External Counterpulsation Therapy for Severe Steno-occlusive Intracranial Stenosis
External Counterpulsation Therapy for Severe Steno-occlusive Intracranial Stenosis
Intracranial stenosis is prevalent among Asians and constitute a common cause of cerebral
 ischemia. While the best medical therapy carries stroke recurrence rates in access of 10% per
 year, intracranial stenting was associated with unacceptable peri-procedural ischemic events.
 Cerebral ischemic events are strongly related to the severity of intracranial stenosis, being
 high in patients with severe intracranial stenosis with poor vasodilatory reserve. Enhanced
 External Counter-Pulsation (EECP) therapy is known to improve myocardial perfusion by
 facilitating the development of collateral blood vessels in the heart. The investigators
 hypothesize that EECP therapy may be useful in patients with severe stenosis of intracranial
 internal carotid (ICA) or middle cerebral artery (MCA).
Among Asian patients, intracranial stenosis is more common and accounts for about 30-50% of
 all strokes. The risk of recurrent stroke or TIA in presence of intracranial stenosis of a
 major intracranial artery and recent TIA/ stroke is about 23% at 1 year despite treatment.
 Recurrence rate for stroke/TIA in intracranial atherosclerosis is dependent on degree of
 stenosis as well as presence of collaterals. In WASID study, patients with more than 70%
 stenosis had greater risk of recurrent event then those with 50-69%. Interestingly, patients
 with more than 70% intracranial stenosis with good collaterals demonstrated a lower risk for
 subsequent cerebral ischemic events.

 The two main mechanisms of ischemic stroke (IS) in these patients are thromboembolism and
 cerebral hemodynamic insufficiency. While Transcranial Doppler (TCD) monitoring can establish
 thrombo-embolic phenomenon and help in planning the appropriate antithrombotic treatment,
 assessment of dynamic cerebral hemodynamic insufficiency remains a complex issue, and may
 serve as a potential target for improving the outcomes (and reducing recurrent cerebral
 ischemia) in patients with severe intracranial stenoses.

 Treatment options for Intracranial stenosis:

 Anti-platelet agents are recommended for secondary prevention of IS. WASID trial compared
 warfarin with INR of 2-3 against aspirin, did not show any difference in outcome of stroke
 recurrence. Furthermore, aspirin was found to be safer as compared to warfarin.

 Use of short-term double antiplatelet therapy is shown to be effective in reducing stroke/TIA
 recurrence risk. In CLAIR study, patients with recent symptoms (</=7 days) and with
 intracranial stenosis were randomized to clopidogrel and aspirin versus aspirin monotherapy.
 Combination anti-platelet therapy reduced micro-embolic signals on TCD on Day 2 and 7. Use of
 double antiplatelet in intracranial stenosis was also supported by findings of SAMMPRIS trial
 in which patient with recent stroke of TIA with 70-99% intracranial stenosis were randomized
 to angioplasty or maximal medical treatment. The 90 day recurrence risk of 5.8% in the
 medical arm was much lower than 10.7% recurrence rate observed in WASID trial.

 Surgical treatment:

 Extracranial to intracranial bypass has been compared with medical management in patients
 with intracranial stenosis and it did not lower the risk of recurrent ischemic stroke.
 Furthermore, it was associated with worse outcome as compared to medical management. Also,
 the recently published COSS study failed to show any benefit of surgical treatment for
 carotid occlusion, largely related to better than expected event rates in the medical arm.

 Endovascular Treatment:

 Endovascular treatment has been used as a potential therapeutic option for intracranial
 atherosclerosis. In 2005, FDA approved self expanding Wingspan stent for use in medically
 refractory patients who harbor 50-99% stenosis of major intracranial artery. In 2011
 Chimowitz et al published results of SAMMPRIS trial, which compared percutaneous
 trans-luminal angioplasty and stenting with medical management. Patients with recent TIA or
 stroke attributed to 70-99% stenosis of intracranial vessels were recruited in this trial.
 Enrollment of this trial was stopped after 451 patients were recruited as angioplasty and
 stenting group was associated with 14.7% event rate (stroke or death) at 30-days as compared
 to medical management arm (5.8% event rate).

 Cerebral vasodilatory reserve:

 The assessment of cerebral vasodilatory reserve (CVR) in patients with persistent arterial
 occlusive disease is important since inadequate CVR in symptomatic patients is considered a
 major risk factor for subsequent ischemic events. By using refined techniques for measuring
 cerebral blood volume (CBV) and cerebral blood flow (CBF), in addition to standard clinical
 and angiographic studies, it is possible to identify a small subgroup of patients with
 impaired CVR who are at risk of subsequent stroke. Accordingly, impaired CVR is often
 regarded as the basis for performing extra-/intracranial (EC/IC) bypass surgery with the aim
 of increasing CBF and restore CVR in this highly selected patient subgroup.

 Identifying patients who are at increased risk for hemodynamic stroke is important because
 they may benefit from flow augmentation procedures, such as carotid endarterectomy, EC-IC
 bypass, or even angioplasty. The cerebral hemodynamic status can be determined by measuring
 CBF before and after vasodilatory challenge, which can be done with either hypercapnia or
 acetazolamide. Acetazolamide, a carbonic anhydrase inhibitor, has been shown to increase CBF
 in healthy subjects by inducing transient vasodilatation.

 Cerebral autoregulation enables a constant CBF over a wide range of systemic blood pressure
 by varying the diameter of the intracranial arterioles. This may fail in some patients with
 severe steno-occlusive disease. TCD can measure vasomotor reactivity (VMR) by assessment of
 flow velocities in response to increasing carbon dioxide levels. This can be performed by
 simple breath-holding test and calculating the so-called 'breath holding index (BHI)', BHI is
 calculated as the relative increase in the MFV during breath holding divided by the time of
 apnea in seconds. In normal persons, the BHI amounts to 1.2±0.6. Silverstrini et al
 prospectively evaluated BHI in case-controlled studies and showed that impaired VMR can help
 to identify patients at higher risk of stroke in a population with asymptomatic carotid
 stenosis or a previously symptomatic carotid occlusion. A decreased VMR suggests failure of
 collateral flow to adapt to the stenosis progression. Various studies, using different
 provocative measures for assessing the VMR, demonstrated a remarkable ipsilateral event rate
 of around 30% (30% risk of stroke/ TIA during about 2 years).

 In a recent study, the investigators demonstrated the phenomenon of 'intracranial steal' in
 patients with persisting intracranial occlusions where, hypercapnia can paradoxically
 decrease the residual flow velocity in the affected vessel at the expected time of normal
 brain vasodilation when blood pool is shifted to non-ischemic areas. The phenomenon of
 "reversed Robin Hood", an analogy with "rob the poor to feed the rich" was replicated by
 acetazolamide-challenged HMPAO-SPECT imaging. The investigators have demonstrated recently
 the value of multimodality evaluation of CVR is feasible and may aid in taking therapeutic
 decisions regarding revascularization procedures.

 Enhanced External Counter Pulsation (EECP) is a new noninvasive therapy used to treat
 patients with angina, congestive heart failure, acute myocardial infarction and cardiogenic
 shock by augmenting blood flow to the cardiac and systemic arterial circuits. EECP's
 hemodynamic effects include 20% to 25% improvement in arterial flow volume in the carotid,
 renal and hepatic arteries, with a 20% to 40% improvement in coronary artery blood flow
 accompanied by a 12% increase in left ventricular (LV) stroke volume.

 EECP as a frontline treatment for revascularization in patients with angina refractory to
 medical therapy has shown similar findings to coronary artery bypass and percutaneous
 coronary interventions including improvement in cardiac functional class, decreased anginal
 episodes, and reduction in nitroglycerin use. EECP has been shown to produce similar
 hemodynamic effects to intra-aortic balloon pumps (IABP), yet is a noninvasive technology
 carrying less implementation risk.

 Lastly, TCD measurements in recovering ischemic stroke patients undergoing EECP have
 demonstrated a significant increase in MCA flow velocities. Peak diastolic augmented
 velocities (PDAV) averaged 72 + 29 cm/second a 196% increase in flow(RMCA), and 78 + 30
 cm/second a 199% increase in flow (LMCA) on EECP, significantly higher than pre-procedural
 EDV (RMCA 37+11cm/second, p=0.014; LMCA 39+9cm/second, p=0.022). Given the altered waveform
 morphology, traditional calculation of MFV using peak systole and end-diastole would fail to
 capture EECP's flow augmentation effects. Augmented MFV (AMFV) was recalculated by
 substituting EDV with a measure derived from the summed average of PDAV and EDV (augmented
 diastolic velocity [ADV]).

 Patients in whom a long stenotic segment involved both terminal ICA and proximal MCA would be
 classified as having a steno-occlusive disease of terminal ICA. Steno-occlusive disease of
 ICA or MCA would be considered severe (>70%) according to the velocity criteria and presence
 of 'blunted' flow spectra in the arterial segment distal to the stenosis. Therefore, tandem
 lesions in a single arterial tree (intracranial ICA and MCA, proximal MCA and distal MCA,
 extracranial ICA and ipsilateral intracranial ICA or extracranial ICA and ipsilateral MCA),
 if associated with blunted flow spectra in distal MCA would qualify the criteria for >70%
 stenosis. Importantly, the TCD diagnostic criteria for intracranial stenosis in our
 neurovascular laboratory have been validated against CT angiography.

 Patients would be randomized (1:1 by using drawing previously prepared chits in a bag) into
 either maximal medical management (plus sham EECP) or maximal medical management plus EECP.
 EECP sessions are planned 5 times/week for a total of 35 sessions. CVR would be measured at
 baseline as well as at 4 months of EECP treatment initiation. Improvement in CVR on
 symptomatic side would be measured by TCD-BHI as well as acetazolamide challenged HMPAO-SPECT
 and compared with patients in medical management (and sham EECP) arm for significant
 difference. Patients will also be followed up for recurrence of stroke/TIA during the study
 period.

 Maximal medical management would be same in both groups as per the current AHA/ASA
 guidelines. Briefly, all ischemic stroke cases with intracranial stenosis receive dual
 antiplatelet agents (aspirin and clopidogrel for 1 month followed by clopidogrel or aspirin
 long term). The investigators aim to keep HbA1c at 7% or less in all cases. Blood pressure
 target in the stroke patients eligible for this study (at least 1 month after acute stroke)
 is less than 140/90mmHg. For lipids, the target LDL is less than 2.6mmol/L.
Inclusion Criteria:

 1. Patients with recent stroke/TIA and severe stenosis of intracranial ICA or MCA and
 impaired CVR within previous three months but not before 3 weeks after acute stroke.
 This is to differentiate between patients with a long-standing fixed-stenosis from
 patients with partially recanalized intracranial artery (masquerading as severe
 stenosis).

 2. Age >21 years

 Exclusion Criteria:

 1. Patients with atrial fibrillation/ arrhythmias.

 2. Within 2 weeks of cardiac catheterization or arterial puncture at femoral puncture
 site.

 3. Decompensated heart failure , usually class 3 or 4

 4. LV EF <30%

 5. Moderate or severe AR

 6. Persistent and uncontrolled hypertension (BP persistently >160/100 mmHg)

 7. Bleeding diathesis

 8. Active thrombophlebitis/ venous disease of lower limbs

 9. Severe lower extremity vaso-occlusive disease

 10. Presence of a documented aortic aneurysm/ dissection requiring surgical repair

 11. Pregnancy