John McMurray MD FESC

John McMurray MD FESC John spoke with CardioPulse on the evolution of heart failure trials and the ones to watch in the coming years  For John McMurray, Professor of Cardiology at the University of Glasgow, UK, heart failure (HF) continues to be an amazing and rapidly advancing area of cardiology. A rich evidence-base and a range of proven drug and device therapies have brought about a remarkable improvement in prognosis for patients with one type of HF—HF with reduced ejection fraction (HFrEF)—over the past two decades. Currently, an unprecedented number of large-scale clinical trials with the potential to deliver game-changing findings are under way and are due to report keenly awaited findings in the next few years. Prior to the arrival of angiotensin-converting enzyme (ACE) inhibitors, a hospitalized HF patient was not expected to live much longer than a year. Continuing advances in developing effective treatment for HF means that it is now impossible to discuss typical rates of survival. The ‘typical’ no longer exists as the field is moving forward so quickly, with new and more effective treatments coming into play regularly. It is no longer unusual, McMurray says, to see patients surviving 10 years after their initial diagnosis. Much of this progress can be attributed to a small number of drugs that were rigorously tested in large-scale trials such as SOLVD-T, RALES, CIBIS-2, MERIT-HF, COPERNICUS, CHARM, EMPHASIS-HF, and PARADIGM-HF. These trials helped to rewrite the clinical guidelines on HFrEF and add some new therapeutic options to the physician’s armoury. But, McMurray says, this is not the end of the story. ‘At the moment, there are more phase III, large-scale morbidity/mortality, trials going on in HFrEF than ever before and they have an amazing array of different approaches. The longest running of these is COMMANDER-HF, which is looking at whether the non-vitamin K oral anticoagulant rivaroxaban might have a role in patients with HF who are in sinus-rhythm. Along with the trial sponsor, Faiez Zannad and colleagues very cleverly designed that trial to be a study of patients not only in sinus rhythm, but with a coronary aetiology for their HF and a recent hospitalization with worsening heart failure—to enrich for people at risk of coronary thrombosis and pulmonary venous thromboembolism’. The second of the new large-scale trials—VICTORIA—is investigating a treatment called vericiguat (a stimulator of the enzyme guanylate-cyclase). ‘There are some pilot data suggesting that vericiguat might reduce left ventricular wall stress which should be a good thing for the failing heart. It also stimulates the same pathway as the most recently proven treatment for HF, sacubitril/valsartan. The latter compound includes a neprilysin inhibitor, and neprilysin is an enzyme that breaks down natriuretic peptides secreted by the heart, the heart’s own protective mechanism. What do natriuretic peptides do? They bind to cell surface receptors and increase intracellular production of cyclic guanosine monophosphate (cGMP)—vericiguat is doing something similar in a different way’. The third trial that McMurray flags up is investigating the effects of a drug to improve systolic performance—omecamtiv mecarbil—which has been described as a selective cardiac myosin-stimulator. McMurray explains: ‘What it does, is to slightly prolong the duration of systole. In patients with HF, one of the characteristic findings is the shortened duration of systole, something that has been recognized for a very long time, perhaps for more than a century. Omecamtiv mecarbil slightly prolongs systole, without increasing myocardial oxygen consumption or intracellular calcium, so we believe it’s a drug that improves systolic performance without all the limitations of the classical inotropic treatments’. Evidence to support the role of the drug has emerged from early phase development work including a study called COSMIC-HF—a proof-of-concept trial that compared omecamtiv mecarbil to placebo. Omecamtiv mecarbil reduced left ventricular volumes, increased ejection fraction, increased stroke volume, reduced natriuretic peptides, and even reduced heart rate which most inotropes increase. A simple but important discovery—that between 30% and 40% of HF patients are iron-deficient—was made by a small team of investigators some time ago. That such a high proportion of patients were so affected seemed to have been hiding in plain sight. When investigators found that giving intravenous iron to these patients improved how they felt and whether they could perform certain tasks such as walking further, their findings were met with some initial scepticism. But the team carried out a second trial, confirming the findings of the first. Next steps are to find out if giving intravenous iron to HF patients might help people to actually live longer or reduce the risk of hospitalization. There are now four concurrent trials underway world-wide with over 6000 patients enrolled, looking at whether intravenous iron might reduce morbidity/mortality. Most intriguing of all the investigations underway now McMurray says, surrounds sodium-glucose co-transporter 2 (SGLT2) inhibitors—originally introduced to treat diabetes. ‘Why are we talking about treatments for blood glucose in patients with heart failure? Because a couple of years ago, for the first time ever, a drug used to treat diabetes was shown to reduce the risk of cardiovascular events’. Empagliflozin was the first of the SGLT2 inhibitors to be studied in a large randomized outcome trial and was found to substantially reduce the risks of cardiovascular death and HF hospitalization in patients with diabetes, most of whom did not have HF. There are various theories about how the drug achieved a large reduction in deaths and the simplest explanation, that it is due to the diuretic effect of these drugs, hasn’t wholly convinced McMurray. Two new trials with different SGLT2 inhibitors (dapagliflozin and empagliflozin) are already underway in patients with established HFrEF, including patients without diabetes. An additional trial with empagliflozin is being undertaken in patients with the other principal HF phenotype, HF with preserved ejection fraction (HFpEF). McMurray says this is very important because, unlike in HFrEF, no trial to date has shown benefit of any treatment in HFpEF. Another large study in patients with HFpEF is PARAGON HF, which is comparing sacubitril/valsartan to valsartan, is already fully recruited and is expected to report in the next 18–24 months. A particularly gratifying aspect of the current wave of big HF trials McMurray notes is that they are all enrolling participants so well. He suggests this reflects the enormous enthusiasm amongst the global HF community to help with trials and develop new treatments for patients. This global aspect of the trials now includes specialists from more than 50 countries. What these ongoing studies add up to, McMurray suggests, is a particularly innovative and intense phase of drug development in HF with potentially practice-changing results fast approaching. Most of the studies he has discussed will come to fruition over the next few years and if they deliver, 2019 onwards may see several game-changing years ahead. He says: ‘A recent analysis put together every HF trial ever published and showed that compared to 1987, which marked the first real evidence of the modern era, the reduction in mortality has been close to 70%—so it’s dramatic, even compared to cancer. I don’t think any area of medicine has seen anything more exceptional than that. When with the modern era of HF therapeutics started, HF had the worst possible prognosis of all the diseases and this has changed dramatically—and it has the potential to change dramatically again because there are now more ongoing, large-scale trials than at any other time and they cover a wide range of therapies. The year 2014 was considered to be a big year in HF with the results of PARADIGM-HF, but these current trials which are due to report over the next few years, will, if they are positive, change the guidelines and the way we treat HF again. So, it looks as if we might be taking some very big steps forward over the coming years and 2019 will be a year to watch’. Conflict of interest: none declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

John McMurray MD FESC

European Heart Journal , Volume Advance Article (20) – May 21, 2018

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
ISSN
0195-668X
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1522-9645
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10.1093/eurheartj/ehy203
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Abstract

John spoke with CardioPulse on the evolution of heart failure trials and the ones to watch in the coming years  For John McMurray, Professor of Cardiology at the University of Glasgow, UK, heart failure (HF) continues to be an amazing and rapidly advancing area of cardiology. A rich evidence-base and a range of proven drug and device therapies have brought about a remarkable improvement in prognosis for patients with one type of HF—HF with reduced ejection fraction (HFrEF)—over the past two decades. Currently, an unprecedented number of large-scale clinical trials with the potential to deliver game-changing findings are under way and are due to report keenly awaited findings in the next few years. Prior to the arrival of angiotensin-converting enzyme (ACE) inhibitors, a hospitalized HF patient was not expected to live much longer than a year. Continuing advances in developing effective treatment for HF means that it is now impossible to discuss typical rates of survival. The ‘typical’ no longer exists as the field is moving forward so quickly, with new and more effective treatments coming into play regularly. It is no longer unusual, McMurray says, to see patients surviving 10 years after their initial diagnosis. Much of this progress can be attributed to a small number of drugs that were rigorously tested in large-scale trials such as SOLVD-T, RALES, CIBIS-2, MERIT-HF, COPERNICUS, CHARM, EMPHASIS-HF, and PARADIGM-HF. These trials helped to rewrite the clinical guidelines on HFrEF and add some new therapeutic options to the physician’s armoury. But, McMurray says, this is not the end of the story. ‘At the moment, there are more phase III, large-scale morbidity/mortality, trials going on in HFrEF than ever before and they have an amazing array of different approaches. The longest running of these is COMMANDER-HF, which is looking at whether the non-vitamin K oral anticoagulant rivaroxaban might have a role in patients with HF who are in sinus-rhythm. Along with the trial sponsor, Faiez Zannad and colleagues very cleverly designed that trial to be a study of patients not only in sinus rhythm, but with a coronary aetiology for their HF and a recent hospitalization with worsening heart failure—to enrich for people at risk of coronary thrombosis and pulmonary venous thromboembolism’. The second of the new large-scale trials—VICTORIA—is investigating a treatment called vericiguat (a stimulator of the enzyme guanylate-cyclase). ‘There are some pilot data suggesting that vericiguat might reduce left ventricular wall stress which should be a good thing for the failing heart. It also stimulates the same pathway as the most recently proven treatment for HF, sacubitril/valsartan. The latter compound includes a neprilysin inhibitor, and neprilysin is an enzyme that breaks down natriuretic peptides secreted by the heart, the heart’s own protective mechanism. What do natriuretic peptides do? They bind to cell surface receptors and increase intracellular production of cyclic guanosine monophosphate (cGMP)—vericiguat is doing something similar in a different way’. The third trial that McMurray flags up is investigating the effects of a drug to improve systolic performance—omecamtiv mecarbil—which has been described as a selective cardiac myosin-stimulator. McMurray explains: ‘What it does, is to slightly prolong the duration of systole. In patients with HF, one of the characteristic findings is the shortened duration of systole, something that has been recognized for a very long time, perhaps for more than a century. Omecamtiv mecarbil slightly prolongs systole, without increasing myocardial oxygen consumption or intracellular calcium, so we believe it’s a drug that improves systolic performance without all the limitations of the classical inotropic treatments’. Evidence to support the role of the drug has emerged from early phase development work including a study called COSMIC-HF—a proof-of-concept trial that compared omecamtiv mecarbil to placebo. Omecamtiv mecarbil reduced left ventricular volumes, increased ejection fraction, increased stroke volume, reduced natriuretic peptides, and even reduced heart rate which most inotropes increase. A simple but important discovery—that between 30% and 40% of HF patients are iron-deficient—was made by a small team of investigators some time ago. That such a high proportion of patients were so affected seemed to have been hiding in plain sight. When investigators found that giving intravenous iron to these patients improved how they felt and whether they could perform certain tasks such as walking further, their findings were met with some initial scepticism. But the team carried out a second trial, confirming the findings of the first. Next steps are to find out if giving intravenous iron to HF patients might help people to actually live longer or reduce the risk of hospitalization. There are now four concurrent trials underway world-wide with over 6000 patients enrolled, looking at whether intravenous iron might reduce morbidity/mortality. Most intriguing of all the investigations underway now McMurray says, surrounds sodium-glucose co-transporter 2 (SGLT2) inhibitors—originally introduced to treat diabetes. ‘Why are we talking about treatments for blood glucose in patients with heart failure? Because a couple of years ago, for the first time ever, a drug used to treat diabetes was shown to reduce the risk of cardiovascular events’. Empagliflozin was the first of the SGLT2 inhibitors to be studied in a large randomized outcome trial and was found to substantially reduce the risks of cardiovascular death and HF hospitalization in patients with diabetes, most of whom did not have HF. There are various theories about how the drug achieved a large reduction in deaths and the simplest explanation, that it is due to the diuretic effect of these drugs, hasn’t wholly convinced McMurray. Two new trials with different SGLT2 inhibitors (dapagliflozin and empagliflozin) are already underway in patients with established HFrEF, including patients without diabetes. An additional trial with empagliflozin is being undertaken in patients with the other principal HF phenotype, HF with preserved ejection fraction (HFpEF). McMurray says this is very important because, unlike in HFrEF, no trial to date has shown benefit of any treatment in HFpEF. Another large study in patients with HFpEF is PARAGON HF, which is comparing sacubitril/valsartan to valsartan, is already fully recruited and is expected to report in the next 18–24 months. A particularly gratifying aspect of the current wave of big HF trials McMurray notes is that they are all enrolling participants so well. He suggests this reflects the enormous enthusiasm amongst the global HF community to help with trials and develop new treatments for patients. This global aspect of the trials now includes specialists from more than 50 countries. What these ongoing studies add up to, McMurray suggests, is a particularly innovative and intense phase of drug development in HF with potentially practice-changing results fast approaching. Most of the studies he has discussed will come to fruition over the next few years and if they deliver, 2019 onwards may see several game-changing years ahead. He says: ‘A recent analysis put together every HF trial ever published and showed that compared to 1987, which marked the first real evidence of the modern era, the reduction in mortality has been close to 70%—so it’s dramatic, even compared to cancer. I don’t think any area of medicine has seen anything more exceptional than that. When with the modern era of HF therapeutics started, HF had the worst possible prognosis of all the diseases and this has changed dramatically—and it has the potential to change dramatically again because there are now more ongoing, large-scale trials than at any other time and they cover a wide range of therapies. The year 2014 was considered to be a big year in HF with the results of PARADIGM-HF, but these current trials which are due to report over the next few years, will, if they are positive, change the guidelines and the way we treat HF again. So, it looks as if we might be taking some very big steps forward over the coming years and 2019 will be a year to watch’. Conflict of interest: none declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

European Heart JournalOxford University Press

Published: May 21, 2018

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