Palliative Care News
Lower blood pressure target of 120 mm Hg greatly reduces cardiovascular complications and deaths in older adults.
According to initial results of a landmark clinical trial released today at the National Institutes of Health, heart attacks, strokes, acute coronary syndrome, heart failure and death due to cardiovascular causes were reduced by almost one-third and risk of death was lowered by almost one-quarter in participants randomized to a systolic blood pressure goal of 120 mm Hg compared to those randomized to the usual goal of 140 mm Hg.
The NIH-sponsored the Systolic Blood Pressure Intervention Trial (SPRINT) enrolled more than 9,300 participants age 50 and older with high blood pressure. Participants were assigned at random to a systolic blood pressure target of 120 mm Hg or the usual target of 140 mm Hg, then had the amount and type of blood pressure medication adjusted to achieve the different blood pressure targets.
The groundbreaking results of this important trial, in which the University of Alabama at Birmingham and the UAB School of Medicine played major clinical and leadership roles, is expected to impact the way physicians across the United States and Puerto Rico treat patients with high blood pressure.
“SPRINT is a large, well designed and well conducted study, and is certain to influence the way clinicians manage the treatment of patients with high blood pressure and impact the decision making of future national guidelines committees,” said Suzanne Oparil, M.D., principal investigator for the UAB hub of the SPRINT trial, UAB professor of Medicine and director of the Vascular Biology and Hypertension Program in UAB’s School of Medicine. “While these results provide important evidence that treating blood pressure to a lower goal in older or high-risk patients can be beneficial and yield better health results overall, patients should talk to their doctor to determine whether this lower goal is best for their individualized care.”
The SPRINT study, which began in the fall of 2009, recruited approximately 100 medical centers and clinical practices throughout the United States and Puerto Rico. UAB was selected by the NIH as one of five hubs to recruit and direct almost 20 of these clinics from Massachusetts to Puerto Rico; UAB-directed clinics recruited more than 1,950 study participants, surpassing the study’s initial goal for UAB’s network. The study’s blood pressure intervention, which was to finish in summer 2016, has finished earlier after the National Heart, Lung and Blood Institute Director Gary H. Gibbons, M.D., took action when the Data and Safety Monitoring Board interpreted the benefits of the lower goal as far outweighing the harms.
“This study provides potentially lifesaving information that will be useful to health care providers as they consider the best treatment options for some of their patients, particularly those over the age of 50,” Gibbons said. “We are delighted to have achieved this important milestone in the study in advance of the expected closure date for the SPRINT trial and look forward to quickly communicating the results to help inform patient care and the future development of evidence-based clinical guidelines.”
The SPRINT study is the largest of its kind to examine how maintaining systolic blood pressure at a lower than currently recommended level will impact cardiovascular and kidney diseases. More data in other areas will continue to be collected into 2016.
“Participants are still continuing in the trial to provide data on more end points and may continue on study drugs,” Oparil said. “SPRINT is a very large and important trial, however, the findings are still preliminary, and we will have to wait for the published paper for details.”
The NIH funded the SPRINT study in 2009 to answer one question: Will treating high blood pressure to a lower blood pressure goal — 120 mm Hg systolic compared to the traditional goal 140 mm Hg — reduce the risk of heart and kidney diseases, stroke, or age-related declines in memory and thinking?
High blood pressure is a leading cause of death and disability in the United States and worldwide. More than 60 percent of people over age 65 have high blood pressure, and the number of people with high blood pressure is increasing.
Experts in blood pressure management, primary care physicians, nephrologists or other health care providers have seen SPRINT participants regularlyfor a period of 4 to 6 years. UAB’s Vascular Biology and Hypertension Research Program Clinic, part of the UAB School of Medicine Division of Cardiovascular Disease and directed by professor of medicine David Calhoun, M.D., was one of several clinics that enrolled patients in Alabama. Athens Internal Medicine had the largest patient population in the study, with the more than 300 enrollees. The UAB Division of Nephrology and Nephrology Associates in Birmingham also participated and enrolled an important subgroup of patients with chronic kidney disease.
In additional to clinical roles, UAB faculty also have leadership roles in the SPRINT trial. Oparil and Cora E. Lewis, M.D., are on the trial-wide steering committee and co-lead the morbidity and mortality committee, in which capacity Oparil, Lewis and their committee members review medical records in order to determine whether trial participants have had a heart attack, heart failure, stroke or other cardiovascular event. Lewis also leads the measurement procedures and quality control committee and serves on the executive committee for the study.
Virginia Wadley Bradley, M.D., professor of medicine in the Division of Gerontology, Geriatrics and Palliative Care, is co-lead of the trial’s MIND committee, which oversees the cognitive and dementia aspects of the trial. Tom Ramsey, a program manager in Preventive Medicine, is the lead author of the trial’s recruitment paper, which is currently under review. Steve Glasser, M.D., professor of medicine in Preventive Medicine is a cardiologist who also is on the trial’s morbidity and mortality committee.
“UAB was selected and is able to be a part of this remarkable study because we put together a great team of investigators and staff to run the hub,” said Lewis, the co-principal investigator of the UAB hub. “We recruited a good diversity of clinics that could bring in diverse patients and achieve the study recruitment goals, we wrote an outstanding application, and we have a lot of relevant experience for all aspects of the trial. We are able to provide all of the logistical support and we have the infrastructure to handle a trial of this scope and magnitude. It was an incredibly competitive selection process.”
While investigators work to publish their cardiovascular results in the coming weeks, there are additional important questions from the trial that will be answered in 2016 after all of the data are collected, including:
- How are the 120 and 140 mm Hg benchmarks going to stack up relative to cognitive function and risks of dementia, especially in patients 75 or older?
- How will the benchmarks affect brain structure in addition to cognitive assessments?
- What do the two levels of blood pressure mean for hypertension as a cause of kidney disease, especially in African Americans?
“A lot of studies will exclude people who have chronic kidney disease, but we intentionally included them in the SPRINT trial,” Lewis said. “We want to know what these two levels will mean for kidney disease. It could be that a more aggressive way of treating hypertension would preserve kidney function, or it could be that after a certain age, the kidneys may need a little more blood pressure to adequately perfuse them — that is to get them an adequate blood supply. We really don’t know. It’s going to be incredible to get some answers to these and other questions.”
The study population was diverse and included women, racial/ethnic minorities, patients with established chronic kidney disease or cardiovascular disease, and the elderly. The investigators point out that the SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other studies included those populations.
When SPRINT was designed, the well-established clinical guidelines recommended a systolic blood pressure of less than 140 mm Hg for healthy adults and less than 130 mm Hg for those with kidney disease or diabetes. Investigators designed SPRINT to determine the potential benefits of achieving systolic blood pressure of less than 120 mm Hg for hypertensive adults 50 years and older who are at risk for developing heart disease or kidney disease, or who already had heart or kidney disease and were at risk of disease progression.
Between 2010 and 2013, the SPRINT investigators randomly divided the study participants into two groups that differed according to targeted levels of blood pressure control. The standard group received blood pressure medications to achieve a target of less than 140 mm Hg. They received an average of two different blood pressure medications. The intensive treatment group received medications to achieve a target of less than 120 mm Hg and received an average of three medications.
“Our results provide important evidence that treating blood pressure to a lower goal in older or high-risk patients can be beneficial and yield better health results overall,” said Lawrence Fine, M.D., chief, Clinical Applications and Prevention Branch at NHLBI. “But patients should talk to their doctor to determine whether this lower goal is best for their individual care.”
The study is also examining kidney disease, cognitive function, and dementia among the patients; however, those results are still under analysis and are not yet available, as additional information will be collected over the next year. The primary results of the trial will be published within the next few months.
In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.
An Arizona drug company will patent the small peptide drug.
University of Alabama at Birmingham — that shows significant ability to lower blood cholesterol in animal models. Capstone Therapeutics Corp. and its joint venture affiliate, LipimetiX Development Inc., recently announced the U.S. Patent application, claiming novel, more potent analogs of its lead peptide, AEM-28.An Arizona drug company will patent a small peptide — developed through research at the
LipimetiX, based in Tempe, Arizona, has supported UAB research by G.M. Anantharamaiah, Ph.D., a professor in the UAB School of Medicine’sDivision of Gerontology, Geriatric and Palliative Care, to identify novel analogs of AEM-28 that have greater efficacy than the parent peptide. The new Apo E mimetic peptide, AEM-28-14, showed a 400 percent greater cholesterol-lowering efficacy and a several-fold increase in drug tolerability. Increased efficacy and tolerance have the potential to increase the safe and effective dose range compared with other AEM-28 analogs. Anantharamaiah’s research at UAB focuses on the use of apolipoprotein mimetic peptides to treat atherosclerosis and cardiovascular disease.
The UAB Institute for Innovation and Entrepreneurship is focused on advancing a strong innovative and entrepreneurial ecosystem at UAB, and has worked to foster the collaboration between Anantharamaiah’s lab and LipimetiX/Capstone to advance treatments developed at UAB to the clinic.
Capstone and LipimetiX last year announced that the parent drug, AEM-28, showed a generally acceptable safety profile and some significant alterations in blood lipid biomarkers in a human Phase 1a/1b/2a clinical trial.
“We believe that the profound cholesterol-lowering effect of a single injection of AEM-28-14, accompanied by the enhanced toleration, will allow us to expand upon the statistically significant VLDL cholesterol and triglyceride reductions seen in our recently completed AEM-28 human clinical studies,” said Dennis Goldberg, Ph.D., president of LipimetiX. “Subject to funding, LipimetiX plans to begin development of AEM-28-14 for cholesterol and triglyceride reduction in patients refractory to available therapeutic modalities.”
AEM stands for chimeric Apolipoprotein E Mimetic peptides. UAB researchers created these small peptides to mimic the function of apolipoprotein E (Apo E), a class of protein essential for metabolism of cholesterol and triglycerides. After a meal, Apo E targets cholesterol- and triglyceride-rich lipoproteins to specific receptors in the liver, decreasing the levels in the blood. Elevated plasma cholesterol and triglycerides are independent risk factors for atherosclerosis, the major cause of cardiovascular, peripheral artery and cerebral artery disease. These diseases can lead to heart attacks, loss of limbs and strokes. Faulty lipid metabolism also contributes to adult onset diabetes, and diabetics are very vulnerable to atherosclerosis and to heart and peripheral artery diseases.
UAB scientists patented the first chimeric Apo E mimetic peptide in 1999, reducing the 299-amino acid native Apo E to a 28-amino acid peptide that has two parts. One part of the peptide attaches to the surface of lipoproteins; the other domain binds to Apo E receptors in the liver.
In 2010, the founding scientist of LipimetiX obtained worldwide right to patents for Apo E mimetic peptides from the UAB Research Foundation, now a part of the UAB Institute for Innovation and Entrepreneurship. LipimetiX has an exclusive license with the UAB Research Foundation for AEM-28 and its analogs.
The UAB Institute for Innovation and Entrepreneurship was formed in 2013 to expand the mission and scope of UAB Research Foundation and serve as the nexus for UAB innovation, entrepreneurial educational models, applied research, management of intellectual property and an entry point for industries seeking to partner with UAB investigators. The UAB Institute for Innovation and Entrepreneurship is focused on advancing a strong innovative and entrepreneurial ecosystem at UAB, and has worked to foster the collaboration between Anantharamaiah’s lab and LipimetiX/Capstone to advance treatments developed at UAB to the clinic.
Virginia Wadley, Ph.D., says until this new JAMA study, whether or not stroke survivors are at-risk over the long term was an unknown.
Stroke has fallen to the fifth-leading cause of death in the United States due to decreases in people dying from it, and this increase in survivors has led to questions about their health in the years following stroke.
In the United States, about 795,000 residents experience a stroke yearly, according to the American Heart Association. Over the last two decades, while accounting for age, disability rates due to stroke increased by 40 percent, according to the State of U.S. Health report.
A new Journal of the American Medical Association study looked at 23,572 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants age 45 years or older without cognitive impairment, which includes failing memory and processing thoughts more slowly. The research team, which included investigators from the University of Alabama at Birmingham, report those who experienced a stroke had an acute decline in cognitive function and also accelerated and persistent cognitive decline over six years.
“Many stroke survivors are monitored for physical and cognitive effects only during the acute rehabilitation period during which the bulk of progress is expected to occur,” said senior study author Virginia Wadley, Ph.D., associate professor in the UAB Division of Gerontology, Geriatrics and Palliative Care. “Whether survivors are at risk for greater or more rapid cognitive decline over subsequent years has been difficult to answer, because there seldom have been pre-stroke cognitive data available for comparison.”
Over the median follow-up of 6.1 years, 515 participants survived incident stroke and 23,057 remained stroke-free.
“We looked at all REGARDS participants’ rates of cognitive change, including those who have and have not gone on to have a stroke, to detect the impact of stroke on cognition,” Wadley said. “Because we could utilize this data set, we were able to find that stroke survivors are vulnerable to a faster rate of decline in various thinking skills in the years following stroke compared to age/disease-related changes in the years prior to stroke and to changes that occur in peers who have not experienced stroke.”
Wadley says this finding has important implications for clinical practice, research and potentially health policy.
“Our findings highlight a need for long-term monitoring and follow-up care for stroke survivors, with a focus on the mounting potential for cognitive impairment in subsequent years. Therapies to support cognitive abilities should be a high priority. And long-term cognitive abilities could be an important domain to evaluate in relation to initial stroke treatments.”
“Our findings highlight a need for long-term monitoring and follow-up care for stroke survivors, with a focus on the mounting potential for cognitive impairment in subsequent years,” Wadley said. “Therapies to support cognitive abilities should be a high priority. And long-term cognitive abilities could be an important domain to evaluate in relation to initial stroke treatments.”
This study was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and REGARDS principal investigators Drs. George and Virginia Howard, both professors in the UAB School of Public Health.
“The Howards’ generous collaborative spirit and enthusiasm for discovery outside the clinic-based paradigms are the reasons for the scope of knowledge being created in this ongoing research,” Wadley said. “We also are indebted to our gracious study participants who are helping us better understand risks for stroke and cognitive decline; knowledge that ultimately will contribute to reducing these adverse outcomes.”
Studies reporting on 207 advanced cancer patients and 122 of their caregivers who participated in a trial called ENABLE III revealed benefits to patients who received care soon after diagnosis versus 12 weeks later.
J. Nicholas Dionne-Odom, Ph.D., also from the University of Alabama, and colleagues examined the effect of early versus delayed initiation of a PC intervention for 122 caregivers of 207 patients with advanced cancer.
Early palliative care offers statistically beneficial effects on patient survival and family caregiver burden, according to articles published in the Journal of Clinical Oncology.
Two papers recently published by University of Alabama at Birmingham School of Nursing researchers in the Journal of Clinical Oncology highlight the need for a “culture shift” by clinicians and the general public to engage palliative care services long before a person reaches the final stage of life.
Two articles reporting on 207 advanced cancer patients and 122 of their family caregivers who participated in the ENABLE III Trial (“Early Versus Delayed Initiation of Concurrent Palliative Oncology Care” and “Benefits of Early Versus Delayed Palliative Care to Informal Family Caregivers of Patients With Advanced Cancer”) reveal that palliative care delivered soon after a diagnosis of advanced cancer had statistically beneficial effects on patient survival and family caregiver depression and burden when compared with care provided 12 weeks later. The one-year survival rate for patients was 63 percent for those who received early palliative care, compared with 48 percent in the group whose care was delayed. These results support integration of palliative care for patients and families as soon as possible after diagnosis.
“Palliative care is about providing an extra layer of support so that patients can live well and families can be supported,” said principal investigator Marie Bakitas, D.N.Sc., professor and Marie L. O’Koren Endowed Chair in the School of Nursing. “These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”
“If patients and clinicians wait to introduce palliative care when a person is actively dying, it limits the full range of services that patients and their families can receive,” said Nick Dionne-Odom, Ph.D., postdoctoral fellow in the School of Nursing and lead author of the family caregiver ENABLE Trial outcomes. “This means palliative care is mistakenly associated solely with end-of-life care. This is unfortunate. Our research shows that integration of palliative care earlier in the cancer trajectory benefits both patients and their family caregivers.”
“These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”
The investigators say that family caregivers who receive this support and education have greater capacity and skills to deliver high-quality support to patients. Likewise, providing patients with palliative care early eases the burden on families, who deliver the majority of care and psychosocial support in the home.
“Anyone who has been through cancer with a family member can attest to the physical, psychological and existential burden it places on both parties,” Dionne-Odom said. “Receiving this extra layer of support early and at the same time as curative medical treatments is vital for helping patients and their family caregivers develop the coping and other skills needed for the ups and downs of their journey.”
Bakitas says two other shifts in the view of palliative care also are needed.
“Reimbursement mechanisms need to incentivize this care to be offered regardless of six-month prognosis, which is the current hospice-benefit requirement,” Bakitas said. “Also, increased clinician education is needed to train both specialists and general practitioners in palliative care.”
Both researchers say mechanisms still need to be identified that explain the effects of early palliative care, and they are looking at the impact of depression and biological mechanisms that might contribute to this explanation.
Bakitas recently was awarded a five-year, $3.5 million National Institute of Nursing Research R01 grant to study whether palliative care provided to advanced heart-failure patients while they are well results in a better quality of life, improved mood, and less symptom distress/burden for patients and/or caregivers when compared to usual heart-failure care. It will test this similar intervention using materials and an approach adapted from the ENABLE cancer intervention.
National Institute of Nursing Research’s five-year grant is for ENABLE: CHF-PC study to determine whether palliative care is a best practice for heart-failure patients.
University of Alabama at Birmingham School of Nursing professor and Marie L. O’Koren Endowed Chair Marie Bakitas, DNSc, has received a five-year, $3.5 million R01 grant from the National Institute of Nursing Research for a study to determine whether palliative care provided when advanced heart-failure patients are still well will result in better quality of life, improved mood, and less symptom distress/burden for patients and/or caregivers, when compared to usual heart-failure care.
This National Institutes of Health randomized controlled trial, “ENABLE: CHF-PC (Educate, Nurture, Advise Before Life Ends: Comprehensive Heartcare for Patients and Caregivers),” will compare the quality of life, symptom burden and mood in 380 older adults with stage III/IV heart failure and their family caregivers. Half of the patient participants will be randomized to the intervention, and half will receive usual heart-failure care.
The focus of this palliative care model is on coaching patients and their family caregivers in problem-solving, communication, symptom management and health care decision-making with a goal of empowering them to be better prepared to meet the challenges of progressive illness.
“Despite treatment advances, 50 percent of heart-failure patients will die within five years,” said Bakitas, who also is associate director of the UAB Center for Palliative and Supportive Care. “Increasing age and rural environment are risk factors associated with the greatest heart-failure complications and death. And, in the year before death, research shows heart-failure patients will experience multiple hospitalizations and personal and economic costs of unrelieved physical and emotional suffering. The overall goal of this study is to test the efficacy of a heart-failure palliative care telehealth model in reducing the suffering and burden from symptoms associated with living with advanced heart failure.”
Palliative care, Bakitas says, has been demonstrated in other diseases to reduce end-of-life suffering, hospital readmissions and health care costs; but only 16 percent of Alabama hospitals have palliative care programs, compared with the national average of 53 percent.
Bakitas adds that, of Alabama’s 67 counties, 55 are categorized as rural, and the incidence of heart failure in these rural counties is greater than that of the state’s urban counties, making an intervention such as this a key to improving quality of life for rural Alabama residents with heart failure and their families.
“There is an urgent need to increase palliative care access to older adults with advanced illness, especially in the South, which has the lowest availability to these services,” she said. “It is critical to understand how to best make this care accessible to this population.”
The focus of this palliative care model is on coaching patients and their family caregivers in problem-solving, communication, symptom management and health care decision-making with a goal of empowering them to be better prepared to meet the challenges of progressive illness, Bakitas says. This is a telehealth intervention, meaning patients and their caregivers do not have to leave home to participate after a single in-person palliative care assessment. The in-person consultation is followed by a series of phone sessions for a period of 48 weeks, specifically tailored to meet the needs of a rural population.
Bakitas and others have demonstrated in advanced cancer that concurrent palliative care offered from the time of advanced diagnosis achieves beneficial quality of life, symptom burden, depression and, in some cases, survival outcomes. The intervention in this study is adapted from Bakitas’ successful palliative care model for cancer (ENABLE: Educate, Nurture, Advise, Before Life Ends).
Advanced heart failure affects nearly 6 million Americans, and less is known about how this illness affects the 80 percent of heart-failure patients ages 65 years and older because research tends to focus on younger patients. Currently, Bakitas says, only 19 percent of Medicare-age heart-failure patients and their family caregivers access palliative care services, compared with more than half of advanced cancer patients.
“Older patients with heart failure and their family caregivers rarely have access to palliative supportive care services because the disease is unpredictable, and in the current health care system, palliative treatment may not be provided until after other medical treatments have been tried,” Bakitas said.
Also important to the study is the impact that palliative care has on caregiver burden. This study will examine the impact of the intervention on caregivers’ self-reported quality of life, mood, health and caregiving burden.
“This is important because caregivers can spend an average of eight hours each day assisting the patient with their care,” she said. “This takes a toll on their physical and psychological well-being. Caregivers will often ignore their own needs, and ultimately, without assistance that this coaching is designed to provide, caregiving studies have documented that they can have higher rates of illness and death.”