European Society of Cardiology Heart Failure (ESC-HF)

2019
May 25 - 28, 2019Athens, Greece

Rivaroxaban Cuts Stroke Risk in Sinus-Rhythm Heart Failure:

COMMANDER-HF
Steve Stiles

May 31, 2019

Patients in the COMMANDER-HF trial, who had heart failure with reduced ejection fraction (HFrEF) and were in sinus rhythm, showed a steep decline in risk for
neurologic events over 4 years after a direct oral anticoagulant (DOAC) was added to their standard meds, compared with similar patients who had no DOAC added.

The trial's post hoc analysis suggests that low-dose rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) protects against some strokes or transient ischemic
attacks (TIA) in such patients without posing an untoward bleeding risk.

But also, researchers say, it supports a role for the CHA2DS2VASc stroke risk prediction tool outside its more familiar realm of atrial fibrillation (AF).

The risk for stroke or TIA fell a significant 31% in patients taking rivaroxaban 2.5 mg twice daily on top of background antiplatelet therapy without an associated jump
in risk for major bleeding, although minor bleeds were more common than in the control group.

A CHA2DS2VASc score greater than 4 was seen to "identify and capture nearly half of stroke events, and use of rivaroxaban appreciably reduced the number needed
to treat to less than 100 per year in this high-risk subset," said Muthiah Vaduganathan, MD, MPH, Brigham and Women's Hospital, Boston.

This points to a need for further studies to determine "whether select populations with heart failure and reduced ejection fraction in sinus rhythm perhaps can be
identified by use of traditional risk scores such as the CHA2DS2VASc score," he concluded in his presentation of the analysis here at European Society of Cardiology
Heart Failure 2019.

The previously reported COMMANDER-HF had in its primary analysis failed to show an advantage for rivaroxaban for the end point of death, myocardial
infarction (MI), or stroke, so cautions are in order in interpreting the post hoc analysis of the negative trial.

But stroke or TIA was at least a component of the primary end point, and the findings are largely consistent with other studies of antithrombotic therapy in heart
failure, so "we believe it's a true signal," Vaduganathan told theheart.org | Medscape Cardiology.

COMMANDER HF had randomly assigned 5022 patients with recent exacerbation of chronic HFrEF and coronary artery disease but no AF to the low-dose
rivaroxaban regimen or placebo.

In addition to the neutral clinical-event outcome, the principal safety end point of fatal bleeding or bleeding into a critical space was not significantly different between
the groups. Nor was the risk for major bleeding by International Society of Thrombosis and Hemostasis (ISTH) criteria.

But in an exploratory analysis, rivaroxaban had been associated with a significant 34% decline in risk for stroke or TIA.

Patients like those in the study face a risk for stroke or TIA approaching that seen in heart-failure patients with AF," Vaduganathan observed when presenting the
analysis. And in COMMANDER-HF, "nearly half of first primary neurological events were either disabling or fatal."

The cumulative risk for stroke was close to 2% at 1 year, but it rose early, plateaued at about 6 months, and stayed elevated.

Because the DOACs are not approved for patients in sinus rhythm with HFrEF, in practice such patients would be treated if an approved indication, such as AF, is
identified on further workup, Mandeep R. Mehra, MD, Brigham and Woman's Hospital in Boston, told theheart.org | Medscape Cardiology.

"What we don't know is the rate of intermittent, paroxysmal, or silent atrial fib in these patients," said Mehra, who is senior author on the analysis. "You know,
technologies like the Apple Watch might actually yield some benefit in heart failure patients if they show atrial fib, if you apply them in a high-risk population."

On the other hand, "we don't understand why patients with heart failure have strokes," observed John J.V. McMurray, MB, MD, University of Glasgow, United
Kingdom, as discussant after the analysis was presented.

Strokes in patients with HF were once thought to be primarily caused by thromboembolism originating in a low-ejection-fraction left ventricle, but more recently it's
been appreciated that ejection fraction and stroke risk are not closely associated, he noted.

"Maybe we should be thinking about that, and be trying hard to detect atrial fibrillation," because that's already a target for oral anticoagulation, McMurray agreed.

Earlier studies of oral anticoagulation in sinus-rhythm heart failure, he pointed out, have not shown a good balance of risk and benefit. That's largely because in such
patients "the risk of stroke is usually relatively low and the risk of bleeding is significant, at least with conventional anticoagulants given at the conventional dose."

He proposed a few explanations for why the risk–benefit equation in COMMANDER-HF was more favorable than in earlier trials. For example, their fairly high rate of
stroke over the follow-up suggests that the study population was at higher risk than in some trials.

Or it may be that the study's safety end-point definition for bleeding — that is fatal bleeding or bleeding into a critical space — was less expansive than the "major
bleeding" end point used in most past trials, McMurray said.

"But I do agree with the COMMANDER-HF investigators in that we all need to think of better ways to identify high-risk patients, and target this treatment to those
patients." Maybe CHA2DS2VASc risk stratification would be effective, or another risk tool, "but that's where we need to go."

In the post hoc analysis, the 31% drop in risk for stroke or TIA over a mean of 21 months was driven by the reduction in ischemic strokes, which made up the
overwhelming majority of events.
Hazard Ratio (HR) for Neurologic End Points, Rivaroxaban vs Placebo, in COMMANDER-HF
End Point HR (95% CI)
Any stroke or TIA 0.69 (0.50–0.95)
Ischemic stroke 0.64 (0.43–0.95)
Hemorrhagic stroke 0.74 (0.25–2.13)
TIA 0.77 (0.34–1.75)

That worked out to a number needed to treat of 164 to prevent 1 stroke or TIA. It fell to less than 100 for patients with a baseline CHA2DS2VASc score greater than 4.

Stroke or TIA Incidence per 100 Patient-Years by CHA2DS2VASc Stratum

End Point Placebo, Rate Rivaroxaban, Rate NNT
Overall 1.9 1.29 164
CHA2DS2VASc ≤4 1.44 1.13 316
CHA2DS2VASc >4 2.56 1.52 96
NNT=number needed to treat to prevent one end point.

Indeed, the HR for stroke or TIA for every CHA2DS2VASc point increase was 1.29 (95% CI, 1.13 - 1.48; P < .001), with history of stroke among the strongest
predictors at HR 2.35 (95% CI, 1.39 - 3.98; P = .002).

"I think the really critical finding in this is that these scores like CHA 2DS2VASc had the exact same performance quality as in atrial fib," Mehra said.

"So in other words, these scores are not just the domain of atrial fib, they're the domain of vascular disease and heart failure, and I think you can apply them more
broadly."

COMMANDER HF was funded by Janssen. Vaduganathan discloses serving on advisory boards for Amgen, AstraZeneca, Bayer, and Baxter Healthcare; and on a
clinical end-point committee for Novartis. Mehra has previously disclosed being a consultant for Abbott, Portola, Bayer, and Xogenex; a trial steering committee
member for Medtronic and Janssen; a scientific advisory board member for NuPulseCV and FineHeart; and a data safety monitoring board member for Mesoblast;
and receiving travel support from Abbott. McMurray has previously disclosed his institution paid for his participation in clinical trial committees by AbbVie,
AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, Dalcor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Stealth, and Theracos; that these sponsors funded some
costs to attend meetings; and it paid for attendance by Novartis and Sanofi-Aventis advisory boards.

European Society of Cardiology Heart Failure (ESC-HF) 2019: Abstract 648. Presented May 26, 2019.

Could a Biomarker Take Aortic Valve Replacement to the New Aortic

Stenosis Frontier?
Steve Stiles

May 29, 2019

Patients with asymptomatic severe aortic valve stenosis should probably be referred early for aortic valve replacement (AVR), especially if they have elevated
natriuretic peptides, concluded researchers after a retrospective analysis of a 14-year single-center experience.

Patients at the center who were advised against AVR because they lacked symptoms, and so were managed conservatively, showed significantly worse survival over
the next few years than those who went on to AVR surgery.

In a multivariate analysis, advanced age and elevated baseline levels of N-terminal B-type natriuretic peptide (NT-proBNP), a biomarker that reflects myocardial
stretch, were significant predictors of death from any cause among those who didn't get the surgery.

The analysis adds to active ongoing research to determine AVR suitability in asymptomatic severe aortic stenosis, one of the valve field's big frontiers now that
transcatheter AVR (TAVR) has broadened its purview to cover symptomatic patients with aortic stenosis at all levels of operative risk.

Anette Borger Kvaslerud

It also suggests that elevated NT-proBNP levels could potentially be used to select patients with asymptomatic severe aortic stenosis at especially high risk for death
who might therefore benefit most from TAVR or surgical AVR, Anette Borger Kvaslerud, PhD, Oslo University Hospital Ullevål, Norway, told theheart.org | Medscape
Cardiology.

Mortality was significantly elevated at NT-proBNP levels higher than 126 pmol/L in the asymptomatic patients compared with those who received AVR, she noted.

Although such a retrospective analysis can only be hypothesis-generating, it suggests that when the natriuretic peptide is higher than that fairly low cut point, "maybe
one should think more about early intervention in those patients," said Kvaslerud, who had presented the analysis here at European Society of Cardiology Heart
Failure 2019.

Indeed, of the 114 asymptomatic patients in the analysis, who represented less than 5% of those with severe aortic stenosis evaluated at the center, 18 later
developed symptoms but were by then considered too fragile or sick to undergo surgery, Kvaslerud said.

Of note, TAVR was primarily a dream for the future, and surgical AVR the only option, during most of the years covered by the analysis.

This and other observational studies suggest that watchful waiting just isn't good enough for most patients with asymptomatic severe aortic stenosis, agreed Chiara
Bucciarelli-Ducci, MBBS, MD, PhD, University of Bristol, United Kingdom, who wasn't involved with the current study.
Whether a patient with even severe aortic stenosis gets any kind of AVR generally hinges on whether they have symptoms, she told theheart.org | Medscape
Cardiology. But when asymptomatic patients do worse without AVR, "it means there are things going on with them that we don't capture with symptoms only; hence,
the need for better biomarkers, whether in the blood or by imaging, to intervene early before they develop symptoms."

The 114 patients with asymptomatic severe aortic stenosis who didn't get surgery were compared with 100 age- and sex-matched patients in the larger cohort with
severe aortic stenosis who went on to AVR. The groups were similar with respect to mean age, body mass index, NT-proBNP level, and prevalence of coronary
disease and diabetes.

Survival Rates for Patients With Severe Aortic Stenosis: Asymptomatic Patients Without AVR vs Those Referred for AVR
End Point Asymptomatic, No AVR (n = 114), % Referred for AVR (n = 100), % P Value
1 year 88 92 .44
2 years 75 83 .19
3 years 63 78 .02

Survival curves for the asymptomatic, nonsurgical patients and those referred for AVR diverged early and continued to separate throughout the mean follow-up to
show a highly significant survival advantage for the AVR group by 4 years ( < .001).

Both age and NT-proBNP levels, but not peak aortic velocity, emerged as significant mortality predictors in the asymptomatic, non-AVR group.

Hazard Ratio (HR) for Predictors of Death From Any Cause in 114 Patients With Asymptomatic Severe Aortic Stenosis, Multivariate Analysis
End Point HR (95% CI) P Value
Age (per 1-y increase) 1.10 (1.02–1.19) .016
Systolic blood pressure 0.98 (0.97–1.00) .087
(per 1 mm Hg increase)
Peak aortic velocity (per m/s) 1.07 (0.62–1.85) .80
NT-proBNP (log pmol/L) 3.51 (1.40–8.83) .008

Bucciarelli-Ducci pointed to several ongoing randomized trials comparing conservative management with AVR in asymptomatic patients with severe aortic stenosis,
and some of them are looking at biomarkers or other signals that might risk-stratify them.

For example, the Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe Aortic Stenosis (EVOLVED) study,
with an estimated 1000 patients, is exploring whether myocardial fibrosis near the aortic valve by cardiac magnetic resonance (CMR) imaging can serve as a risk
predictor.

It's unknown whether such fibrosis precedes or follows the natriuretic peptide responses to aortic valve disease, "that's why the research is ongoing to understand the
best early predictor," Bucciarelli-Ducci said.

Other trials underway in this population include Early Surgery for Patients With Asymptomatic Aortic Stenosis (ESTIMATE), with an estimated 360 patients; Evaluation
of Transcatheter Aortic Valve Replacement Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis (EARLY TAVR), with 1109 patients; and
Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis (AVATAR), with an estimated 312 patients.

Kvaslerud reports no conflicts. Bucciarelli-Ducci has previously disclosed being a consultant for Circle Cardiovascular Imaging.

European Society of Cardiology Heart Failure (ESC-HF) 2019: Abstract 833. Presented May 25, 2019.

Less Is More: Loop Diuretic Withdrawal May Be Safe in Selected Heart

Failure Outpatients
Steve Stiles

May 28, 2019

Selected patients with heart failure who are doing well on optimal guideline-directed medical therapy, including furosemide, may be safely taken off loop diuretics
without raising their risk for dyspnea, decompensation, or other ill effects, suggests a randomized study.

Importantly, the study entered patients with a history of hospitalization for acute HF who were consistently stable on good medical therapy. In fact, about 60% of the
188 patients were in NYHA functional class 1 when they were randomly assigned to either go off or continue their maintenance doses of furosemide.

"This was a very low-risk group. They had no recent admissions and were optimized on drugs, and they tended to be younger than we see in some trials of
decompensated heart failure," said Andréia Biolo, MD, ScD, Hospital de Clinicas de Porto Alegre, Brazil. The mean age for patients in both groups was 59 years.

That means their prognosis was "fairly favorable" and their prospects for living many more years were quite good. Such patients would likely welcome the opportunity
to take one fewer medication among the many generally prescribed in heart failure, she told theheart.org | Medscape Cardiology after presenting the first Brazilian
Research Network in Heart Failure (ReBIC-1) study here at European Society of Cardiology Heart Failure 2019.

There are also good clinical reasons why furosemide withdrawal, when safely possible, may be a prudent idea, Biolo observed. Intensive loop diuretic therapy can
cause neurohormonal activation and compromise renal function, among other potential adverse effects, and possible long-term risks of lower maintenance doses
aren't well understood.

The current study asked whether it is safe to withdraw loop diuretics in low-risk stable patients with heart failure, "and we know safety trials, to be definitive, actually
require a very large sample size," noted G. Michael Felker, MD, MHS, Duke University, Durham, North Carolina, as invited discussant after the ReBIC-1 presentation.

"I think smaller trials can give a clue and a suggestion that a treatment or process of care might be safe, but I don't think they're able to provide definitive evidence of
safety."

However, for lower-risk stable, medically well-managed patients like those in the study, "I think these data definitely support the concept of a trial of furosemide
withdrawal as part of an overall strategy of optimizing care," he said.
"Most of what we do in heart failure care is to focus on increasing intensity of treatment," Felker noted. "But when we think about optimization, it doesn't always mean
increasing doses. It means having people on the right regimen. For drugs like diuretics that are focused on symptomatic management of congestion, maybe the
correct dose is a lower dose."

It may be relatively few patients with a history of HF decompensation that the current findings apply to, cautioned Martin Schulz, PhD, professor of pharmacy, Freie
Universität Berlin, who wasn't involved in ReBIC-1.

The trial's inclusion and exclusion criteria produced a population that was well treated, with literally everyone on beta blockers and 90% on ACE inhibitors or
angiotensin receptor blockers, and with strikingly high usage of other guideline-based medications, he told theheart.org | Medscape Cardiology.

That in itself suggests the population was unusual, given the typically high rates of undertreatment and noncompliance in such patients.

Clinical trial populations, he noted, often don't well represent broad clinical practice. "Probably in the real world, they would be higher risk" and wouldn't respond as
well to furosemide withdrawal.

Biolo said in an interview that probably fewer than half of patients with a history of heart-failure hospitalization resemble those in ReBIC-1.

The trial entered patients in NYHA class 1 or 2 with a left ventricular ejection fraction (LVEF) ≤45% who had been stable on optimal medical therapy, including
furosemide at 40 to 80 mg/d, for at least 6 months.

It excluded patients with severe valvular, renal, pulmonary, or liver disease; and those with acute coronary syndromes, stroke, or coronary revascularization in the
previous 3 months.

The 95 assigned to furosemide withdrawal and 93 to maintenance furosemide were similar with respect to LVEF, which averaged 32% for both groups, and in
distribution of NYHA class; three-fourths of both groups were male.

There were no differences between the groups in dyspnea symptoms, self-assessed using a visual analog scale (P = .50), one of the two primary end points,
throughout the 90-day follow-up.

Nor was there a significant difference (P = .16) in re-initiation or intensification of furosemide, the other primary end point, which was decided by clinicians blinded to
patients' assigned group in accordance with predefined criteria. They included worsening symptoms or NYHA functional class and a weight gain of more than 2 kg.

A blinded adjudication committee decided whether any furosemide change qualified as a primary end point, which was defined as any temporary IV loop diuretic
administration or any oral loop diuretic given for more than 4 days.

There were five hospitalizations in the withdrawal group and three in the maintenance group (5.3% and 3.2%, respectively), no deaths in the withdrawal group, and
two deaths in the maintenance group. None of the differences came close to significance in the study that, at any rate, was underpowered for clinical outcomes.

Nor were there significant 90-day differences in change in natriuretic peptide levels, 6-minute walk distance, or body weight.

Biolo proposed that a side benefit of furosemide withdrawal for patients, in addition to a less daunting pill regimen and less discomfort from the drug's effects, may be
improved tolerance, allowing greater optimization, of renin-angiotensin-system-inhibiting agents, "the life-saving drugs that they must use."

Biolo and Schulz had no disclosures. Felker has previously disclosed receiving research grants from Johnson & Johnson, Roche Diagnostics, Critical Diagnostics,
and BG Medicine.

European Society of Cardiology Heart Failure (ESC-HF) 2019: Abstract 646. Presented May 26, 2019.

Ultrasound 'Lung Comets' Reveal Subclinical Congestion, Hint at

Treatment-Target Value in HF Outpatients
Steve Stiles

May 27, 2019

ATHENS, Greece — A small but groundbreaking randomized trial has strengthened the case for lung ultrasound (LUS) examinations, which can show likely
subclinical pulmonary congestion, in outpatients with heart failure (HF).

The blinking appearance of "B lines" on LUS images, an artifact caused by echo differences between tissue and accumulated fluid, is a confirmed diagnostic and
prognostic indicator of congestion. More B lines, also called ultrasound lung comets for the way they streak across the scan from the pleural line, mean more fluid.

The current study suggests the lines could potentially serve as a target for managing volume-depletion therapy, in that adding diuretics in response to them might
improve clinical outcomes.

There was a marginally significant 48% decline in 6-month risk for a clinical composite primary endpoint, driven by a more highly significant 75% drop in urgent clinic
visits for worsening HF in recently discharged patients whose outpatient diuretic therapy was guided by B lines on LUS.

Scans were obtained using highly portable, pocket-sized systems in all patients, and clinicians who used their findings to adjust diuretics in those assigned to guided
therapy didn't follow a defined treatment protocol.

Because of that, the patient population numbering only about 120 from one center, the marginal primary outcome, and other reasons, the study dubbed LUS-HF is
more food for thought than an endorsement of LUS-guided HF therapy.

"We propose lung ultrasound as a tool to complement clinical examination and to detect subclinical congestion," said Mercedes Rivas-Lasarte, MD, Hospital de la
Santa Creu i Sant Pau, Barcelona, Spain, during the presentation of LUS-HF here at European Society of Cardiology Heart Failure (ESC-HF) 2019.

"The lung-ultrasound guided strategy was safe and reduced the number of decompensations," Lasarte said. "We think that lung ultrasound is a rapid, easy,
inexpensive, and broadly available tool that may be recommended in heart failure follow-up to improve outcomes."

However, regarding the use of B lines on LUS to guide diuretic therapy, Lasarte added, "We have to take our study as a proof of concept, and we think that
multicenter studies are needed to confirm our results and to test harder endpoints."

Even though there was no treatment protocol in the study, how clinicians managed diuretics for the patients was a good reflection of real-world practice, said Peter S.
Pang, MD, Indiana University, Indianapolis, an emergency physician and early adopter of LUS in patients with HF.
The trial's primary endpoint, which included mortality and urgent clinic visit or rehospitalization for worsening HF, may have been significantly reduced in the LUS-
guided group, "but I think we need to be careful how we interpret the positive trial because it was driven only by urgent heart-failure visits," Pang, who was not
involved in LUS-HF, told theheart.org | Medscape Cardiology.

Still, that can be important. "I think it's fair to say that many patients don't want to come back to the doctor to say they feel worse. So perhaps by using lung ultrasound
as a measure of congestion, we can make patients feel better."

Lung ultrasound is safe and it sharpens diagnosis and prognostic evaluations, "so adding it to the bedside examination is strongly encouraged," Pang said.

As for whether resolution or improvement of B lines on serial lung scans after diuretic intensification predicts improved clinical outcomes, "the jury is still out."

The reported number needed to treat with LUS-guided therapy to avoid one primary endpoint was a mere five patients, Pang had pointed out earlier as the invited
discussant following Lasarte's presentation.

That indicates an absolute risk reduction of 20%, "an impressive finding, in fact so impressive that we should be cautious. It is unlikely such an effect size would be
observed in other populations or in larger studies," he said.

"The good thing about this technology is that it's very easy to do. It's noninvasive, and once you have the ultrasound in your hand, there's no additional cost to it,"
Mandeep R. Mehra, MD, Brigham and Woman's Hospital, Boston, who is not connected to LUS-HF, observed for theheart.org | Medscape Cardiology.

Although he is cautious about the magnitude of its significance, "this study is at least a step in the right direction. But it's small study, and its confounding by detection
of a problem is not to be ignored," he said. That is, because all the patients received LUS, clinicians treating those in the control group could potentially have become
aware of and been influenced by the ultrasound findings.

"I always look at these kinds of data with some degree of skepticism."

The LUS-HF design specified that only clinicians who treated patients in the guided-therapy group would have access to the ultrasound results. Treating physicians
could take their lead from the scans on any treatment adjustments.

Indeed, they "were strongly directed to change treatment in relation to number of B lines," Lasarte said when presenting LUS-HF.

The trial included 124 patients recently discharged from hospitalization with a primary diagnosis of acute HF. They were required to have had dyspnea and X-ray
evidence of pulmonary congestion, high age-adjusted natriuretic peptide levels, but no severe lung diseases.

They were randomized single-blind prior to discharge to receive standard care with guidance from LUS in 61 patients and without LUS guidance in 63 patients. The
groups were similar at baseline with respect to mean left-ventricular ejection fraction, natriuretic peptide levels, cardiovascular and pulmonary comorbidities, 6-minute
walk distance, and number of B lines on LUS.

Natriuretic peptides were measured and LUS performed thereafter at 2 weeks, 1 month, 3 months, and 6 months.

Six-month rates for death or urgent clinic visits or rehospitalization for worsening HF were 23% in the LUS-guided group and 40% in the control group, for a hazard
ratio (HR) of 0.52 (95% CI, 0.27 - 0.99; P = .046).

There were no significant differences in natriuretic peptide levels, measures of quality of life, or the individual components of the primary endpoint except for urgent
visits for worsening HF, a prespecified secondary endpoint.

Six-Month Secondary Endpoint Outcomes, LUS-HF

Endpoints LUS Guidance, Non-LUS Guidance, n = 63 P

n = 61
Urgent visits for worsening heart failure, % 5 21 .008
Change in 6-minute walk distance, m +60 +37 .023
Proportion receiving loop diuretics, % 91 75 .023

Other potential applications for LUS using hand-held ultrasound systems in the chronic HF setting, Pang said, include use in a broader population to monitor for signs
of impending decompensation, in the hope that early therapy can avoid hospitalization. "The promise for that is great," he said.

"It's not going to replace things like history or physical exam, but maybe it's another thing to add that helps us better decide how to treat patients. That's what I think it
adds more than anything else."

Lasarte has reported no relevant financial relationships. Pang has previously disclosed consulting for Baxter, Bristol-Myers Squibb, and Novartis; and receiving
support from Bristol-Myers Squibb, Roche, Novartis, Ortho Diagnostics, and Abbott. Mehra has previously disclosed being a consultant for Abbott, Portola, Bayer, and
Xogenex; a trial steering committee member for Medtronic and Janssen; a scientific advisory board member for NuPulseCV and FineHeart; and a data safety
monitoring board member for Mesoblast; and receiving travel support from Abbott.

ESC-HF 2019. Presented May 25, 2019. Late breaking trial I, Abstract 25.

TARGET: Could a 'Controlled Diuresis' Device Avoid Pitfalls of Diuretics

in Acute HF?
Steve Stiles

May 27, 2019

ATHENS — A bedside device that both measures urine output and delivers saline to maintain a preset degree of volume reduction from loop diuretics could
potentially take some of the worry out of aggressive diuresis when treating patients for acute heart failure (HF) decompensation, a small early experience suggests.
In the single-arm TARGET trial, actually two sequential studies, the automatic fluid-management system was able to maintain net fluid loss at a programmed level
after furosemide infusion, for example 200 mL/h, without compromising hemodynamics or renal function in 19 patients with acute HF and preexisting chronic kidney
failure.

Sometimes such patients are "underdiuresed" as clinicians try to avoid excessive dosing of loop diuretics, which may deplete intravascular fluid volume so rapidly that
it triggers defensive hormonal responses that preserve sodium and water, so-called diuretic resistance.

But underdiuresis, which is increasingly thought to worsen clinical outcomes in acute HF, may be at least as bad for the patient as overdiuresis, Piotr Ponikowski, MD,
PhD, Medical University, Wroclaw, Poland, one of the study's authors, told theheart.org | Medscape Cardiology.

The TARGET study, he said, suggests that a strategy of controlled diuresis — saline infusion programmed to compensate for any excess volume depletion — allows
forceful diuresis and removal of "a huge volume of urine" without provoking diuretic resistance or worsening renal function. "And at least in our small study, it is safe."

The controlled-diuresis device, which was called RenalGuard when it was originally explored, mostly unsuccessfully, for prevention of contrast-induced nephropathy,
now answers to the name of Reprieve (Reprieve Cardiovascular).

Ponikowski presented the TARGET study here at European Society of Cardiology Heart Failure (ESC-HF) 2019 concurrent with its online release May 25 in
the European Journal of Heart Failure. It follows a promising but even smaller experience reported at last year's ESC-HF sessions.

Both Ponikowski and the invited discussant, Andrew J. Coats, MD, DSc, MBA, University of Warwick, Coventry, United Kingdom, cautioned that the Reprieve
experience in so few patients can't be conclusive. But it is ready, they said, to move forward in much larger trials.

"It's fascinating to look back as we approach 100 years of diuretic use that we really don't know the fundamentals of how best to use them," Coats said. For years,
clinicians have hesitated to be aggressive with loop diuretics out of fear of causing diuretic resistance and damaging the kidneys. But the Reprieve system could
potentially "enable greater care and confidence that we can push the diuretics and not overdiurese in terms of volume depletion." But "clearly that's many trials away,"
Coats added.

"I do think that diuresis that is targeted to the plasma refill rate is an important concept," Mandeep R. Mehra, MD, director of the Heart and Vascular Center at Brigham
and Woman's Hospital in Boston, Massachusetts, told theheart.org | Medscape Cardiology. "If you take out too much fluid, and the plasma refill rate from the
interstitial tissues is not keeping pace, that's when you cause renal failure and renal dysfunction."

The current experience suggests the Reprieve system may partially alleviate such concerns and is ready to be explored further in clinical trials, agreed Mehra, who
was not associated with TARGET.

"The most promising thing in the data was the preservation of renal function while achieving that diuresis. So I find it very interesting and very intriguing," he said. But
he wonders whether the apparent success in TARGET could be replicated more broadly in clinical practice, especially given the complexity of setting up patients with
the device —for example, they are connected to it by both an IV line and a Foley catheter.

"The device appears to me to be fairly cumbersome, so I don't know how useful it would be from patient to patient, and the scalability," he said.

TARGET entered 19 patients hospitalized with a primary diagnosis of acute HF and showing clinical congestion despite standard background meds. They were
required to have a systolic blood pressure of at least 100 mm Hg, an estimated glomerular filtration rate (eGFR) from 25 to <90 mL/min/1.73 m2, and elevated
natriuretic peptides.

The group included patients with both reduced and preserved ejection fractions, and with HF of either ischemic or nonischemic origin.

Performance of the system over at least 24 hours was compared to conventional diuretic management in the preceding and subsequent 24-hour periods, with the
patients serving as their own controls.

Using the Reprieve system, each of the first 10 patients (TARGET-1 cohort) received 40 mg furosemide as an IV bolus followed by 1 hour of fluid replacement
matched to urine output; the device was then set for a negative fluid balance of 100 mL/hour.

The second (TARGET-2) cohort of 9 patients received furosemide at the same dosage, and only after excretion of >200 mL of volume within 4 hours was the
Reprieve device engaged, set at a net fluid output of 200 mL/h.

In both cases, ongoing furosemide dosages were adjusted by clinicians to maintain the target net negative fluid balance, Ponikowski reported. There was no
consistent protocol, but usually it was given at 10 mg/h.

Table. Diuretic Use and Fluid Balance in the TARGET-2 Cohort Before, During, and After Reprieve Controlled Diuresis

During 24 During 24 P value P value

During
Parameter Hours Pre- Hours Post- (Reprieve vs (Reprieve vs
Reprieve
Reprieve Reprieve Pre) Post)
Urine
2078 7867 2533 < .001 < .001
Excretion (mL)
Net Fluid
1944 3748 2494 < .01 .06
Loss (mL)*
Total

Furosemide 76 262 80 < .001 < .001

Dosage (mg)

*Urine output minus added saline infusion

In both cohorts, the level of diuresis achieved during the middle period of Reprieve use was significantly greater than in either the preceding or subsequent 24-hour
periods.

In the TARGET-1 cohort, use of the Reprieve system did not lead to greater dosing of furosemide compared to the periods before and after Reprieve.

But in the TARGET-2 cohort that received an initial furosemide challenge, significantly more furosemide was given during the Reprieve period than either period
before or after use of the device.
There was evidence of a renoprotective effect from controlled diuresis. Markers of renal function improved significantly in the combined TARGET-1 and TARGET-2
cohorts throughout the middle Reprieve period.

Table. Biomarkers of Renal Function and Injury at Baseline, 12 Hours, and Conclusion of Reprieve Therapy, Combined TARGET-1 and TARGET-2 Cohorts

Parameter Baseline 12 h End of Reprieve P value

Serum Creatinine
1.45 1.31 1.26 .0002
(mg/dL)
Serum BUN (mg/dL) 33 31 30 .001
Plasma Cystatin C
1.6 1.5 1.4 .02
(mg/dL)

BUN=blood urea nitrogen

In the TARGET-2 cohort, urinary sodium excretion went up slightly but nonsignificantly from a mean concentration of 91 mmol/L at baseline to 105 mmol/L at 6 hours
(P = .15), where it plateaued for the remainder of the Reprieve period. Median sodium excretion throughout the Reprieve treatment period was 9.7 mmol/h.

Symptom status, jugular venous pressure, central venous pressure, and markers of pulmonary congestion all improved significantly throughout the Reprieve period in
the combined TARGET-1 and 2 cohorts. Levels of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) did not change significantly during the same period.

Serum potassium decreased significantly in the combined cohorts during the Reprieve period, from an average of 4.1 mmol/L at baseline to 3.6 mmol/L at the end.

TARGET was sponsored by Reprieve Cardiovascular, from which Ponikowski discloses receiving consultancy fees and honoraria for speaking. Mehra has previously
disclosed being a consultant for Abbott, Portola, Bayer, and Xogenex; a trial steering committee member for Medtronic and Janssen; a scientific advisory board
member for NupulseCV and FineHeart; and a data safety monitoring board member for Mesoblast; and receiving travel support from Abbott.

European Society of Cardiology Heart Failure (ESC-HF) 2019. Late breaking trial I, Abstract 22. Presented May 25, 2019.

European Journal of Heart Failure. Published online May 25, 2019. Abstract