triple therapy, and there is little evidence to guide the decision, according to the guidelines.

Nonetheless, a recent evidence review by the American College of Chest Physicians concluded that the benefits of 12 months of an oral anticoagulant plus aspirin or clopidogrel outweighed the risks in patients with atrial fibrillation, comorbid acute coronary syndrome, and CHADS2 scores of at least 2, indicating high stroke risk. Short-term triple therapy also had a favorable benefit-risk ratio for coronary stent patients at high risk for stroke, the review concluded.

“The choice of a specific regimen can be complex, and referral to a vascular neurologist should be considered,” Dr. Goldstein emphasized.

Additional considerations

Stroke prophylaxis generally continues indefinitely but might be revised over time based on patient response and adverse effects, Dr. Goldstein said.

For example, about 70% of patients with recent ischemic stroke have hypertension, which is crucial to treat to prevent a secondary stroke. But while patients might leave the hospital on a relatively permissive antihypertensive regimen, effective long-term control should be tighter, requiring close follow-up, Dr. Smith said.

“Good communication in the form of accurate and appropriately detailed hospital and skilled nursing facility discharge summaries is essential to delivering optimal care,” he added. “This is a place where a well-structured transitional case management program really makes a difference.”

At The Queen's Medical Center in Honolulu, transitional case managers call stroke patients and families after hospital discharge to answer questions and discuss the importance of staying on treatment. The stroke center team saw a drop in hospital readmissions as more patients were followed this way, said its director, Cherylee Chang, MD, FACP, a critical care neurologist.

But assessing long-term adherence still can be difficult, said Dr. Chang. “We do all these things like put patients on statins because this is recommended in the guidelines, but we can't be sure that patients are taking them, or did they stop it on their own? It's the same case for blood pressure medications,” she added.

Internists can help by cross-checking the discharge list, asking which medications patients are taking, educating patients about their benefits and risks, and addressing questions directly or with the help of the prescribing subspecialist.

If internists suspect recurrent stroke, they should refer patients to the emergency department of a Joint Commission-certified Acute Stroke Ready Hospital, Primary Stroke Center, or Comprehensive Stroke Center, Dr. Goldstein said. “There are a variety of reasons for recurrence or worsening of symptoms,” he added. “Management plans vary accordingly.”