TIA

The overall goal for management of a patient with transient neurological deficits is first to establish the cause of the symptoms and distinguish ischaemic insult from one of the mimics of TIA. The next objective is to risk-stratify the patients for early recurrent events and determine whether hospitalisation is needed or whether the work-up can be done on an expedited outpatient basis. One of the most important interventions to begin immediately (after brain imaging has ruled out intracranial haemorrhage) is antithrombotic therapy. This should be started on the day of initial evaluation. To maximise the benefit of stroke risk reduction, early intervention for all modifiable risk factors is needed. Evidence suggests that rapid evaluation and treatment in well-designed systems of care, such as dedicated TIA clinics, can significantly reduce the risk of second strokes. [36] [53]

Initiation of therapies to prevent second ischaemic events should be instituted immediately based on the most likely aetiology.

• Antiplatelet agents are primary therapy for atherosclerotic disease.[A Evidence]
• Anticoagulation is preferred for cardioembolic events.[A Evidence]

Aggressive risk-factor modification should be initiated including:

• Statins therapy [47]
• Antihypertensive therapy[A Evidence]
• Lifestyle modification
• Carotid endarterectomy or stenting.[B Evidence]

Neuroprotective agents remain a promising but unproven future direction for the treatment of cerebrovascular ischaemia, although results to date in studies on stroke have been disappointing. [54]

All patients should be counselled to seek care in an emergency department immediately, in case of new stroke symptoms.

Risk stratification for early stroke

Regardless of whether the work-up and treatment is performed in the inpatient or outpatient setting, speed is critical. Older guidelines recommended initial testing and secondary prevention therapy within a week; modern guidelines recommend this occurs in the first 1 to 2 days after TIA or as soon as possible. [37] [55]

TIA is most appropriately recognised as a medical urgency/emergency due to its well-recognised risk to precede a disabling stroke in much the same way as unstable angina can occur shortly before a fatal MI. The risk of stroke in the first 3 months after TIA is 10.5%. Half of these strokes occur in the first 2 days, which emphasises the narrow window of time to initiate evaluation and secondary prevention measures. [56]

Risk assessment should be performed to predict those who may be at risk for early stroke after TIA. High-risk patients (ABCD2 score of 6 or 7) have an 8.1% risk of stroke within 2 days and are reasonable candidates for hospital admission for facilitated evaluation and immediate initiation of appropriate secondary prevention. This also has the potential to shorten time to thrombolysis if an early stroke occurs. Intermediate-risk patients (ABCD2 score of 4 or 5) have a 4.1% risk of stroke within 2 days and may be considered for hospital/emergency department observation, or expedited clinic evaluation, depending on local availability. Low-risk patients (ABCD2 score of 0 to 3) have a 1% risk of stroke within 2 days and are likely to be safe for prompt outpatient evaluation and management. The ABCD2 score, or refinements such as the ABCD3 or ABCD3-I, is not a substitute for individualised judgement, but can aid in decision-making. [50] [51]

The argument for hospitalisation of high-risk patients hinges on both the need to rapidly coordinate the set of investigations needed for determining aetiology and preferred secondary prevention treatment, and also on reducing time to thrombolysis if a stroke should occur in the early post-TIA period. Guidelines recommend that hospitalisation be considered for any patient with a first TIA in the prior 1 to 2 days, and hospitalisation is generally recommended for high-risk patients. [55] Additional factors that may influence the decision to admit include significant comorbid illness such as concern for new cardioembolic source or severe carotid stenosis, socioeconomic barriers to expedited follow-up, or lack of reliable home support to observe and if necessary call emergency medical services for new stroke symptoms. [37]

Patients with transient neurological deficits who have abnormalities on the MRI diffusion-weighted imaging are at increased risk for early stroke. [57]

[National Stroke Association: ABCD2 score] (external link)

Patients with atherosclerotic or small-vessel TIA

Antiplatelet agents such as aspirin, aspirin/dipyridamole, or clopidogrel form the primary therapy for atherosclerotic disease and should be started in the first 24 hours after intracranial haemorrhage is ruled out.[A Evidence] Once started, it should be continued as maintenance for life. [58] Any of these 3 agents are considered acceptable first-line options based on cost, patient risk, tolerance, and patient preference. [25] Evidence from a single randomised trial in a Chinese population suggests benefit from a combination of aspirin and clopidogrel for the particularly high-risk period of the first 90 days after TIA. [59] A similar trial is ongoing in the US. [60] Whether to consider dual antiplatelet therapy as first line for the early management of TIA will depend on subsequent studies demonstrating that the benefit is generalisable to other populations. Switching antiplatelet agents after a TIA could be considered, but evidence does not exist that this practice reduces future stroke risk. Anticoagulation is not superior to antiplatelet therapy for non-cardioembolic stroke or TIA and carries higher haemorrhage risk. [61]

• Aspirin: the use of low-dose aspirin after TIA or small stroke was able to reduce second strokes or death by 15% to 18%. [58] [62] [63] There does not appear to be a clear dose effect for aspirin, since comparison between 325 mg and 1200 mg of aspirin found the same 15% reduction in second ischaemic events, although there was more GI upset in the higher-dose group. [63] [A Evidence]
• Aspirin/dipyridamole: has been found to be more effective than aspirin alone with the ESPS2 trial finding an 18% reduction in risk of stroke with aspirin alone compared with 37% reduction with the combination therapy. [64] [A Evidence] The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) also compared aspirin with the combination aspirin/dipyridamole, with combination therapy able to reduce the absolute rate of second ischaemic events by 1% annually. [65] Other than bleeding, the most common adverse effect is headache. [64] [65] Dipyridamole is not recommended as monotherapy. Direct comparison between aspirin/dipyridamole and clopidogrel in the PRoFESS trial showed similar rates of recurrent stroke with these two agents. [66]
• Clopidogrel: the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, comparing clopidogrel versus aspirin in patients at risk of ischaemic events, demonstrated significant reduction in the annual rate of combined endpoint of stroke, MI, and vascular death, from 5.83% with aspirin to 5.32% with clopidogrel. [67] [A Evidence] Limitations of this study include the fact that the results were not significant for reduction of stroke as a lone endpoint. Diarrhoea and rash may be side effects of clopidogrel, but peptic ulcers are less likely than with aspirin. Clopidogrel can rarely cause thrombotic thrombocytopenic purpura. Clopidogrel is the preferred agent for patients with aspirin allergy.
• Clopidogrel plus aspirin: the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack trial found greater benefit with dual therapy than aspirin alone for the limited 90-day period after TIA in Chinese patients. [59] In another trial, over a longer period (18 months), the combination of aspirin plus clopidogrel demonstrated a non-significant difference in reducing major vascular events yet significantly increased life-threatening or major bleeding compared with clopidogrel monotherapy. [68] Combined, these studies suggest that combination therapy may be of greatest benefit for the short time after TIA when risk of recurrence is highest. However, combination therapy is not likely to have a favourable risk/benefit ratio beyond the first 3 months after TIA. An ongoing trial in the US is evaluating the combination of aspirin and clopidogrel. [60] Whether to consider dual antiplatelet therapy as first line for the early management of TIA will depend on subsequent studies demonstrating that the benefit is generalisable to other populations.
• Ticagrelor: in the Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack trial, ticagrelor was not found to be superior to aspirin. However, it has been argued that this medication could be used as monotherapy (off-label) if it is felt that a patient is intolerant to other antiplatelet therapy, or if other antiplatelet therapy has failed. [69]

Patients should also be started on statin and antihypertensive therapy if appropriate. Patients with significant (>50%) symptomatic ipsilateral carotid stenosis should be referred to a vascular surgeon for treatment.

Patients with cardioembolic TIA

Anticoagulation therapy is superior to antiplatelet therapy for prevention of cardioembolic strokes and should be started within the first 2 weeks; the author favours early initiation following cardioembolic TIA. [58] [70] [71] [A Evidence]

Warfarin to a goal INR of 2.0 to 3.0 or novel oral anticoagulants (e.g., dabigatran, rivaroxaban, apixaban, and edoxaban) are considered first-line options for patients with atrial fibrillation. Anticoagulation reduces the risk for second strokes in patients with atrial fibrillation by two-thirds. [70] Patients with mechanical heart valves should be treated with warfarin. Mitral mechanical prosthetic valves require a higher INR goal (i.e., 2.5 to 3.5). [72] Addition of aspirin to warfarin is suggested for mechanical valvular disease associated with cardioembolic cerebrovascular accident, but the combination is not routinely recommended for rheumatic valve disease. [25]

Evidence supports the efficacy and safety of novel oral anticoagulants in prevention of cardioembolic stroke due to atrial fibrillation; meta-analyses suggest these agents have a favourable risk-benefit profile compared with warfarin. [73] [74] They have the significant advantage of fast onset and eliminate the need for monitoring. They share the disadvantages of higher drug cost and inability to reliably monitor anticoagulant effect using prothrombin time, INR, or PTT. They are contraindicated in people with mechanical heart valves. Use of any of the new oral anticoagulants should be considered a contraindication to intravenous thrombolysis regardless of level of prothrombin time, INR, or PTT. These novel oral anticoagulants appear to be cost effective compared with warfarin, especially for patients who are difficult to maintain in therapeutic range using warfarin. [75] [76]

Dabigatran is a direct thrombin inhibitor that has been shown to prevent stroke in patients with non-valvular atrial fibrillation as well as, or better than, warfarin, with a similar risk of bleeding. [77] [78] [79]

Rivaroxaban is an oral factor Xa inhibitor demonstrated to reduce stroke risk in patients with non-valvular atrial fibrillation and has been found to be non-inferior to warfarin with similar bleeding risk. [80]

Apixaban is an oral factor Xa inhibitor also demonstrated to reduce stroke risk as well as or better than warfarin in patients with non-valvular atrial fibrillation and was found to have lower bleeding risk. [81]

Edoxaban is an oral factor Xa inhibitor demonstrated to reduce stroke risk as well as, or better than, warfarin in patients with non-valvular atrial fibrillation, and was found to have a lower bleeding risk. [82]

Aspirin, or aspirin plus clopidogrel, [25] [58] should be used only if anticoagulation is contraindicated. Aspirin is inferior to anticoagulation therapy in stroke prevention for patients with atrial fibrillation but may be the only option for a patient with a contraindication to anticoagulants. The combination of clopidogrel and aspirin carries a similar haemorrhagic risk as warfarin, and so is not recommended as an alternative to anticoagulation in patients with a haemorrhagic contraindication.

Anticoagulation is recommended for cardioembolic TIA in conjunction with stable ischaemic heart disease. [83] Guidelines recognise increased bleeding risk with the combination of anticoagulation and antiplatelet therapy and do not recommend this for routine use in stable coronary artery disease in conjunction with atrial fibrillation. [25] [83] A meta-analysis found no incremental benefit of combination therapy over anticoagulation alone.[84] Uncertainty about the benefit of combination therapy is especially true with the new oral anticoagulants for which experience is more limited. Combination therapy is recommended when a cardioembolic cerebral ischaemic event on therapeutic anticoagulation has occurred in the setting of mechanical heart valves. [25] Routine combination anticoagulant and antiplatelet therapy is not recommended for cardioembolic TIAs due to atrial fibrillation. [25]

Data on early use of heparin or low molecular weight heparin after acute stroke offer mixed results, with a decrease in early stroke recurrence matched by an equal increase in early intracranial haemorrhage and is not recommended. [54] The use of bridging heparin or low molecular weight heparin versus aspirin acutely after cardioembolic TIA until warfarin is therapeutic is controversial, but aspirin as a bridging agent is reasonable given its proven role in the acute setting.

Patients should also be started on statin and antihypertensive therapy if appropriate.

Statin therapy in patients with TIA

Statin therapy has been demonstrated to provide benefit acutely after cerebrovascular ischaemia and can be started on presentation.[B Evidence] The SPARCL trial utilised high-dose atorvastatin after acute CVA, which led to an absolute risk reduction of second stroke of 2.2% over the next 5 years. [48]High-intensity statin therapy is recommended for all patients <75 years of age with TIA, and moderate-intensity statin therapy is recommended for patients >75 years of age with TIA. [47]

Guidelines define statin intensity as follows. [47]

• High-intensity statin therapy: daily dose lowers LDL cholesterol, on average, by approximately ≥50%.
• Moderate-intensity statin therapy: daily dose lowers LDL cholesterol, on average, by approximately 30% to <50%.
• Low-intensity statin therapy: daily dose lowers LDL cholesterol, on average, by approximately <30%.

Statin therapy has the strongest evidence base for reducing stroke risk but treatment with either nicotinic acid or gemfibrozil can be considered if the HDL is low.

Antihypertensive therapy in patients with TIA

Control of chronic BP results in a 30% to 40% risk reduction in stroke. [25] [A Evidence] Diuretics, angiotensin-II receptor antagonists, and angiotensin-converting enzyme (ACE) inhibitors have all been studied and found effective in reducing stroke risk, but the optimal agent or combination has not been determined.

While the recommendation is to allow permissive hypertension to a BP of 220/120 mmHg in the hyperacute period after stroke (to improve perfusion to the at-risk penumbra), after TIA there is little rationale for permissive hypertension, and initiation of antihypertensive therapy is reasonable the day of, or following, the TIA as long as there are no neurological deficits. [54]

BP reduction appears to reduce second stroke rates without a threshold for benefit, and so lowering BP is recommended even in patients without a prior history of hypertension, as long as their BP is above normal and they would tolerate the reduction. [25] Caution is advised in lowering BP in patients with severe carotid stenosis prior to endarterectomy.

BP reduction should be considered in all patients with above-normal BP (i.e., defined as ≥120/80 mmHg) after TIA. [25] Lifestyle modifications including salt restriction, weight loss, healthy diet, exercise, and limited alcohol consumption are considered reasonable interventions for most people with above-normal BP; however, antihypertensive therapy should be started in patients with a BP of ≥140/90 mmHg. The goal BP should be individualised for each patient. [25]

Patients with carotid stenosis

For patients with significant (≥50%) symptomatic ipsilateral carotid stenosis, referral to vascular surgery for carotid endarterectomy is appropriate as long as the patient is neurologically stable, with surgery within 2 weeks of the event preferred. [20] [25] [B Evidence] Benefit is strongest for patients with stenosis of >70% but not complete occlusion. A good candidate should have a life expectancy long enough to be able to obtain the long-term benefit of stroke reduction in return for an upfront surgical risk that should be lower than 6% to 7%. [85]

Carotid stenting is an alternative procedure for carotid stenosis especially for patients who are poor candidates for carotid endarterectomy due to surgical risk. [86] Endovascular treatment of intracranial stenosis has not been demonstrated to be better than aggressive medical therapy. [25] [49][87]

Optimisation of glycaemic control in patients with TIA

In diabetic patients with TIA, existing guidelines for glucose control should be followed. A goal HbA1c of <53 mmol/mol (<7%) is recommended for most patients. [25]

Lifestyle modification in patients with TIA

• Patients with TIA who smoke are strongly advised to stop.
• Alcohol consumption should be eliminated or reduced in heavy drinkers.
• Reduction in weight is encouraged to goal BMI of 18.5 to 24.9 kg/m^2.
• Moderate-intensity physical exercise for 30 minutes on 3 to 4 days per week should be considered. [25] [  ] [  ]

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