Clinical trial makes surprising find about best treatment for stroke

Some things never get old – such as being published in the New England Journal of Medicine with results from a 50-center nationwide clinical trial that changes the standard of care for stroke patients worldwide.

Lead investigator Marc Chimowitz, MBChB, a neurosciences professor and SmartState endowed chair, said he's been surprised but gratified at the extent of national coverage of the research study that has landed headlines in newspapers from The New York Times to The Washington Post.

Dr. Marc Chimowitz views a brain scan of one of his patients.

"Large clinical trials are my passion because they have the potential to impact not just the care of the people you take care of one-on-one but potentially patients worldwide."

The new study reveals that aggressive medical therapy is safer and more effective than placing a stent in the brain to ward off a second stroke in high-risk patients with a narrowed brain artery. Investigators published the results from the Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (Sammpris) trial on Sept. 7 online in the New England Journal of Medicine. 

"There were two surprising findings in this study," Chimowitz said. "First, stents did not perform as well as we had anticipated, which has important implications for clinical practice because stenting is increasingly being used to treat these patients worldwide. The second surprising finding was the large gains demonstrated through the use of aggressive medical therapy on its own. This is the first stroke-related trial to include lifestyle change therapy and protocol-driven management of multiple risk factors such as high blood pressure and raised cholesterol," he said.

"Based on the results of this study, stroke patients with recent symptoms and intracranial arterial blockage of 70 percent or greater should be treated with aggressive medical therapy alone that follows the regimen used in this trial as closely as possible."

The National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH (National Institutes of Health) and which funded the trial, halted new enrollment in the study in April because early data showed significantly more strokes and death among stented patients at the 30- day mark when compared to the group who received aggressive medical management alone.

According to Walter Koroshetz, M.D., NINDS deputy director, "This study provides an answer to a longstanding question by physicians, what to do to prevent a devastating second stroke in a high risk population. Although technological advances have brought intracranial stenting into widespread practice, we have now learned that this particular device does not lead to a better health outcome." 

Though glad for the media exposure to raise awareness of the study's findings, Chimowitz said he wishes media had not focused so much on the poor outcome in the patients who were stented and whether the FDA erred in approving the stent for humanitarian use in these very high risk patients.

"I would have preferred if the media had paid more attention to the positive aspects of the trial regarding patient outcomes, particularly the aggressive medical management protocol we designed for patients in this trial that lowered the risk of stroke by 50 percent. I think it was a lost opportunity for readers to see how important risk factor management and a healthy lifestyle is in lowering your risk of stroke."

Study Details
Stroke is the fourth leading cause of death in the U.S. Stenosis, a blockage or narrowing of a brain artery caused by the build up of plaque, accounts for more than 50,000 of the 795,000 strokes that occur annually nationwide. Stenosis is particularly common in African Americans, Hispanics, Asian Americans, and people with diabetes.

The Sammpris study enrolled 451 patients at 50 sites across the U.S. The investigators looked at whether patients had a second stroke or died within 30 days of enrollment, or had a stroke in the same area of the brain from 30 days to the end of follow-up. They had hypothesized that compared to aggressive medical therapy alone, the addition of intracranial stenting system would decrease the risk of stroke or death by 35 percent during two years.

Instead they found that 14.7 percent of patients (33) in the stenting group experienced a stroke or died within the first 30 days after enrollment, compared with 5.8 percent (13) of patients treated with medical therapy alone. There were five stroke-related deaths within 30 days, all in the stenting group, and one non-stroke related death in the medical management group. Over a mean follow-up of 11.9 months, 20.5 percent of patients in the stenting group and 11.5 percent of patients in the medical group had a study primary endpoint (stroke or death within 30 days or stroke in the same area of brain beyond 30 days), which demonstrates a highly significant difference in favor of the aggressive medical management on its own. Based on these data, the Data and Safety Monitoring Board recommended the NINDS stop new enrollment, and the institute issued a clinical alert. All patients will continue to be followed for two years to determine the long-term effects of both interventions. 

With aggressive medical management, the medical group in this trial had a 30-day rate of stoke of death of 5.8 percent and a one year primary endpoint rate of 12.2 percent. In comparison, patients in a previous NIH trial, also led by Chimowitz, showed that in patients with similar entrance criteria to Sammpris who were treated with less intensive medical management had a 30-day rate of stroke and death of 10.7 percent and a one year rate of primary endpoint of 25 percent, suggesting that the aggressive medical management in this trial was effective in lowering the risk of stroke

Science at its Best
To do a study on this scale takes extensive effort and coordination of many different specialists, said Chimowitz. "The infrastructure and personnel required to run and implement a trial like this is enormous." The clinical coordinating center at MUSC consists of faculty and staff overseeing the research nationwide at 50 sites. This includes Tanya Turan, M.D., a neurologist at MUSC who oversees the risk factor management at all 50 sites and is on the executive committee; Janice Malloy, the trial administrator who oversees the $20 million budget; Genny Starr, a research nurse who helps manage the patients enrolled at MUSC; Jessica Peterson, who deals with IRB and FDA issues related to the trial; and administrative assistants Meghan Steiner, Jessica Kandl, Shelly Caskey and Samantha Minkin who help arrange investigator meetings for more than 100 participants, and help with risk factor management. The Risk Factor Advisory Committee consisted of experts at MUSC in hypertension —Brent Egan, M.D., lipids — Maria Lopes-Virella, M.D., Ph.D., and diabetes — Kathie Hermayer, M.D., and the Cardiology Adjudication Committee at MUSC consisted of doctors Eric Powers, Terrence X. O'Brien, Grady Hendrix and Salvatore Chiaramida.

Other contributors include Zoran Rumboldt, M.D., in radiology, who read all of the brain imaging studies for the 451 patients in the trial; doctors Robert Adams, Christine Holmstedt, Edward Jauch, Julio Chalela, Angela Hays, and Christos Lazaridis, stroke neurologists and neuro ICU doctors who helped screen for study patients; and neurointerventionists doctors Aquilla Turk, Raymond Turner, and Imran Chaudry, who helped enroll patients in the trial and performed the stenting procedures for the trial at MUSC.

MUSC's clinical coordinating center took the lead in running and implementing the 50 multi-center research study. Pictured from left are part of the MUSC Sammpris team: Dr. Marc Chimowitz, Shelly Caskey, Meghan Steiner, Jessica Kandl, Dr. Tanya Turan, Genny Starr, R.N., Samantha Minkin and Janice Malloy.

Outside of MUSC, there are other groups involved in regular collaboration, including the data management and statistical center, NIH, FDA, corporate partners, the retail pharmacy chain where patients get the study drugs from nationwide, the commercial lifestyle modification personnel, and the investigators and coordinators at the 50 sites.
Even though the logistics can be complicated, studies such as this are essential to advancing science, Chimowitz said. "The study is an example of how a randomized trial that has been carefully designed to avoid bias favoring one treatment over another can yield results that are unexpected, but that are reliable and able to lead to a change in everyday medical practice worldwide."

How the study defines aggressive medical management

• a daily dosage of 325 milligrams of aspirin;
• 75 milligrams a day of clopidogrel, a medication used to prevent blood clots, for 90 days after enrollment;
• and intensive management of key stroke risk factors — high blood pressure and high levels of low density lipoprotein (LDL), the unhealthy form of cholesterol.

All patients also participated in a lifestyle modification program which focused on quitting smoking, increasing exercise, weight loss in overweight patients, healthy diet and controlling risk factors such as diabetes, high blood pressure and cholesterol.

For more data and study details, visit the New England Journal of Medicine's website: http://tinyurl.com/44yhttn.