MUSC background

MUSC Stroke Neurologist Leads the SAMMPRIS Trial

The SAMMPRIS TRIAL PTAS and Aggressive Medical Management vs. Aggressive Medical Management Alone in Patients with Severe Intracranial Arterial Stenosis

Two strategies for preventing recurrent stroke in patients with ere atherosclerotic intracranial arterial stenosis (70%-99% wing of the arteries deep in the brain) were pitted against one another in the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis; Clinical Trials Identifier:  NCT00576693).  The 50- site trial was led by Marc I. Chimowitz, MBCHB, Professor of Neurosciences and Associate Dean for Faculty Development at MUSC.

In one corner was aggressive medical management, including dual antiplatelet therapy (325 mg/d of aspirin and 75 mg/d of clopidogrel for 90 days); intensive control of risk factors to maintain systolic blood pressure at less than 140 mm Hg (<130 mm Hg if patient was diabetic), low-density lipoprotein cholesterol at less than 70 mg/dL, and hemoglobin A1c at less than 7%; and lifestyle modifications such as smoking cessation and weight loss (see SAMMPRIS-Defined Treatment Targets).

In the other corner was percutaneous transluminal angioplasty and stenting (PTAS), a procedure in which a surgeon threads a microcatheter into a blocked artery to reopen it (usually with a balloon) and then places a stent to keep it open. The study used the Wingspan stent (Boston Scientific; Natick, MA, sold to Stryker Inc, Fremont, CA) for the PTAS intervention arm because it is the only stent approved by the US Food and Drug Administration (FDA) for use in these patients. Patients randomized to the PTAS intervention arm also received aggressive medical management of stroke risk factors.

The SAMMPRIS results, published in the September  15,  2011 issue of the New England Journal of Medicine (NEJM),1 point to a clear winner—aggressive medical management alone. Indeed, because outcomes with stenting were substantially worse than expected and those with aggressive medical therapy were substantially better than expected, enrollment in the study was stopped early for safety reasons.

SAMMPRIS-Defined Treatment Targets For Recurrent Stroke Risk Factors*

Risk FactorsTreatment Target
Primary
   HypertensionSystolic blood pressure, <140 mm
Hg (<130 mm Hg in diabetics)
   High low-density lipoprotein cholesterol levels<70 mg/dL
Secondary
   DiabetesHemoglobin A1c level, <7%
   Non-high-density cholesterol levels<100 mg/dL
   SmokingSmoking cessation
   Overweight/obeseBody mass index (BMI) <25 kg/m2
   Physical inactivityModerate intensity exercise at least 3
times per week for 30 minutes
*These are SAMMPRIS-defined treatment targets specifically for high-risk study patients with a previous stroke or transient ischemic attack and 70% to 99% intracranial arterial stenosis. For detailed recent recommendations on controlling risk factors for secondary prevention of stroke in a variety of patients, see Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42;227-276. Available at stroke.ahajournals.    org/content/42/1/227.full

A total of 451 patients underwent randomization, 224 in the stenting arm and 227 in the aggressive medical management arm. The stenting group had a significantly higher 30-day rate of stroke or death than the aggressive medical management group (14.7% [33 patients] vs 5.8% [13 patients]). At the time enrollment was stopped, no difference was seen in the rate of nonfatal ischemic strokes in the territory of the qualifying artery after 30 days (13 patients in each group). Follow-up of already enrolled patients will continue until March 2013.

The stage for SAMMPRIS was set in 2005 with FDA approval of the Wingspan stent and publication of the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID; Clinical Trials Identifier: NCT00004728) trial.2 The Wingspan stent received approval from the FDA under a humanitarian device exemption for use in patients with atherosclerotic intracranial arterial stenosis of 50% to 99% who had experienced a stroke that was refractory to medical therapy. WASID showed that those with 70% to 99% intracranial arterial stenosis who had experienced a stroke or transient ischemic attack (TIA) in the past 30 days were at highest risk of recurrent stroke. Building on these findings, SAMMPRIS showed that combined used of aspirin and clopidogrel for 90 days followed by aspirin alone, coupled with intensive management of stroke risk factors, achieved impressive results in these high-risk patients. Importantly, the same level of benefit with aggressive medical management was seen in the two-thirds of SAMMPRIS patients who had their qualifying TIA or stroke while already receiving antithrombotic therapy.

The effect of SAMMPRIS on clinical practice will be profound. According to Chimowitz, “the study results fundamentally change clinical practice because they show that stenting in this patient population is unsafe and that aggressive medical management seems to be substantially more effective than usual medical management.” On the basis of SAMMPRIS evidence, clinicians should no longer use stents in patients with a recent stroke or TIA (<30 days) and intracranial arterial stenosis of 70% to 99%. The Wingspan stent was also approved for patients with 50% to 69% stenosis, and opinions differ on treatment recommendations for these patients, who were not included in the SAMMPRIS trial. In Chimowitz’s opinion, implanting such stents in patients with 50% to 69% intracranial stenosis or with no symptoms for the past 30 days would be ill advised because these patients are at much lower risk of stroke and the stent is very unlikely to offer any additional benefit over medical therapy alone. While acknowledging the importance of the SAMMPRIS findings to clinical practice, Raymond Turner, M.D., Co-Director of the  MUSC Comprehensive Stroke and Cerebrovascular Program, believes  the  study  affects  only  a  specific  subgroup  of  stroke patients and that it is important to carefully delineate the patient population whose treatment will and will not be affected by the study’s  findings:  “The  SAMMPRIS  study  specifically  looked only at patients with a TIA or nondisabling stroke within 30 days that was caused by intracranial arterial stenosis of 70% or greater. [It] did not include patients with symptoms caused by arterial dissection, aneurysm, intracranial stenosis of less than 70% or extracranial disease (such as carotid bifurcation stenosis or vertebral artery origin stenosis) or patients who were experiencing an acute stroke. In these patient groups, stents are still beneficial.” SAMMPRIS will affect not only clinical practice but also the design of future clinical trials for stroke therapies. Chimowitz believes that SAMMPRIS will lead to the inclusion of an aggressive medical management arm in many such trials.  Indeed, he is already part of the Steering Committee of another trial that plans to compare aggressive medical management alone to aggressive medical management plus carotid endarterectomy or stenting for patients with asymptomatic carotid stenosis.

Why the stents were associated with worse than expected outcomes and aggressive medical therapy with better than expected outcomes in SAMMPRIS remains uncertain. To qualify for the SAMMPRIS trial, patients had to have experienced a recent TIA or stroke, and Chimowitz suspects that their intracranial plaque may still have been unstable, perhaps increasing the risk of thromboembolism during stenting. The better than expected outcome of patients receiving aggressive medical therapy alone was likely related to the combination of dual antiplatelet therapy, intensive risk factor management and lifestyle interventions; however, lifestyle modifications probably had minimal impact in the first 30 days after enrollment since the lifestyle program had not yet been fully implemented.

Some have questioned the feasibility of implementing SAMMPRIS-defined aggressive medical management in real- world clinical practice. Chimowitz counters that the main purpose of a clinical trial is to improve patient care by pointing the way toward clinical practices that are better than currently standard ones. He also notes that what is feasible for medical management has changed dramatically in recent years. In the past decade, the introduction and widespread use of statins to control lipid levels and of new medications for hypertension and diabetes have made medical management of stroke risk factors far more effective. Substantial  evidence  exists  to  show  that  statins  are  protective against both incident and recurrent  stroke.3,4,5  More  tools have also become available to assist patients in making lifestyle modifications (smoking cessation, weight loss, regular exercise), such as the Nationwide Better Health INTERVENT program used in the SAMMPRIS study. Such programs provide a health coach, who, after assessing the patient’s current health, lifestyle and readiness for change, develops a personal action plan and then follows up regularly by telephone with the patient to monitor his or her adherence to the plan and to help provide motivation. Studies have shown that such interventions can help patients make progress toward goals set by national guidelines for blood pressure, lipid levels and other risk factors.6,7

Detailed assessment of the effect of rigorous stroke risk factor management on outcome beyond 30 days will require analysis of follow-up data for patients already enrolled in SAMMPRIS. Such follow-up data will also help determine the longer-term outcome of patients treated with stenting in the trial. If long-term benefit with stenting is noted, then further research and technical advancements will be needed to mitigate the short-term risks in order for endovascular therapy to become a widely accepted option for the treatment of patients with intracranial stenosis, especially those that have recurrent events while receiving aggressive medical management.

References

1 Chimowitz MI, Lynn MJ, Derdeyn CP, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis.

N Engl J Med. 2011 Sep 15;365(11):993-1003. Epub 2011 Sep 7.

2 Chimowitz MI, Lynn MJ, Howlett-Smith H, et al; Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis. N Engl J Med. 2005 Mar 31;352(13):1305-16.

3 Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol.    2009;8:453– 463.

4 O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121 000 patients. Am J Med. 2008;121:24 –33.

5 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transientischemic attack.

N Engl J Med. 2006;355:549 –559.

6 Gordon NF, Salmon RD, Franklin BA, et al. Effectiveness of therapeutic lifestyle changes in patients with hypertension, hyperlipidemia, and/or hyperglycemia. Am J Cardiol. 2004;94:1558-1561.

7 Gordon NF, English C, Contractor AS, et al. Effectiveness of three models for comprehensive cardiovascular disease risk reduction. Am J Cardiol 2002;89:1263-1268. N Engl J Med. 2005 Mar 31;352(13):1305-16.

STROKE STATISTICS

Nationala

  • Seven million Americans have experienced a stroke (2008 prevalence: 3%)
  • More than 795,000 US strokes occur annually, 185,000 of which are recurrent
  • Stroke accounted for 135,952 US deaths in 2007, 1 in 18 of all deaths
  • Stroke’s cost in 2007 was $40.9 billion
  • The percentage of stroke victims younger than 65 years is nearly 30%
  • African Americans and Hispanics are significantly more likely to have a stroke, especially stroke at a young age, than whites
  • Each year, 55,000 more women than men have a stroke

South Carolinab

  • One-third of all South Carolinians have high blood pressure, one of the primary risk factors for stroke and recurrent stroke
  • African Americans are 53% more likely to die of stroke than whites in South Carolina
  • In 2008, 20% of stroke deaths were among those younger than 65 years (vs. 14.7% nationally [2007 data])
  • African Americans in South Carolina are more likely to experience stroke younger (<65 years); for ischemic stroke, the greatest disparity in rates compared with whites is for ages 35 to 44 yearsc

a Data from Roger VL, Go AS, Lloyd-Jones DM, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2011 update: a report from the American Heart Association. Circulation. 203:e18-e209.

b Unless otherwise indicated, data are from Stroke Systems of Care Study Committee Report (S*26). South Carolina Department of Health and Environmental Control. Nov 30, 2010. Available at https://www.scdhec.gov/Health/docs/Stroke%20Systems%20of%20Care%20Study%20Committee%20Report%20%28S%2026%29.pdf. Accessed November 18, 2011.

c Data from Feng W, Nietert PJ, and Adams RJ. Influence of age on racial disparities in stroke admission rates, hospital charges, and outcomes in South Carolina. Stroke. 2009, 40:3096-3101.

AMERICA'S POOR REPORT CARD FOR CONTROLLING STROKE RISK FACTORS

Hypertension

  • 33.5% rate among men and women older than 20 years
  • 44.0% rate in African American adults (among the highest in world)
  • 48.0% of patients aware they have hypertension have achieved control

Hyperlipidemia

  • An estimated 33.6 million adults older than 20 years have total serum cholesterol levels >240 mg/dL, with a prevalence of 15.0%
  • Data from the 2005-2006 National Health and Nutrition Examination Survey showed that 35.5% of persons with high levels of low-density lipoprotein cholesterol had not been screened previously, 24.9% were screened but not told they had high cholesterol and 39.6% were treated inadequately

Diabetes

  • In 2008, an estimated 18.3 million Americans had diagnosed diabetes mellitus, representing 8.0% of the adult population
  • An estimated 7.1 million had undiagnosed diabetes mellitus
  • 36.8% had abnormal fasting glucose levels (i.e., prediabetes)

Smoking

  • 23.1% of men and 18.3% of women continued to be cigarette smokers in 2008
  • In 2009, 19.5% of students in grades 9 to 12 reported current tobacco use

Obesity

  • 33.7% of US adults are obese (body mass index >30 kg/m2)
  • 67.4% of US adults are either obese or overweight

Physical Inactivity

  • 36.0% of adults reported engaging in no vigorous activity (i.e., one that causes heavy sweating and increased breath and heart rate)
  • 29.9% of girls and 17.0% of boys in grades 9 to 12 reported no 60-minute session of moderate-to-vigorous physical activity (i.e., one that causes increased heart or breathing rate) in the past 7 days (Recommendation for that age group: 5 times per week)

Data from Roger VL, Go AS, Lloyd-Jones DM, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.