The primary objective is to assess in a 2x2 crossover design, whether compared to placebo dapagliflozin 10 mg od for 13 weeks improves LV distensibility, measured with echocardiography in patients with early HFpEF (LVEF >= 50%), defined as…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
-Change from baseline or placebo in echocardiographically determined E/E*/LVEDV
(LV distensibility) after 13 weeks of treatment with dapagliflozin 10 mg od.
-Change in mean LV E* after 13 weeks of treatment with dapagliflozin 10mg od.
Secondary outcome
Change from baseline or placebo in 6 minute walk distance, Quality of Life
(Kansas City Cardiomyopathy Questionnaire), plasma levels of NT-proBNP,
collagen, renal function and inflammatory markers and echocardiographically
determined left atrial dimensions and function, additional diastolic LV
function (E/E*) parameters, LV systolic function and pulmonary artery pressures
after 13 weeks of treatment with dapagliflozin 10mg od.
Safety criteria: adverse events (AE), AE of special interest (AESI), serious
AE, withdrawal from trial medication due to AE, clinically relevant changes in
laboratory measurements from baseline, assessment of vital status
Background summary
Heart failure (HF) with preserved ejection fraction (EF; HFpEF) currently
accounts for >50% of all HF cases and its prevalence relative to HF with
reduced EF (HFrEF) continues to rise at a rate of 1% per year. Outcomes in
patients with HFpEF and HFrEF are equally poor with 5-year mortality rates up
to 75% in both HF phenotypes. In contrast to HFrEF, modern HF pharmacotherapy
did not improve outcome in HFpEF, which is related to incomplete understanding
of HFpEF pathophysiology, patient heterogeneity, suboptimal trial designs and
lack of insight into primary pathophysiological processes. In the conceptual
framework of HFpEF treatment, emphasis may need to shift from a *one size fits
all* strategy to an individualized approach based on phenotypic patient
characterization and diagnostic and pathophysiological stratification of
myocardial disease processes.
High diastolic left ventricular (LV) stiffness in HFpEF:
HFpEF is characterized by high diastolic left ventricular (LV) stiffness7,8. In
the absence of endocardial or pericardial disease, high diastolic LV stiffness
results from increased myocardial stiffness, which is regulated by the
extracellular matrix (ECM) and the cardiomyocytes9-12.
ECM-derived myocardial stiffness: Collagen importantly determines ECM-based
stiffness, through regulation of its total amount, expression of collagen type
I, and degree of collagen crosslinking, which are increased and linked to
diastolic LV dysfunction13 and outcome14 in patients with HFpEF.
Cardiomyocyte derived myocardial stiffness: Increased cardiomyocyte stiffness
importantly contributes to high diastolic LV stiffness in HFpEF9-11.
Cardiomyocyte stiffness is mainly determined by the elastic sarcomeric protein
titin, which functions as a bidirectional spring, responsible for early
diastolic recoil and late diastolic distensibility15. Titin-based cardiomyocyte
stiffness results from dynamic changes in expression of stiff (N2B) and
compliant (N2BA) isoforms and from post-translational modifications including
titin isoform phosphorylation and oxidative changes of the N2B segment15,16.
Phosphorylation of titin at its N2B segment by protein kinase G (PKG) acutely
increases its compliance15-17. Myocardial PKG activity results from upstream
stimulation by natriuretic peptide (NP) and nitric oxide (NO) mediated
activation of cyclic guanosine monophosphate (cGMP)17. In HFpEF, myocardial
cGMP-PKG signalling is downregulated because of impaired upstream NP and NO
bioavailability, which hampers PKG-mediated titin phosphorylation resulting in
subsequent increased titin-based cardiomyocyte stiffness and cardiomyocyte
hypertrophy17.
Comorbidities induce structural and functional remodelling in HFpEF:
HFpEF patients are generally older, more often female and have high prevalence
of cardiovascular and non-cardiovascular comorbidities, such as obesity,
metabolic syndrome, diabetes mellitus type 2 (T2DM), salt-sensitive
hypertension, atrial fibrillation (AF), chronic obstructive pulmonary disease,
anemia and renal dysfunction1,18-20. Metabolic risk factors, especially
obesity, are highly prevalent in patients with HFpEF (80% of HFpEF patients are
overweight or obese21), induce systemic inflammation and endothelial
dysfunction and adversely affect myocardial and systemic structural and
functional remodeling in HFpEF 22-25. A recently published new paradigm for
HFpEF, proposes that comorbidities drive myocardial dysfunction and remodeling
in HFpEF through systemic inflammation and coronary microvascular endothelial
dysfunction6. The latter affects LV diastolic dysfunction through macrophage
infiltration, resulting in interstitial fibrosis, and through altered paracrine
signalling to cardiomyocytes, which become hypertrophied and stiff because of
downregulation of cGMP-PKG signalling6. Improving cardiomyocyte
cGMP-PKG-mediated titin phosphorylation was recently proposed as a viable
option to improve LV compliance in HFpEF26.
Cardiac effects of sodium glucose co-transporter 2 (SGLT2) inhibitors:
Recent experimental studies demonstrate that sodium glucose co-transporter 2
(SGLT2) inhibitors exert beneficial myocardial pleiotropic effects, including
improvement of inflammation, oxidative stress27,28, remodeling28,29 and
mitochondrial function30. Dapagliflozin improved echocardiographically
determined LV filling pressures in T2DM patient with stable HF after 6 months
of treatment31. Empagliflozin was recently demonstrated to directly improve
diastolic stiffness in human and experimental HFpEF32. In cardiomyocytes
isolated from LV biopsies from HFpEF patients, empagliflozin substantially
improved cardiomyocyte stiffness through enhanced phosphorylation of
myofilamentary proteins including titin32. In addition, in a co-culture model
of human cardiac microvascular endothelial cells (CMECs) and rat adult
cardiomyocytes it was demonstrated that CMECs exert a direct positive effect on
cardiomyocyte contractility and relaxation. This positive effect on
contractility and relaxation, mediated by CMEC-derived NO, was diminished after
CMEC stimulation with tumor necrosis factor-α (TNF-α), and was restored by
empagliflozin33. Furthermore, empagliflozin restored NO bioavailability and
reduced mitochondrial and cytoplasmic reactive oxygen species production after
TNF-α stimulation in CMECs33. Through these methods of action, SGLT2-inhibitors
could be especially relevant as potential treatment strategy to improve cardiac
microvascular function, lower cardiomyocyte stiffness and improve LV
distensibility in patients with HFpEF.
Natriuretic peptides in HFpEF:
In HFpEF, plasma levels of natriuretic peptides (NPs) are lower than in HFrEF
with a substantial portion of patients even having normal values34-37. Indeed,
multiple invasive studies in HFpEF demonstrated low or even normal (NTpro)BNP
levels, despite elevated LV filling pressures38-40. These low or normal NPs
levels in HFpEF have been attributed to low LV diastolic wall stress because of
concentric LV remodeling37, a cushioning effect of epicardial fat, which
dampens LV diastolic distension23 and to metabolic comorbidities inducing a
relative state of NP deficiency41-44, which is specifically associated with the
obesity HFpEF phenotype23,24. Finally, low levels of NPs expression were
confirmed in LV myocardial biopsies of HFpEF patients, who had four times lower
myocardial pro-B-type natriuretic peptide 108 (pro-BNP 108) content than HFrEF
patients17.
Prognostic value of natriuretic peptides in HFpEF:
Despite these low levels of NPs in HFpEF, NPs predicted prognosis in several
HFpEF outcome trials and registries45-49. In the Coordinating Study Evaluating
Outcomes of Advising and Counseling in Heart Failure (COACH) trial, BNP levels
were lower in HFpEF than in HFrEF but for a similar elevation in BNP prognosis
was equally poor in both conditions46. In the I-PRESERVE trial, baseline
log-transformed NT-proBNP was the strongest predictor of all three outcomes49
and the incidence of unfavorable outcome was especially elevated in the highest
quartile48.
Value of natriuretic peptides in predicting therapeutic responsiveness in HFpEF:
Apart from predicting prognosis, NPs also predicted outcome of two HFpEF
trials. The I-PRESERVE48 and TOPCAT47 trials indeed demonstrated a positive or
better outcome in HFpEF patients with respectively below median NT-proBNP or
lower tercile NPs and suggested therapeutic responsiveness in HFpEF to be
linked to NPs baseline plasma level. A similar link between therapeutic
responsiveness and myocardial structural remodeling was proposed by the
PARAMOUNT trial as it observed sacubitril/valsartan to reduce left atrial
volume only in patients with below median values of plasma biomarkers involved
in profibrotic processes50. In this trial, baseline value of plasma fibrosis
biomarkers also correlated with plasma NT-proBNP50.
Natriuretic peptides for pathophysiological stratification in HFpEF:
Plasma NT-proBNP levels are positively correlated with cardiac magnetic
resonance T1 mapping derived myocardial fibrosis in individuals from the
Multiethnic Atherosclerosis Study51 and HFpEF patients52. Diffuse interstitial
myocardial fibrosis, assessed by magnetic resonance imaging derived T1 mapping
was recently shown to predict invasively measured LV stiffness in patients with
HFpEF53. Hence, this suggests that plasma NTproBNP levels could be used as a
potential biomarker in HFpEF patients for identification of myocardial
structural ECM-based remodeling with high NTproBNP levels being associated with
more advanced myocardial interstitial fibrosis.
Natriuretic peptide levels as entry criterion in HFpEF trials:
Markedly elevated NT-proBNP levels were used as entry criteria in large phase 3
HFpEF trials54-56. A relatively high NPs cutoff level increases the likelihood
that recruited trial patients indeed have HF and enriches the event rate in the
studied population. However, setting high NPs entry criteria will also skew the
recruited HFpEF study population towards a more myocardial fibrotic phenotype,
which could be much less responsive to the investigated therapeutic
intervention. Therefore, HFpEF patients in whom high diastolic LV stiffness is
predominantly caused by elevated cardiomyocyte stiffness could potentially be
more rseponsive to therapy.
Diagnostic and pathophysiological stratification for patient tailored therapy:
The STADIA-HFpEF trial investigating the capability of dapagliflozin to improve
diastolic LV distensibility in *early HFpEF* is designed exactly for this
purpose. As dapagliflozin was shown to directly ameliorate cardiomyocyte
titin-based stiffness in human HFpEF, dapagliflozin could especially be of
therapeutic benefit in HFpEF patients with metabolic risk factors in whom high
diastolic LV stiffness is primarily caused by increased cardiomyocyte derived
stiffness. In contrast, HFpEF patients with more advanced levels of myocardial
fibrosis (characterized by high cardiac MR T1 derived ECV and prominently
elevated NT-proBNP levels) are more likely to be therapeutically unresponsive.
The STADIA-HFpEF trial aims to select a more homogeneous HFpEF patient
population (metabolic HFpEF phenotype) in an earlier stage of disease
progression (defined by lesser degrees of myocardial fibrosis), with a higher
likelihood of responsiveness to therapeutic modulation of LV diastolic
distensibility by dapagliflozin.
Study objective
The primary objective is to assess in a 2x2 crossover design, whether compared
to placebo dapagliflozin 10 mg od for 13 weeks improves LV distensibility,
measured with echocardiography in patients with early HFpEF (LVEF >= 50%),
defined as cardiac MRI T1 derived extracellular volume <29%.
Study design
Single-center, Prospective, Controlled, Double-blind, Randomized, 2x2
crossover, Interventional, Exploratory.
Intervention
Recruited early HFpEF patients are subjected to a 2x2 crossover design study,
in which patients are randomized to placebo or dapagliflozin 10 mg od for 13
weeks followed by a washout period of 8 weeks and subsequent allocation to
either dapagliflozin 10 mg od (if first treatment period was placebo) for 13
weeks or placebo (if first treatment period was dapagliflozin) for 13 weeks.
Study burden and risks
The risks to patients participating in the study will be minimized by
compliance with the in- and exclusion criteria and close clinical monitoring.
All patients will be instructed to continue their (previously initiated)
standard of care cardiovascular (CV) medication. The overall tolerability and
safety profile of dapagliflozin, outlined in the current investigator brochure
(IB)supports safe administration of dapagliflozin.
In this study, the effect of dapagliflozin will be evaluated in patients with
HFpEF, regardless of the presence of DM. However, DM is a well-known risk
factor for HFpEF, therefore it is expected to be present in a significant
number of subjects in the STADIA-HFpEF study. Previous studies have
demonstrated that the use of SGLT2 inhibitors is safe in patients with both DM
and HF. Moreover, some studies have even shown an improvement in cardiovascular
outcomes in these patients. Therefore, addition of a SGLT2 inhibitor to
metformin is now recommended for patients with DM by the American Diabetes
Association(ADA)/European Association for the Study of Diabetes (EASD) in a
recent consensus paper. However, abovementioned studies included DM patients
with cardiovascular risk factors.
Dapagliflozin reduces tubular glucose transport by a maximum of 55% and reduces
renal glucose reabsorption leading to urinary excretion of excess glucose. The
amount of glucose excretion is dependent upon the blood glucose concentration
and renal function. Therefore, dapagliflozin has a low propensity to cause
hypoglycaemia in patients with normal glucose blood level and is safe for
administration to patients without DM (see IB).
Patients with T2D at randomization will continue their T2D treatment. Patients
are eligible for adjustments in their anti-diabetes treatment at the discretion
of their diabetes health care provider. Diabetes medications at baseline and
any changes throughout the study, will be recorded in the eCRF.
The most common notorious side effect of SGLT2 inhibitors in patients with DM
is diabetic ketoacidosis (DKA). Therefore, subjects with DM included in the
STADIA-HFpEF trial will be emphasized to contact a physician when perceiving
clinical symptoms (polydipsia, polyuria, nausea, vomiting, headache) suggesting
ketoacidosis.
Because of the selection of *early* HFpEF patients, combined with the possible
effect of SGLT2 inhibitors, patients may experience a prompt improvement of
clinical HF symptoms.
Oosterpark 9
Amsterdam 1091AC
NL
Oosterpark 9
Amsterdam 1091AC
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years at time of screening
2. Symptomatic chronic heart failure patients with diagnosis of heart failure
and:
• NYHA class II-IV
• Preserved systolic LV function, defined by: LVEF >= 50% and LV end-diastolic
volume index <97 ml/m2
• Evidence of diastolic LV dysfunction and at least 1 out of the 5 following
additional criteria:
1) H2FPEF score >= 6;
2) HFA-PEFF score >= 5;
3) Paulus criteria 2007 met;
4) Pulmonary capillary wedge pressure > 15 mmHg at rest or > 25 mmHg with
exercise assessed with right heart catheterization;
5) ASE/EACVI 2009 recommendations for diastolic dysfunction met.
3. Cardiac MRI T1 derived extracellular volume <29% at screening
4. Oral diuretics, if prescribed to the patient according to local guidelines
and at the
discretion of the investigator, should be stable for at least 1 week prior to
baseline visit
5. Signed and dated written informed consent in accordance with GCP and local
legislation prior to admission to the trial
Exclusion criteria
1. Reduced systolic LV function, defined by: LVEF <50% measured at any time
point in the history of the patient
2. Obstructive coronary artery disease with evidence of ischemia
3. Myocardial infarction (i.e., increase in cardiac enzymes in combination with
symptoms of ischemia or newly developed ischemic ECG changes), coronary artery
bypass graft surgery or other major cardiovascular surgery, stroke or TIA in
past 90 days prior to screening visit
4. More than mild valve stenosis
5. More than moderate aortic and/or mitral valve regurgitation
6. Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis),
accumulation diseases (e.g. hemochromatosis, Fabry disease), muscular
dystrophies, cardiomyopathy with reversible causes (stress cardiomyopathy),
hypertrophic (obstructive) cardiomyopathy or known pericardial constriction
7. History of mitral valve plasty or replacement
8. Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm
documented by ECG at screening
9. Acute decompensation with necessity to treat with intravenous loop diuretics
10. Systolic blood pressure >=180 mmHg (confirmed with second measurement after
5 minutes). If SBP >150 mmHg and <180 mmHg, the patient should be receiving at
least 3 antihypertensive drugs at screening or baseline visit
11. Symptomatic hypotension and/or a SBP <100 mmHg at screening or baseline
visit
12. Impaired renal function, defined as eGFR < 30 ml/min/1.73 m2
13. Indication of liver disease, defined by serum levels of either ALT (SGPT),
AST (SGOT), or alkaline phosphatase above 3x upper limit of normal as
determined at screening or history of cirrhosis with evidence of portal
hypertension such as varices
14. Hemoglobin <9 g/dl at screening
15. Chronic obstructive pulmonary disease, more than GOLD class 2
16. Pulmonary function test with FEV1/FVC <80%
17. Primary pulmonary arterial hypertension
18. Type 1 Diabetes Mellitus
19. History of ketoacidosis
20. Gastrointestinal surgery or GI disorder that could interfere with trial
medication absorption in the investigator*s opinion
21. Any documented active or suspected malignancy or history of malignancy
within 2 years prior to screening, except appropriately treated basal cell
carcinoma of the skin or in situ carcinoma of uterine cervix or low risk
prostate cancer (biopsy Gleason score of <= 6 and clinical stage T1c or T2a)
22. Presence of any disease other than heart failure that imposes a life
expectancy of less than 1 year
23. Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2
inhibitor within 3 months prior to screening visit. Discontinuation of a SGLT-2
inhibitor or combined SGLT-1 and 2 inhibitor for the purposes of study
enrolment is not permitted
24. Currently enrolled in another investigational device or drug trial
25. Pregnancy or lactation
26. Chronic alcohol or drug abuse or any condition that, in the investigator*s
opinion, makes them unreliable trial patients or unlikely to complete the trial
27. Known allergy or hypersensitivity to dapagliflozin or other SGLT-2
inhibitors
28. Any other clinical condition that would jeopardize patients safety while
participating in this trial, or may prevent the patient from adhering to the
trial protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004552-11-NL |
| CCMO | NL72196.018.19 |