Room for improvement in reperfusion strategies in U.S. hospitals

December 12, 2014 – The DCRI’s Tracy Wang, MD, MHS, MSc, and others found that hospitals often fail to achieve guideline-recommended reperfusion targets for STEMI patients.

U.S. hospitals often fail to use available tools to achieve guideline-recommended reperfusion targets for acute ST-segment elevation myocardial infarction (STEMI) patients who require interhospital transfer, according to a new study by DCRI researchers.

The study, conducted by Amit Vora, MD, MPH; DaJuanicia Holmes, MS; Matthew Roe, MD, MHS; Christopher Granger, MD; Laine Thomas, PhD; Tracy Wang, MD, MHS, MSc; and colleagues from other institutions, was published online this week in the journal JAMA Internal Medicine.

Earlier research has established the importance of rapid reperfusion for improving outcomes for STEMI patients. Primary percutaneous coronary intervention (pPCI) is the preferred method of reperfusion for such patients, if it can be performed in a timely manner. However, only one-third of acute care hospitals in the United States have full-time PCI capability. Many patients are therefore treated with fibrinolysis, which can be administered in most centers within 30 to 60 minutes of arrival, instead of PCI. Because there are limited data on patterns of reperfusion among patients requiring transfer to a PCI-capable hospital, the researchers sought to determine how interhospital transfer times are associated with reperfusion strategies for STEMI patients in U.S. hospitals.

To do so, they examined patient data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines (ACTION Registry-GWTG), the largest ongoing quality improvement database of acute myocardial infarction in the United States. The registry contains detailed information on cardiac patients, including demographic and clinical characteristics, care processes, and in-hospital outcomes. The researchers identified 22,481 patients eligible for PCI or fibrinolysis who were transferred from 1,771 STEMI referring centers to 366 STEMI receiving centers.

Of these patients, 6,642 (29.5%) received pretransfer fibrinolytic therapy, whereas 15,839 (70.5%) were directly transferred for pPCI. The median estimated interhospital drive time was 57 minutes. In cases where the estimated drive time exceeded 30 minutes, only 42.6% of transfer patients were treated with pPCI within 120 minutes, while only 52.7% of eligible patients with a drive time exceeding 60 minutes received fibrinolysis. Of the 15,437 patients with estimated drive times of 30 to 120 minutes who were eligible for fibrinolysis or pPCI, 5296 (34.3%) received pretransfer fibrinolysis, with a median time of 34 minutes for initiation of therapy. After fibrinolysis, the median time to transfer to the STEMI receiving center was 49 minutes, and 97.1% of patients underwent follow-up angiography. There was no significant difference in mortality risk for patients treated with fibrinolysis (3.7%) versus pPCI (3.9%), but fibrinolysis patients did have a higher bleeding risk (10.7% versus 9.5%).

These results, the researchers concluded, illustrate that many U.S. hospitals are failing to utilize either pPCI or fibrinolysis optimally to achieve guideline-recommended reperfusion targets for STEMI patients. The authors recommended that hospitals consider making greater use of fibrinolysis in cases where transfer times prevent timely pPCI.

Stroke patients discuss need for patient involvement in research

December 3, 2014 – The first publications from the PROSPER study, headed by Adrian Hernandez, MD, MHS, appeared last month in the journal Circulation: Cardiovascular Quality and Outcomes.

The first publications from the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study appeared last month in the journal Circulation: Cardiovascular Quality and Outcomes.

Strokes kill almost 130,000 Americans each year, making them the fourth-leading cause of death in the nation. Those who survive the initial stroke still face a poor prognosis: between 15% and 30% of stroke victims die within one year. Despite this, there is little quality research available on the effectiveness of existing stroke treatments.

Last year, PROSPER’s principal investigator, Adrian Hernandez, MD, MHS, received a $2 million grant from the Patient-Centered Outcomes Research Institute to conduct comparative-effectiveness research on stroke treatments. This research includes the participation of stroke patients. Three of these patients, who are also PROSPER co-investigators, discuss their experiences and the need for patient involvement in stroke research in the Circulation article.

“As patients, we must accept the responsibility of being advocates for our own health care, and we cannot do so if we are not empowered by a fundamental understanding of medical research,” they write. “To date, health care research and the general public have largely existed in separate domains. Yet, recent efforts to integrate patients into research teams hold significant promise for narrowing this gap and encouraging a much-needed paradigm shift.”

Hernandez and the DCRI’s Emily O’Brien, PhD; Ying Xian, MD, PhD; Gregg Fonarow, MD; DaiWai Olson, PhD, RN; Lee Schwamm, MD, also published a companion piece in the same issue.

DCRU’s work with PER977 featured in New England Journal of Medicine

November 25, 2014 – Robert Noveck, MD, PhD, and his co-authors discussed the DCRU’s phase I study of the small-molecule reversal agent.

The DCRU’s work in conducting an early-phase study of a new anticoagulant reversal agent was highlighted in a recent issue of the New England Journal of Medicine.

In an extended letter to the editor, DCRU Medical Director Robert Noveck, MD, PhD, and his co-authors discuss the phase I study of PER977, an investigational drug created by Perosphere, Inc. PER977 is a small-molecule agent created to reverse the effects of edoxaban, a factor Xa inhibitor manufactured by Daiichi Sankyo.

The phase I study, conducted at the DCRU’s early-phase facility, was a double-blinded, placebo-controlled trial comparing PER977 with placebo in 80 healthy patients. Patients received escalating, single intravenous doses of PER977 either alone or after being dosed with edoxaban. The patients who received PER977 after edoxaban had their whole-blood clotting times back to within 10 percent of their normal baseline values within 10 minutes.

The researchers also speculated that PER977 might be effective with other anticoagulants.

“PER977 binds in a similar way to the new oral factor Xa inhibitors, edoxaban, rivaroxaban and apixaban, and to the oral thrombin inhibitor, dabigatran,” the group wrote in the letter.

“In thromboelastographic studies and rat-tail–transection bleeding assays, PER977 has been shown to reverse anticoagulation with each of the new oral agents.”

Phase II studies of PER977 are already in progress, they added.

Major bleeding is a common complication of antithrombotic therapy, and many new anticoagulants have no known reversal agents. An effective reversal agent for these drugs would allow clinicians to regulate their patients’ blood flow more safely and effectively.

In addition to Noveck, the letter’s authors were Jack E. Ansell, MD, of Hofstra North Shore–LIJ School of Medicine; Sasha H. Bakhru, PhD, Bryan E. Laulicht, PhD, Solomon S. Steiner, PhD, and James C. Costin, MD, of Perosphere; and Michael Grosso, MD, Karen Brown, PhD, and Victor Dishy, MD, of Daiichi Sankyo Pharma Development.

Putting knowledge into practice: Rapid response saves a life at the AHA

November 19, 2014 – DCRI cardiologist whose work focuses on the importance of everyone learning CPR had to use those skills to save a man who had experienced sudden cardiac arrest at the AHA.

At the 2014 American Heart Association (AHA) Scientific Sessions in Chicago, several DCRI faculty members and a cardiology fellow had to put their expertise into practice when medical emergencies arose. Their fast reactions helped safe a man’s life and were integral in helping two other people.

On Sunday evening, just hours after sharing late-breaking results of a study on the need for fast responses for cardiac arrest, Drs. Monique Anderson (pictured, below), DCRI Director Eric Peterson, and Tracy Wang left a reception and found a man collapsed face down on the floor. They immediately ran to help and found he had no pulse and wasn’t breathing.

monique-anderson-newsAnderson, whose research focuses on the importance of immediate cardiopulmonary resuscitation (CPR) after cardiac arrest, yelled for one of the doctors to call 9-1-1 as she began chest compressions. Within a few rounds of compressions, the man was breathing again and able to sit up on his own. Peterson stayed on the phone with 9-1-1 until paramedics arrived on the scene and then helped them assess the patient’s vital signs, while Wang helped with the other injuries suffered by the patient in the initial fall. It was the first time Anderson had ever performed CPR outside a hospital setting.

The man was later taken to the hospital and was reported to be in stable condition.

“Panic can set in quickly even with the best-trained professionals, but having somebody there who knew what they were doing, doing CPR, was really key to successfully saving this person,” Peterson said. “And once it was all done, it was such an amazing feeling. This is what we all do and talk about in research, now coming to life.”

“As soon as we saw the man on the floor, we knew we had to get to him,” said Anderson. “We assessed the situation, we called for help, and initiated the information we have learned and practiced.”

For Wang, this was her second encounter with a medical emergency just within the span of a few days. On her flight to Chicago, a passenger had a seizure and Wang quickly jumped into action to help.

Elsewhere at the AHA on Sunday evening, cardiology fellow Ann Marie Navar-Boggan, MD, PhD, was in a dinner meeting when another person collapsed. Many doctors rushed to the person’s aid, but Navar-Boggan was the only one who called 9-1-1 to get paramedics on the scene.

Anderson has dedicated her career to educating people about how to act quickly when someone experiences sudden cardiac arrest. She has made it her goal to teach as many people as possible how to perform compression-only CPR, which can significantly improve cardiac arrest survival rates if performed soon after onset. She organized a CPR Day for DCRI personnel several years ago and has participated in numerous CPR training events throughout North Carolina. Her experience at the AHA only confirmed how important it is for everyone to know what to do when faced with medical emergencies.

“I want to reiterate how vital it is for people to act fast in emergency situations and encourage everyone over the age of 13 to learn compression-only CPR,” she said. “This knowledge can really help save lives.”

Read the AHA blog coverage of this story. The News & Observer also covered Anderson’s life-saving CPR efforts.

AHA 2014: Study finds many Medicare patients with low ejection fraction after heart attack are not receiving ICDs

November 19, 2014 – Out of more than 10,000 patients with weak heart function after their heart attack, less than 10 percent received an ICD.

Studies have shown no improved survival benefit if patients with reduced ejection fraction rates (weak heart function) receive an implantable cardioverter defibrillator (ICD) within the first 40 days after having a heart attack. But a new study found that less than 10 percent of Medicare patients who would have qualified for an ICD at the time of a heart attack actually had one implanted within a year.

Sean-Pokorney-newsThe study results were presented Monday at the 2014 American Heart Association Scientific Sessions. The DCRI’s Sean Pokorney, MD, MBA was the lead author (pictured, right).

Guidelines recommend a 40-day waiting period after a patient has had a heart attack to assess ICD candidacy. This allows providers to see whether the ejection fraction can improve with medication therapy. For this study, researchers used data from the ACTION registry and more than 400 Get With The Guidelines hospitals to assess how many Medicare patients with a low ejection fraction received an ICD within a year of having a heart attack.

Out of more than 10,000 patients with weak heart function after their heart attack, less than 10 percent received an ICD. Although this varied by site, all hospitals had implantation rates below 20 percent.

“With the 40-day waiting period recommended by the guidelines, these patients are transitioning between hospital- and community-based health care settings. The clinician that was treating a patient in the hospital is often not the same person the patients sees after discharge,” said Pokorney. “We need to increase communication between care providers and provide better patient education to optimize ICD use.”

Because the study population included older patients for whom one can argue the risks of the procedure may outweigh any potential benefit to ICD implantation, researchers looked at outcomes associated with ICD use. They found a 36 percent lower risk of death in patients who had received the device similar to prior studies; lower death rates were seen in both patients older and younger than 80 years of age.

“Not all of these patients may have remained eligible for ICDs in follow-up,” said Pokorney, “as some of these patients may have had improvement of their ejection fractions or developed other reasons why ICDs are not helpful; however, these cannot fully account for why only 10 percent of patients are receiving ICDs. Addressing this large gap by targeting early cardiology follow-up could improve care for a significant number of patients.”

Other Duke and DCRI co-authors were Anita Chen; Laine Thomas, PhD; Sana Al-Khatib, MD; Eric Peterson, MD, MPH, and Tracy Wang, MD, MHS, MSc.

AHA 2014: Apixaban a cost-efficient alternative to warfarin

November 18, 2014 – Researchers found that apixaban had a cost-effectiveness ratio of $76,365/life year gained compared to warfarin.

The improved clinical outcomes associated with the anticoagulant apixaban translate to a significant and cost-effective increase in life expectancy in patients with atrial fibrillation (AF), according to a recent study by DCRI researchers and their colleagues.

The study, based on data collected during the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, was presented in a poster session Monday at the 2014 Scientific Sessions of the American Heart Association in Chicago.

The results of the original ARISTOTLE trial demonstrated that apixaban was superior to warfarin at preventing major bleeding, stroke, and death in AF patients. In this study, the researchers sought to assess the cost-effectiveness of apixaban versus warfarin in the context of the U.S. health care system.

To do this, they examined patient data on resource use during ARISTOTLE, including service dates, intensive care days, and number of days on each drug. The daily cost of each drug was estimated by calculating the acquisition cost for warfarin and apixaban for 10 years, after which time apixaban was valued at projected costs of generic substitutes. The cost of physician and monitoring services was estimated using current Medicare fees. The researchers then determined patient survival rates by conducting a statistical analysis of ARISTOTLE patient data.

After 2 years, health care costs for patients in the U.S. cohort of ARISTOTLE (3,417), excluding study drug and monitoring, averaged $306 less with apixaban than warfarin ($6,257 vs. $6,563). This difference, however, was more than offset by higher apixaban anticoagulation costs ($6,160 vs. $1,181), resulting in an overall increase of $4,673 per patient. Estimating lifetime costs for each drug, the researchers found gains in life expectancy cost $17,564 more for patients on apixaban, yielding a cost-effectiveness ratio of $76,365/life year gained.

In the context of apixaban’s superiority in improving clinical outcomes, the researchers concluded, these findings show that apixaban is a cost-effective alternative to warfarin.

The study’s authors include the DCRI’s Patricia Cowper, PhD; Shubin Sheng, PhD; Kevin Anstrom, PhD; Judith Stafford, MS; Linda Davidson-Ray, MA; Renato Lopes, MD, PhD; John Alexander, MD, MHS; Christopher Granger, MD; and Daniel Mark, MD, MPH; Lars Wallentin, MD, PhD, of Uppsala University; Hemant Phatak, PhD, of Bristol-Myers Squibb; Jack Ansell, MD, of Lenox Hill Hospital, New York; Paul Dorian, MD, MSc, of the University of Toronto; Steen Husted, MD, DSc, of Aarhus University Hospital; John McMurray, MD, of Western Infirmary and the British Heart Foundation Glasgow Cardiovascular Research Center; and P. Gabriel Steg, MD,  of Hôpital Bichat-Claude Bernard.

AHA 2014: Routine addition of MVr to CABG in patients with moderate IMR may not be warranted

November 18, 2014 – Peter Smith, MD, was the lead author of the study, which was published in the New England Journal of Medicine.

In a late-breaking session at the 2014 American Heart Association Scientific Sessions in Chicago, researchers presented findings that the routine addition of mitral valve repair (MVr) to coronary artery bypass graft (CABG) surgery in patients with moderate ischemic mitral regurgitation (IMR) may not be warranted.

The study was conducted by principal investigator Peter Smith, MD (pictured here), and John Alexander, MD, MHS, of Duke and colleagues from other institutions throughout the United States and Canada.

peter-smith-archiveThe purpose of this clinical trial, which is part of the Cardiothoracic Surgical Trials Network, was to look at CABG surgery versus CABG plus MVr in patients who have moderate IMR. The results were published simultaneously in the New England Journal of Medicine.

The Cardiothoracic Surgical Trials Network—with support from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, and the Canadian Institutes of Health Research—aims to improve cardiovascular disease outcomes by providing a framework of support to cultivate, coordinate, and conduct multiple collaborative proof-of-concept studies and interventional protocols. Duke University is one of 10 core clinical centers participating.

Regarding Duke’s participation with the network, Alexander said, “The [Cardiothoracic Surgical Trials] Network has offered an exciting opportunity to collaborate with others in the US and Canadian cardiac surgery community in the conduct of important clinical trials and to develop a collaborative community of clinical researchers in cardiac surgery.”

As one of four valves in the heart, the mitral valve helps prevent blood from flowing backward into the lungs. Sometimes leakage (regurgitation) can happen. This is typically caused by a problem with the valve itself or the muscle surrounding the valve. In IMR, the leakage is due to a problem with the surrounding muscle. In this study, researchers sought to determine whether, for people who have a medium amount of leakage (IMR) and have coronary artery disease, it is necessary to repair the mitral valve at the same time a surgeon is already doing the CABG surgery.

In a randomized trial of 301 patients who were assigned either CABG surgery alone or CABG plus MVr, researchers found at one year that MVr had no effect on left ventricular remodeling as measured by left ventricular end systolic volume index and echocardiographic measure of left ventricular reverse modeling (primary endpoint). Furthermore, many patients assigned to CABG surgery alone and more with IMR who got CABG surgery alone had improvement in mitral regurgitation at one year. However, there was a higher rate of adverse neurologic events and more supraventricular arrhythmias in patients assigned to MVr. And there were no observed differences in major adverse cardiac events.

“We believe that our study will be practice changing and provides greater insight into a problem that has vexed cardiac surgeons for decades,” said Smith (pictured). The investigators concluded the routine addition of MVr to CABG in this patient population may not be warranted.

AHA 2014: Researchers present highly anticipated IMPROVE-IT results

November 17, 2014 – Adding ezetimibe to statin therapy further lowered cholesterol levels and resulted in fewer cardiovascular events in patients following heart attack.

More than a decade ago, researchers from Brigham and Women’s Hospital (BWH) demonstrated that a high dose statin, which lowered cholesterol further than a regular dose statin, provided better clinical outcomes. But questions remained about whether further reducing cholesterol would be even more effective in reducing cardiovascular-related events.

robert-califf-newsNow, results of the highly anticipated IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), co-led by researchers at BWH and Duke Medicine, indicate that adding a second drug, ezetimibe, that blocks cholesterol absorption, resulted in a significant 6.4 percent reduction in the number of cardiovascular events.

The findings, presented as a late breaking clinical trial at the American Heart Association Scientific Sessions on Nov. 17, 2014, clarify a long-standing question in cardiac care about whether reducing cholesterol to even lower levels might improve outcomes. Complete publication of the data is expected in the coming months.

“There is a lot of evidence that demonstrates that low cholesterol is better, and our findings suggest that even lower is even better,” said Christopher Cannon, MD, principal investigator of IMPROVE-IT and a cardiologist and researcher in the TIMI Study Group at BWH. “More broadly, the results of IMPROVE- IT re-emphasize the central role of lowering LDL cholesterol for the treatment of high risk patients.”

In this multicenter, double-blind, placebo-controlled international randomized trial, researchers enrolled 18,144 patients with acute coronary syndrome (ACS), described as heart attacks or worsening chest pain, and all were treated according to the previously existing guidelines with a statin (simvastatin).

In the control group, patients who received statin therapy alone reached a median LDL cholesterol level of 69 mg/dl for a median of six years. Researchers found that when patients received the non-statin medication ezetimibe, in addition to the statin (ezetimibe/simvastatin combination/brand name VYTORIN), LDL cholesterol was reduced 20 percent further to a median level of 54 mg/dl, and this led to a statistically significant 6.4 percent reduction in the number of cardiovascular events. (p=0.016) After seven years, the combined rate of cardiac death, heart attack, stroke, hospitalization for worsening chest pain, or need for revascularization, was reduced from 34.7 percent in the control group to 32.7 percent in the group that received the combination therapy. Additionally, researchers report that approximately two cardiovascular events were prevented in the trial for every 100 patients treated, with the difference driven by reductions in heart attack or stroke.

“This trial demonstrates the importance of careful measurement of long-term outcomes in randomized trials for medicines that are taken for chronic diseases,” said Robert Califf, MD, vice chancellor for clinical research at Duke and co-study chair of the trial (pictured, above). “We were looking for a small effect and we found an effect very close to what we expected, clearly favoring the group taking ezetimibe/simvastatin. The trial confirmed the existing safety profile of ezetimibe.”

“Our findings suggest that, among this population of ACS patients, we may want to consider changes to our clinical guidelines, which might include an LDL cholesterol target of closer to 55, or lower,” said Eugene Braunwald, MD, co-study chair, and founding chairman of the TIMI Study Group at BWH.

Additional data from the trial will be presented at the AHA meeting on Tuesday in a trial update session. The presentation, the first additional analysis of the study database led by the Duke Clinical Research Institute, will focus on the population of individuals who completed the study on medication.

“We are using this analysis as a first look at the findings of the primary analysis, and to look at the data among patients only during the time that they actually remained on treatment during the study,” said Michael Blazing, MD, associate professor of medicine and director of outpatient services at the Duke Heart Center who will present the findings of the on-treatment group in the Tuesday session.

Ezetimibe is a drug approved to lower plasma cholesterol levels by decreasing absorption of LDL cholesterol in the small intestine, and is additive to the role that statins play in lowering cholesterol. Ezetimibe and the ezetimibe/simvastatin are sold by Merck, which sponsored and provided funding for this study.