WHY MAJORITY OF HFpEF RANDOMIZED CONTROLLED TRIALS FAIL?

PART - I

In a large population, same size doesn’t fit all,

A size that fits everyone has to be the tailored size.

Abstract:

Today Heart Failure with Preserved Ejection Fraction (HFpEF) remains the one of
toughest gordian knots in cardiovascular medicine with no visible effective and
acceptable therapies. Owing to the complexity, urgency and gravity of the problem of
HFpEF, the present article has been divided into two parts – PART I deals with the
description of the problem and in PART II the authors suggest innovative
methodologies to deal with the problem globally.

All the while we have been searching for a size which fits HFpEF, a less understood
complex syndrome due to maladaptive changes in structural, functional, and
biochemical aspects of the myocyte. Inflammation appears to be the underlying
string which weaves together nitrosative / oxidative stress, endothelial dysfunction,
downregulation of NO bioavailability / NO mediated signaling, impaired myocardial
bioenergetics, disturbed calcium handling, concentric hypertrophy etc. Most of the
Heart Failure with Reduced Ejection Fraction (HFrEF) Randomized Controlled Trials
(RCT’s) are positive, while the majority of HFpEF RCT’s are either neutral, borderline
or negative leading to a huge vacuum in the therapeutic space of HFpEF. While few
understand the statistical complexity of RCT’s, many pretend to do so. Endeavour
has been made in the present article to make the underlying concepts loud and lucid
without going into statistical complexities. Attempts are being made to negotiate this
problem by adopting / experimenting with innovative designs, enrichment trials,
adaptive trials, umbrella trials, basket trials, and machine learning-based trials
leading to what may be termed as “precision medicine, precision diagnosis and
precision therapy”.
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We have compared two recent negative HFpEF Clinical Trials (TOPCAT, INDIE /
NEAT) with one positive HFrEF Clinical Trial (CASTLE-AF), one negative HFrEF
Clinical Trial (IRONOUT-HF) and one positive HFmEF / HFbEF Clinical Trial
(REDUCE LAP-HF I) in order to understand why majority of HFpEF Clinical Trials
fail.

(Keywords: HFpEF, HFrEF, TOPCAT, CASTLE-AF, IRONOUT-HF)

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Catheter Ablation for Atrial Fibrillation with Heart Failure.

Nassir FM, Johannes B, Dietrich A, Jürgen S, Lucas B, Luc J, for the CASTLE-AF
Trial Group et al. N England J Med. 2018; 378(5):417-27.

Trial Summary:

Hypothesis: Catheter ablation is superior to medical therapy (rate or rhythm control)

with regard to death or hospitalization for heart failure in HFrEF with atrial fibrillation
(AF).

Background: HFrEF is often associated with AF (vicious twins) as a co morbid

condition. Such patients have increased risk of stroke, hospitalization for heart failure
(HF), and death. The 2002 Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) trial was the first and largest study (n = 4,060) to compare
rate-control and rhythm-control strategies for the treatment of non-valvular AF. In
high risk patients AFFIRM demonstrated no survival advantage between rate-control
and rhythm-control strategies.

Methods: Based on the above hypothesis the 2018 CASTLE-AF (Catheter Ablation
versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction
and Atrial Fibrillation) investigators randomized 363 patients to catheter ablation
versus medical therapy and assessed for a primary outcome of death or
hospitalization for HF. Inclusion criteria were Age ≥ 18 years, Symptomatic
paroxysmal or persistent AF, AF episodes had to be documented in the last 3
months prior to enrollment by ECG, holter, loop recorder, or implanted device,
Failure of antiarrhythmic drug therapy or patients unwillingness to take
antiarrhythmic drugs, Left ventricular dysfunction with left ventricular ejection fraction
≤ 35% (measured within last 6 weeks), NYHA class II-IV and implanted defibrillator
for primary or secondary prevention.

Out of 363 patients, 179 patients underwent catheter ablation and 184 patients
treated with medical therapy (rate or rhythm control) for atrial fibrillation as well as
guidelines-based therapy for HF. All the patients had New York Heart Association
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(NYHA) class II, III, or IV heart failure, a left ventricular ejection fraction (LVEF) of
35% or less, and an implanted defibrillator. The primary end point was a composite
of death from any cause or hospitalization for worsening HF.

Results: The median follow-up was 37.8 months. in the ablation group the primary
composite end point occurrence was significantly less than in the medical therapy
group. (Table: 3).

In the ablation group fewer deaths were reported from any cause. There were also
less number of hospitalizations for worsening HF.

Conclusion: Compared to medical therapy Catheter ablation for AF in patients with

HF was associated with a significantly lower rate of primary composite end point
occurrence of death from any cause or hospitalization for worsening HF. (Table: 3 )

Clinical Perspective:

CASTLE-AF provides data proving that catheter ablation is associated with improved
rhythm control in patients with AF and symptomatic HFrEF. It also improves
cardiovascular outcomes in this population, with lower rates of death and
hospitalization for HF. The inclusion of a rate control arm in CASTLE-AF is a critical
first step towards considering catheter ablation as a first-line treatment option for AF
in patients with HFrEF. More good quality RCT’s are needed before catheter ablation
can be fully established as a first-line treatment option for AF with HFrEF.

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Effect of oral iron repletion on exercise capacity in patients with heart failure
with reduced ejection fraction and iron deficiency

Gregory DL, Rajeev M, Adrian FH, Steven EM, Andrew S, Michael FG, Tang WH
W, et al. For IRONOUT-HF Trial Group. JAMA. 2017. 317(19):1958-66.

Trial Summary:

Hypothesis: In patients with iron deficiency and symptomatic HFrEF, oral iron
replacement improves exercise capacity.

Background: Iron plays an important role in oxygen delivery. It is crucial for the
production of red blood cells. It is also a cofactor for enzymes needed for cellular
respiration and vascular homeostasis. About 50% of patients with symptomatic
HFrEF have iron deficiency which has been linked with reduced exercise capacity,
quality of life, and increased mortality. In the 2009 Ferinject Assessment in Patients
with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial, patients with
symptomatic HFrEF and iron deficiency (with or without anemia) given IV iron
replacement had improvements in functional capacity, HF symptoms, and quality of
life. IRONOUT-HF trial was conducted to see if inexpensive and readily available
oral iron replacement would confer similar benefits.

Methods: The 2017 IRONOUT-HF (Iron Repletion Effects on Oxygen Uptake in

Heart Failure) trial investigators randomized 225 patients with symptomatic HFrEF
(LVEF < 40% with NYHA II-IV symptoms) and iron deficiency (either ferritin 15-
100ng/mL or 100-299 ng/ML with TSat < 20%) to either oral iron polysaccharide (150
mg twice daily) or placebo. The Primary Endpoint was increase in peak oxygen
uptake (VO2 max) on cardiopulmonary exercise testing (CPET).

Results: There was no significant improvement in the primary endpoints (VO2 max
on CPET) or in the secondary outcomes (6-minute walk distance, NT pro BNP
levels, quality of life). Iron markers were only modestly improved with oral iron
therapy. This points out to the fact that route of administration is very important in
increasing iron stores.
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Conclusion: In patients with iron deficiency (ferritin 15-100 or 100-299 with
transferrin saturation < 20%) and symptomatic HFrEF (LVEF ≤ 40% with NYHA II-
IV), oral iron replacement had no significant positive effect on primary endpoints
(VO2 max on CPET). (Table: 4)

Clinical Perspective: IRONOUT-HF trial results suggest that there is currently no

role for routine oral iron supplementation iron deficient HFrEF patients. However
FAIR-HF trial randomized 459 patients with symptomatic HFrEF (defined as LVEF ≤
40% with NYHA II-III symptoms or LVEF ≤ 45% with NYHA III symptoms) and
concomitant iron deficiency (ferritin < 100 ug/L or ferritin 100-299 ug/L with iron
saturation < 20%) with mild or no anemia (hemoglobin 9.5-13.5 g/dL) and assessed
the effects of administration of IV ferric carboxymaltose versus placebo on functional
status. FAIR-HF showed that the use of IV iron repletion resulted in a 20% absolute
increase moderate improvement in HF symptoms, 17% absolute increase in the
number of patients with improvement to NHYA class I or II, a mean 35 meter
increase in 6-minute walk distance at 24 weeks and lower rate of first cardiac
hospitalization. However there was no significant difference in adverse event rate
between the IV iron and placebo groups. One may conclude that IV iron therapy
better replenishes the iron stores of the body than the oral route iron therapy. This
probably explains why FAIR-HF trial is positive and IRONOUT-HF trial is negative.

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A transcatheter intracardiac shunt device for heart failure with preserved
ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm,
phase 1. Gerd H, Chris H, Dan B, Frank ES, Scott M, Finn G, REDUCE LAP-HF I
Phase 1 Trial Group et al,. LANCET 2016;387(10025):1298–04.

A Transcatheter Inter Atrial Shunt Device for the Treatment of Heart Failure
with Preserved Ejection Fraction (REDUCE LAP-HF I): A Phase 2, Randomized,
Sham-Controlled Trial. Ted F, Laura M, Rami K, Sheldon L, Mark JR, Pim VDH
REDUCE LAP-I PHASE 2 TRIAL GROUP et al. Circulation 2018;137:364-75.

Trial Summary:

Hypothesis: Partial equalization of atrial pressures using an inter atrial shunt device
(IASD, Corvia Medical, Qp:Qs 1.2 to 1.3) lowers pulmonary capillary wedge pressure
(PCWP), improves quality of life and exercise capacity in patients with HFmEF and
HFpEF.

Background: HFmEF / HFpEF patients have increased LAP, PCWP & LVEDP
during rest as well as exercise. Theoretically an artificial shunt created across the
IAS with an IASD can attenuate the LAP, PCWP & LVEDP. Feldman et al conducted
the first randomized, sham-controlled trial to evaluate the IASD in HF with EF =>
40%. In an earlier non-randomized, open-label studies, a transcatheter inter atrial
shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary
wedge pressure (PCWP), less symptoms, and greater quality of life and exercise
capacity in patients with HFmEF / HFpEF.

Methods: REDUCE LAP-HF I was a phase 2, (Reduce Elevated Left Atrial Pressure
in Patients with Heart Failure) is a randomized, parallel-group, blinded multicenter
trial in patients with New York Heart Association (NYHA) class III or ambulatory class
IV HF. Fourty four patients were randomized (1:1) to the IASD vs. a sham procedure
(femoral venous access with intracardiac echocardiography but no IASD placement).
The participants and investigators assessing the participants during follow-up were
blinded to treatment assignment. The primary effectiveness endpoint was exercise
PCWP at 1 month. The primary safety endpoint was major adverse cardiac,
cerebrovascular, and renal events (MACCRE) at 1 month. PCWP during exercise
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was compared between treatment groups using a mixed effects repeated measures
model analysis of covariance that included data from all available stages of exercise.

Results: A total of 94 patients were enrolled, of which n=44 met inclusion/exclusion

criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean
age was 70±9 years and 50% were female. At 1 month, the IASD resulted in a
greater reduction in PCWP compared to sham-control (P=0.028 accounting for all
stages of exercise). Peak PCWP decreased by 3.5±6.4 mmHg in the treatment
group vs. 0.5±5.0 mmHg in the control group (P=0.14). There were no peri-
procedural or 1-month MACCRE in the IASD group and 1 event (worsening renal
function) in the control group (P=1.0).

Conclusions: In patients with HFmEF and HFpEF, IASD implant (Corvia Medical)
reduces PCWP during exercise. Further high quality trials will be required to prove
that these beneficial mechanistic effects of IASD will improve symptoms and
outcomes in HFmEF and HFpEF patients.

Clinical Perspective: Feldman et al report a novel therapy for patients with heart
failure with preserved ejection fraction (HFpEF, EF > 50%) or mid-range EF (EF 40-
50%) utilizing an implanted device to create an atrial shunt (Inter Atrial Shunt Device
[IASD]). The objective of the IASD is to dynamically (at rest and during exercise)
decompress left atrial pressure overload associated with HFpEF and HF with mid-
range EF. Feldman et al conducted a randomized, sham-controlled trial to evaluate
the mechanistic effect of the IASD on invasively measured pulmonary capillary
wedge pressure (PCWP). At 1 month after randomization, the IASD treatment group
had a significantly greater reduction in PCWP during exercise compared to the
control group. In addition, PCWP during passive leg raise and also during 20W of
exercise decreased to a greater degree in the patients randomized to IASD
compared to sham-control. In patients with HFmEF / HFrEF creation of an interatrial
shunt with the IASD unloads the left atrium and reduces PCWP during exercise. This
hemodynamic study demonstrates the beneficial mechanistic effect of the IASD. The
IASD could have beneficial clinical effects in patients with HFpEF and HF mid-range
EF. A larger trial to examine the effects of the IASD on symptoms, quality of life,
exercise capacity, and clinical outcomes such as HF hospitalization is warranted.
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The REDUCE LAP-HF I phase I study was an open-label, single-arm, study
designed to assess the performance and safety of a transcatheter inter atrial shunt
device (IASD) in patients 44 years of age with symptoms of HFpEF despite
pharmacological therapy, LVEF≥40%, and an increased PCWP at rest (>15 mmHg)
or during exercise (>25 mmHg). IASD placement proved to be safe and well
tolerated and was accompanied by a reduction in PCWP pressure in 31 out of 60
(52%) patients at rest, 34 out of 59 (58%) patients during exertion, and 23 (39%) of
59 in both, rest and exercise. Moreover, mean exercise PCWP was lower at 6
months compared to baseline. (Table: 5)

The REDUCE LAP-HF I Phase 2, randomized, sham-ontrolled trial that included 44

symptomatic HF patients with EF ≥ 40% (IASD group; n = 22 and control group; n =
22) showed that treatment with IASD System II reduced significantly PCWP during
exercise, relative to the sham group. (Table: 6)

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Spironolactone for heart failure with preserved ejection fraction.

Bertram P, Marc AP, Susan FA, Robin B, Inder S. A, Brian C, For TOPCAT trial
Group et al. N England J Med 2014; 370(15):1383-92.

Trial Summary:

Hypothesis: Spironolactone an aldosterone antagonist reduces Cardiovascular

mortality, aborts cardiac arrest, or HF hospitalizations in HFpEF patients when
compared to placebo. The hypothesis was based on evidence from Randomized
Aldactone Evaluation Study (RALES) and Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trials.

Methods: TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an

Aldosterone Antagonist) investigators randomized 3,445 HFpEF patients in a
multicenter study involving 233 sites in 6 countries in 3 distinct geographic regions:
North America (United States and Canada); Eastern Europe (Russia and the
Republic of Georgia); and South America (Argentina and Brazil) for evaluating the
effectiveness and safety of spironolactone (15mg titrated to 45mg) compared to
placebo in patients with HFpEF: Spironolactone (n=1,722), Placebo (n=1,723),
Enrolment: 2006-2012, Mean follow-up: 3.3 years, Analysis: Intention-to-treat.

Results: It was a negative trial with no significant Spironolactone treatment effect

(primary endpoint hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 0.77 to 1.04).
Interestingly the hazard ratio varied across geographies. Interestingly in the
Americas (HR: 0.82; 95% CI: 0.69 to 0.98; p = 0.026) treatment effect was
significant, but not in Eastern Europe (HR: 1.10; 95% CI: 0.79 to 1.51; interaction p =
0.12). Possible factors responsible for the paradox are genetic, non-genetic, racial
characteristics, medical infrastructure, medical practice patterns etc. Most of the
hospitalizations in Russia / Georgia were based on ischemia rather than HF
consistent with ischemic heart disease prevalence data from the I-PRESERVE
(Irbesartan in Heart Failure With Preserved Systolic Function) and EVEREST
(Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with
Tolvaptan) trials.

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Conclusion: In patients with HFpEF, Spironolactone did not significantly reduce the
incidence of the primary composite outcomes. Additionally Spironolactone had no
treatment effect in Russia and Georgia where event rates were extremely low. The
hospitalizations were skewed with Georgia getting 200% of its enrollment target
followed by another 666 more enrollments for Eastern Europe (Russia and the
Republic of Georgia). But for this skewed enrollment the outcomes could have been
positive. In conclusion Spironolactone does not reduce the primary endpoint of CV
mortality, aborted cardiac arrest, or HF hospitalizations when compared to placebo.
(Table: 7)

Clinical Perspective: The lack of favourable evidence from clinical-outcome trials

involving patients with HFpEF is reflected in current guidelines. There are no specific
evidence based recommendations for the management of HFpEF. In the absence of
proven therapies, HFpEF treatment remains empirical with extra attention being
conferred to co morbidities.

All good quality RCT’s should expect the unexpected, and should have in built
mechanisms to identify, explain and manage such situations. Most HFrEF RCT’s are
positive leading to multiple effective regimens (e.g. beta blockers, ACE-
inhibitors/ARBs, Aldosterone antagonists). In dire contrast majority of the HFpEF
RCT’s are either neutral, borderline or negative creating substantial vacuum in the
HFpEF therapeutic space.

Post hoc analysis indicated marked regional differences in event rates In the
Americas (the United States, Canada, Brazil, and Argentina) and Eastern Europe
(Russia and Georgia) as shown in the Table: 7. Spironolactone significantly reduced
the rate of the primary outcome among patients enrolled on the basis of an elevated
BNP level but not among those enrolled on the basis of a previous hospitalization for
HF. Marked regional variation in event rates was observed, with patients in the
placebo group who were enrolled in Eastern Europe (Russia or Georgia) having a
much lower likelihood of a primary-outcome event than those enrolled in the
Americas. This discrepancy in event rates was unexpected. Regional heterogeneity
of coexisting conditions and medical practice patterns as well as differential use of
hospitalization with added difficulty of diagnosing HFpEF may explain the
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paradoxical outcomes. While Positive Primary outcomes were observed in the
Americas (where event rates are high and most of the patients are in the BNP
stratum) Negative Primary outcomes were observed in the Eastern Europe (where
event rates are very low and most of the patients are in the hospitalization stratum).

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Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.

Margaret MR, Kevin J, James AL, Gabe AK, Barry AB, Horng HC, INDIE / NEAT
HFpEF Trial Group et al. N England J Med. 2015; 373(24):2314-24.

Trial Summary:

Hypothesis: In patients with heart failure with preserved ejection fraction (HFpEF,
LVEF ≥ 50%) and mild-moderate (NYHA II-III) symptoms, the long-acting nitrate
isosorbide mononitrate improves activity tolerance.

Background: It is well known that long-acting nitrates provide symptomatic benefit

in patients with angina. However they do not improve mortality in any cardiac
condition. In smaller trials long-acting nitrates improved exercise tolerance in HFrEF
patients probably by improving cardiac filling pressures.

Methods: INDIE / NEAT-HfpEF (Inorganic Nitrite Delivery to Improve Exercise

Capacity in Heart Failure with Preserved Ejection Fraction / Nitrate's Effect on
Activity Tolerance in Heart Failure with Preserved Ejection Fraction) trial
investigators randomized 110 patients with chronic HFpEF. It was a Multicenter,
double-blind, placebo-controlled, double crossover study: Isosorbide Mononitrate
(n=51), Placebo (n=59), Setting: 20 sites in the United States, Duration of follow-up:
6 weeks, Analysis: Intention-to-treat. The study assessed the effect of extended-
release isosorbide mononitrate on daily activity tolerance in HFpEF patients who
predominantly had mild to moderate symptoms (NYHA II-III).

Results: In HFpEF patients with mild-moderate (NYHA II-III) symptoms, activity

levels appear to be reduced by the addition of long-acting nitrate isosorbide
mononitrate. Long acting nitrate therapy on HFpEF patients lead to a borderline
significant reduction in total activity units. Additionally there was a 20-minute
absolute reduction in activity time per day. However there was no effect on 6-minute
walk distance, quality of life, or clinical biomarkers.

After a 6 week treatment period, Isosorbide Mononitrate use was associated with a
borderline significant decrease in total activity. The activity was measured using
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continuous accelerometry. Increased doses of Isosorbide Mononitrate resulted in
progressive decrease in daily activity. Although accelerometer units are difficult to
quantify, an analysis of total hours of activity per day suggested about a 20-minute
absolute reduction in activity time with nitrate therapy (Table: 8).

Conclusion: Accelerometer units are not a common measure of activity in patients

with HFpEF. However the accelerometer findings were supported by the failure of
Isosorbide Mononitrate to improve 6-minute walk distance, subjective dyspnea on
several validated patient questionnaires, and cardiac biomarkers. HFpEF patients on
Isosorbide mononitrate were less active. They did not have better quality of life or
submaximal exercise capacity as compared to placebo group.

Clinical Perspective: Exercise intolerance is a salient feature of HFpEF. It leads to

sedentary behaviour, deconditioning, and frailty. In early studies in patients with
HFrEF, long-acting nitrates improved activity tolerance. Nitrates are commonly
prescribed for symptom relief in HF. The effects of nitrates in patients HFpEF have
not been studied in sufficient detail. Nitrates might decrease pulmonary congestion
and improve exercise capacity. The hemodynamic effects of nitrates might attenuate
with exertion in HFpEF. However, the unique pathophysiology, multiple co-
morbidities, and poly pharmacy that are characteristic of HFpEF tend to limit
hemodynamic improvements and predispose to hypotension. Nitrates are commonly
used for symptom control in HFrEF. However there is no authentic data to support
and justify the administration of nitrates to HFpEF patients. The beneficial effect of
nitrates in HFrEF need not be expected in HFpEF due to well known differences in
epidemiology, pathophysiology, and response to treatment between HFpEF and
HFrEF. INDIE / NEAT-HFpEF TRIAL was designed and launched to explore the
probable role of nitrates in HFpEF. This trial suggests that there is currently no role
for long-acting nitrates in patients with HFpEF. In fact nitrates may actually lead to
worsening symptoms and functional capacity. (Table: 8) However nitrates may be
administered for indications such as angina in HFpEF patients.

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WHY MAJORITY OF HFpEF RCT’s FAIL?

With the major chunk of the HF patients being in the HFpEF category which has no
evidence based effective therapy at the moment, we submit probable reasons as to
why HFpEF RCT’s give neutral, borderline positive or negative results. Those
therapies which appear to be theoretically acceptable but could not pass RCT’s
cannot be recommended by Regulatory Bodies and Guideline Committee Faculty.
This portends gloom for the HFpEF patients as well as the medical fraternity. The
RCT’s which have been enumerated and the stratification of HF based on LVEF are
given in the Tables 8 & 9.

After analysing the above 5 recent Land Mark Clinical Trials in HF, we found that
there are multiple factors responsible for the failure of HFpEF RCT’s as shown in the
Table: 9 and Table: 10. These factors and possible solutions will be discussed in
Part-II of this article.

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Page 16 of 28
 Table 1: CASTLE-AF TRIAL PRIMARY OUTCOME

Catheter Ablation (n=179) Medical Therapy (Rate or

Rhythm Control) (n=184)

Death / hospitalization for 51 (28.5%) 82 (44.6%);

HF
HR 0.62 (95% CI 0.43-0.87); p = 0.007; NNT = 6

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 Table 2: IRONOUT- HF TRIAL PRIMARY OUTCOME

oral iron PLACEBO P

polysaccharide
(150MG twice daily)

Peak VO2 (16 1218 (95% CI 892 to 1187 (95% CI 902 [p=0.46]
weeks) 1500) to 1425)

Peak VO2 (16 23 (95% CI -84 to -2 (95% CI -110 to [p=0.46]

weeks, change 142) 104)
from baseline)

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 Table 3: REDUCE LAP-HF I PHASE 1 TRIAL PRIMARY OUTCOME

(DECREASE IN PCWP) at 6 months,

DEVICE REST EXERCISE REST/EXERCISE

IASD(Corvia Medical) 31 (52%) 34 (58%) 23 (39%)

6 months MACCRE 0 (P=0.0%).

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 Table 4: REDUCE LAP-HF I PHASE 2 TRIAL PRIMARY OUTCOME

DEVICE EFFECTIVENESS SAFETY

(DECREASE IN PCWP) (1 MONTH MACCRE)

IASD (Corvia Medical) 3.5±6.4 mmHg (P=0.028) 0 (P=0.0%).

SHAM (CONTROL) 0.5±5.0 mmHg (P=0.14) 1 (P=1.0%)

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Table 5: TOPCAT TRIAL PRIMARY OUTCOME

GEOGRAPHY SPIRONOLACTONE PLACEBO

AMERICAS (US, 242 (27.3%) 280 (31.8%).

CANADA, BRAZIL,
ARGENTINA)

EASTERN EUROPE 78 (9.3%) 71 (8.4%)

(RUSSIA / GEORGIA)

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 Table 6: INDIE / NEAT HFpEF TRIAL PRIMARY OUTCOME

ACTIVITY ISOSORBIDE PLACEBO

MONONITRATE (120 mg)

Accelerometer units (AU) 8922 (8500-9345) 9303 (8884-9723)

(−381 AU; 95% [CI], −780 to 17; P = 0.06)

Hours of activity per day 9.01 (8.75-9.27) 9.31 (9.05-9.56)

(−0.30 hours; 95% CI, −0.55 to −0.05; P = 0.02).

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 Table 7: HF RCT’s

RCT OUTCOME DRUG / DEVICE

CASTLE-AF HFrEF POSITIVE CATHETER ABLATION

IRONOUT-HF HFrEF NEGATIVE ORAL IRON

REDUCE LAP-HF I PHASE 1 POSITIVE IASD (Corvia Medical)

REDUCE LAP-HF I PHASE 2

HFmEF/ HFpEF

TOPCAT HFpEF NEGATIVE SPIRONOLACTONE

INDIE / NEAT HFpEF NEGATIVE AIRONITE

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 Table 8: HF STRATIFICATION BY LVEF

HFpEF Heart Failure With Preserved LVEF => 50%

Ejection Fraction

HFmEF / Heart Failure With Mid Range / LVEF 40% to 49%

HFbEF Borderline Ejection Fraction

HFrecEF Heart Failure With Recovered LVEF improved from <40% to

Ejection Fraction > 40%

HFrEF Heart Failure With Reduced Ejection LVEF =< 40%

Fraction

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 Table 9: HFpEF versus HFrEF DIFFERENTIAL RCT OUTCOMES

HFpEF HFrEF

Inclusion criteria Not Well Standardized Well Standardized

Non-CV burden Massive Less

Diagnostic Dilemmas Numerous Very Few

Genetic Factors Not Fully Understood Better Understood

Non-Genetic Factors Not Fully Understood Better Understood

Racial Factors Not Fully Understood Better Understood

Geographic Factors Not Fully Understood Better Understood

Heterogeneity Extreme Less

Phenotypes Not Fully Understood Better Understood

Pathophysiology Not Fully Understood Better Understood

Co-Morbidities Numerous Few

RCT’s Mostly Neutral / Borderline / Negative Mostly Positive

Therapies Nil Numerous

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 Table 10: DIAGNOSTIC DILEMMAS OF HFpEF : AN EXAMPLE

LVEF CUT OFF VALUE

LVEF CUT OFF RANDOMIZED CONTROLLED TRIAL

=>50 % INDIE / NEAT-HFPEF, DILATE-1, RELAX, Aldo-DHF, RAAM-

PEF, ZILE et al., KITZMAN et al 1, 2 & 3, KOSMALA et al

40% - 50% PEP-CHF,

=> 45 % TOPCAT, I-PRESERVE, ELANDD, DIG, RALI-DHF,

SOCRATES-PRESERVED, PARAMOUNT,

=>40 % REDUCE LAP-HF I PHASE 1 & PHASE 2,

CHARM-PRESERVED, J-DHF,

No Specific CHAMPION
LVEF Cut-Off

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 Table No: 11 ClinicalTrials.gov Identifiers

CASTLE-AF NCT00643188

IRONOUT-HF NCT02188784

REDUCE LAP-HF TRIAL NCT01913613

REDUCE LAP-HF RANDOMIZED TRIAL I NCT02600234

REDUCE LAP-HF TRIAL II NCT03088033

REDUCE LAP-HF III Corvia Protocol 1701 NCT03191656

TOPCAT NCT00094302

INDIE / NEAT-HFPEF NCT02742129

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The REDUCE LAP-HF investigators randomized 44 participants, with Crossover
Assignment, Triple masking (Participant, Care Provider, Outcomes Assessor) and
intention to treat with the official title being “REDUCE LAP-HF RANDOMIZED TRIAL
I: A Study to Evaluate the Corvia Medical, Inc. IASD® System II
to REDUCE Elevated Left Atrial Pressure in Patients With Heart Failure”

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