Cerebrovascular Disease: Decision Making Including Optimal Medical Therapy

Aspirin Monotherapy

Most guidelines recommend aspirin monotherapy (100–325 mg daily) throughout the perioperative period, followed by 75–325 mg daily thereafter. The Aspirin and Carotid Endarterectomy (ACE) trial, showed that lower-dose aspirin (81–325 mg daily) was superior to higher doses (650–1300 mg daily) in reducing stroke/MI/death at 30 days in CEA patients (3.7% vs. 8.2%, P = 0.002). However, recent evidence suggests that antiplatelet monotherapy is less effective than combination therapy in many ischemic TIA/stroke patients.

Combination Antiplatelet Therapy

Three RCTs (CHANCE, POINT, FASTER ) randomized 10,447 patients <24 hours of minor ischemic stroke (NIHSS ≤3) ^8–10 or “high-risk TIA” (ABCD score ≥4) ^, to aspirin monotherapy or short-term aspirin + clopidogrel combination therapy. A meta-analysis showed that, at 90 days, aspirin + clopidogrel significantly reduced nonfatal ischemic/hemorrhagic stroke, nonfatal ischemic stroke, moderate–severe functional disability and poor quality of life vs. aspirin alone.

A British Medical Journal Guideline Panel concluded that the evidence was robust enough to recommend prescribing aspirin + clopidogrel for 21 days, followed by clopidogrel monotherapy in patients presenting with acute, high-risk TIA/minor ischemic stroke. This was because most stroke prevention occurred in the first 10 days after symptom onset. Limiting combination therapy to 21 days reduced late bleeding complications. A number of guidelines now recommend aspirin + clopidogrel therapy for 21 days in patients with minor non-cardioembolic ischemic stroke who have not received intravenous tissue plasminogen activator, or for 21 days, or 21–30 days in patients with a high-risk TIA or minor ischemic stroke.

However, no guideline has advised surgeons regarding combination antiplatelet therapy in recently symptomatic patients with 50%–99% stenoses awaiting urgent CEA. This is mainly because they were excluded from CHANCE/POINT, in addition to concerns about increased perioperative bleeding complications with combination therapy. Accordingly, whilst there is good evidence supporting a 21-day prescription of aspirin + clopidogrel in patients with TIA/ischemic stroke without a 50%–99% stenosis, there is no RCT evidence that the balance of benefit vs. risk also favors combination therapy in patients with 50%–99% stenoses awaiting CEA.

Other evidence favoring combination therapy prior to CEA comes from a prospective audit, where there was a 48–72-hour delay between patients being seen in a TIA clinic and undergoing CEA. During this time, 13% experienced recurrent stroke/ TIAs. When a decision was made to start aspirin + clopidogrel in the TIA clinic (once CT/MRI excluded parenchymal hemorrhage), recurrent clinical events prior to CEA fell fivefold from 13% to 3%, in association with a fourfold reduction in spontaneous embolization on transcranial Doppler (TCD), from 21% to 5%. From the surgeon’s perspective, performing CEA in patients on aspirin + clopidogrel was not associated with significantly increased bleeding complications (3%). Similar observations were made by the Vascular Study Group of New England ( n = 5264), which reported that re-exploration for neck hematoma was 1.5% on no antiplatelet therapy, 1.2% on aspirin monotherapy, 0.7% on clopidogrel monotherapy and 1.4% on aspirin + clopidogrel combination therapy.

Accordingly, clinicians now face three clinical scenarios where early institution of combination antiplatelet therapy may be the preferred option — a patient with: (1) 0%–49% stenosis with no other cause for TIA/stroke on neurovascular work-up; (2) recent TIA/stroke and a 50%–99% stenosis, where CEA/CAS is not being considered; and (3) recent TIA/stroke and a 50%–99% stenosis where urgent CEA/CAS is planned.

Data extrapolation from “non-carotid stenosis” patients with TIA/minor stroke for scenarios 1 and 2 support a 300-mg loading dose of clopidogrel plus 162–325 mg of aspirin (see Chapter Algorithm). Patients then receive 75 mg clopidogrel daily and 162–325 mg aspirin daily from days 2–7, followed by 75 mg clopidogrel and 75–81 mg aspirin daily through days 8–21. The patient then reverts to long-term clopidogrel monotherapy (75 mg daily). In patients with 0%–49% stenosis, an alternative would be aspirin + dipyridamole, with dosages detailed in the Chapter Algorithm. Similarly, aspirin plus full-dose dipyridamole can be considered in patients with 50%–99% symptomatic stenoses (higher risk of recurrent stroke), where a decision has been made not to undergo CEA/CAS (see Chapter Algorithm).

In the third scenario, several options are available (see Chapter Algorithm). Whilst CHANCE, POINT and FASTER only included patients <24 hours of symptom onset, if the surgeon is happy to perform expedited CEA in patients prescribed aspirin + clopidogrel, it is reasonable to start combination therapy even if patients present >24 hours after TIA/minor stroke onset (especially the first 10 days) which is the highest risk period for recurrent stroke. Parenchymal hemorrhage should be excluded on CT/MRI and the patient should receive 300–325 mg aspirin, if not already on aspirin, followed by 75–81 mg aspirin daily in combination with 75 mg clopidogrel daily from day 1 (without a 300-mg loading dose). Expedited CEA, with careful control of postoperative BP, should be performed, as uncontrolled post-CEA hypertension increases the risk of hyperperfusion syndrome, intracranial hemorrhage (ICH) and neck hematoma formation. Aspirin can be stopped on day 1 after CEA and clopidogrel (75 mg daily) continued indefinitely, unless contraindicated.

If the surgeon is unwilling to perform CEA in patients prescribed aspirin + clopidogrel, an alternative would be 300–325 mg aspirin from day 1–14 and then reduce the long-term aspirin dose to 75–81 mg daily, in combination with dipyridamole MR 200 mg BD from day 1, following advice about potential side effects (see Chapter Algorithm). This regime was equally effective in reducing TCD-detected micro-emboli as aspirin + clopidogrel in patients with ≥50% symptomatic stenoses.

Antiplatelet Strategies Prior to CAS

CAS patients are prescribed combination antiplatelet therapy, mainly based on coronary stenting RCT data, but supported by one RCT involving 47 patients with 70%–99% carotid stenosis who underwent CAS (38 symptomatic, 9 asymptomatic).

Ticlopidine is rarely prescribed in TIA/stroke patients due to a less favorable adverse effect profile. Accordingly, it is reasonable to prescribe 300–325 mg aspirin daily for up to 14 days, followed by 75–81 mg daily, if not already taking aspirin. Clopidogrel (75 mg daily) is started 3 days prior to CAS, or as a 300-mg loading dose in urgent cases. Combination therapy should continue for at least 4 weeks post-CAS. Thereafter, patients revert to either aspirin or clopidogrel monotherapy. Long-term aspirin + clopidogrel therapy is rarely prescribed, unless for cardiac reasons, because the risks of long-term aspirin + clopidogrel combination therapy outweigh the benefits of monotherapy after TIA/ischemic stroke.

If intolerant of, or allergic to, aspirin and clopidogrel, 200 mg BD of dipyridamole monotherapy should be considered. It is also important to prescribe gastric protection with proton pump inhibitors that do not interact with clopidogrel (e.g., pantoprazole) in patients prescribed combination antiplatelet therapy to reduce gastrointestinal bleeding complications.

Assessment of Antiplatelet “High On-Treatment Platelet Reactivity” (HTPR)

A recent meta-analysis of pooled data from several platelet function testing platforms showed a higher risk of recurrent TIA/stroke, myocardial infarction (MI) or vascular death in TIA/ischemic stroke patients with vs. without “antiplatelet HTPR” (previously referred to as “antiplatelet resistance”) on any antiplatelet regimen (OR 2.93; 95% CI: 1.90–4.51).

Aspirin-HTPR has been reported in 23%–57% and clopidogrel-HTPR in 50%–75% of patients with 50%–99% asymptomatic carotid stenosis (ACS), with the prevalence being positively influenced by the shear-stress levels to which platelets are exposed in the platelet function testing platform. The prevalence of aspirin-HTPR can vary between 9.5% and 64% and the prevalence of clopidogrel-HTPR between 0% and 83% in patients with ≥50% symptomatic stenoses. However, no studies have been adequately powered to definitively determine whether ex vivo HTPR status predicts the risk of clinical events in asymptomatic or symptomatic patients in the perioperative or non-perioperative periods. Accordingly, evidence does not currently support routine alteration of antiplatelet therapy based on ex vivo antiplatelet-HTPR testing outside of research studies/clinical trials.

Combination Antiplatelet and Direct Oral Anticoagulant Therapy in Carotid Stenosis

There is interest in the potential benefits of combining antiplatelet therapy with low-dose direct oral anticoagulant (DOAC) therapy in patients with vascular disease. In the COMPASS trial, patients with coronary artery disease, peripheral arterial disease, or carotid disease (prior CEA/CAS or ≥50% ACS) were randomized to 100 mg aspirin monotherapy ( n = 9126), combination therapy with low-dose rivaroxaban (2.5 mg BD) and 100 mg aspirin daily ( n = 9152), or 5 mg BD of rivaroxaban monotherapy ( n = 9117). Patients were excluded if they suffered a non-lacunar ischemic stroke within 1 month of randomization or had a history of hemorrhagic or lacunar stroke.

Approximately 7% of COMPASS patients had a history of carotid disease. In this subgroup, there was no statistically significant benefit for combination therapy with low-dose rivaroxaban + aspirin, versus aspirin alone in preventing stroke, MI or cardiovascular death (HR 0.63; 95% CI: 0.38–1.05; P = 0.07). However, there was no significant increase in major bleeding risks (HR 1.18; 95% CI: 0.55–2.51; P = 0.67). There was also no benefit for rivaroxaban 5 mg BD vs. aspirin alone, in reducing major vascular events (HR 1.01; 95% CI: 0.65–1.56), but “higher-dose” rivaroxaban increased major bleeding risks (HR 2.34; 95% CI: 1.21–4.52; P = 0.009). Accordingly, there is no current evidence to recommend routine combination therapy with low-dose rivaroxaban and aspirin in carotid stenosis patients.

Clinical Features

Should a Small Intracranial Aneurysm Affect Decision-Making?

About 3%–5% of symptomatic patients will have an incidental, small intracranial aneurysm and there has been concern that these aneurysms might increase early/late stroke risks after CEA. NASCET reported that 90/2885 patients (3.1%) had 99 intracranial aneurysms. The majority (83%) were <5 mm, with a 0.3% incidence of aneurysm >10 mm (usual threshold for neurosurgical /neuroradiological intervention). The 5-year risk of ipsilateral stroke in CEA patients was 10% with a non-repaired aneurysm, versus 14.8% in patients without an aneurysm. The 5-year risk of ipsilateral stroke in OMT patients was 22.7% with a non-repaired aneurysm, versus 22.5% in those without an aneurysm. The evidence, therefore, suggests that small intracranial aneurysms do not significantly increase risks of early/late stroke after CEA.

Recency of Symptoms

Most guidelines have adopted a 6-month threshold as being “recently symptomatic.” This permits substantial leeway regarding CEA timing, especially with an assumption amongst some surgeons that intervening early after symptom onset increases perioperative risks. The momentum for changing practice and intervening early after symptom onset was driven by a 2003 CETC meta-analysis of the benefit conferred by CEA, stratified for delays from randomization to CEA. ^, In reality, CEA was performed an average of 7 days after randomization (PM Rothwell, personal communication). Table 92.2 details the results of this meta-analysis stratified for delays to CEA, stenosis severity and patient sex. The benefit conferred by CEA was greatest the earlier CEA was performed. Greater benefit was also observed in patients with 70%–99%, versus 50%–69% stenosis. Males gained greater benefit than women (as delays increased) and after about 4–6 weeks, CEA may not confer significant benefit over OMT in female patients. However, RCTs randomizing women to early vs. late interventions have not been performed.

Another important finding was that stroke risk in the first 7–14 days after symptom onset was higher than previously assumed. In a series of 549 patients who experienced their stroke after a TIA, 43% of strokes occurred within 7 days of the index TIA. In a CETC meta-analysis, the 5-year risk of ipsilateral stroke in OMT patients was 18% in patients with 50%–69% stenosis and 26% in patients with 70%–99% stenosis (see Table 92.1 ). However, data from natural history studies suggest that early stroke risk in patients with 50%–99% stenosis may be much higher, ranging from 5%–8% at 48 hours, 4%–17% at 72 hours, 8%–22% at 7 days and 11%–25% at 14 days ( Table 92.3 ). This suggests that many high-risk patients were not randomized within ECST/NASCET and the benefit conferred by intervening in the first 7–14 days after symptom onset might be even higher than previously thought. Finally, studies have reported high rates of stroke/TIA whilst awaiting CEA. In Blaser’s series, there was a 10% risk of TIA/stroke during a median 10-day period between investigation and CEA, whilst a Leicester study noted a 13% risk of TIA/stroke in the 48–72-hour period between being seen in a TIA clinic and undergoing CEA. Kastrup et al. also reported a 12% risk of new MR Diffusion Weighted Image lesions over a median of 7 days between investigation and CEA.

These data have driven a worldwide move towards performing CEA (CAS) as soon as possible after symptom onset, preferably within 7–14 days.

Timing of CEA After Disabling Stroke

There is much debate about the optimal timing of CEA (CAS) in patients with disabling stroke. This is because of concerns about hemorrhagic transformation of an ischemic infarct, which is associated with higher rates of disability and death. The 2017 ESVS carotid guidelines advise that revascularization should be deferred in patients with 50%–99% stenosis who experience a disabling stroke (Modified Rankin Score ≥3), where the area of infarction exceeds one third of the middle cerebral artery territory, or who have altered consciousness/drowsiness (Class I, Level C). When a decision has been made to perform CEA/CAS in these patients (after a suitable period of recovery), it is vital to actively manage post-CEA hypertension to prevent postoperative ICH.