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LOS ANGELES (March 31, 2020) - In a new pre-clinical study published this week in the journal Leukemia, the research team of Children's Hospital Los Angeles investigator Hisham Abdel-Azim, MD, MS, worked with colleagues to engineer T-cells to identify and target multiple sites on acute lymphoblastic leukemia cells instead of just one. The early collaboration points the way to future clinical trials to test the therapy.

Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer. Though most children respond well to chemotherapy, some experience resistant or relapsed disease. CAR-T therapy was developed to bridge the gap for those children for whom chemotherapy was not enough.

The therapy uses the patient's T-cells, isolating and genetically modifying them to recognize CD-19, a protein (antigen) found on leukemia cells. When the T-cells are introduced back into the patient, the immune system attacks the cancer. Though initial treatment using CAR-T offered meaningful results, nearly half of patients who received the therapy later relapsed because the cancer stopped producing the protein CD-19 and became invisible to the T-cells.

Dr. Abdel-Azim collaborated with Nabil Ahmed, MD, MPH, of Baylor College of Medicine and Texas Children's Hospital, to engineer a T-cell that targets not only CD19, but also two other proteins found on leukemia cells, CD-20 and CD-22.

"It's like using a trident to attack the cancer instead of a spear," says Dr. Ahmed. The team used this three-pronged weapon against leukemia cells in pre-clinical studies and developed new methods to monitor how well it worked.

The new CAR T-cells, named TriCAR T-cells, targeting CD-19/20/22 are significantly more effective than T-cells that target CD-19 alone, according to the study's findings. When the leukemia cells stopped producing CD-19, making them invisible to the FDA-approved CAR-T cells, Dr. Abdel-Azim's cells were still effective. "These newer CAR-T cells bind to more cancer cells and these connections are much stronger," says Dr. Abdel-Azim. "Not only do they bind better, but they are binding again and again." These connections show just how effective the new CAR-T cells are in killing leukemia cells. More T-cell binding means a stronger fight against the cancer.

Though a clinical trial will be needed before the new CAR-T therapy could be used on patients, the early
lab results point the way to a path that could be significantly more effective in battling resistant leukemia.

Just like attacking more than one antigen is more effective in the fight against leukemia, so too is combining investigative forces. "Scientific findings like these would not be possible without collaboration," says Dr. Abdel-Azim.

WASHINGTON--Obese patients may lose more weight if they undergo bariatric surgery before they develop diabetes, suggests a study accepted for presentation at ENDO 2020, the Endocrine Society's annual meeting. The research will be published in a special supplemental issue of the Journal of the Endocrine Society.

Both obesity and diabetes are common, serious and costly in United States. More than one-third of U.S. adults are affected by these two conditions. Among patients ]have obesity and diabetes, bariatric surgery can lead to remission of both of these diseases. "However, which population could have the most benefit from the surgery, and the possible impact of diabetes on the success of their weight-loss surgery is still unknown," said lead researcher Elif A. Oral, M.D., of the University of Michigan.

"Our study suggests that having bariatric surgery before developing diabetes may result in greater weight loss from the surgery, and together with data that is available from other studies, bariatric surgery may potentially prevent or delay diabetes from developing," Oral said.

The researchers analyzed data from 714 patients in the Michigan Bariatric Surgery Cohort (MI-BASiC) to see whether diabetes before surgery could have any impact on weight loss outcomes five years or more after receiving bariatric surgery. The patients underwent either gastric bypass (380 patients) or sleeve gastrectomy (334 patients), which are the two most commonly used surgery types in the United States.

All of the patients either had a body mass index (BMI) of more than 40, or a BMI of 35-39.9 with diabetes. BMI is a measure of body fat based on height and weight.

The study found patients without diabetes had a 1.6 times higher chance than those who already have diabetes of achieving successful weight loss (achieving excess body weight loss of at least 50% or more) regardless of the surgery type. They also found the presence of diabetes before surgery diminished weight loss by 1.2 BMI points, which is roughly 10-15% of the total BMI points patients lost on average.

Even after adjusting the effect of time, surgery type, age, gender and pre-surgery weight, the absolute weight loss, percentage of total weight loss and percentage of excess weight loss among individuals with diabetes were still significantly lower than individuals without diabetes.

"Further research is needed to understand why diabetes diminishes the weight loss effect of bariatric surgery," Oral said.

What The Study Did: This case series reports a cluster-spreading event in Huai'an (about 435 miles northeast of Wuhan) in Jiangsu Province, China, where a patient with SARS-CoV-2 may have transmitted the virus to eight other healthy individuals through bathing in a public bath center.

Authors: Qilong Wang, M.D., Ph.D., of the Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University in Huai'an, China, and Hongbing Shen, M.D., Ph.D., of the School of Public Health, Nanjing Medical University in Nanjing, China, are the corresponding authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(10.1001/jamanetworkopen.2020.4583)

Editor's Note:  The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: Nearly 200 radiologists who interpreted about 251,000 digital breast tomosynthesis (DBT) and 2 million digital mammography screening examinations were included in this observational study that evaluated recall and cancer detection rates.

Authors: Brian L. Sprague, Ph.D., of the University of Vermont in Burlington, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(10.1001/jamanetworkopen.2020.1759)

Editor's Note:  The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Researchers in Leicester have shown that the function of the heart can be significantly improved in patients with type 2 diabetes through exercise.

The study, which was funded by the National Institute for Health Research (NIHR) and conducted at the NIHR Leicester Biomedical Research Centre (BRC) - a partnership between Leicester's Hospitals, the University of Leicester and Loughborough University - also showed that a low-energy diet did not alter heart function in the same patient group.

Dr Gaurav Gulsin, a BHF Clinical Research Fellow at the University of Leicester, trainee heart doctor, and a lead author of the study, said: "Heart failure is one of the most common complications in people with type 2 diabetes, and younger adults with type 2 diabetes already have changes in their heart structure and function that pose a risk of developing heart failure. We wanted to confirm the abnormalities in the structure and function of the heart in this patient population using the latest scanning techniques, and explore whether it is possible to reverse these through exercise and/or weight loss."

Eighty-seven patients between 18 and 65 years of age with type 2 diabetes were recruited to the study. Participants underwent echocardiography and a magnetic resonance imaging (MRI) scan to confirm early heart dysfunction, and exercise tests to measure cardiovascular fitness. They were then randomised into one of three groups: routine care, supervised aerobic exercise training, or a low-energy meal replacement programme. Each programme had a 12-week duration. Seventy-six patients completed the full 12 weeks. Thirty six healthy volunteers were enrolled as a control group.

The study found that patients who followed the supervised exercise programme had significantly improved heart function compared with the control group, and had also increased their exercise capacity. Whilst the low energy diet did not improve heart function, it did have favourable effects on the structure of the heart, vascular function and led to the reversal of diabetes in 83 per cent of this arm of the study population.

Gerry McCann, NIHR Research Professor and Professor of Cardiac Imaging at the University of Leicester and a consultant cardiologist at Leicester's Hospitals, was senior author on the study. He said: "Through this research we have shown that lifestyle interventions in the form of regular exercise training may be important in limiting and even reversing the damage to heart structure and function seen in younger adults with type 2 diabetes. While losing weight has a beneficial effect on heart structure, our study shows that on its own it does not appear to improve heart function.

"It may seem obvious, but if we can empower patients with type 2 diabetes to make changes to their daily routines through exercise and healthy eating, we may help them reduce the risk of heart failure and even early death. By using imaging techniques such as MRI we can actually show them the benefits their changes are making to their hearts."

The research team recognised the study population was relatively small. In addition, nearly 1 in 5 patients in the exercise arm of the study did not complete all 36 sessions, which may limit its application in future clinical practice.

An international clinical trial that used genetic testing to guide which antiplatelet medication was given to patients following percutaneous coronary intervention (PCI) did not meet its stated goal for cutting in half the incidence of serious adverse cardiovascular events, such as heart attack and stroke, in the year following the procedure. However, researchers reported a 34% reduction in these adverse events at one year, as well as a significant reduction in the number of events per patient, according to study results presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

The primary endpoint of TAILOR-PCI--the largest cardiology trial to test the effectiveness of using genetic testing to guide treatment choice--was to demonstrate a 50% reduction at one year in the combined rate of death, heart attack, stroke, a blood clot in a stent (stent thrombosis) or a recurrent heart attack-like presentation. While the trial missed this mark, researchers observed a 34% drop in these events in the year following PCI. The trial also revealed a statistically significant 40% reduction in the total number of events per patient receiving genetically guided treatment compared with patients who received standard treatment.

"Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetically guided therapy, with approximately one-third fewer adverse events in the patients who received genetically guided treatment compared with those who did not," said Naveen L. Pereira, MD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, and co-principal investigator of the study.

Pereira added that a post hoc analysis, performed after the researchers knew the study's results, found a nearly 80% reduction in the rate of adverse events in the first three months of treatment among patients who received genetically guided therapy compared with those who did not. This period immediately after PCI is when patients are at the highest risk for adverse events, he said.

"We now know from clinical practice and other studies that antiplatelet drug therapy is critical during the first three months after PCI," he said. "This finding suggests that the lion's share of the benefit of genetically guided therapy may occur during this high-risk period. Because this wasn't a pre-planned analysis, we can't draw firm conclusions from it, but it merits further study."

Patients with arterial blockages who undergo PCI--the insertion of a stent or stents to prop arteries open--are commonly prescribed the antiplatelet medication clopidogrel, along with aspirin, for a year after the procedure to help prevent blood clots that can cause heart attack, stroke and other complications. However, studies have suggested that people who have a genetic variant in a liver enzyme known as CYP2C19 are unable to fully metabolize clopidogrel, reducing the effectiveness of the medication and leaving them at increased risk of developing blood clots and serious adverse cardiovascular events. Such patients may be good candidates to receive alternative antiplatelet medication.

In the U.S., about 30% of people carry the genetic variant that makes them less capable of metabolizing and, hence, activating clopidogrel, Pereira said. The proportion increases to 50% among people of Asian heritage. A simple-to-perform genetic test can identify whether a patient carries the abnormality, Pereira said. However, no prospective clinical trials have shown that outcomes are better for patients who have the abnormality when the test is used to guide their treatment. For this reason, guidelines published by the American College of Cardiology and the American Heart Association do not currently recommend that patients be tested for the abnormality before being prescribed clopidogrel, Pereira added.

The TAILOR-PCI trial was designed to fill this knowledge gap. The trial enrolled 5,302 patients who had been treated for an arterial blockage with one or more stents. Their median age was 62 years, and 75% were men. Patients were randomly assigned either to a group that was tested for the genetic variant affecting clopidogrel metabolism or to a group that received standard treatment without genetic testing. In the first group, 35% of patients were found to have the genetic variant and were prescribed another antiplatelet medication, ticagrelor, while those without it got clopidogrel. In the second group, everyone was prescribed clopidogrel. Patients were enrolled at 40 medical centers in the U.S., Canada, Mexico and South Korea and followed for one year.

Among patients who carried the genetic variant, the primary endpoint occurred in 35 (4%) in the group that received genetically guided treatment, compared with 54 (5.9%) in the conventionally treated group at one year.

Pereira said that the reduction in the number of adverse events per patient also has important clinical implications. "Multiple adverse events represent a higher burden on the patient, so it is encouraging to see a significant reduction in cumulative events with genetically guided therapy," he said.

Among patients with the genetic variant, there were no differences in the safety endpoint of TIMI major bleeding (fatal bleeding, bleeding in the brain or any bleeding that requires medical assessment or treatment) or minor bleeding between those receiving genetically guided treatment (16 patients, 1.9%) and those in the conventional treatment arm (14 patients, 1.6%) at one year.

Pereira said that recent improvements in the standard of care following PCI may have contributed to the trial not achieving its primary endpoint. When the TAILOR-PCI trial was designed in 2012, around 10% to 12% of patients who received a stent could be expected to have a major adverse event, such as a heart attack, stroke or stent thrombosis, within a year. Over the course of the trial, the standard of care evolved through greater use of drug-coated stents and other treatments, which reduced the expected rate of adverse events in a year to about 5%. This change in technology substantially improved care for patients, but at the same time may have made it more difficult for the trial to reach its goal of a 50% reduction in adverse events with the number of patients enrolled, Pereira said.

No special expertise in laboratory testing is required to perform the genetic test, Pereira said. In the trial, the tests were done by study coordinators who did not have a background in laboratory medicine and who were able to perform the tests in a consistent, reproducible fashion after receiving brief training.

The next step, he said, will be to analyze the cost effectiveness of genetically guided therapy. The National Heart, Lung, and Blood Institute has also funded an extended follow-up study to evaluate the effect of genotype guidance beyond the 12-month follow-up period of TAILOR PCI.

People with symptomatic peripheral artery disease (PAD) who took the blood thinner rivaroxaban with aspirin after undergoing a procedure to treat blocked arteries in the leg (lower extremity revascularization) had a 15% reduction in the risk of major adverse limb and cardiovascular events when compared with those receiving aspirin alone, according to research presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC). Data also showed that while patients taking rivaroxaban had higher rates of bleeding, there was no excess in severe bleeding events such as intracranial or fatal bleeds, which is a common concern when using anticoagulants, even at a low dose.

An estimated 10 million U.S. adults and 200 million people worldwide have PAD, which is associated with leg pain, difficulty walking, poor circulation that can lead to non-healing wounds and a high rate of limb loss. People with PAD are at very high risk of serious adverse events, including acute limb ischemia--think a "heart attack or stroke of the leg"--that can lead to limb amputation or death if not treated quickly. PAD is also associated with a high risk of heart attack, stroke and even death. Patients with symptomatic PAD are commonly treated with procedures to open arteries in the leg to improve symptoms and prevent limb loss, but they remain at very high risk of ischemic limb and cardiovascular events.

VOYAGER PAD is an international trial designed to evaluate whether rivaroxaban, a medication used to treat or prevent dangerous blood clots, added to aspirin is better than aspirin alone in reducing these events in symptomatic patients undergoing lower limb revascularization. Researchers said this study answers important questions remaining after the COMPASS trial, which demonstrated that low-dose rivaroxaban plus aspirin versus aspirin alone significantly reduced major adverse heart events in stable people with coronary artery disease and PAD.

"We found adding low-dose rivaroxaban after peripheral artery intervention significantly reduced the spectrum of complications that we fear most in PAD, which is acute limb ischemia, major vascular amputation, heart attack and stroke. This benefit was not only seen early on but was also maintained over time," said Marc P. Bonaca, MD, associate professor and director of vascular research at the University of Colorado School of Medicine and the study's lead author. "These data provide evidence of an antithrombotic regimen that effectively reduces risk, and although bleeding rates were higher, the overall risk-benefit remains quite favorable and could have a profound impact on patients' lives."

The study fills a void in the treatment of people with PAD undergoing limb revascularization, as there have been few studies in this population in this setting. Furthermore, there are no Class I recommendations for antithrombotic therapy beyond aspirin or clopidogrel and none specific to the post-revascularization setting for people with PAD. Bonaca said the study could save lives, noting that prespecified risk-benefit analyses showed that if 10,000 patients are treated for a year with this strategy versus placebo, 181 events would be prevented at a cost of 29 bleeds, but with no difference in intracranial or fatal bleeds.

"In contrast to actual heart attacks of the heart, many patients and clinicians are unfamiliar with acute limb ischemia, the risk and the poor outcomes associated with severe complications of PAD," Bonaca said, adding that many clinicians default to dual antiplatelet therapy (DAPT) using aspirin and a P2Y12 receptor blocker such as clopidogrel. He said that while this is the standard of care to prevent thrombosis following coronary interventions, there is little evidence on its clinical utility in patients with PAD and the one trial evaluating this question showed DAPT increased bleeding.

Unlike prior studies that recruited stable PAD patients or reported outcomes in PAD patients as subgroups of coronary disease trials, VOYAGER PAD only enrolled patients who had symptomatic PAD that required limb revascularization. A total of 6,564 patients at 542 medical centers in 34 countries were randomly assigned in a double-blind, one-to-one fashion to receive either rivaroxaban 2.5 mg twice daily and aspirin 100 mg daily or placebo and aspirin 100 mg daily for a median of 28 months. A limited course of clopidogrel was allowed at the discretion of the treating doctor. One out of 4 patients needed lower limb revascularization due to critical limb ischemia, while 3 out of 4 undergoing the procedure reported claudication and symptoms of leg pain. About two-thirds underwent endovascular revascularization treatment with stenting and balloons, while one-third had surgery to bypass the blockage. Patients averaged 67 years of age, and 74% were male.

At 28 months median follow-up, patients who took rivaroxaban plus aspirin had a significant reduction in the composite primary endpoint of acute limb ischemia, major amputation for vascular cause, heart attack, ischemic stroke or cardiovascular death when compared with those receiving aspirin alone, with an event rate of 17.3% vs. 19.9%, respectively.

The principal safety outcome was TIMI major bleeding (a standard definition and assessment of bleeding events), and while these bleeds were more frequent in patients taking rivaroxaban plus aspirin compared with those receiving aspirin alone (occurring in 2.7% vs. 1.9% of patients, respectively), Bonaca reported this difference was not statistically significant. The total difference in the number of events was 18, with 62 occurring in the rivaroxaban group and 44 in the placebo group. Researchers found no difference in intracranial bleeds (0.6% in the rivaroxaban group and 0.9% in the control group) or fatal bleeding (0.21% vs. 0.21%). ISTH major bleeding was significantly higher with rivaroxaban compared with aspirin alone, occurring in 140 (5.9%) patients versus 100 (4.1%) patients, respectively. There were six fatal bleeds in each arm.

"We saw a very profound reduction in acute limb ischemia," Bonaca said. "There were very few take-back bleeds, those that require people to return to the procedure room to control the bleeding, at the time of the intervention and although the rates of TIMI major bleeding, the primary safety outcome, were higher with rivaroxaban, there was no difference in irreversible harm events like intracranial or fatal bleeding." The efficacy and safety results were consistent across all major subgroups, including patients with critical limb ischemia and regardless of the type of revascularization or surgery received.

The direct oral anticoagulant rivaroxaban dramatically cut the likelihood of serious venous thromboembolism (VTE) in people recovering from lower limb orthopedic surgery requiring immobilization in comparison with enoxaparin, another anticoagulant agent, according to research presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

The new data revealed that rivaroxaban cut the risk of major VTE by 75% without increasing the risk of bleeding, a common concern in patients taking a blood thinner. This international, double-blind, randomized controlled trial is the first to compare rivaroxaban against enoxaparin, a low molecular weight heparin, for clot prevention in people recovering from non-major orthopedic surgeries who often must restrict movements of the affected limb for a period of time to promote healing. However, even a brief period of reduced mobility can heighten a person's risk of developing dangerous blood clots that can lead to deep vein thrombosis (DVT), a condition where clots form in the veins of the legs, or pulmonary embolism, when clots travel and get lodged in the lungs.

"We must prevent VTEs in these patients because some can lead to pulmonary embolism, which can be fatal," said Nadia Rosencher, MD, senior consultant and anesthesiologist at Paris University, France, and one of the study authors. "This study represents a major step forward in our treatment of patients after many orthopedic procedures because it proves that we can more effectively prevent thrombosis with a once-daily oral medication versus a daily injection with the same safety."

Rosencher said taking injections of enoxaparin can be very cumbersome for patients, who sometimes require a nurse to help administer the medication. Additionally, this is a young population with a median age of 40 years, who often need to get back to work or caring for a family without added complications.

Rivaroxaban works by blocking the activity of the clotting protein factor Xa. It's known to be a strong anticoagulant, so researchers said they were somewhat surprised and reassured to find that bleeding risk was the same as with enoxaparin.

While most contemporary clinical guidelines recommend using anticoagulants to prevent blood clots after major orthopedic surgeries, including total knee and total hip replacements, that put patients at higher risk for VTEs, there is less agreement about prophylactic thrombosis treatment in patients at moderate risk for clots--for example, those undergoing ankle surgery, ligament repair or knee arthroscopy. Millions of people in the U.S. undergo these procedures each year and may need blood thinning to prevent clots from forming.

"In Europe, all the guidelines agree that some level of thromboprophylaxis should be given, but overall there is no agreement on what should be done for the patient population who remains at moderate risk for clots because of being immobilized during their recovery," Rosencher said. "In many ways these data are a win-win for patients--a pill with no jump in major bleeding events."

The study included 3,604 patients from 10 countries who were deemed to be at moderate VTE risk post-surgery by the investigator. Patients had to be immobilized for more than 15 days to be included. Patients were randomly assigned to receive rivaroxaban (10 mg once daily by mouth) or enoxaparin (40 ml once daily by subcutaneous injection). Because it was double-blinded, all patients received an injection and a tablet, so people in the rivaroxaban group took a daily pill but also got a placebo injection. Overall, patients had a median of 28 days of reduced mobility--1 in 3 were immobilized for one to two months, and 2 in 3 had to restrict activity for two weeks and up to one month.

The primary efficacy outcome of major VTE was the composite of symptomatic distal or proximal DVT, pulmonary embolism or VTE-related death during the treatment period and follow-up for one month, or asymptomatic proximal DVT at the end of treatment, which occurred in 4 out of 1,661 patients (0.24%) in the rivaroxaban group and 18 of 1,640 of patients (1.1%) in the enoxaparin group. Prespecified secondary outcomes were major and clinically relevant nonmajor bleeding, defined based on other studies, overt thrombocytopenia (low platelet count) and death from any cause. Bleeding rates did not differ between the rivaroxaban and enoxaparin groups (1.08% and 1.04%, respectively, for major plus nonmajor clinically relevant bleeding; 0.57% and 0.69%, respectively, for major bleeding). There were no deaths in either arm except one that occurred at the end of study follow-up and after a liver transplant.

"We saw a high number of patients in the low molecular weight heparin group with proximal asymptomatic DVT by compression ultrasounds, and these are quite dangerous as they can lead to pulmonary embolism that carries a high death toll," Rosencher said. "We expect to see expanded indications for rivaroxaban in other patients based on these data."

Rivaroxaban is currently approved by the U.S. Food and Drug Administration to prevent DVT that may lead to a pulmonary embolism after elective knee or hip replacement surgery; in some countries, it has a broader label to include use after lower-limb orthopedic surgery.

Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive, according to research presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

A cardiac arrest is caused by a disruption of electrical activity in the heart that causes it to stop beating. It differs from a heart attack, in which a blockage in an artery serving the heart blocks blood flow but the heart keeps beating. Sometimes, however, a heart attack can trigger a cardiac arrest. A person who has a cardiac arrest typically loses consciousness immediately.

It is estimated that over 400,000 people in the U.S. have out-of-hospital cardiac arrest each year. Cardiopulmonary resuscitation, or CPR, and early defibrillation by administering an electric shock to the heart to restore its rhythm to normal are the only treatments that have been shown to improve survival after a cardiac arrest, which is fatal in over 80% of cases. To date, no new medications have been shown to improve long-term survival in people who have had a cardiac arrest, said Francis Kim, MD, professor of medicine at the University of Washington in Seattle and the study's lead author.

Kim and his research team were hoping sodium nitrite, a salt best known for being used to cure meats like ham and bacon, might yield a new option. Sodium nitrate is also an antioxidant (a substance that reduces damage caused by oxygen) that is added to prepared foods to prevent spoilage and has been used by paramedics and emergency room physicians to treat cyanide poisoning. Findings from animal studies suggested that when blood flow and, in turn, delivery of oxygen to the heart is blocked, the body can convert sodium nitrite into nitric oxide, a gas that relaxes the blood vessels and increases blood flow to the brain and heart tissues. In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%. In a previous first-in-humans study, Kim and his research team found that intravenous sodium nitrite could be safely given to out-of-hospital cardiac arrest patients.

The goal of the current study was to determine whether an injection of sodium nitrite given during resuscitation for an out-of-hospital cardiac arrest could increase the number of patients who were admitted to or discharged from the hospital alive.

In the study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose or a high dose of sodium nitrite or a placebo. The drug was in an unmarked syringe and injected by a paramedic during active resuscitation in the field. Neither the paramedics, the hospital emergency room staff or anyone else involved in the patients' care knew which patients had received sodium nitrite and which had received the placebo. Since the patient was unconscious and since sodium nitrite should be given as soon as possible after the heart stops, informed consent was not possible. Kim said that under these emergency conditions and under FDA guidance they were allowed to give sodium nitrite or placebo without formal consent.

Patients' average age was around 64 years and 66% were male. They had had one of three types of cardiac arrest: ventricular fibrillation (22%), asystole (43%) or pulseless electrical activity (29%). The primary endpoint was the proportion of patients who survived to hospital admission and the secondary endpoint was the proportion who survived to hospital discharge. Safety data were also collected to determine whether sodium nitrite had harmful effects on blood pressure.

Results showed no statistically significant differences between the groups who received the placebo, low-dose sodium nitrite or high-dose sodium nitrite on survival to either hospital admission or discharge.

"Sodium nitrite did not harm the patients who suffered out-of-hospital cardiac arrest, but it didn't help them either," Kim said. "Many treatments that work in animal models don't translate to effectiveness in humans, and we now know that sodium nitrite is in this category. Although we are very disappointed with these results, they do close a chapter on the potential of sodium nitrite as a treatment for out-of-hospital cardiac arrest, which is in itself a contribution to scientific knowledge. The majority of patients who suffer out-of-hospital cardiac arrest do not survive and new treatments are urgently needed, so it's an important area of research."

The results of VOYAGER PAD found that people with peripheral artery disease (PAD) who took the blood thinner rivaroxaban with aspirin after undergoing lower extremity revascularization--a procedure to treat blocked arteries in the leg--had a significant reduction in the risk of major adverse limb and cardiovascular events when compared with those receiving aspirin alone. Data also showed that patients taking rivaroxaban had higher rates of bleeding, but there was no excess in severe bleeding events such as intracranial or fatal bleeds. Adding clopidogrel at the time of revascularization did not offer any added clinical benefit and, when added to rivaroxaban and aspirin, appeared to increase ISTH major bleeding early in treatment, according to a subgroup analysis from VOYAGER PAD presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

People with symptomatic PAD commonly undergo lower extremity revascularization to open blocked arteries and restore blood flow to the legs and feet. These patients face a high risk of both major adverse limb events and major adverse cardiovascular events. Yet, to date, there are no Class I recommendations for antithrombotic therapy and only very limited evidence supporting the use of clopidogrel following revascularization procedures for PAD. Amid a lack of evidence, many clinicians have defaulted to using dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker such as clopidogrel, which is the standard of care for similar coronary artery interventions, researchers said. But they stressed that there is no quality evidence to support use of clopidogrel plus aspirin in people with PAD undergoing lower extremity revascularization.

"This was a prespecified subgroup analysis to look at whether the use of clopidogrel modified the benefits seen with rivaroxaban and aspirin or increased the risks [of bleeding]," said William R. Hiatt, MD, professor of medicine/cardiology at the University of Colorado School of Medicine, Chief Science Officer at CPC Clinical Research and the study's lead author. "We found that in this [clinical] setting, where we are treating patients with symptomatic PAD with lower extremity revascularization procedures, the addition of clopidogrel [atop] rivaroxaban and aspirin does not provide any further benefit, but did increase bleeding risks, so there doesn't seem to be a compelling reason to use it."

In this prespecified subgroup analysis, half of the 6,564 randomized patients enrolled in VOYAGER PAD (median age of 67 years) also received clopidogrel at the time of their lower extremity revascularization procedure, which was at the discretion of their treating physician and was allowed for up to six months. Patients receiving clopidogrel were more likely to undergo endovascular procedures (90.7%) than undergo surgery (9.3%); the use of clopidogrel is common in endovascular procedures.

After a median follow-up of 28 months, data revealed a 15% reduction in the risk of major limb or cardiovascular complications among those taking rivaroxaban, which was unaffected by the addition of clopidogrel, Hiatt said. TIMI major bleeding, the main safety endpoint, was reported in 2.7% of those taking clopidogrel along with rivaroxaban and aspirin compared with 2.6% of patients who were taking rivaroxaban and aspirin and did not receive clopidogrel. In addition, ISTH major bleeding, a secondary bleeding scale, occurred in 6.5% of those taking clopidogrel plus rivaroxaban and aspirin, and was less at 5.4% in those taking rivaroxaban and aspirin without clopidogrel. Minor TIMI bleeding events occurred in 1.67% of the clopidogrel group and 1.26% of those who were not taking it. Intracranial bleeds were infrequent and similar among those taking and not taking clopidogrel, respectively.

An estimated 10 million U.S. adults and 200 million people worldwide have PAD, narrowed or blocked arteries, mostly in the legs. PAD is a serious condition often characterized by leg pain, difficulty walking, poor circulation and a high rate of non-healing wounds. It also heightens the risk of serious adverse events, including acute limb ischemia--a "heart attack or stroke of the leg"--that can lead to limb amputation or death if not treated quickly. PAD is also linked to higher rates of heart attack and stroke.

"People with PAD tend to be undertreated, yet they are at very high risk," Hiatt said. "I hope that these data will lead to more education and improve how we care for these patients. From these unique data we see the benefit and risks of rivaroxaban plus aspirin were consistent regardless of concomitant use of clopidogrel. However, with higher rates of bleeding when clopidogrel is added to rivaroxaban and aspirin, these findings do not support the routine use of clopidogrel after lower extremity revascularization in these patients if they are on rivaroxaban and aspirin."

How increased bleeding with clopidogrel, particularly in the first six months of use, may affect other outcomes is being explored. The study is limited in that use of clopidogrel was not controlled and was allowed at the discretion of the treating physician.

For people with cancer, the oral blood thinner apixaban is at least as effective as dalteparin, a low molecular weight heparin given by injection, in preventing a repeat venous thromboembolism (VTE), or blood clot, with no excess in major bleeding events, according to Phase 3 trial results presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

It is estimated that 1 in 5 blood clots occur in people with cancer. This population has a much higher risk of developing dangerous VTEs, including deep vein thrombosis (DVT), a blood clot that forms deep inside a vein (usually in a leg) and, more worrisome, pulmonary embolism, which happens when a clot travels and gets lodged in a lung, which can be fatal. Experts say there are many reasons why people with cancer are more susceptible to clotting; for example, the cancer itself can thicken the blood, making it stickier and many cancer therapies and surgeries can inflame blood vessels and limit patients' movement so clots can form more easily.

The aim of the Caravaggio study--the largest study to evaluate the treatment of VTE in cancer--was to assess whether the direct oral anticoagulant apixaban is non-inferior to subcutaneous dalteparin for preventing a recurrent VTE in people with cancer and to evaluate the risk of bleeding. The data revealed that recurrent VTE, the study's primary endpoint, occurred in 32 of 576 patients (5.6%) in the apixaban group and 46 of the 579 patients (7.9%) in the dalteparin group over six months of follow-up, a difference that was not statistically significant. Moreover, major bleeding events, defined by the ISTH guidelines, were similar in the apixaban and dalteparin groups, occurring in 22 patients (3.8%) compared with 23 patients (4.0%), respectively. The proportion of patients who were free of a recurrent VTE, major bleeding events and death during the study period was 73.3% in the apixaban group and 68.6% in the dalteparin group.

"VTE is a major cause of complications and death in these patients, and the high risk of recurrent blood clots and bleeding in patients with cancer make anticoagulant treatment challenging and, therefore, specific studies in these patients are necessary," said Giancarlo Agnelli, MD, professor of internal medicine at the University of Perugia, Italy, and lead author of this investigator-initiated, open-label trial. "Our data show that apixaban is at least as effective as dalteparin--the current gold standard treatment--without any excess in major bleeding, which is a common concern when giving blood thinners. These results should expand the proportion of patients with cancer-associated VTE who can be treated with oral apixaban, which is less cumbersome for patients because it's a pill, not a daily injection."

The Caravaggio trial enrolled 1,170 patients with a cancer-associated VTE at the time of diagnosis at 119 sites in nine European countries, Israel and the U.S. Participants were consecutively randomized to receive oral factor-Xa inhibitor apixaban at a dose of 10 mg twice daily for seven days followed by 5 mg twice daily, or subcutaneous dalteparin 200 units per kg once daily for one month followed by 150 units per kg once daily thereafter for a total of six months. The primary study outcome of recurrent VTE was confirmed by an independent adjudication committee unaware of the treatment patients received.

Patients were 68 years old on average. Pulmonary embolism, a blood clot in the lung, with or without DVT was present in 55% of patients, while 45% had an isolated DVT. Most patients (80.3%) had symptoms suggestive of a blood clot, while 20% had unsuspected VTE that was found through imaging tests performed for reasons other than clinical suspicion of VTE. Most patients (97%) in both the apixaban and dalteparin arms had an active cancer at the time of enrollment; 94.3% of patients in the apixaban arm and 91% in the dalteparin arm had a solid tumor of which 32.6% and 32.3% were located in the gastrointestinal tract, including the pancreatic and hepatobiliary cancer, which was of interest given that major bleeding events from blood thinners often occur in the gastrointestinal tract (GI) system.

Agnelli said that while previous studies have shown other direct oral anticoagulants (edoxaban and rivaroxaban) to be as effective as low molecular weight heparin, there is a trade-off given the observed increase in bleeding, particularly in people with gastrointestinal cancers. He said, for this reason, the most recent guidelines, which have long recommended low-molecular-weight heparin for cancer-associated VTEs, added the use of these agents with the exception of patients with GI cancers.

Agnelli said of note in this study, apixaban was not associated with an increase in GI bleeding compared to dalteparin; major GI bleeding occurred in 1.9% of apixaban and 1.7% of dalteparin-treated patients.

"This is the only trial in cancer-associated thrombosis where a DOAC (direct-acting oral anticoagulant) is not associated with increased GI bleeding, in spite of the inclusion of a substantial proportion of GI cancers," he said.

Interestingly, Agnelli reported that apixaban was more effective than dalteparin at preventing recurrent VTE in patients younger than age 65. Agnelli and team will be conducting several subgroup analyses to determine if certain patients benefit more from one approach.

The results of this study cannot be extrapolated to people with brain tumors, known cerebral metastases or acute leukemia, as they were not enrolled for safety reasons. Researchers added that, as with a large majority of studies on the treatment of VTE, the sample size of the study was powered for recurrent VTE, the primary outcome, and was not powered to make definitive conclusions about bleeding.

Three months after undergoing renal denervation (RDN)--a procedure that delivers energy to overactive nerves leading to the kidney to decrease their activity--patients with untreated high blood pressure had statistically significant reductions in average blood pressure over 24 hours compared with patients who underwent a sham procedure and experienced no major adverse effects, according to results from the SPYRAL-HTN OFF MED pivotal trial presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

"These results show that RDN offers an effective alternative approach to traditional medications that require patient adherence for reducing blood pressure," said Michael Böhm, MD, of Saarland University Medical Center in Hamburg, Germany and lead author of the study. "Furthermore, the findings show that RDN lowers blood pressure not just during the day but also throughout the night and early-morning periods when risk is highest for [adverse] clinical events and the effect of some medications on blood pressure is reduced."

High blood pressure, also known as hypertension, is a leading cause of heart attacks, strokes and death. It is estimated that 46% of adults in the U.S. have high blood pressure based on the 2017 ACC/AHA High Blood Pressure in Adults guideline.

Blood pressure-reducing medications are often insufficiently effective, Böhm said. Earlier research has shown that among adults in the U.S. who take high blood pressure medication, approximately half still have elevated blood pressure. In addition, some people with high blood pressure either do not want to take medication or cannot take it due to intolerable side effects, he said. For these reasons, effective non-drug treatments for high blood pressure are needed.

The kidneys help to regulate blood pressure by removing salt and excess water from the body. However, overactivity of the sympathetic nerves in the arteries leading to the kidneys can contribute to high blood pressure. RDN works by delivering an electrical current that decreases the overactivity of these nerves. Pilot studies have shown that, compared with a sham procedure, RDN reduces blood pressure.

RDN is performed in a hospital catheterization lab (cath lab) under local anesthesia and with imaging guidance. A catheter is threaded from the femoral artery in the thigh to the arteries that serve the kidneys. There, the catheter delivers pulses of radiofrequency energy to the nerves in the arteries. Patients typically spend one night in the hospital after the procedure.

The SPYRAL-HTN OFF MED pivotal trial was designed in collaboration with the U.S. Food and Drug Administration (FDA) to provide statistically significant evidence of whether RDN could reduce blood pressure in patients not taking blood pressure-reducing medication.

The study, which was conducted at 46 sites in nine countries (the U.S., Germany, Greece, Australia, Canada, Japan, the United Kingdom, Austria and Ireland), enrolled 331 patients whose average systolic blood pressure (SBP; the top number) over 24 hours was between 140 and 170 mm Hg. Their average age was 53 years, and 67% were men. Most had obesity, with an average body mass index of 31. Around 5% also had Type 2 diabetes. A condition of enrollment was that patients either had not been taking any blood pressure-reducing medications or had discontinued those medications at least three weeks before their blood pressure was measured at study entry.

Patients were randomly assigned to receive either RDN or a sham procedure in which a catheter was inserted and only an angiography (X-ray of the blood vessels) was performed. A total of 166 patients were assigned to RDN and 165 to the sham procedure. Patients did not know whether they were receiving RDN or the sham procedure. The doctors and nurses who measured patients' blood pressure and treated them after the procedure also did not know which group patients were in.

At the end of three months, the primary efficacy endpoint was the change in average 24-hour SBP, adjusted for SBP at study entry. The secondary efficacy endpoint was the change in average blood pressure measured in the doctor's office at three months, adjusted for office blood pressure at study entry. Major adverse safety events were also assessed at three months, including rates of death, stroke, changes in kidney function or any injury to the arteries surrounding the kidney.

For the primary and secondary efficacy endpoints, the difference between groups was -3.9 mm Hg for 24-hour SBP and -6.5 mm Hg for office SBP, both favoring the RDN group, with a 99.9% probability that RDN was superior to the sham procedure.

No deaths, strokes or changes in kidney function occurred during the three-month follow-up period, Böhm said. He added that these results may not demonstrate the total decrease in blood pressure achieved with RDN given the short follow-up period due to ethical and safety concerns that patients needed to be restarted on antihypertensive medications. In other studies of RDN, however, patients' blood pressure has continued to decline at six months or more after the procedure, he said.

"This study establishes RDN as an additional option beyond exercise or lifestyle modification for patients with high blood pressure who are unwilling to take or cannot tolerate medication," Böhm said, adding that the study results will be included in an application for FDA approval of the RDN device used in the trial for the treatment of patients who are not taking blood pressure-reducing medication. Currently there are no RDN devices approved for use in the U.S.

Results from a companion study, the SPYRAL-HTN ON MED trial, which is testing the safety and effectiveness of RDN in patients who are taking up to three blood pressure-reducing medications, are expected in about 18 months. The results of that study will also be included in the application for FDA approval of the RDN device, Böhm said.

WASHINGTON--The international medical team that accomplished the world's first documented drone delivery of insulin for a patient living in a remote community described the project in an ENDO 2020 abstract that will be published in the Journal of the Endocrine Society.

The 16-minute test flight from Galway, Ireland, to the Aran Islands about 12 miles off the west coast of Ireland took place Sept. 13 last year, according to the drone project's principal investigator, Derek O'Keeffe, M.D., Ph.D., a consultant endocrinologist at National University of Ireland Galway. O'Keeffe said that after severe storms disrupted healthcare access in Ireland in recent years, they wanted to find a solution for future disasters when people with diabetes in remote regions may be stranded for days without their lifesaving diabetes medicines.

"We now have the drone technology and protocols in place to deliver diabetes medications and supplies in an actual disaster if needed," he said. "This is a milestone in improving patient care."

The large autonomous (self-flying) drone flew "beyond visual line of sight" during commercial flight operations in regulated airspace, O'Keeffe said. The project team's yearlong planning required approvals from aviation, pharmaceutical and clinical regulatory agencies.

Endocrinologist Spyridoula Maraka, M.D., M.S., of the University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, said the team had to address several healthcare delivery issues to send a prescription medicine via an unmanned aircraft operating a 4G cellular network using GPS waypoints.

"Insulin can be outside the fridge for hours, but it can't be exposed to extreme heat, so we put it in an insulated parcel with temperature monitoring en route," Maraka said. "We also put a security lock on the parcel in case the drone did not arrive at the right place."

Because legally a pharmacist must dispense a prescription drug, she arranged for a pharmacist to dispense the insulin and another diabetes medication, glucagon before loading them to the drone for delivery.

Another unique aspect of the project, according to Maraka, is that the drone returned with a blood sample collected from the patient for monitoring blood glucose control (HbA1c). "We wanted to find a way to monitor glycemic control remotely," she said. "It was the full circle of care, which has not been done by drone before."

Maraka stressed that this ability for remote diagnostics could save lives. "A patient with type 1 diabetes could develop life-threatening diabetic ketoacidosis after more than one day without insulin," she said. "A blood specimen would allow us to properly diagnose and treat the condition."

Pathogenic fungi pose a huge and growing threat to global food security.

Currently, we protect our crops against fungal disease by spraying them with anti-fungal chemistries, also known as fungicides.

However, the growing threat of microbial resistance against these chemistries requires continuous development of new fungicides.

A consortium of researchers from the University of Exeter, led by Professor Gero Steinberg, combined their expertise to join the fight against plant pathogenic fungi.

In a recent publication, in the prestigious scientific journal Nature Communications, they report the identification of novel mono-alkyl chain lipophilic cations (MALCs) in protecting crops against Septoria tritici blotch in wheat and rice blast disease.

These diseases challenge temperate-grown wheat and rice, respectively, and so jeopardise the security of our two most important calorie crops.

The scientists' journey started with the discovery that MALCs inhibit the activity of fungal mitochondria.

Mitochondria are the cellular "power-house", required to provide the "fuel" for all essential processes in the pathogen.

By inhibiting an essential pathway in mitochondria, MALCs cut down the cellular energy supply, which eventually kills the pathogen.

Whilst Steinberg and colleagues show that this "mode of action" is common to the various MALCs tested, and effective against plant pathogenic fungi, one MALC that they synthesised and named C18-SMe2+ showed unexpected additional modes of action.

Firstly, C18-SMe2+ generates aggressive molecules inside the mitochondria, which target life-essential fungal proteins, and in turn initiate a "self-destruction" programme, which ultimately results in "cellular suicide" of the fungus.

Secondly, when applied to crop plants, C18-SMe2+ "alerts" the plant defence system, which prepares the crop for subsequent attack, thereby increasing the armoury of the plant against the intruder.

Most importantly, the Exeter researchers demonstrate that C18-SMe2+ shows no toxicity to plants and is less toxic to aquatic organisms and human cells than existing fungicides sprayed used in the field today.

Professor Steinberg said: "It is the combined approach of Exeter scientists, providing skills in fungal cell biology (myself, Dr Martin Schuster), fungal plant pathology (Professor Sarah J. Gurr), human cell biology (Professor Michael Schrader) and synthetic chemistry (Dr Mark Wood) that enabled us to develop and characterise this potent chemistry.

"The University has filed a patent (GB 1904744.8), in recognition of the potential of this novel chemistry in our perpetual fight against fungi.

"We now seek partners/investors to take this development to the field and prove its usefulness under 'real agricultural conditions'. Our long-term aim is to foster greater food security, in particular in developing nations."

Professor Steinberg added: "I always wanted to apply my research outside of the ivory tower of academia and combine the fundamental aspects of my work with a useful application.

"The visionary approach of the Biological Sciences Research Council (BBSRC) provided me with this opportunity, for which I am very grateful. In my mind, this project is a strong example of translational research that benefits the public."

Professor Sarah Gurr said: "This is such a timely and important study. We are increasingly aware of the growing burden of plant disease caused by fungi and of our need to safe-guard our calorie and commodity crops better.

"The challenge is not only to discover and describe the mode of action of new antifungals but to ensure that chemistries potent against fungi do not harm plants, wildlife or human health.

"This new antifungal is thus an exciting discovery and its usefulness may extend beyond crops into the realms of fungal disease in humans and, indeed to various applications in the paint and preservative industries. This merits investment!"

Invasive procedures such as bypass surgery and stenting--commonly used to treat blocked arteries--are no better at reducing the risk for heart attack and death in patients with stable ischemic heart disease than medication and lifestyle changes alone. However, such procedures offer better symptom relief and quality of life for some patients with chest pain, according to two new, milestone studies.

The studies, designed to settle a decades-old controversy in cardiology, appear online March 30 in the New England Journal of Medicine. While researchers released preliminary findings last November at the American Heart Association annual meeting, the papers published today report the official outcomes of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), the largest and one of the most consequential studies of its kind.

Funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, the trial followed more than 5,000 patients with stable heart disease and moderate to severe heart disease for a median of 3.2 years. It compared an initial conservative treatment strategy to an invasive treatment strategy. The conservative treatment strategy involved medications to control blood pressure, cholesterol, and angina (chest discomfort caused by inadequate blood to the heart), along with counseling about diet and exercise. The invasive treatment strategy involved medications and counseling, as well as coronary procedures performed soon after patients recorded an abnormal stress test. The trial allowed tests that assess coronary blood flow restriction, called ischemia, to determine who could participate in the study.

"Previous studies have reached similar conclusions as ISCHEMIA, but they were criticized for not including patients who had severe enough disease to benefit from the procedures. ISCHEMIA studied only patients with the most abnormal stress tests," said Yves Rosenberg, M.D., study co-author and chief of NHLBI's Atherothrombosis and Coronary Artery Disease Branch. "These findings should be applied in the context of careful attention to lifestyle behaviors and guideline-based adherence to medical therapy, and will likely change clinical guidelines and influence clinical practice."

He cautioned patients in the meantime to confer with their doctors to determine what strategies are best for them.

Coronary artery disease, which is caused by narrowed arteries that reduce blood to the heart, is the most common type of heart disease. It affects about 18 million Americans and is the leading cause of death in the United States.
Symptoms can vary, but some people do not have them at all and may not know they have heart disease until they experience chest pain, a heart attack, or sudden cardiac arrest.

To find out whether an invasive or conservative strategy would be more effective in reducing these kinds of events, researchers studied the impact of both on heart attack, hospitalization for unstable angina, heart failure, resuscitated cardiac arrest, and cardiovascular death. An additional key outcome of study was quality of life.

From August 2012 to January 2018, ISCHEMIA enrolled 5,179 patients who were an average of 64 years old, at 320 sites in 37 countries. Most participants had a history of chest pain, with 21% reporting daily or weekly chest pain. About 35% had no chest pain one month prior to enrollment.

The patients then were randomly assigned to receive either the conservative, medical therapy alone (unless their symptoms worsened), or medical therapy and an invasive intervention soon after having an abnormal stress test. Over the five years of the trial, 21% of patients in the conservative treatment group ended up having a stent implant or bypass surgery; the rest continued medication alone. Of those in the intervention group, revascularization was performed in 79%, three-quarters of them receiving stents and the others, bypass surgery.

By the end of the trial, the death rate between the two groups proved to be essentially the same: among the participants who had invasive procedures, 145 died, compared to 144 who received medication alone. The overall rate of disease-related events was similar among those who took medication alone: 352 experienced an event such as heart attack, compared to 318 who had invasive procedures.

Researchers noted one caveat; patients in the conservative strategy had fewer cardiovascular events during the first two years of the study. However, the invasive strategy patients had fewer events during the last two years, researchers noted, because of an uptick in heart attacks in that group in the first six months.

"We have known and confirmed in this study that stent and surgical procedures have a risk of some heart damage," said Judith Hochman, M.D., study chair, co-lead author and Senior Associate Dean for Clinical Sciences NYU Grossman School of Medicine. "However, we saw that the heart damage related to a procedure was not as serious in terms of the risk of subsequent death compared to heart attacks that occurred spontaneously, unrelated to any procedure."

The long-term follow-up of patients will be needed to better determine the true difference in prognosis between these two groups.

For patients with angina, or chest pain, the comparative benefits of an invasive procedure over medical therapy alone were more consistent throughout the trial.

"ISCHEMIA showed an impressive, sustainable improvement in patients' symptoms, function and quality of life with an invasive strategy for up to four years of follow-up," said John Spertus, M.D., M.P.H., director of health outcomes research at Saint Luke's Mid America Heart Institute in Kansas City, MO., and co-principal investigator for the ISCHEMIA quality of life analysis. "However, this benefit was only observed in roughly two-thirds of those who had angina at baseline and no benefit was seen in those who had no symptoms."

"Taken together, the quality of life and clinical results suggest that there is no need for invasive procedures in patients without symptoms," said David Maron, M.D., director of the Stanford Prevention Research Center at Stanford University and the study's lead author and principal investigator. "For those with angina, our results show it is just as safe to begin treating with medication and lifestyle change, and then if symptoms persist, discuss invasive treatment options."

Two other ISCHEMIA companion studies produced other key results. ISCHEMIA-Chronic Kidney Disease (CKD) and quality of life studies, also published in the New England Journal of Medicine, did not show a reduced risk for death and heart attack for participants who had advanced chronic kidney disease, stable coronary disease, as well as moderate or severe ischemia with the invasive treatment compared to the conservative treatment. There were no benefits in quality of life, even if participants had angina symptoms.