First EDition: News for and about the practice of Emergency Medicine

Magnesium given at stroke onset didn’t improve functional outcomes

BY MICHELE G. SULLIVAN

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Magnesium sulfate infused within 2 hours of stroke symptom onset failed to improve clinical outcomes, according to results from the randomized, placebo-controlled Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial.

The drug did not shift functional outcomes at 3 months in FAST-MAG to a more favorable distribution nor, in secondary endpoints, did it change outcome scores as measured by the modified Rankin Scale or National Institutes of Health Stroke Scale.

At 3 months, a little more than half of each group had a modified Rankin Scale score of 2 or lower and about 65% of each group had a National Institutes of Health Stroke Scale score of 8 or lower, both of which indicate good functional recovery. About 15% of each group had died, Dr. Jeffrey L. Saver and his colleagues reported (N. Engl. J. Med. 2015;372:528-36).

The trial randomized 1,700 patients with suspected ischemic stroke to either magnesium sulfate or placebo infusions while en route to a hospital in an emergency vehicle.

In animal models of stroke, magnesium sulfate has been shown to exert vasodilatory and direct neuroprotective and glioprotective effects, said Dr. Saver, director of the clinical stroke program at the University of California, Los Angeles, and his coauthors.

Slow transport of magnesium across the blood-brain barrier may explain why FAST-MAG didn’t replicate these earlier findings. Magnesium levels in the cerebrospinal fluid peak 4 hours after parenteral administration in the presence of an intact blood-brain barrier and more quickly in regions of focal ischemia where the blood-brain barrier is disrupted. Despite a rapid increase in serum levels, brain tissue levels may not have risen quickly enough to yield a benefit, the researchers speculated.

[email protected]

Glucose level may predict mortality in acute heart failure

BY MARY ANN MOON

FROM THE EUROPEAN HEART JOURNAL

Blood glucose level may predict 30-day mortality in adults who present with acute heart failure, regardless of whether the patients have preexisting diabetes, based on a study by Dr. Maneesh Sud of the University of Toronto and his associates.

Hyperglycemia occurs in up to 40% of acute heart failure patients. If prognostic, blood glucose levels at ED presentation “may serve as a screen to identify high-risk patients who warrant formal testing for diabetes, allowing for prompt referral to prevent further morbidity and mortality,” the researchers said.

The researchers analyzed data from two large population-based cohorts of patients hospitalized for acute HF during a 3-year period.  Of the 16,524 patients, 44% had preexisting diabetes (Eur. Heart J. 2015 [doi:10.1093/eurheartj/ehu462].

Among patients with established diabetes, a blood glucose level exceeding 11.1 mmol/L was associated with significantly increased all-cause 30-day mortality with a hazard ratio (HR) of 1.48. Among patients without established diabetes, a blood glucose level exceeding 6.1 mmol/L increased all-cause 30-day mortality with an HR of 1.26; that risk rose in a dose-dependent fashion with increasing glucose levels and reached 1.5 at the level of 11.1 mmol/L.

In severe trauma, 1:1:1 transfusion protocol linked to less exsanguination

BY MARY ANN MOON

FROM JAMA

Among profoundly injured trauma patients with major bleeding, early (24 hour) and late (30 day) mortality were similar between those who received transfusions of plasma, platelets, and red blood cells in a 1:1:1 ratio and those who received transfusions in a 1:1:2 ratio in a phase III clinical trial of 680 adults.

Transfusion protocols for such patients have been “predominantly guided by tradition rather than evidence from large, multicenter randomized trials,” said Dr. John B. Holcomb of the Center for Translational Injury Research, University of Texas Health Science Center, Houston, and his associates in the PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial. In the last decade, many clinicians changed over to the 1:1:1 ratio because it is more balanced and more closely replicates the ratio present in whole blood than does the traditional 1:1:2 ratio.

The researchers described the study as the first multicenter randomized trial to use approved blood products to compare the two transfusion ratios with mortality as the primary end point. The 680 adults enrolled in the study were treated for severe injury with major bleeding during a 16-month period at 12 Level 1 trauma centers in North America.

Overall 24-hour mortality was not significantly different, at 12.7% in the 1:1:1 group and 17% in the 1:1:2 group, and 30-day mortality also was not significantly different at 22.4% and 26.1%, respectively.  However, exsanguination, the predominant cause of death within 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs. 14.6%), and significantly more patients in the 1:1:1 group achieved anatomic homeostasis (86.1% vs. 78.1%). Thus, clinicians “should consider using a 1:1:1 transfusion protocol,” Dr. Holcomb and his associates said (JAMA 2015 Feb. 3 [doi:10.10001/jama.2015.12]).

There also were no significant differences between the two study groups in 23 complications, including transfusion-related complications. “Despite significant concerns that the 1:1:1 group would experience higher rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, venous thromboembolism, and sepsis, no differences were detected between the two treatment groups,” the researchers noted.

Stress tests in ED lead to unneeded cardiac interventions

BY NICOLA GARRETT

FROM JAMA INTERNAL MEDICINE

Noninvasive testing in the emergency department of patients who have chest pain and have not had a myocardial infarction can result in overdiagnosis and unnecessary interventions, based on the results of a retrospective analysis.

After 6 months of follow-up, 0.33% of 421,774 privately insured patients who presented to the emergency department (ED) with chest pain were hospitalized with an MI. There was no difference in the rate of MIs in patients who did and did not undergo exercise and stress electrocardiography, myocardial perfusion scintigraphy (MPS), or coronary CT angiography, Dr. Andrew. J. Foy of Penn State Milton S. Hershey Medical Center in Hershey, Pa., and his colleagues reported in an article published online in JAMA Internal Medicine (2015 Jan. 26 [doi:10.1001/jamainternmed.2014.7657]).

However, interventions were increased without a concomitant reduction in MI in patients who underwent tests in the ED. “Overdiagnosis is a legitimate concern in this patient population,” the study authors wrote.

Using data from the analysis, the researchers estimated that an unnecessary catheterization is performed in 1 of every 27 patients who undergo MPS instead of an initial strategy of no testing.

“When viewed in the broader context of the approximately 6 million ED visits for a chief symptom of chest pain, for every 100,000 patients who undergo MPS instead of an initial strategy of no testing, approximately 3,700 patients will undergo an unnecessary catheterization,” they wrote.   

New treatment options outlined for acute-onset, severe hypertension in pregnancy

BY NICOLA GARRETT

FROM OBSTETRICS AND GYNECOLOGY

The American College of Obstetricians and Gynecologists has added nifedipine as a first-line treatment for acute-onset severe hypertension during pregnancy and the postpartum period in an updated opinion from its Committee on Obstetric Practice.

The update, released on Jan. 22, points to studies showing that women who received oral nifedipine had their blood pressure lowered more quickly than with either intravenous labetalol or hydralazine – the traditional first-line treatments – and had a significant increase in urine output. Concerns about neuromuscular blockade and severe hypotension with the use of nifedipine and magnesium sulphate were not borne out in a large review, the committee members wrote, but they advised careful monitoring since both drugs are calcium antagonists.

The committee opinion includes model order sets for the use of labetalol, hydralazine, and nifedipine for the initial management of acute onset severe hypertension in women who are pregnant or post partum with preeclampsia or eclampsia (Obstet. Gynecol. 2015;125:521-5).

While all three medications are appropriate in treating hypertensive emergencies during pregnancy, each drug has adverse effects.

For instance, parenteral hydralazine can increase the risk of maternal hypotension. Parenteral labetalol may cause neonatal bradycardia and should be avoided in women with asthma, heart disease, or heart failure. Nifedipine has been associated with increased maternal heart rate and overshoot hypotension.

“Patients may respond to one drug and not another,” the committee noted.

The ACOG committee also called for standardized clinical guidelines for the management of patients with preeclampsia and eclampsia.

“With the advent of pregnancy hypertension guidelines in the United Kingdom, care of maternity patients with preeclampsia or eclampsia improved significantly and maternal mortality rates decreased because of a reduction in cerebral and respiratory complications,” they wrote. “Individuals and institutions should have mechanisms in place to initiate the prompt administration of medication when a patient presents with a hypertensive emergency.”

The committee recommended checklists as one tool to help standardize the use of guidelines.

“Drip-and-ship” thrombolysis remains common for ischemic stroke

BY MICHELE G. SULLIVAN

AT THE INTERNATIONAL STROKE CONFERENCE

NASHVILLE, TENN.  – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm. While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have  influenced the findings.

[email protected]

Three trials cement embolectomy for acute ischemic stroke

BY MITCHEL L. ZOLER

NASHVILLE, TENN.  – Treatment of selected patients with acute ischemic stroke underwent a dramatic, sudden shift with reports from three randomized, controlled trials that showed substantial added benefit and no incremental risk with the use of catheter-based embolic retrieval to open blocked intracerebral arteries when performed on top of standard thrombolytic therapy.

The three studies, each run independently and based in different countries, supported the results first reported last October and published online in December (N. Engl. J. Med. 2015;372:11-20) from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) study. These were the first contemporary trial results to show a jump in functional outcomes with use of a stent retriever catheter to pluck out the occluding embolus from an artery in the stroke patient’s brain to restore normal blood flow.

All three of the newly-reported studies stopped before reaching their prespecified enrollment levels because of overwhelming evidence for embolectomy’s incremental efficacy.

With four reports from prospective, randomized trials showing similar benefits and no added harm to patients, experts at the International Stroke Conference uniformly anointed catheter-based embolectomy the new standard of care for the small percentage of acute, ischemic-stroke patients who present with proximal, large-artery obstructions and also match the other strict clinical and imaging inclusion and exclusion criteria used in the studies.

“Starting now, in patients with an acute ischemic stroke due to proximal vessel occlusion, rapid endovascular treatment using a retrieval stent is the standard of care,” Dr. Mayank Goyal declared from the plenary-session podium. He is a professor of diagnostic imaging at the University of Calgary (Canada) and an investigator in two of the three trials presented at the conference, which was sponsored by the American Heart Association.

“Today the world changed. We are now in a new era, the era of highly-effective intravascular recanalization therapy,” said Dr. Jeffrey L. Saver, professor of neurology and director of the Stroke Center at the University of California, Los Angeles, and lead investigator for one of the new studies.

In three of the four studies, the researchers did not report specific numbers on how selective they were in focusing in on the ischemic stroke patients most likely to benefit from this treatment, but the one study that did, EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial), run at nine Australian centers and one in New Zealand, showed the extensive winnowing that occurred. Of 7,796 patients with an acute ischemic stroke who initially presented, 1,044 (13%) were eligible to receive thrombolytic therapy (alteplase in this study). And from among these 1,044 patients, a mere 70 – less than 1% of the initial group – were deemed eligible for randomization into the embolectomy trial. The top three reasons for exclusion of patients who qualified for thrombolytic treatment from the trial was an absence of a major-vessel occlusion (45% of the excluded patients), presentation outside of the times when enrollment personnel were available (22%), and poor premorbid function (16%).

But subgroup analyses in three of the four studies (EXTEND-IA with a total of 70 patients was too small for subgroup analyses) showed no subgroup of patients who failed to benefit from embolectomy, including elderly patients who in some cases were nonagenarians.

The unusual confluence of having four major trials showing remarkably consistent results meant that the stroke experts gathered at the meeting focused their attention not on whether stent retrievers should now be widely and routinely used in appropriate patients but instead on how this technology will roll out worldwide.

“From here on out we are obligated to treat patients with this technology at centers that can do this, and we are obligated to have more centers that can provide it,” said Dr. Kyra J. Becker, professor of neurology and neurological surgery and codirector of the Stroke Center at the University of Washington, Seattle. Dr. Becker had no involvement in any of the stent retriever trials. “I had been a doubter of this technology,” primarily because results reported at the International Stroke Conference a couple of years ago failed to prove the efficacy of clot retrieval in ischemic stroke patients, she noted. “Our ability to select appropriate patients and do it in a timely fashion hadn’t gotten to where it had to be until now,” Dr. Becker said in an interview.

“We only enrolled patients with blockages, we treated them quickly, and we used much better devices to open their arteries,” Dr. Saver added, explaining why the new studies succeeded when earlier studies had not.

The trial led by Dr. Saver, SWIFT-PRIME (SOLITAIRE™ FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), enrolled 195 patients at 39 sites in the United States and in Europe. At 90 days after treatment, 59 patients (60%) among those treated with thrombolysis plus embolectomy had a modified Rankin Scale score of 0-2, compared with 33 patients (36%) among those treated only with thrombolysis (in this trial intravenous treatment with tissue plasminogen activator), a highly significant difference for the study’s primary endpoint.

“For every two and half patients treated, one more patient had a better disability outcome, and for every four patients treated, one more patient was independent at long-term follow-up,” Dr. Saver said. Safety measures were similar among patients in the study’s two arms.

The EXTEND-IA results showed a 90-day modified Rankin Scale score of 0-2 in 52% of the embolectomy patients, compared with 28% of those treated only with thrombolysis. The study’s co–primary endpoints were median level of reperfusion at 24 hours after treatment, 100% with embolectomy and 37% with thrombolysis only, and early neurologic recovery, defined as at least an 8-point drop from the baseline in the National Institutes of Health Stroke Scale score or a score of 0 or 1 when assessed 3 days after treatment. Patients met this second endpoint at an 80% rate with embolectomy and a 37% rate with thrombolysis only. Results of EXTEND-IA appeared in an article published online concurrently with the meeting report (N. Engl J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414792]).

The third, and largest, of the three studies presented at the conference, ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), enrolled 316 patients at 11 centers in Canada, 6 in the United States, 3 in South Korea, and 1 in Ireland. After 90 days, 53% of patients in the embolectomy arm had achieved a modified Rankin Scale score of 0-2, this study’s primary endpoint, compared with 29% of patients in the thrombolysis-only arm (treatment with alteplase). These results also appeared in an article published online concurrently with the conference report (N. Engl. J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414905]).

SWIFT PRIME was sponsored by Covidien, which markets the stent retriever used in the study. Dr. Saver and Dr. Goyal are consultants to Covidien. EXTEND-IA used stent retrievers provided by Covidien. ESCAPE received a grant from Covidien. Dr. Becker had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

Views on the News
Results warrant embolectomy scale-up

Many U.S. centers have interventionalists who already perform endovascular treatments within intracerebral arteries, but the issue is can they do this form of embolectomy in the high-quality, highly-reliable, rapid way that it was done in these trials? Stent-retriever catheters are relatively straightforward to use by operators who are experienced doing vascular procedures in the brain, but they don’t deliver this treatment by themselves. You need a team that is focused on doing it quickly, and that will be the kind of training we’ll need to roll out this treatment broadly. We achieved it for stroke thrombolytic treatment through the Target Stroke program (JAMA 2014;311:1632-40), so we know that we can achieve this sort of goal. Delivering embolectomy requires more people and more technology than thrombolysis, but it is not rocket science; it just needs a system.

Embolectomy will not replace routine thrombolysis treatment; it will piggyback on top of it. The percentage of patients with a proximal occlusion in a large artery is relatively small. The results we have seen suggest that using embolectomy plus thrombolysis has no adverse-effect downside, compared with thrombolysis alone. Once routine use of embolectomy becomes established, we can directly compare catheter treatment only against combined embolectomy and thrombolysis. My impression today is that what we’d compare is transporting stroke patients directly to a center that can perform embolectomy against taking patients to the closest center that can treat them with thrombolysis and then transporting them to the center that performs embolectomy.

The results of these three new studies plus the previously-reported results from MR CLEAN are not exactly a game changer, because many centers were already performing embolectomy but in a limited way. Now we have the data to give us confidence to do it routinely and to know which patients to select for embolectomy. Because many centers are already doing this, it will not take 5 years to diffuse the technology. Embolectomy is already a treatment cited in the guidelines, but now it will be a level 1A recommendation.

The significance of the new reports is that they will have a dramatic impact on public health systems and in the triage of patients with stroke. It will affect how patients get triaged, and will allow us to identify which patients should go to which centers. I believe we will soon develop clinical examination tools that will allow prehospital providers to discern patients with mild strokes who can go to the nearest center that can administer thrombolysis and which patients need to go to comprehensive centers that can perform embolectomy. We now need to do what we did for thrombolysis, and help centers develop the expertise to do embolectomy as a team and to shave minutes off the delivery at every step of the process. It’s clear that it is the time from stroke onset to getting the artery open that is the key to improved patient outcomes.

If I have my way, we will launch later this year a big effort to focus on improving embolectomy delivery. Now that we know for certain that it works we need to turn the crank and make sure that as many patients as possible who qualify get this treatment.

Dr. Lee H. Schwamm is professor of neurology at Harvard Medical School, and director of acute stroke services at Massachusetts General Hospital, both in Boston. He is a consultant to Penumbra and has received research support from Genentech. He made these comments in an interview.

Magnesium given at stroke onset didn’t improve functional outcomes

BY MICHELE G. SULLIVAN

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Magnesium sulfate infused within 2 hours of stroke symptom onset failed to improve clinical outcomes, according to results from the randomized, placebo-controlled Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial.

The drug did not shift functional outcomes at 3 months in FAST-MAG to a more favorable distribution nor, in secondary endpoints, did it change outcome scores as measured by the modified Rankin Scale or National Institutes of Health Stroke Scale.

At 3 months, a little more than half of each group had a modified Rankin Scale score of 2 or lower and about 65% of each group had a National Institutes of Health Stroke Scale score of 8 or lower, both of which indicate good functional recovery. About 15% of each group had died, Dr. Jeffrey L. Saver and his colleagues reported (N. Engl. J. Med. 2015;372:528-36).

The trial randomized 1,700 patients with suspected ischemic stroke to either magnesium sulfate or placebo infusions while en route to a hospital in an emergency vehicle.

In animal models of stroke, magnesium sulfate has been shown to exert vasodilatory and direct neuroprotective and glioprotective effects, said Dr. Saver, director of the clinical stroke program at the University of California, Los Angeles, and his coauthors.

Slow transport of magnesium across the blood-brain barrier may explain why FAST-MAG didn’t replicate these earlier findings. Magnesium levels in the cerebrospinal fluid peak 4 hours after parenteral administration in the presence of an intact blood-brain barrier and more quickly in regions of focal ischemia where the blood-brain barrier is disrupted. Despite a rapid increase in serum levels, brain tissue levels may not have risen quickly enough to yield a benefit, the researchers speculated.

[email protected]

Glucose level may predict mortality in acute heart failure

BY MARY ANN MOON

FROM THE EUROPEAN HEART JOURNAL

Blood glucose level may predict 30-day mortality in adults who present with acute heart failure, regardless of whether the patients have preexisting diabetes, based on a study by Dr. Maneesh Sud of the University of Toronto and his associates.

Hyperglycemia occurs in up to 40% of acute heart failure patients. If prognostic, blood glucose levels at ED presentation “may serve as a screen to identify high-risk patients who warrant formal testing for diabetes, allowing for prompt referral to prevent further morbidity and mortality,” the researchers said.

The researchers analyzed data from two large population-based cohorts of patients hospitalized for acute HF during a 3-year period.  Of the 16,524 patients, 44% had preexisting diabetes (Eur. Heart J. 2015 [doi:10.1093/eurheartj/ehu462].

Among patients with established diabetes, a blood glucose level exceeding 11.1 mmol/L was associated with significantly increased all-cause 30-day mortality with a hazard ratio (HR) of 1.48. Among patients without established diabetes, a blood glucose level exceeding 6.1 mmol/L increased all-cause 30-day mortality with an HR of 1.26; that risk rose in a dose-dependent fashion with increasing glucose levels and reached 1.5 at the level of 11.1 mmol/L.

In severe trauma, 1:1:1 transfusion protocol linked to less exsanguination

BY MARY ANN MOON

FROM JAMA

Among profoundly injured trauma patients with major bleeding, early (24 hour) and late (30 day) mortality were similar between those who received transfusions of plasma, platelets, and red blood cells in a 1:1:1 ratio and those who received transfusions in a 1:1:2 ratio in a phase III clinical trial of 680 adults.

Transfusion protocols for such patients have been “predominantly guided by tradition rather than evidence from large, multicenter randomized trials,” said Dr. John B. Holcomb of the Center for Translational Injury Research, University of Texas Health Science Center, Houston, and his associates in the PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial. In the last decade, many clinicians changed over to the 1:1:1 ratio because it is more balanced and more closely replicates the ratio present in whole blood than does the traditional 1:1:2 ratio.

The researchers described the study as the first multicenter randomized trial to use approved blood products to compare the two transfusion ratios with mortality as the primary end point. The 680 adults enrolled in the study were treated for severe injury with major bleeding during a 16-month period at 12 Level 1 trauma centers in North America.

Overall 24-hour mortality was not significantly different, at 12.7% in the 1:1:1 group and 17% in the 1:1:2 group, and 30-day mortality also was not significantly different at 22.4% and 26.1%, respectively.  However, exsanguination, the predominant cause of death within 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs. 14.6%), and significantly more patients in the 1:1:1 group achieved anatomic homeostasis (86.1% vs. 78.1%). Thus, clinicians “should consider using a 1:1:1 transfusion protocol,” Dr. Holcomb and his associates said (JAMA 2015 Feb. 3 [doi:10.10001/jama.2015.12]).

There also were no significant differences between the two study groups in 23 complications, including transfusion-related complications. “Despite significant concerns that the 1:1:1 group would experience higher rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, venous thromboembolism, and sepsis, no differences were detected between the two treatment groups,” the researchers noted.

Stress tests in ED lead to unneeded cardiac interventions

BY NICOLA GARRETT

FROM JAMA INTERNAL MEDICINE

Noninvasive testing in the emergency department of patients who have chest pain and have not had a myocardial infarction can result in overdiagnosis and unnecessary interventions, based on the results of a retrospective analysis.

After 6 months of follow-up, 0.33% of 421,774 privately insured patients who presented to the emergency department (ED) with chest pain were hospitalized with an MI. There was no difference in the rate of MIs in patients who did and did not undergo exercise and stress electrocardiography, myocardial perfusion scintigraphy (MPS), or coronary CT angiography, Dr. Andrew. J. Foy of Penn State Milton S. Hershey Medical Center in Hershey, Pa., and his colleagues reported in an article published online in JAMA Internal Medicine (2015 Jan. 26 [doi:10.1001/jamainternmed.2014.7657]).

However, interventions were increased without a concomitant reduction in MI in patients who underwent tests in the ED. “Overdiagnosis is a legitimate concern in this patient population,” the study authors wrote.

Using data from the analysis, the researchers estimated that an unnecessary catheterization is performed in 1 of every 27 patients who undergo MPS instead of an initial strategy of no testing.

“When viewed in the broader context of the approximately 6 million ED visits for a chief symptom of chest pain, for every 100,000 patients who undergo MPS instead of an initial strategy of no testing, approximately 3,700 patients will undergo an unnecessary catheterization,” they wrote.   

New treatment options outlined for acute-onset, severe hypertension in pregnancy

BY NICOLA GARRETT

FROM OBSTETRICS AND GYNECOLOGY

The American College of Obstetricians and Gynecologists has added nifedipine as a first-line treatment for acute-onset severe hypertension during pregnancy and the postpartum period in an updated opinion from its Committee on Obstetric Practice.

The update, released on Jan. 22, points to studies showing that women who received oral nifedipine had their blood pressure lowered more quickly than with either intravenous labetalol or hydralazine – the traditional first-line treatments – and had a significant increase in urine output. Concerns about neuromuscular blockade and severe hypotension with the use of nifedipine and magnesium sulphate were not borne out in a large review, the committee members wrote, but they advised careful monitoring since both drugs are calcium antagonists.

The committee opinion includes model order sets for the use of labetalol, hydralazine, and nifedipine for the initial management of acute onset severe hypertension in women who are pregnant or post partum with preeclampsia or eclampsia (Obstet. Gynecol. 2015;125:521-5).

While all three medications are appropriate in treating hypertensive emergencies during pregnancy, each drug has adverse effects.

For instance, parenteral hydralazine can increase the risk of maternal hypotension. Parenteral labetalol may cause neonatal bradycardia and should be avoided in women with asthma, heart disease, or heart failure. Nifedipine has been associated with increased maternal heart rate and overshoot hypotension.

“Patients may respond to one drug and not another,” the committee noted.

The ACOG committee also called for standardized clinical guidelines for the management of patients with preeclampsia and eclampsia.

“With the advent of pregnancy hypertension guidelines in the United Kingdom, care of maternity patients with preeclampsia or eclampsia improved significantly and maternal mortality rates decreased because of a reduction in cerebral and respiratory complications,” they wrote. “Individuals and institutions should have mechanisms in place to initiate the prompt administration of medication when a patient presents with a hypertensive emergency.”

The committee recommended checklists as one tool to help standardize the use of guidelines.

“Drip-and-ship” thrombolysis remains common for ischemic stroke

BY MICHELE G. SULLIVAN

AT THE INTERNATIONAL STROKE CONFERENCE

NASHVILLE, TENN.  – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm. While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have  influenced the findings.

[email protected]

Three trials cement embolectomy for acute ischemic stroke

BY MITCHEL L. ZOLER

NASHVILLE, TENN.  – Treatment of selected patients with acute ischemic stroke underwent a dramatic, sudden shift with reports from three randomized, controlled trials that showed substantial added benefit and no incremental risk with the use of catheter-based embolic retrieval to open blocked intracerebral arteries when performed on top of standard thrombolytic therapy.

The three studies, each run independently and based in different countries, supported the results first reported last October and published online in December (N. Engl. J. Med. 2015;372:11-20) from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) study. These were the first contemporary trial results to show a jump in functional outcomes with use of a stent retriever catheter to pluck out the occluding embolus from an artery in the stroke patient’s brain to restore normal blood flow.

All three of the newly-reported studies stopped before reaching their prespecified enrollment levels because of overwhelming evidence for embolectomy’s incremental efficacy.

With four reports from prospective, randomized trials showing similar benefits and no added harm to patients, experts at the International Stroke Conference uniformly anointed catheter-based embolectomy the new standard of care for the small percentage of acute, ischemic-stroke patients who present with proximal, large-artery obstructions and also match the other strict clinical and imaging inclusion and exclusion criteria used in the studies.

“Starting now, in patients with an acute ischemic stroke due to proximal vessel occlusion, rapid endovascular treatment using a retrieval stent is the standard of care,” Dr. Mayank Goyal declared from the plenary-session podium. He is a professor of diagnostic imaging at the University of Calgary (Canada) and an investigator in two of the three trials presented at the conference, which was sponsored by the American Heart Association.

“Today the world changed. We are now in a new era, the era of highly-effective intravascular recanalization therapy,” said Dr. Jeffrey L. Saver, professor of neurology and director of the Stroke Center at the University of California, Los Angeles, and lead investigator for one of the new studies.

In three of the four studies, the researchers did not report specific numbers on how selective they were in focusing in on the ischemic stroke patients most likely to benefit from this treatment, but the one study that did, EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial), run at nine Australian centers and one in New Zealand, showed the extensive winnowing that occurred. Of 7,796 patients with an acute ischemic stroke who initially presented, 1,044 (13%) were eligible to receive thrombolytic therapy (alteplase in this study). And from among these 1,044 patients, a mere 70 – less than 1% of the initial group – were deemed eligible for randomization into the embolectomy trial. The top three reasons for exclusion of patients who qualified for thrombolytic treatment from the trial was an absence of a major-vessel occlusion (45% of the excluded patients), presentation outside of the times when enrollment personnel were available (22%), and poor premorbid function (16%).

But subgroup analyses in three of the four studies (EXTEND-IA with a total of 70 patients was too small for subgroup analyses) showed no subgroup of patients who failed to benefit from embolectomy, including elderly patients who in some cases were nonagenarians.

The unusual confluence of having four major trials showing remarkably consistent results meant that the stroke experts gathered at the meeting focused their attention not on whether stent retrievers should now be widely and routinely used in appropriate patients but instead on how this technology will roll out worldwide.

“From here on out we are obligated to treat patients with this technology at centers that can do this, and we are obligated to have more centers that can provide it,” said Dr. Kyra J. Becker, professor of neurology and neurological surgery and codirector of the Stroke Center at the University of Washington, Seattle. Dr. Becker had no involvement in any of the stent retriever trials. “I had been a doubter of this technology,” primarily because results reported at the International Stroke Conference a couple of years ago failed to prove the efficacy of clot retrieval in ischemic stroke patients, she noted. “Our ability to select appropriate patients and do it in a timely fashion hadn’t gotten to where it had to be until now,” Dr. Becker said in an interview.

“We only enrolled patients with blockages, we treated them quickly, and we used much better devices to open their arteries,” Dr. Saver added, explaining why the new studies succeeded when earlier studies had not.

The trial led by Dr. Saver, SWIFT-PRIME (SOLITAIRE™ FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), enrolled 195 patients at 39 sites in the United States and in Europe. At 90 days after treatment, 59 patients (60%) among those treated with thrombolysis plus embolectomy had a modified Rankin Scale score of 0-2, compared with 33 patients (36%) among those treated only with thrombolysis (in this trial intravenous treatment with tissue plasminogen activator), a highly significant difference for the study’s primary endpoint.

“For every two and half patients treated, one more patient had a better disability outcome, and for every four patients treated, one more patient was independent at long-term follow-up,” Dr. Saver said. Safety measures were similar among patients in the study’s two arms.

The EXTEND-IA results showed a 90-day modified Rankin Scale score of 0-2 in 52% of the embolectomy patients, compared with 28% of those treated only with thrombolysis. The study’s co–primary endpoints were median level of reperfusion at 24 hours after treatment, 100% with embolectomy and 37% with thrombolysis only, and early neurologic recovery, defined as at least an 8-point drop from the baseline in the National Institutes of Health Stroke Scale score or a score of 0 or 1 when assessed 3 days after treatment. Patients met this second endpoint at an 80% rate with embolectomy and a 37% rate with thrombolysis only. Results of EXTEND-IA appeared in an article published online concurrently with the meeting report (N. Engl J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414792]).

The third, and largest, of the three studies presented at the conference, ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), enrolled 316 patients at 11 centers in Canada, 6 in the United States, 3 in South Korea, and 1 in Ireland. After 90 days, 53% of patients in the embolectomy arm had achieved a modified Rankin Scale score of 0-2, this study’s primary endpoint, compared with 29% of patients in the thrombolysis-only arm (treatment with alteplase). These results also appeared in an article published online concurrently with the conference report (N. Engl. J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414905]).

SWIFT PRIME was sponsored by Covidien, which markets the stent retriever used in the study. Dr. Saver and Dr. Goyal are consultants to Covidien. EXTEND-IA used stent retrievers provided by Covidien. ESCAPE received a grant from Covidien. Dr. Becker had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

Views on the News
Results warrant embolectomy scale-up

Many U.S. centers have interventionalists who already perform endovascular treatments within intracerebral arteries, but the issue is can they do this form of embolectomy in the high-quality, highly-reliable, rapid way that it was done in these trials? Stent-retriever catheters are relatively straightforward to use by operators who are experienced doing vascular procedures in the brain, but they don’t deliver this treatment by themselves. You need a team that is focused on doing it quickly, and that will be the kind of training we’ll need to roll out this treatment broadly. We achieved it for stroke thrombolytic treatment through the Target Stroke program (JAMA 2014;311:1632-40), so we know that we can achieve this sort of goal. Delivering embolectomy requires more people and more technology than thrombolysis, but it is not rocket science; it just needs a system.

Embolectomy will not replace routine thrombolysis treatment; it will piggyback on top of it. The percentage of patients with a proximal occlusion in a large artery is relatively small. The results we have seen suggest that using embolectomy plus thrombolysis has no adverse-effect downside, compared with thrombolysis alone. Once routine use of embolectomy becomes established, we can directly compare catheter treatment only against combined embolectomy and thrombolysis. My impression today is that what we’d compare is transporting stroke patients directly to a center that can perform embolectomy against taking patients to the closest center that can treat them with thrombolysis and then transporting them to the center that performs embolectomy.

The results of these three new studies plus the previously-reported results from MR CLEAN are not exactly a game changer, because many centers were already performing embolectomy but in a limited way. Now we have the data to give us confidence to do it routinely and to know which patients to select for embolectomy. Because many centers are already doing this, it will not take 5 years to diffuse the technology. Embolectomy is already a treatment cited in the guidelines, but now it will be a level 1A recommendation.

The significance of the new reports is that they will have a dramatic impact on public health systems and in the triage of patients with stroke. It will affect how patients get triaged, and will allow us to identify which patients should go to which centers. I believe we will soon develop clinical examination tools that will allow prehospital providers to discern patients with mild strokes who can go to the nearest center that can administer thrombolysis and which patients need to go to comprehensive centers that can perform embolectomy. We now need to do what we did for thrombolysis, and help centers develop the expertise to do embolectomy as a team and to shave minutes off the delivery at every step of the process. It’s clear that it is the time from stroke onset to getting the artery open that is the key to improved patient outcomes.

If I have my way, we will launch later this year a big effort to focus on improving embolectomy delivery. Now that we know for certain that it works we need to turn the crank and make sure that as many patients as possible who qualify get this treatment.

Dr. Lee H. Schwamm is professor of neurology at Harvard Medical School, and director of acute stroke services at Massachusetts General Hospital, both in Boston. He is a consultant to Penumbra and has received research support from Genentech. He made these comments in an interview.

Magnesium given at stroke onset didn’t improve functional outcomes

BY MICHELE G. SULLIVAN

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Magnesium sulfate infused within 2 hours of stroke symptom onset failed to improve clinical outcomes, according to results from the randomized, placebo-controlled Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial.

The drug did not shift functional outcomes at 3 months in FAST-MAG to a more favorable distribution nor, in secondary endpoints, did it change outcome scores as measured by the modified Rankin Scale or National Institutes of Health Stroke Scale.

At 3 months, a little more than half of each group had a modified Rankin Scale score of 2 or lower and about 65% of each group had a National Institutes of Health Stroke Scale score of 8 or lower, both of which indicate good functional recovery. About 15% of each group had died, Dr. Jeffrey L. Saver and his colleagues reported (N. Engl. J. Med. 2015;372:528-36).

The trial randomized 1,700 patients with suspected ischemic stroke to either magnesium sulfate or placebo infusions while en route to a hospital in an emergency vehicle.

In animal models of stroke, magnesium sulfate has been shown to exert vasodilatory and direct neuroprotective and glioprotective effects, said Dr. Saver, director of the clinical stroke program at the University of California, Los Angeles, and his coauthors.

Slow transport of magnesium across the blood-brain barrier may explain why FAST-MAG didn’t replicate these earlier findings. Magnesium levels in the cerebrospinal fluid peak 4 hours after parenteral administration in the presence of an intact blood-brain barrier and more quickly in regions of focal ischemia where the blood-brain barrier is disrupted. Despite a rapid increase in serum levels, brain tissue levels may not have risen quickly enough to yield a benefit, the researchers speculated.

[email protected]

Glucose level may predict mortality in acute heart failure

BY MARY ANN MOON

FROM THE EUROPEAN HEART JOURNAL

Blood glucose level may predict 30-day mortality in adults who present with acute heart failure, regardless of whether the patients have preexisting diabetes, based on a study by Dr. Maneesh Sud of the University of Toronto and his associates.

Hyperglycemia occurs in up to 40% of acute heart failure patients. If prognostic, blood glucose levels at ED presentation “may serve as a screen to identify high-risk patients who warrant formal testing for diabetes, allowing for prompt referral to prevent further morbidity and mortality,” the researchers said.

The researchers analyzed data from two large population-based cohorts of patients hospitalized for acute HF during a 3-year period.  Of the 16,524 patients, 44% had preexisting diabetes (Eur. Heart J. 2015 [doi:10.1093/eurheartj/ehu462].

Among patients with established diabetes, a blood glucose level exceeding 11.1 mmol/L was associated with significantly increased all-cause 30-day mortality with a hazard ratio (HR) of 1.48. Among patients without established diabetes, a blood glucose level exceeding 6.1 mmol/L increased all-cause 30-day mortality with an HR of 1.26; that risk rose in a dose-dependent fashion with increasing glucose levels and reached 1.5 at the level of 11.1 mmol/L.

In severe trauma, 1:1:1 transfusion protocol linked to less exsanguination

BY MARY ANN MOON

FROM JAMA

Among profoundly injured trauma patients with major bleeding, early (24 hour) and late (30 day) mortality were similar between those who received transfusions of plasma, platelets, and red blood cells in a 1:1:1 ratio and those who received transfusions in a 1:1:2 ratio in a phase III clinical trial of 680 adults.

Transfusion protocols for such patients have been “predominantly guided by tradition rather than evidence from large, multicenter randomized trials,” said Dr. John B. Holcomb of the Center for Translational Injury Research, University of Texas Health Science Center, Houston, and his associates in the PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial. In the last decade, many clinicians changed over to the 1:1:1 ratio because it is more balanced and more closely replicates the ratio present in whole blood than does the traditional 1:1:2 ratio.

The researchers described the study as the first multicenter randomized trial to use approved blood products to compare the two transfusion ratios with mortality as the primary end point. The 680 adults enrolled in the study were treated for severe injury with major bleeding during a 16-month period at 12 Level 1 trauma centers in North America.

Overall 24-hour mortality was not significantly different, at 12.7% in the 1:1:1 group and 17% in the 1:1:2 group, and 30-day mortality also was not significantly different at 22.4% and 26.1%, respectively.  However, exsanguination, the predominant cause of death within 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs. 14.6%), and significantly more patients in the 1:1:1 group achieved anatomic homeostasis (86.1% vs. 78.1%). Thus, clinicians “should consider using a 1:1:1 transfusion protocol,” Dr. Holcomb and his associates said (JAMA 2015 Feb. 3 [doi:10.10001/jama.2015.12]).

There also were no significant differences between the two study groups in 23 complications, including transfusion-related complications. “Despite significant concerns that the 1:1:1 group would experience higher rates of multiple inflammatory-mediated complications, such as acute respiratory distress syndrome, multiple organ failure, infection, venous thromboembolism, and sepsis, no differences were detected between the two treatment groups,” the researchers noted.

Stress tests in ED lead to unneeded cardiac interventions

BY NICOLA GARRETT

FROM JAMA INTERNAL MEDICINE

Noninvasive testing in the emergency department of patients who have chest pain and have not had a myocardial infarction can result in overdiagnosis and unnecessary interventions, based on the results of a retrospective analysis.

After 6 months of follow-up, 0.33% of 421,774 privately insured patients who presented to the emergency department (ED) with chest pain were hospitalized with an MI. There was no difference in the rate of MIs in patients who did and did not undergo exercise and stress electrocardiography, myocardial perfusion scintigraphy (MPS), or coronary CT angiography, Dr. Andrew. J. Foy of Penn State Milton S. Hershey Medical Center in Hershey, Pa., and his colleagues reported in an article published online in JAMA Internal Medicine (2015 Jan. 26 [doi:10.1001/jamainternmed.2014.7657]).

However, interventions were increased without a concomitant reduction in MI in patients who underwent tests in the ED. “Overdiagnosis is a legitimate concern in this patient population,” the study authors wrote.

Using data from the analysis, the researchers estimated that an unnecessary catheterization is performed in 1 of every 27 patients who undergo MPS instead of an initial strategy of no testing.

“When viewed in the broader context of the approximately 6 million ED visits for a chief symptom of chest pain, for every 100,000 patients who undergo MPS instead of an initial strategy of no testing, approximately 3,700 patients will undergo an unnecessary catheterization,” they wrote.   

New treatment options outlined for acute-onset, severe hypertension in pregnancy

BY NICOLA GARRETT

FROM OBSTETRICS AND GYNECOLOGY

The American College of Obstetricians and Gynecologists has added nifedipine as a first-line treatment for acute-onset severe hypertension during pregnancy and the postpartum period in an updated opinion from its Committee on Obstetric Practice.

The update, released on Jan. 22, points to studies showing that women who received oral nifedipine had their blood pressure lowered more quickly than with either intravenous labetalol or hydralazine – the traditional first-line treatments – and had a significant increase in urine output. Concerns about neuromuscular blockade and severe hypotension with the use of nifedipine and magnesium sulphate were not borne out in a large review, the committee members wrote, but they advised careful monitoring since both drugs are calcium antagonists.

The committee opinion includes model order sets for the use of labetalol, hydralazine, and nifedipine for the initial management of acute onset severe hypertension in women who are pregnant or post partum with preeclampsia or eclampsia (Obstet. Gynecol. 2015;125:521-5).

While all three medications are appropriate in treating hypertensive emergencies during pregnancy, each drug has adverse effects.

For instance, parenteral hydralazine can increase the risk of maternal hypotension. Parenteral labetalol may cause neonatal bradycardia and should be avoided in women with asthma, heart disease, or heart failure. Nifedipine has been associated with increased maternal heart rate and overshoot hypotension.

“Patients may respond to one drug and not another,” the committee noted.

The ACOG committee also called for standardized clinical guidelines for the management of patients with preeclampsia and eclampsia.

“With the advent of pregnancy hypertension guidelines in the United Kingdom, care of maternity patients with preeclampsia or eclampsia improved significantly and maternal mortality rates decreased because of a reduction in cerebral and respiratory complications,” they wrote. “Individuals and institutions should have mechanisms in place to initiate the prompt administration of medication when a patient presents with a hypertensive emergency.”

The committee recommended checklists as one tool to help standardize the use of guidelines.

“Drip-and-ship” thrombolysis remains common for ischemic stroke

BY MICHELE G. SULLIVAN

AT THE INTERNATIONAL STROKE CONFERENCE

NASHVILLE, TENN.  – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm. While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have  influenced the findings.

[email protected]

Three trials cement embolectomy for acute ischemic stroke

BY MITCHEL L. ZOLER

NASHVILLE, TENN.  – Treatment of selected patients with acute ischemic stroke underwent a dramatic, sudden shift with reports from three randomized, controlled trials that showed substantial added benefit and no incremental risk with the use of catheter-based embolic retrieval to open blocked intracerebral arteries when performed on top of standard thrombolytic therapy.

The three studies, each run independently and based in different countries, supported the results first reported last October and published online in December (N. Engl. J. Med. 2015;372:11-20) from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) study. These were the first contemporary trial results to show a jump in functional outcomes with use of a stent retriever catheter to pluck out the occluding embolus from an artery in the stroke patient’s brain to restore normal blood flow.

All three of the newly-reported studies stopped before reaching their prespecified enrollment levels because of overwhelming evidence for embolectomy’s incremental efficacy.

With four reports from prospective, randomized trials showing similar benefits and no added harm to patients, experts at the International Stroke Conference uniformly anointed catheter-based embolectomy the new standard of care for the small percentage of acute, ischemic-stroke patients who present with proximal, large-artery obstructions and also match the other strict clinical and imaging inclusion and exclusion criteria used in the studies.

“Starting now, in patients with an acute ischemic stroke due to proximal vessel occlusion, rapid endovascular treatment using a retrieval stent is the standard of care,” Dr. Mayank Goyal declared from the plenary-session podium. He is a professor of diagnostic imaging at the University of Calgary (Canada) and an investigator in two of the three trials presented at the conference, which was sponsored by the American Heart Association.

“Today the world changed. We are now in a new era, the era of highly-effective intravascular recanalization therapy,” said Dr. Jeffrey L. Saver, professor of neurology and director of the Stroke Center at the University of California, Los Angeles, and lead investigator for one of the new studies.

In three of the four studies, the researchers did not report specific numbers on how selective they were in focusing in on the ischemic stroke patients most likely to benefit from this treatment, but the one study that did, EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial), run at nine Australian centers and one in New Zealand, showed the extensive winnowing that occurred. Of 7,796 patients with an acute ischemic stroke who initially presented, 1,044 (13%) were eligible to receive thrombolytic therapy (alteplase in this study). And from among these 1,044 patients, a mere 70 – less than 1% of the initial group – were deemed eligible for randomization into the embolectomy trial. The top three reasons for exclusion of patients who qualified for thrombolytic treatment from the trial was an absence of a major-vessel occlusion (45% of the excluded patients), presentation outside of the times when enrollment personnel were available (22%), and poor premorbid function (16%).

But subgroup analyses in three of the four studies (EXTEND-IA with a total of 70 patients was too small for subgroup analyses) showed no subgroup of patients who failed to benefit from embolectomy, including elderly patients who in some cases were nonagenarians.

The unusual confluence of having four major trials showing remarkably consistent results meant that the stroke experts gathered at the meeting focused their attention not on whether stent retrievers should now be widely and routinely used in appropriate patients but instead on how this technology will roll out worldwide.

“From here on out we are obligated to treat patients with this technology at centers that can do this, and we are obligated to have more centers that can provide it,” said Dr. Kyra J. Becker, professor of neurology and neurological surgery and codirector of the Stroke Center at the University of Washington, Seattle. Dr. Becker had no involvement in any of the stent retriever trials. “I had been a doubter of this technology,” primarily because results reported at the International Stroke Conference a couple of years ago failed to prove the efficacy of clot retrieval in ischemic stroke patients, she noted. “Our ability to select appropriate patients and do it in a timely fashion hadn’t gotten to where it had to be until now,” Dr. Becker said in an interview.

“We only enrolled patients with blockages, we treated them quickly, and we used much better devices to open their arteries,” Dr. Saver added, explaining why the new studies succeeded when earlier studies had not.

The trial led by Dr. Saver, SWIFT-PRIME (SOLITAIRE™ FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), enrolled 195 patients at 39 sites in the United States and in Europe. At 90 days after treatment, 59 patients (60%) among those treated with thrombolysis plus embolectomy had a modified Rankin Scale score of 0-2, compared with 33 patients (36%) among those treated only with thrombolysis (in this trial intravenous treatment with tissue plasminogen activator), a highly significant difference for the study’s primary endpoint.

“For every two and half patients treated, one more patient had a better disability outcome, and for every four patients treated, one more patient was independent at long-term follow-up,” Dr. Saver said. Safety measures were similar among patients in the study’s two arms.

The EXTEND-IA results showed a 90-day modified Rankin Scale score of 0-2 in 52% of the embolectomy patients, compared with 28% of those treated only with thrombolysis. The study’s co–primary endpoints were median level of reperfusion at 24 hours after treatment, 100% with embolectomy and 37% with thrombolysis only, and early neurologic recovery, defined as at least an 8-point drop from the baseline in the National Institutes of Health Stroke Scale score or a score of 0 or 1 when assessed 3 days after treatment. Patients met this second endpoint at an 80% rate with embolectomy and a 37% rate with thrombolysis only. Results of EXTEND-IA appeared in an article published online concurrently with the meeting report (N. Engl J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414792]).

The third, and largest, of the three studies presented at the conference, ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), enrolled 316 patients at 11 centers in Canada, 6 in the United States, 3 in South Korea, and 1 in Ireland. After 90 days, 53% of patients in the embolectomy arm had achieved a modified Rankin Scale score of 0-2, this study’s primary endpoint, compared with 29% of patients in the thrombolysis-only arm (treatment with alteplase). These results also appeared in an article published online concurrently with the conference report (N. Engl. J. Med. 2015 Feb. 11 [doi:10.1056/NEJMoa1414905]).

SWIFT PRIME was sponsored by Covidien, which markets the stent retriever used in the study. Dr. Saver and Dr. Goyal are consultants to Covidien. EXTEND-IA used stent retrievers provided by Covidien. ESCAPE received a grant from Covidien. Dr. Becker had no relevant disclosures.

[email protected]

On Twitter @mitchelzoler

Views on the News
Results warrant embolectomy scale-up

Many U.S. centers have interventionalists who already perform endovascular treatments within intracerebral arteries, but the issue is can they do this form of embolectomy in the high-quality, highly-reliable, rapid way that it was done in these trials? Stent-retriever catheters are relatively straightforward to use by operators who are experienced doing vascular procedures in the brain, but they don’t deliver this treatment by themselves. You need a team that is focused on doing it quickly, and that will be the kind of training we’ll need to roll out this treatment broadly. We achieved it for stroke thrombolytic treatment through the Target Stroke program (JAMA 2014;311:1632-40), so we know that we can achieve this sort of goal. Delivering embolectomy requires more people and more technology than thrombolysis, but it is not rocket science; it just needs a system.

Embolectomy will not replace routine thrombolysis treatment; it will piggyback on top of it. The percentage of patients with a proximal occlusion in a large artery is relatively small. The results we have seen suggest that using embolectomy plus thrombolysis has no adverse-effect downside, compared with thrombolysis alone. Once routine use of embolectomy becomes established, we can directly compare catheter treatment only against combined embolectomy and thrombolysis. My impression today is that what we’d compare is transporting stroke patients directly to a center that can perform embolectomy against taking patients to the closest center that can treat them with thrombolysis and then transporting them to the center that performs embolectomy.

The results of these three new studies plus the previously-reported results from MR CLEAN are not exactly a game changer, because many centers were already performing embolectomy but in a limited way. Now we have the data to give us confidence to do it routinely and to know which patients to select for embolectomy. Because many centers are already doing this, it will not take 5 years to diffuse the technology. Embolectomy is already a treatment cited in the guidelines, but now it will be a level 1A recommendation.

The significance of the new reports is that they will have a dramatic impact on public health systems and in the triage of patients with stroke. It will affect how patients get triaged, and will allow us to identify which patients should go to which centers. I believe we will soon develop clinical examination tools that will allow prehospital providers to discern patients with mild strokes who can go to the nearest center that can administer thrombolysis and which patients need to go to comprehensive centers that can perform embolectomy. We now need to do what we did for thrombolysis, and help centers develop the expertise to do embolectomy as a team and to shave minutes off the delivery at every step of the process. It’s clear that it is the time from stroke onset to getting the artery open that is the key to improved patient outcomes.

If I have my way, we will launch later this year a big effort to focus on improving embolectomy delivery. Now that we know for certain that it works we need to turn the crank and make sure that as many patients as possible who qualify get this treatment.

Dr. Lee H. Schwamm is professor of neurology at Harvard Medical School, and director of acute stroke services at Massachusetts General Hospital, both in Boston. He is a consultant to Penumbra and has received research support from Genentech. He made these comments in an interview.