Focus on new strategies as incidence of HF continues to escalate
The incidence of HF continues to rise in the United States, leaving many cardiologists searching for new strategies to care for their patients.
The numbers are staggering. One million HF hospitalizations occur each year in the United States and an additional 2 million hospitalizations occur for which HF may be a contributing cause. Patients with a diagnosis of HF are estimated to make more than 3 million physician visits each year, with estimated direct and indirect costs hovering at $40 billion.
Development of new HF therapies continues; however, challenges remain, including the rising incidence of diastolic HF, or HF with preserved ejection fraction (HFpEF); barriers to well-designed trials; and a lack of personalized care.
Part two of this Cardiology Today expert round table focuses on the current and future care of patients with HF, with particular attention on treatment strategies under examination, education and training, and prevention.
Carl J. Pepine, MD
Cardiology Today Chief Medical Editor
Division Director Emeritus, Eminent Scholar Emeritus and Professor of Medicine, Division of Cardiovascular Medicine, University of Florida College of Medicine
Javed Butler, MD, MPH
Professor of Medicine and Director, Heart Failure Research, Emory University
James L. Januzzi Jr., MD
Associate Professor of Medicine, Harvard Medical School
Roman W. Desanctis Endowed Distinguished Clinical Scholar
Director, Cardiac Intensive Care Unit, Massachusetts General Hospital
Bertram Pitt, MD
Professor of Internal Medicine, University of Michigan School of Medicine
Randall C. Starling, MD, MPH
Vice Chairman, Cardiovascular Medicine
Section Head, Heart Failure Center Heart & Vascular Institute, Cleveland Clinic
John R. Teerlink, MD
Professor of Medicine, University of California, San Francisco
Director, Heart Failure Program San Francisco VA Medical Center
Director, Clinical Echocardiography San Francisco VA Medical Center
Importance of phenotyping
James L. Januzzi Jr., MD: One issue is the problem of phenotyping — understanding why patients developed derangement in renal function, for example. Some patients are terribly volume-overloaded and the reason for their cardiorenal syndrome is severe right heart congestion, and these patients need aggressive unloading. Other patients have severe cardiorenal disease and their renal dysfunction is entirely independent of their degree of congestion, and aggressive attempts at decongestion might actually worsen their renal function. Understanding the phenotype is critically important.
We presented data at the 2012 American Heart Association Scientific Sessions on circulating biomarkers of cardiac congestion and renal injury to more specifically phenotype patients likely to develop cardiorenal syndrome from congestion. We found that kidney injury markers, such as NGAL, identify renal dysfunction, but it is not specific to congestion. If you simply take a BNP value, adding it together with a NGAL result, you can in fact identify those patients most likely to benefit from aggressive decongestion, whereas a low BNP and high NGAL may identify a patient with advanced medical renal disease probably responding negatively to aggressive care. Ultimately, it is about understanding the phenotype that will help us decide on what therapies we might need.
Different approaches examined
Carl J. Pepine, MD: What I take away is that we do not have a strategy for approaching these hospitalized patients that optimizes all the tools we have, whether biomarkers, ultrafiltration or something else, to come out with a patient who is at very low risk for recurrence.
Bertram Pitt, MD: Economics are driving a new imperative. The 30-day hospital readmission rate that hospitals were being penalized for because of high readmission rates is already coming down. That is prompting several new strategies. Over the next few years, I anticipate intense interest in this area and many different approaches.
We are starting one approach with a new way of delivering diuretics. We have a new pump that will subcutaneously deliver furosemide. We plan to give 80 mg furosemide to high-risk patients when they start to tip over and see whether we can prevent them from needing readmission. We are talking about linking this to some of the monitoring systems, like implantable catheters, and trying to administer the furosemide before patients have severe pulmonary and peripheral congestion requiring hospitalization.
I am sure that many of us will be involved with efforts such as this in the future because of the unmet need and tremendous economic imperatives.
Pepine: What about vagus nerve stimulation?
Randall C. Starling, MD, MPH: We don’t know a lot about vagus nerve stimulation at the moment. In animal studies, it appears to have a lot of potential. The testing being done now is in the setting of chronic outpatient HF (Class III). In one clinical trial, we will look at about 600 patients who will be followed in an event-driven fashion to determine reductions in mortality and HF hospitalizations.
Data we have today suggest that vagal nerve stimulation is associated with beneficial remodeling. The heart gets smaller, the ejection fraction goes up. The trends are positive for all the biology, the biomarkers, anything that you want to measure. We will likely have to wait a number of years before there is evidence from that clinical trial. I see it fitting into the domain of chronic outpatient care and not most likely in the setting of acute HF therapies.
John R. Teerlink, MD: Another approach that has emerged in the acute setting is the development of new drugs to substitute for drugs that we think can cause harm. There is concern about adverse effects of dobutamine and milrinone in the acute clinical setting, for example. A range of new therapies along those lines, such as stresscopin, have been developed.
There is attention on omecamtiv mecarbil, a cardiac-myosin activator. This agent does not stimulate any extra signaling pathways in terms of increasing calcium or cyclic AMP. In preliminary studies, it has shown improvement in cardiac function without any other adverse events. It works by a mechanism of action that perhaps allows you to have a free lunch; it’s a unique aspect of our biology that the myosin head splits ATP and uses the energy without doing any work. It does that before it connects and does a power stroke on the actin fibers, so that if you use a medication such as omecamtiv mecarbil to increase that transition state, you can get more myosin heads doing the work that they’ve already spent the energy prepared to do. That is one of the theories why omecamtiv mecarbil seems to be able to do this as a relative free lunch. We will hopefully soon present the results of the 600-patient ATOMIC-AHF trial.
Pitt: New strategies aside, the application of old methods may be useful, too. Dr. Butler and I are involved with a trial organized by Alan Maisel, MD. We plan to study patients with acute HF and a high galectin 3 level and randomly assign them to an aldosterone-blocking strategy. I am also planning a study in patients who are currently contraindicated to receive an aldosterone blocker who have a glomerular filtration rate <30 to ≥15 mL/min/1.73 m2. We are proposing to give them a potassium-binding polymer simultaneously with an aldosterone blocker. We hope to reduce the risk for hyperkalemia and will analyze whether, in this very high-risk group, it is safe and feasible to apply this strategy.
There are many opportunities, but all have to be proven. We don’t want to change things unless we are really sure that it is safe and effective. That’s our challenge.
Starling: A suite of trials are under way within the US HF network. The common theme relates to the problem that about 25% of patients hospitalized for acute HF decompensation will have worsening renal function. Some strategies, including even lower-dose nesiritide than tested in the ASCEND-HF trial, are being tested. One example is the ongoing ROSE trial. That trial also has another arm, which will evaluate use of an old therapy of low-dose dopamine at 2 mcg/kg/min. We are probably two to three patients away from finishing enrollment and that information should be forthcoming within the next year.
Teerlink: We also have new therapies designed to improve renal function. Unfortunately, so far, they have not been successful. In the PROTECT trial, the adenosine A1 antagonist rolofylline did not show benefits. A new A1 antagonist is being studied and we will see where that leads.
My personal hope was with bardoxolone. It improved renal function in an early trial with diabetic nephropathy patients, but unfortunately the larger BEACON trial ended up showing multiple adverse events. This is another direction in terms of finding ways to protect the kidney or improve renal function and will be important.
Januzzi: The overall discussion in the HF world now is much more about personalizing care, focusing on the individual phenotype and, at least for cardiorenal syndrome, we have argued that rather than using the diagnosis of HF as an objective tool we should champion biomarkers. As Dr. Teerlink said, it could be NGAL or KIM-1 or NAG, all of this alphabet soup of kidney injury markers; it is very likely that’s how we will define it moving into the future.
Pepine: What is the current state of heart transplantation?
Starling: Transplantation is an exciting area that has been with us for more than 30 years. It is generally associated with good outcomes and excellent survival. The big problems we face are supply and demand. Supply of hearts for transplants in the United States has been the limiting factor, literally the same at 2,100 transplants per year for the last decade. There doesn’t seem to be any light at the end of the tunnel with respect to increasing access to donors.
There is an active area of investigation being utilized in the PROCEED study sponsored by TransMedics. The donor heart is taken and put in an organ perfusion system similar to the Langendorf. It is hoped that this clinical trial will show that longer ischemic times for donor heart preservation beyond 4 hours can be successfully transplanted.
Januzzi: How many more transplants can we possibly achieve with a better preservation strategy?
Starling: There is no specific answer. Only about 20% to 30% of donors that are identified by an organ procurement agency wind up having what is considered to be an acceptable heart. A big limitation is age, as well as many other factors. It is a flat supply with a demand that some estimate the pool of US patients that could benefit from transplantation — those with advanced HF — is conservatively 100,000. Less conservative estimates have been as high as 250,000 to 300,000. There have been no major changes in immunosuppression in the last decade. And lastly, coronary artery vasculopathy, which is certainly a significant problem, remains an area that we’ve made no major impact on. The great hope was that mTOR inhibitors like everolimus would have a major impact. A paper published in November in the American Journal on Transplantation showed that intimal thickness by IVUS in patients who receive everolimus (Afinitor, Zortress; Novartis) is attenuated. But we really haven’t seen this translate into 5- and 10-year results of a decrease in MACE and longer-term survival.
Transplantation is a great therapy for a small number of patients.
Pepine: What is going on in left ventricular assist device use?
Javed Butler, MD, MPH: For acute HF, we have learned that patients who come to the hospital in cardiogenic shock, in a dire situation, LVAD therapy is not very helpful in terms of outcomes. So we have moved back a bit to relatively more stable patients, perhaps on inotropes. The number of LVADs being placed continues to increase. The more exciting opportunity right now is whether we can move the paradigm even further upstream, and look at patients with advanced HF who are not necessarily inotrope-dependent but have advanced lifestyle-limiting symptoms. That’s what the REVIVE-IT trial will look at.
Pitt: REVIVE-IT is a NHLBI-sponsored trial looking to extend the indication to implant an LVAD in Class III without inotrope-dependence, and maybe eventually Class IIb. The real challenge is picking those who will need devices because we do not want to get into the situation we have with defibrillators. We have placed thousands of people on defibrillators and only a few will ever need them. Here, the risks and costs are much greater. We need to figure out how to find the right patients.
Januzzi: It will require a multidisciplinary approach. There won’t be one simple answer. No question, with some of the tools available, we can sort out those patients most likely to benefit from this approach. The real challenge is going to be whether we can identify what is low risk.
Pitt: This is a high-risk and high-cost strategy that we should at least provide some guidelines for prioritization. I don’t think we ever can say that a particular patient will never receive a device, but we hope to provide the clinician with a priority score which would allow selecting those patients at greatest risk earlier than those at lower risk. Once a procedure is “out of the box” and “on the market,” it is very hard to do. Now is the time to be working on this before it gets to that point.
Starling: We have a wonderful resource called the INTERMACS Registry, an effort funded by the NHLBI with collaboration from the FDA and CMS. We learned after 5 years of data collection that very sick patients have high mortalities if we put in durable LVADs. They need a sternotomy, which is a big operation. The field is evolving now toward shock teams, teams of interventional cardiologists, cardiac surgeons, HF specialists that can rapidly deploy extracorporeal membrane oxygenation (ECMO). There is ongoing work with percutaneous assist devices that can be inserted through the femoral artery, with or without a cut down, and deliver 3 L to 5 L of flow. There’s another device that can be inserted by a transseptal into the left atrium to generate flow via a centrifugal pump. It delivers about 3 L to 5 L of flow.
We are evolving toward this acute shock therapy, stabilizing those patients, figuring out what’s the best therapy for them, whereas durable LVADs are moving more toward a more stable advanced HF.
Spotlight on HF education, training
Pepine: In the last 2 years, we now have an advanced HF fellowship and certification and qualifications from the American Board of Internal Medicine (ABIM). This is the newest discipline that we have in cardiology. How do you think this will affect the field?
Januzzi: As the non-HF specialist at the round table, it is incredibly important to establish a culture around HF to lead. HF is a problem of every single physician in modern medicine, and general cardiologists, nurse practitioners, internists all have to understand HF because it is rising at such an epidemic rate that it will no longer be just the problem of the advanced HF-boarded physician. It is the role of such physicians to lead and educate first and foremost because there is no way that the outcomes of patients with HF are going to be improved by the relatively small number of advanced HF specialists in the United States.
Pepine: How many training programs do we have now that are certified for advanced HF?
Starling: We are in the midst of certifying training programs in HF. I do not know the exact number, but as of July 2012, programs started to be notified. I would guess there are less than 30 right now. There have been two cycles of the board exam administered through the ABIM. Currently, there are about 480 board-certified specialists in HF and cardiac transplant medicine in the United States.
My chief of cardiology when I was training, the late Dick Lewis, came to me one day and asked if the ACC should have a heart transplantation committee. I served on that committee as it was formulated when Sharon A. Hunt, MD, was the first chair. In the last 20 years, transplantation has become the small niche of what we do; the bigger niche is now mechanical support and HF therapies in general.
It is a very positive move that this specialty has been formed. Moving forward, I believe it will play a big role for advocacy, as well as care of the patient with advanced HF.
Prevention of readmissions
Pepine: Another issue is the Medicare concerns relative to readmissions, which clearly is a policy element here. Will that spurn the development of new strategies to prevent readmissions?
Pitt: It already has spurred new approaches, including post-discharge clinics. Recently, I have heard that there is already a decrease in readmissions for pneumonia and HF.
Januzzi: There has been increased use in short-stay units. If a patient re-presents, rather than being admitted to the hospital, the use of ED-based observation unit management has risen. I can’t recall in the last 20 years any issue that has led to so much froth or so many different strategies being looked at to improve care. It’s quite remarkable.
Butler: You have to be a bit circumspect. There are two sorts of outcomes. One is mortality and the second is quality of life. Hospitalization is somewhere in the middle. All these activities, which are primarily financially driven, can most certainly motivate a lot of action. If all we end up doing is to move care from the hospital setting to somewhere else without meaningfully impacting either mortality or quality of life, I’m not certain whether we have done a substantial good to the patients. You can change things at both ends, either before a patient is hospitalized by using observational units or after they are discharged by increasing use of hospice care or nursing homes. Either way, the main issues of improving survival and quality of life remain.
Teerlink: Dr. Butler makes a very good point. I work in the VA Medical Center. Within the VA system during the time period we saw a mild increase in rehospitalization rates that was associated with a commensurate decrease in mortality. I don’t think all readmissions are necessarily bad, and I’m a little concerned that this could lead to some unanticipated adverse effects.
Pitt: We have tried to limit the length of stay in the United States. After we performed the EPHESUS trial we looked carefully at mortality and morbidity in post-MI patients in Europe vs. North America using propensity matching. Mortality rates in Europe and North America were similar, but hospital readmission rates were lower in Europe in large part, I believe, because patients had a much longer hospital stay. In North America, particularly in the United States, the focus on short hospital stays has resulted in our paying less attention to comorbid conditions. Once the patients are discharged they just bounce right back. This is the law of unintended consequences.
Starling: We reported in a letter published in The New England Journal of Medicine a few years ago that hospitals with the lowest mortality rates were associated with high readmission rates. It was not definitive, but an observation. Karyn E. Joynt, MD, MPH, published a perspective on readmissions in NEJM in 2012. She cautioned about focusing on readmissions as a quality metric in the context that mortality rates are lower in centers with high readmission rates. There’s also a report out of Ontario that has shown that when they have intensive outpatient HF disease management they lower mortality, but guess what happens to their readmission rate? It goes up.
Januzzi: That is prudent application of good treatment. If you see that in an intensive program that your outpatient management is probably not working, it’s the logical step and it’s a calculated risk not to admit the patient.
Starling: We are all under the gun to reduce our readmission rates and lengths of stay, but we have to be mindful of how are we going to give the very best care to our patients.
The future of HF care
Pepine: Gentlemen, will you give our readers your take-home message on the future of HF care?
Pitt: There are tremendous opportunities for young people going into HF as a specialty, especially in the three major areas in which we haven’t made any progress: acute HF, diastolic HF and prevention of HF.
Teerlink: Within the acute HF area, we need agents to improve or protect renal function, as well as deal with volume issues. Second, we need vasodilators that can be readily used to improve outcomes. Third, we need agents to improve cardiac performance without causing adverse events.
Januzzi: Near-term and longer-term prospects include development of novel HF therapies, as well as novel strategies to deliver established therapies in a more targeted manner utilizing tools to better phenotype patients individually, rather than looking at every HF patient exactly the same way. The hope would be, as in oncology and other specialties using personalized approaches to attack difficult-to-treat disease processes, that a personalized approach would be more useful to improve outcomes of patients with risk for HF, both established HF and advanced end-stage HF.
Butler: I see the glass as more than half full, despite the fact that we had a decade full of negative trials in acute HF. We learned a lot from it, and I think we will do trials better in the future based on the lessons learned. We will better phenotype patients and match the right drug to the right patient. We can also expect a lot of investigations to better understand and treat HFpEF. We can look forward to a very exciting decade in front of us.
Starling: We are dealing with an epidemic of HF. I think we all agree that primary and secondary prevention is important, but there will be a lag time before we see the fruits of that labor. For the short term, education and training and building multidisciplinary teams at our medical centers that can take care of these patients is going to be important. There is great potential in connected care — the ability to develop virtual visits to monitor patients with new technology. And, critically important at all levels, is risk stratification, whether that involves placing patients in the hospital, discharging patients from the hospital or deploying advanced therapies.
Pepine: I thank all of you and am certain that our readers will find your stimulating comments on the HF dilemma useful.
View Part 1 of this Round Table here.
Disclosures: Butler reports consulting for Bayer, BH Medicine, Gambro, Medtronic, Novartis, Ono and Trevena. Januzzi reports receiving grant support from BG Medicine, Critical Diagnostics, Roche Diagnostics, Siemens, Singulex and Thermo-Fisher. Pepine reports no relevant financial disclosures. Pitt reports consulting for Amorcyte, AuraSense Therapeutics, Bayer, Mesoblast, Pfizer, Relypsa, scPharmaceuticals, Stealth Peptides and Takeda; serving on a data and safety monitoring board for Novartis (ATMOSPHERE); stock options for AuraSense, BG Medicine, Relypsa and scPharmaceuticals; serving on a clinical events committee for Juventis; and has a patent pending for site-specific delivery of eplerenone to the myocardium. Starling reports no relevant financial disclosures. Teerlink reports research grants/honoraria from Amgen, Corthera, Cytokinetics, Novartis, Servier and Trevena.