SAMMPRIS

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Chimowitz MI, et al. "Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis". The New England Journal of Medicine. 2015. 365(11):993-1003.
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Clinical Question

In patients with recent TIA/CVA due to 70-99% intra-cranial artery stenosis, does percutaneous transluminal angioplasty and stenting (PTAS) in addition to aggressive medical therapy decrease recurrent stroke?

Bottom Line

In patients with recent TIA/CVA due to 70-99% intra-cranial arterial stenosis, angioplasty and stenting was associated with an increased risk of recurrent stroke compared to medical therapy alone.

Major Points

Atherosclerosis resulting in stenosis of the major intracranial (IC) arteries (carotid siphon, MCA, vertebral, and basilar) is an important etiology of ischemic stroke. In the US, IC stenosis causes about 50,000 ischemic strokes every year. Patients with recent TIA/CVA and intra-cranial (IC) artery stenosis of 70 to 99% are at particularly high risk for recurrent strokes. The WASID trial placed the 30-day rate of stroke or death at 10.7% and a 1-year rate at 25%. [1]

The self-expanding Wingspan stent was FDA approved in 2005 (3 years prior to the start of this trial) for patients with history of TIA/CVA and IC stenosis of 50-99% while on anti-platelet therapy. In the phase I trial and two registries, the 30 day rate of stroke in patients ranged between 4.4% to 9.6%. [2] [3] [4] Percutaneous transluminal angioplasty and stenting (PTAS) was increasingly being used to prevent recurrent stroke, but it had not yet been compared to medical management alone.

SAMMPRIS randomized patients with 70 to 99% IC artery stenosis who had a TIA or ischemic stroke within 30 days of enrollment to treatment with angioplasty and stenting using the Wingspan system in addition to aggressive medical therapy, or to aggressive medical therapy alone. Aggressive medical therapy included: aspirin 325 mg daily, clopidogrel 75 mg daily for 90 days, and intensive risk factor modification (target BP<140/90mmHg or <130/80 in diabetics; LDL <70mg/dL). The trial was stopped prematurely because the primary outcome of stroke or death within 30 days of enrollment was significantly higher in patients who received PCAS compared to medical therapy alone (14.7% vs. 5.8%; P=0.06). Of note, the peri-procedural rate of stroke in patients who underwent PCAS was higher than expected in Phase I/II Wingspan stent trials, and the rates in the medical therapy arm were lower than expected compared to data from the WASID trial. In the stenting arm, the main cause of early ischemic strokes was attributed to occlusion of perforating vessels.

At the end of the study, with a median followup of 32 months, the rate of the primary outcome (combined rate of stroke or death within 30 days after enrollment, ischemic stroke in the territory of the qualifying artery beyond 30 days, and stroke or death within 30 days after revascularization of the qualifying lesion during follow-up) was higher in the stenting arm compared with the medical therapy arm (19.7% vs. 12.6% at year 1, and 23.9% vs. 14.9% at year 3). These differences were drively largely by the outcomes within 30 days, since the rates beyond 30 days were similar between the two arms. [5]

Guidelines for stroke prevention issued in 2014 by the American Heart Association/American Stroke Association (AHA/ASA) concluded that stenting with the Wingspan system for patients with TIA/CVA attributable to high-grade intracranial artery stenosis is NOT recommended. [6]

Guidelines

AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack (2014, adapted)

  • For patients with stroke or TIA attributable to severe stenosis (70%–99%) of a major intracranial artery, stenting with the Wingspan stent system is not recommended as an initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA (Class III; Level of Evidence B).
  • For patients with stroke or TIA attributable to severe stenosis (70%–99%) of a major intracranial artery, the usefulness of angioplasty alone or placement of stents other than the Wingspan stent is unknown and is considered investigational (Class IIb; Level of Evidence C).

Design

  • Multicenter, randomized controlled trial
  • N=451 patients with recent TIA/CVA due to IC artery stenosis
    • Percutaneous transluminal angioplasty and stenting (PTAS) in addition to medical therapy (n=224)
      • In 16 (7%) crossover patients, angioplasty and stenting was not performed or aborted.
    • Medical therapy only (n=227)
      • In 9 (4%) crossover patients, angioplasty and stenting was done after repeat CVA after initial event
  • Setting: 50 centers in the US
  • Enrollment: Oct 2008 - April 2011
  • Median follow-up: 11.9 months at publication; 32 months at study end
  • Analysis: Intention-to-treat
  • Primary outcome: Combined rate of stroke or death within 30 days after enrollment, ischemic stroke in the territory of the qualifying artery beyond 30 days, and stroke or death within 30 days after revascularization of the qualifying lesion during follow-up

Population

Inclusion Criteria

  • Age 30-80 years
  • TIA/CVA within 30 days of enrollment attributed to 70–99% stenosis of a major IC artery (carotid artery, MCA stem M1, vertebral artery, or basilar artery) diagnosed by TCD, MRA, or CTA
  • In patients 30–49 years, must meet at least one additional criteria to increase likelihood that symptomatic IC stenosis is due to atherosclerosis:
    • Insulin-dependent diabetes for at least 15 years
    • History of any of following: MI, CABG, coronary angioplasty or stenting, carotid endarterectomy/stenting, or PVD surgery
    • At least 2 of the following atherosclerotic RFs:
      • HTN (BP ≥ 140/90 or on therapy)
      • LDL ≥ 130mg/dl or HDL < 40mg/dl or fasting TG≥ 150mg/dl or on lipid lowering therapy
      • Smoking
      • Diabetes of <15 years duration
      • FHx: MI, CABG, coronary angioplasty/stenting, CVA, CEA/stenting; PVD surgery in parent or sibling who was <55 years for men or <65 for women
    • Documentation by non-invasive vascular imaging or catheter angiography of any of following attributed to atherosclerosis:
      • Any stenosis of another artery (including EC carotid, vertebral, another IC artery, subclavian, coronary artery, iliac, femoral, other lower or upper extremity arteries, mesenteric artery or renal artery)
      • Aortic arch atheroma
      • Any aortic aneurysm

Exclusion Criteria

  • Tandem IC or EC stenosis (70%–100%) proximal or distal to target IC lesion
  • Bilateral IC artery stenoses of 70%–99% but uncertain which artery is symptomatic (such as in patients with pontine, midbrain, or temporal, occipital symptoms)
  • Any previous stenting, angioplasty, or endarterectomy of target lesion ever or any other EC or IC artery within 30 days prior to enrollment
  • Presence of intraluminal thrombus proximal to or at target lesion OR radiographic evidence of severe calcification at target lesion
  • Any aneurysm proximal to or distal to stenotic IC artery
  • IC tumor (except meningioma) or any IC vascular malformation
  • Thrombolytic therapy within 24 hours prior to enrollment
  • Progressive neurological signs within 24 hours prior to enrollment OR severe neurological deficit that renders patient dependent on iADLs
  • Brain infarct within previous 30 days of enrollment that is of sufficient size (> 5 cms) to be at risk of hemorrhagic conversion during or after stenting
  • ICH: Hemorrhagic infarct within 14 days prior to enrollment or within 15 – 30 days that is associated with mass effect, any history of a primary intracerebral (parenchymal) hemorrhage (ICH), other ICH (subarachnoid, subdural, epidural) within 30 days, any untreated chronic subdural hematoma of greater than 5 mm in thickness
  • IC arterial stenosis due known ethologies other than atherosclerosis (e.g. arterial dissection, Moya Moya disease, vasculitis, CNS infections, Fibromuscular Dysplasia, radiation induced etc).
  • Presence of risk of cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, MI within three months, dilated cardiomyopathy, left atrial spontaneous echo contrast, EF <30%
  • Comorbidities that may limit survival to <3 years
  • Pregnancy or of childbearing potential and unwilling to use contraception for the duration of this study
  • Known allergy or contraindication to aspirin, clopidogrel, heparin, nitinol, contrast, local or general anesthesia
  • Indication for warfarin or heparin beyond enrollment (excluding SQ heparin for DVT prophylaxis while hospitalized

Baseline Characteristics

  • Age: 60
  • Male gender: 60%
  • Race: 71.2% white, 23.3% black, 5.5% other
  • Hypertension: 89.6%
  • Diabetes: 46.4%
  • Lipid disorder: 89.5%
  • Smoking history: 37.4% never smokers; 35.3% former smokers; 27.3% current smokers
  • History of CAD: 23.5%
  • History of prior stroke: 26.2%
  • Qualifying event: 65.2% stroke; 34.8% TIA
  • Already receiving anti-thrombotic therapy: 63.4%
  • Median time to randomization: 7 days
  • Symptomatic qualifying artery: 20.9% ICA, 43.7% MCA, 13.4% vertebral, 22.2% basilar
  • Stenosis of symptomatic qualifying artery: 80.5% mean percentage stenosis
    • 70–79% stenosis: 46.5%
    • 80–89% stenosis: 42%
    • 90–99% stenosis: 11.6%

Interventions

  • Patients were randomized to percutaneous transluminal angioplasty and stenting (PTAS) in addition to medical therapy vs. medical therapy only.
  • Both groups received aggressive medical management, which included:
    • Aspirin 325 mg daily for entire follow-up
    • Clopidogrel 75mg daily for 90 days
    • Protocol-driven risk factor management: target SBP <140mmHg (130mmHg in diabetics) and LDL <70 mg/dl
      • Intervent USA (lifestyle modification program) targeted at management of DM, elevated non–HDL cholesterol levels, smoking, excess weight, and insufficient exercise
      • Antihypertensive agents (one from each class), statin (Rosuvastatin), and antithrombotic agents provided to patients
  • In stenting arm, patients received stenting within 3 business days after randomization under general anesthesia
    • Patients who have not previously been on daily clopidogrel for longer than 5 days were loaded with 600 mg of clopidogrel between 6 and 24 hours prior to the procedure

Outcomes

Comparisons are aggressive medical therapy only vs. PTAS plus aggressive medical therapy.

Primary Outcomes

  • Stroke or death within 30 days after enrollment or after revascularization for qualifying lesion beyond 30 days: 11.5% vs. 20.5% (P=0.009)
    • Ischemic stroke or death at 30 days: 5.8% vs. 14.7%; stroke or death at 1 year: 12.2% vs. 20.0%
    • Ischemic stroke in territory of qualifying artery within 30 days: 4.4% vs. 10.3% (1 fatal 0.4%)
    • Ischemic stroke in other territory within 30 days: 0.9% vs. 0%
    • Symptomatic brain hemorrhage within 30 days: 0% vs. 4.5% (4 fatal 1.8%)
    • Non–stroke-related death within 30 days: 0.4% vs. 0%
    • Ischemic stroke in territory of qualifying artery beyond 30 days after enrollment: 5.7% vs. 5.8%

Secondary Outcomes

  • Any stroke or death: 16.3% vs. 23.2% (P=0.06)
    • Death: 3.1% vs. 3.1%
    • Any stroke: 14.1% vs. 22.3% (P=0.03)
  • Death no. (%): 7 (3.1) vs. 7 (3.1), P= 0.95
  • Any stroke no. (%): 32 (14.1) vs. 50 (22.3), P=0.03
  • Disabling or fatal stroke: 5.7% vs. 8.5% (P=0.21)
  • MI: 3.1% vs. 2.2% (P=0.60)
  • Major non–stroke-related hemorrhage: 1.8% vs. 4.5 (P=0.10)
  • Any major hemorrhage: 2.2% vs. 9.8% (P= <0.001)

Criticisms

  • Data from SAMMPRIS has been extrapolated to support the use of dual anticoagulants for up to 3 months in the context of stroke or TIA attributed to IC arterial stenosis but there has been no published head-to-head trials comparing dual anti-platelets compared to ASA or plavix alone in this context.
  • It should also be noted that the ASA dose used in this trial is the higher limit of the ASA dose commonly used in secondary stroke prevention, and results of studies performed in multiple vascular indications suggest the best balance of the efficacy and safety of aspirin appears to be approximately 75 mg/d to 100 mg/d

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institutes of Health
  • Investigator-Sponsored Study Program of AstraZeneca, donates rosuvastatin (Crestor) to study patients.
  • Walgreens pharmacies provide study medications, except rosuvastatin, to patients at a discounted price (paid for by the study).
  • Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third-party distribution of devices and continues to provide funding for site monitoring and study auditing
  • Nationwide Better Health–INTERVENT provided the lifestyle modification program to the study at a discounted rate

Further Reading

  1. Chimowitz MI et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N. Engl. J. Med. 2005. 352:1305-16.
  2. Zaidat OO et al. The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis. Neurology 2008. 70:1518-24.
  3. Bose A et al. A novel, self-expanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: the Wingspan study. Stroke 2007. 38:1531-7.
  4. Fiorella D et al. US multicenter experience with the wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results. Stroke 2007. 38:881-7.
  5. Derdeyn CP et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014. 383:333-41.
  6. Derdeyn CP et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014. 383:333-41.