The purpose of this trial is to determine the safety and efficacy of TAVR via a transfemoral approach in HF patients with moderate AS as compared with OHFT with regard to the composite of death, stroke, hospital admissions, symptoms, functional…
ID
Source
Brief title
Condition
- Other condition
- Heart failures
Synonym
Health condition
aorta stenose
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Hierarchical occurrence within efficacy assessment time interval (EATI) of:
1. All-cause death
2. Disabling stroke
3. Hospitalizations related to heart failure, symptomatic aortic valve disease
or non-disabling stroke
-or -
4. Clinically significant worsening of heart failure (heart failure
hospitalization equivalent).
5. Change in KCCQ relative to baseline
Secondary outcome
Key secondary endpoints:
• Major adverse cardiac or cerebrovascular events (MACCE) defined as the
composite of all-cause death, all stroke, and hospitalizations for heart
failure or symptomatic aortic valve disease or clinically significant worsening
of heart failure (heart failure hospitalization equivalent) within EATI..
• Hierarchical occurrence within EATI of:
1. All-cause death
2. Disabling stroke
3. Hospitalizations related to heart failure, symptomatic aortic valve disease
or non-disabling stroke or clinically significant worsening of heart failure
(heart failure event)
• All-cause death within EATI.
Other clinical secondary endpoints:
1. All-cause death
a. Cardiovascular death
b. Non-cardiovascular death
2. All stroke
a. Disabling stroke
b. Non-disabling stroke
3. Transient ischemic attack
4. Myocardial infarction
5. Need for surgical aortic valve replacement or TAVR
6. Renal failure requiring renal replacement therapy
7. Hospitalizations for heart failure and/or aortic valve disease
8. Composite of all-cause death, disabling stroke, and renal failure requiring
renal replacement therapy
9. Composite of all-cause death and disabling stroke
10. Change in quality of life from baseline to 1 month, 6 months, 1 year, and
at 2 and 3 years if available (assessment with generic and disease specific
measures):
a. Kansas City Cardiomyopathy Questionnaire (KCCQ)
b. Medical Outcomes Study Short-Form 36 (SF-36)
c. EuroQol Dimensions (EQ-5D)
11. Changes in NYHA class from baseline to 1 month, 6 months, 1 year, and at 2
and 3 years if available
12. Changes in CCS angina grading scale from baseline to 1 month, 6 months, 1
year, and at 2 and 3 years if available
13. Changes in 6-minute walk test from baseline to 1 month, 6 months, 1 year,
and at 2 and 3 years if available
14. Changes in NT-proBNP (or BNP) from baseline to 1 month, 6 months, 1 year,
and at 2 and 3 years if available
15. Changes in heart failure management (medications and devices) from baseline
to 1 month, 6 months, 1 year, and at 2 and 3 years if available
Background summary
In comparison to conventional surgical aortic valve replacement (SAVR),
transcatheter aortic valve implantation/replacement (TAVR) does not require
open sternotomy or cardiopulmonary bypass. Various access strategies are
possible but the retrograde transarterial transfemoral route is the preferred
approach and does not mandate general anesthesia. TAVR is thus less invasive in
comparison to SAVR. Over the last decade several device iterations, refined
accessories, expertise and improved implantation techniques have matured the
transcatheter heart valve (THV) technology. All-cause 30-day mortality in
patients with a high operative risk undergoing TAVR in randomized trials and
large registries averages around 5%. The incidence of major stroke is similar
to what can be expected from SAVR.(3) Other procedure related access site and
bleeding complications and the incidence of paravalvular leakage have declined
substantially.(4, 5) In aggregate and in contrast with SAVR, TAVR is associated
with more access site complications, conduction disorders and need for
permanent pacemakers but with less bleedings and new-onset atrial fibrillation.
Hospital stay is typically shorter. Randomized trials comparing TAVR with SAVR
in patients at high operative risk confirm at least similar clinical outcome
with TAVR and suggest improvements in quality of life at a favorable
cost-benefit ratio. Joint cardiac surgery and cardiology guidelines from both
sides of the Atlantic position TAVR as a valid treatment option for patients
with symptomatic severe aortic stenosis who are inoperable or have a high
estimated risk of mortality with SAVR. From a regulatory perspective two THV
designs obtained CE mark in 2007 in Europe, other designs have followed. The US
Food and Drug Administration (FDA) approved use of a device for TAVR in 2
stages in November 2011 and September 2012. In current clinical practice TAVR
is increasingly being used in elderly patients regardless of the (high-) risk
profile. This shift to TAVR application in lower risk and younger patients is
evaluated in various clinical trials but its adoption for this indication is
already happening in Europe.
Current practice for patients with moderate aortic stenosis and heart failure
includes optimal medical therapy, and watchful waiting for the progression of
the aortic stenosis severity from moderate to severe, in which case a
percutaneous or surgical intervention is deemed according to current evidence.
Information gained from the conduct of this study may be of benefit to future
patients with the same medical condition.
Implantation of a THV in the subcoronary position may result in one or more of
the following: improved valvular function, alleviation of symptoms related to
heart failure, improved quality of life and survival. A consequence of heart
failure is an increased peripheral vascular resistance, which in turn
accentuates heart failure due to increased afterload. Moderate aortic stenosis
increases the afterload, which further augments end-diastolic pressure, oxygen
consumption, and favors concentric remodeling. By reducing trans-aortic
gradient we expect a reduction in afterload, an improvement in myocardial
function and prevention of adverse remodeling.
Study objective
The purpose of this trial is to determine the safety and efficacy of TAVR via a
transfemoral approach in HF patients with moderate AS as compared with OHFT
with regard to the composite of death, stroke, hospital admissions, symptoms,
functional status and quality of life.
Study design
International, multi-center, randomized, open-label, clinical trial comparing
the safety and efficacy of TAVR with the SAPIEN 3 or SAPIEN 3 Ultra THV and
OHFT versus OHFT in HF patients, with moderate AS.
All patients are followed from randomization until at least 1 year after
randomization of the last patient. Patients are followed from randomization
until 1 year after randomization for the last patient (efficacy assessment time
interval [EATI]).
Intervention
Transcatheter Aortic Valve Replacement with the Edwards SAPIEN 3 Transcatheter
Heart Valve (THV), model 96000TFX or Edwards SAPIEN 3 Ultra Transcatheter Heart
Valve (THV), model 9750TFX.
Study burden and risks
The potential risks associated with overall TAVR procedure including potential
access complications associated with standard cardiac catheterization, balloon
valvuloplasty, the potential risks of conscious sedation and/or general
anesthesia, and the use of angiography:
• Death
• Cardiovascular or vascular injury, such as perforation or damage (dissection)
of vessels, ventricle, atrium, septum myocardium or valvular structures that
may require intervention
• Thoracic bleeding
• Myocardial infarction
• Neurological changes including stroke/transient ischemic attack, with or
without permanent disability
• Embolization: air, calcific valve material, or thrombus
• Heart failure (low cardiac output)
• Hemorrhage requiring transfusion or intervention
• Hematoma (changes at the access site)
• Hypertension (high blood pressure)/ hypotension (low blood pressure)
• Renal insufficiency/renal failure
• Respiratory insufficiency/respiratory failure (shortness of breath)
• Allergic reaction to contrast media or device materials
• Arrhythmia
• Conduction system injury, which may require a permanent pacemaker
• Fever
• Exercise intolerance (weakness)
• Abnormal lab values and electrolyte imbalance
• Infection including endocarditis, incisional site infection/inflammation and
septicemia
• Retroperitoneal bleed
• Pericardial effusion or cardiac tamponade
• Systemic peripheral ischemia/nerve injury
• Arteriovenous (AV) fistula or pseudoaneurysm
• Reoperation
• Restenosis
• Pleural effusion
• Pulmonary edema
• Bleeding
• Anemia (including hemolytic anemia)
• Syncope
• Heart murmur
• Inflammation
• Angina
In addition to the risks listed above, additional potential risks specifically
associated with the use of a THV include, but may not be limited to, the
following:
• Cardiac arrest
• Cardiogenic shock
• Cardiac failure or low cardiac output
• Transvalvular flow disturbance
• Bleeding
• Device explant
• Device embolization
• Device migration or malposition requiring intervention
• Device thrombosis requiring intervention
• Plaque dislodgement
• Valve deployment in unintended location
• Mechanical failure of delivery system, and/or accessories
• Emergency cardiac surgery
• Endocarditis
• Hemolysis
• Non-emergent reoperation
• Nonstructural dysfunction
• Paravalvular or transvalvular leak
• Structural valve deterioration
• Valve regurgitation
• Valve stenosis
• Valve thrombosis
• Coronary flow obstruction
• Injury at the site of venous, arterial or ventricular access that may require
repair
All the listed risks may include the symptoms associated with the above
mentioned medical conditions. All efforts will be made by the Steering
Committee to minimize these risks by selecting qualified investigators and
study sites (see the measures listed below and page 76 of the protocol):
• The investigators in this study will be selected based on their experience in
treating patients with aortic stenosis and performing TAVR procedures.
• Investigators will be trained in proper procedure performance and device
operation prior to patient treatments. Training may include didactic and
hands-on training with the Edwards SAPIEN 3 and SAPIEN 3 Ultra devices.
• Well defined clinical study protocol, including specific inclusion/ exclusion
criteria to enroll appropriate subjects in the trial.
• Close patient monitoring during the TAVR procedure and follow-up period.
• Ongoing monitoring of study data and results, including the use of
independent Clinical Events Committee (CEC) and Data Monitoring Board (DSMB).
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Listed location countries
Age
Inclusion criteria
1. Age >=18 years
2. Heart failure with NYHA class >= 2
3. Under appropriate and stable guideline-directed HF therapy for a minimum of
1 month prior to randomization. Note: Patients are expected to be on
appropriate pharmacologic therapy and if indicated CRT for heart failure. (12,
13) Patients with aortic stenosis may not be able to tolerate maximal doses of
heart failure medications and no specific guidelines exist for the medical
treatment of heart failure in the setting of aortic stenosis. It is expected
that the heart failure PI will review the medical therapy and confirm that it
is appropriate for the patient*s condition.
4. Moderate AS confirmed by the echo core lab. Moderate AS is defined as an
aortic valve area (AVA) >1.0 cm2 and <=1.5 cm2 on rest echo or if <=1.0 cm2 at
rest and low-flow AS is suspected when the an AVA > 1.0 cm2 with low dose
dobutamine stress echo (DSE). Patients with AVA<1.0 cm2 but with an indexed AVA
of >0.6 cm2/m2 on either rest or DSE are also eligible. Similarly, patients
with AVA >1.5 cm2 but with indexed AVA<0.9 cm2/m2 on either rest of DSE are
also eligible.
Note: Typically such cases will demonstrate,
• Mean trans-aortic gradient (MG) >= 20 mmHg and < 40 mmHg at rest and aortic
valve area (AVA) > 1.0 cm2 and <=1.5 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6
cm2) at rest
OR
• Mean trans-aortic gradient (MG) >= 20 mmHg and < 40 mmHg and aortic valve area
(AVA) <=1.0 cm2 at rest AND MG < 40 mmHg and aortic valve area (AVA)
>1.0 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) with low dose dobutamine
stress echo (DSE).
In atypical cases (for example mean gradient is below 20 mmHg but valve area is
consistent with moderate AS or in case of BSA being elevated due to obesity),
the final eligibility determination in regards to diagnosis of moderate AS will
be made by the echocardiographic core lab.
In indeterminate cases calcium score may also be used to assess the presence of
moderate AS.
5. Left ventricular (LV) ejection fraction (EF) < 50% at rest
6. Anatomically suitable for transfemoral TAVR with the SAPIEN 3 or SAPIEN 3
Ultra THV
7. Able to provide independent informed consent (i.e., not requiring a legally
authorized representative)
Exclusion criteria
1. LVEF < 20% or persistent need for intravenous inotropic support
2. Hospitalization for acute decompensated HF within 2 weeks prior to
randomization
3. Cardiac resynchronization therapy (CRT) device implantation within 1 month
prior to randomization
4. Coronary artery revascularization (PCI or CABG) within 1 month prior to
randomization
5. In need and suitable for revascularization per heart team consensus
6. Severe aortic and/or mitral regurgitation
7. Congenital unicuspid or congenital bicuspid aortic valve
8. Concomitant non-aortic valvular disease with a formal indication for valve
surgery per established guidelines (ESC/ACC/AHA)
9. Previous aortic valve replacement (mechanical or bioprosthetic)
10. Severe RV dysfunction
11. Previous stroke with permanent disability (modified Rankin score >= 2)
12. Severe lung disease as indicated by FEV1 <30% predicted or need for chronic
daytime supplemental oxygen therapy
13. Severe chronic kidney disease: glomerular filtration rate (GFR) < 30 mL/min
by MDRD or need for renal replacement therapy
14. Gastrointestinal (GI) bleeding within the past 3 months
15. Liver cirrhosis Child-Pugh C
16. Active systemic infection, including active endocarditis
17. Unwilling to accept blood transfusion
18. Evidence of intracardiac mass, thrombus or vegetation
19. Absence of minimum amount of aortic valve calcification necessary for TAVR
with the SAPIEN 3 or SAPIEN 3 Ultra THV
20. Hypersensitivity or contraindication to clopidogrel, aspirin, or to oral
anticoagulation if indicated (e.g. subject in atrial fibrillation)
21. Sensitivity to contrast media which cannot be adequately pre-medicated
22. Women of child-bearing potential
23. Clinical signs of dementia
24. Other medical, social, or psychological conditions that precludes
appropriate consent and follow-up
25. Life expectancy < 2 years due to cancer or other non-cardiac chronic
diseases
26. Unwillingness to undergo follow-up investigations
27. Currently participating in an investigational drug or another device trial
that has not reached its primary endpoint (excluding registries)
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 |
|---|---|
| ClinicalTrials.gov | NCT02661451 |
| CCMO | NL56596.078.16 |