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The Predilatation in Transcatheter Aortic
Valve Implantation Trial
(The DIRECT Trial)
References
• Sack S, Kahlert P, Khandanpour S, Naber C, Philipp S, Mohlenkamp S, Sievers B, Kalsch H, Erbel R.
Revival of an old method with new techniques: balloon aortic valvuloplasty of the calcified aortic stenosis
in the elderly. Clin Res Cardiol 2008;97:288-97.
• Grube E, Naber C, Abizaid A, Sousa E, Mendiz O, Lemos P, Kalil Filho R, Mangione J, Buellesfeld L.
Feasibility of transcatheter aortic valve implantation without balloon pre-dilation: a pilot study. JACC
Cardiovasc Interv 2011;4:751-7.
• Fiorina C, Maffeo D, Curello S, Lipartiti F, Chizzola G, D'Aloia A, Adamo M, Mastropierro R, Gavazzi E,
Ciccarese C, Chiari E, Ettori F. Direct transcatheter aortic valve implantation with self-expandable
bioprosthesis: feasibility and safety. Cardiovasc Revasc Med 2014;15:200-3.
• Mendiz OA, Fraguas H, Lev GA, Valdivieso LR, Favaloro RR. Transcatheter aortic valve implantation
without balloon predilation: a single-center pilot experience. Catheter Cardiovasc Interv 2013;82:292-7.
Patient evaluation by
Heart Team
TAVI
1:1 Randomization
BAV No-BAV
Primary endpoint: Device success based on
VARC-2
Secondary endpoint: In-hospital death, stroke, PPM,
mortality
N= 170
randomized
patients
The DIRECT Trial
4 International TAVI Centers
Hippokration Hospital: Core Lab
Clinical Trials gov: NCT02448927
Sponsored by Medtronic, USA
Inclusion criteria
1. Diameter of >5mm for Evolut R and >6mm for CoreValve of the vessel.
2. Aortic valve diameter of ≥20mm and ≤29mm as measured by echo.
3. Ascending aorta diameter ≤ 43mm at the sinotubular junction.
4. Severe aortic stenosis, defined as aortic valve area of < 1.0 cm2 (or aortic valve area index of < 0.6 cm2/m2) by the continuity equation,
AND mean gradient > 40 mmHg or maximal aortic valve velocity > 4.0 m/sec by resting echocardiogram.
5. STS score of ≥ 8 OR LogEuroSCORE> 20%, OR
I. 80 years old OR
II. 65 years old with 1 or 2 (but not more than two) from the following criteria:
a) Liver cirrhosis (Class A or B).
b) Pulmonary insufficiency: VMS<1 liter.
c) Previous heart surgery (CABG, vascular surgery).
d) Porcelain aorta.
e) Pulmonary artery systolic pressure >60 mmHg and high risk for heart surgery.
f) Relapsing pulmonary embolism.
g) Right ventricular insufficiency.
h) Thoracic wall injuries that contraindicate an open heart surgery.
i) History of radiation therapy of the mediastinum.
j) Connective tissue disease that contraindicates an open heart surgery.
k) Frailty/cachexia.
6. Patients will be informed on the nature of the study and provide written consent.
Exclusion criteria I
1. A known hypersensitivity or contraindication to any of the following which cannot be adequately
pre-medicated: aspirin or heparin and bivalirudin, ticlopidine and clopidogrel, nitinol (titanium or
nickel), contrast media
2. Ongoing sepsis, including active endocarditis.
3. Any percutaneous coronary or peripheral interventional procedure with a bare metal or drug
eluting stent performed within 30 days prior to Heart Team assessment.
4. Echocardiographic evidence of LV or LA thrombus.
5. Mitral or tricuspid valve insufficiency (> grade II).
6. Previous aortic valve replacement (mechanical or bioprosthetic).
7. Recent (within 6 months of Heart Team assessment) cerebrovascular accident (CVA) or transient
ischemic attack (TIA).
8. Patients with:
Femoral, iliac or aortic vascular disease (stenosis etc) that precludes the insertion of a transcatheter
sheath.
OR Symptomatic carotid or vertebral artery disease (> 70% stenosis).
Exclusion criteria II
9. The patient has a bleeding diathesis, coagulopathy or denies blood transfusion.
10. Estimated life expectancy of less than 12 months due to associated non-cardiac co-morbid
conditions.
11. Creatinine clearance < 20 ml/min.
12. Active gastritis or ulcer.
13. Pregnancy.
14. Severe left ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20%.
15. Unicuspid or bicuspid aortic valve.
16. Mixed aortic valve disease (aortic stenosis and aortic regurgitation> 2+).
17. Liver failure (Child-Pugh class C).
18. Severe dementia (resulting in either inability to provide informed consent for the study/procedure,
prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate
rehabilitation from the procedure or compliance with follow-up visits).
19. Extreme aortic valve calcification and calcific asymmetry (if semiquantitively measured: grade 4,
Agatston score: grade 4 AgS>5000 AU).
20. Aortic valve area of < 0.4 cm2.
Primary Outcome
Device success definition - VARC 2 criteria:
• Absence of procedural mortality AND
• Correct positioning of a single prosthetic heart valve into the proper anatomical location AND
• Intended performance of the prosthetic heart valve (no prosthesis–patient mismatch and mean aortic
valve gradient <20 mmHg or peak velocity <3 m/s, AND no moderate or severe prosthetic valve
regurgitation)
Patient-prosthesis mismatch
Insignificant Moderate Severe
Effective Orifice Area indexed
(BMI<30kg/m2)
>0.85 cm2/m2 0.85-0.65 cm2/m2 <0.65 cm2/m2
Effective Orifice Area indexed
(BMI≥30kg/m2)
>0.70 cm2/m2 0.70-0.60 cm2/m2 <0.60 cm2/m2
Primary Outcome
Device success definition VARC 1 criteria:
• Successful vascular access, delivery and deployment of the device and successful retrieval of the
delivery system
• Correct position of the device in the proper anatomical location
• Intended performance of the prosthetic heart valve (aortic valve area 1.2 cm2 and mean aortic valve
gradient <20 mmHg or peak velocity<3 m/s, without moderate or severe prosthetic valve AR)
• Only one valve implanted in the proper anatomical location
Secondary Outcomes
Participating Centers
Onassis Cardiac Surgery
Centre, Athens, Greece
Heart Institute,
Hadassah Hebrew
University Medical
Center, Israel
First Department of
Cardiology, Hippokration
Hospital, Athens Greece
Naval hospital,
Athens, Greece
Study Population (May 2015-January 2018)
Total (n=138) Completed Follow-up
1 month 12 months
First Department of Cardiology, Hippokration
Hospital, Athens Greece
94 (68.1%) 92 (97.9%) 57 (60.61%)
Athens Naval Hospital, Athens, Greece 11 (8%) 11 (100%) 2 (18.2%)
Onassis Cardiac Surgery Centre, Athens, Greece 22 (15.9%) 21 (95.5%) 7 (31.8%)
Heart Institute, Hadassah Hebrew University
Medical Center, Israel
11 (8%) 9 (81.8%) 4 (36.4%)
Baseline CharacteristicsTotal (n=138) BAV (n=68) No BAV (n=70)
Mean Age (years) 82.05±7.62 82.56±7.92 81.56±7.33
Gender (male) 71(51.4%) 34 (50%) 37 (52.9%)
BMI (kgr/m2) 27.06±4.44 26.78±3.82 27.34±4.99
Logistic
Euroscore (%)
24.53±11.25 26.48±10.28 22.75±11.88
Hypertension (%) 110 (79.7%) 53 (77.9%) 57 (81.4%)
Diabetes (%) 48 (34.8%) 22 (32.4%) 26 (37.1%)
Smoking (%) 10 (7.2%) 5 (7.4%) 5 (7.1%)
Family history of
CAD (%)
11 (8%) 6 (8.8%) 5 (7.1%)
COPD (%) 31 (22.5%) 15 (22.1%) 16 (22.9%)
CKD (%) 27 (19.6%) 16 (23.5%) 11 (15.7%)
Baseline Echocardiographic Characteristics
Total (n=138) BAV (n=68) No BAV (n=70)
Vmax (m/s) 4.45±0.65 4.56±0.63 4.36±0.65
Mean Gradient
(mmHg)
49.38±15.14 50.66±15.14 48.12±15.15
Peak Gradient
(mmHg)
81.25±23.54 83.88±23.50 78.62±23.46
AVA (cm2) 0.66±0.15 0.64±0.15 0.68±0.15
AVAi (cm2/m2) 0.36±0.08 0.36±0.08 0.37±0.08
Ejection Fraction
(%)
50.69±9.79 51.44±9.33 49.97±10.23
PASP (mmHg) 46.94±13.63 47.63±13.44 46.31±13.89
Primary Endpoint
Device success (with PPM)
Total BAV NO-BAV P
71.8% (74/103) 74.5% (38/51) 69.2% (36/52) 0.55
Device success definition - VARC 2 criteria:
• Absence of procedural mortality AND
• Correct positioning of a single prosthetic heart valve into the proper anatomical location AND
• Intended performance of the prosthetic heart valve (no prosthesis–patient mismatch and mean aortic
valve gradient <20 mmHg or peak velocity <3 m/s, AND no moderate or severe prosthetic valve
regurgitation)
Primary Endpoint
Device success (without PPM)
Total BAV NO-BAV P
90.7% (117/129) 87.3% (55/63) 93.9% (62/66) 0.19
Device success definition VARC 1 criteria:
• Successful vascular access, delivery and deployment of the device and successful retrieval of the
delivery system
• Correct position of the device in the proper anatomical location
• Intended performance of the prosthetic heart valve (aortic valve area 1.2 cm2 and mean aortic valve
gradient <20 mmHg or peak velocity<3 m/s, without moderate or severe prosthetic valve AR)
• Only one valve implanted in the proper anatomical location
Device Failure Reasons
• 2 TAV in TAV, 1 pt with post tavi velocities >3m/s and 10 pts
with PVL>mild (including the one with valve in valve): total
12 device failure
• 17 pts with PPM
Device failureTAV in TAV
Device failureTAV in TAV
DeathPeriprocedural – In hospital – 30 days
Total BAV NO-BAV
0% (0/138) 0% (0/68) 0% (0/70)
StrokePeriprocedural – In hospital – 30 days
Total BAV NO-BAV
0.7% (1/138) 0% (0/68) 1.4% (1/70)
Non disabling stroke day 1 day after intervention
(Israel)
Post TAVI Echocardiographic Characteristics
Total (n=138) BAV (n=68) No BAV (n=70)
Vmax (m/s) 2.07±0.47 2.05±0.47 2.1±0.47
Mean Gradient
(mmHg)
10.31±4.93 9.2±4.5 11.24±5.1
Peak Gradient
(mmHg)
19.40±8.26 18.54±8.7 20.09±7.9
AVA (cm2) 1.85±0.42 1.90±0.38 1.79±0.46
AVAi (cm2/m2) 1.03±0.24 1.07±0.22 0.98±0.25
Ejection Fraction
(%)
51.94±9.11 52.65±8.49 51.28±9.68
PASP (mmHg) 41.60±12.91 42.31±11.63 41.07±13.87
Periprocedural ComplicationsPacemaker Implantation
Total BAV NO-BAV P
31.8% (35/110) 31.5% (17/54) 32.1% (18/56) 0.64
• 28 patients had already pacemaker. In 2 pts implantation took place after discharge.
• Out of 35 patients that received pacemaker, in 30 pts Evolut R was implanted, in 5
Corevalve and in 0 Evolut pro
Periprocedural ComplicationsPacemaker Implantation per Center
Onassis Cardiac
Surgery Centre
First Department
of Cardiology,
Hippokration
Hospital
Heart Institute,
Hadassah
Hebrew
University
Medical Center,
Israel
Athens Naval
Hospital
Pacemaker
implantation rate
22.2% 33.3% 40% 30%
Periprocedural ComplicationsMajor Vascular Complications
Total BAV NO-BAV p
4.3% (6/138) 2.9% (2/68) 5.7% (4/70) 0.43
Definition:
• Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudo-
aneurysm OR
• Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula,
pseudoaneurysm, haematoma, irreversible nerve injury, compartment syndrome, percutaneous closure device failure)
leading to death, life-threatening or major bleedinga, visceral ischaemia, or neurological impairment OR
• Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible
end-organ damage OR
• The use of unplanned endovascular or surgical intervention associated with death, major bleeding, visceral ischaemia or
neurological impairment OR
• Any new ipsilateral lower extremity ischaemia documented by patient symptoms, physical exam, and/or decreased or
absent blood flow on lower extremity angiogram OR
• Surgery for access site-related nerve injury OR
• Permanent access site-related nerve injury OR
Total BAV NO-BAV p
12.8% (19/138) 5.9% (4/68) 21.4% (15/70) 0.008
Periprocedural ComplicationsMinor Vascular Complications
Definition:
• Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula,
pseudoaneuysms, haematomas, percutaneous closure device failure) not leading to death, life-threatening or
major bleedinga, visceral ischaemia, or neurological impairment OR
• Distal embolization treated with embolectomy and/or thrombectomy and not resulting in amputation or
irreversible end-organ damage OR
• Any unplanned endovascular stenting or unplanned surgical intervention not meeting the criteria for a major
vascular complication OR
• Vascular repair or the need for vascular repair (via surgery, ultrasound-guided compression, transcatheter
embolization, or stent-graft) OR
• Percutaneous closure device failure Failure of a closure device to achieve haemostasis at the arteriotomy site
leading to alternative treatment (other than manual compression or adjunctive endovascular ballooning)
Total BAV NO-BAV p
Total 8% (11/138) 8.8% (6/68) 7.1% (5/70) 0.76
Stage 1 5.8% (8/138) 7.4% (5/68) 4.3% (3/70) 0.49
Stage 2 0.7% (1/138) 0% (0/68) 1.4% (1/70)
Stage 3 1.4% (2/138) 1.5% (1/68) 1.4% (1/70)
Periprocedural ComplicationsAKI
Definition:
Stage 1:
Increase in serum creatinine to 150–199% (1.5–1.99 × increase compared with baseline) OR increase of ≥0.3
mg/dl (≥26.4 mmol/l) OR
Urine output <0.5 ml/kg/h for >6 but <12 h
Stage 2:
Increase in serum creatinine to 200–299% (2.0–2.99 × increase compared with baseline) OR
Urine output <0.5 ml/kg/h for >12 but <24 h
Stage 3:
Increase in serum creatinine to ≥300% (>3 × increase compared with baseline) OR serum creatinine of ≥4.0
mg/dl (≥354 mmol/l) with an acute increase of at least 0.5 mg/dl (44 mmol/l) OR
Urine output <0.3 ml/kg/h for ≥24 h OR
Anuria for ≥12 h
Bleeding TOTAL BAV NO-BAV p
All bleeding 12.3% (17/138) 10.3% (7/68) 14.3% (10/70) 0.48
Major 4.3% (6/138) 2.9% (2/68) 5.7% (4/70) 0.69
Minor 8% (11/138) 7.4% (5/68) 8.6% (6/70)
Blood transfusion 32.6% (45/138) 27.9% (19/68) 37.1% (27/70) 0.25
Number of blood
units
1.64±0.84 1.61±0.85 1.65±0.85 0.74
Periprocedural ComplicationsBleeding
Life-threatening or disabling bleeding
Fatal bleeding (BARC type 5) OR
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular
with compartment syndrome (BARC type 3b and 3c) OR
Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR
Overt source of bleeding with drop in haemoglobin ≥5 g/dl or whole blood or packed red blood cells (RBCs) transfusion ≥4 units (BARC
type 3b)
Major bleeding (BARC type 3a)
Overt bleeding either associated with a drop in the haemoglobin level of at least 3.0 g/dl or requiring transfusion of two or three units of
whole blood/RBC, or causing hospitalization or permanent injury, or requiring surgery AND Does not meet criteria of life-threatening or
disabling bleeding
Minor bleeding (BARC type 2 or 3a, depending on the severity)
Any bleeding worthy of clinical mention (e.g. access site
haematoma) that does not qualify as life-threatening, disabling,
or major
PVL TOTAL BAV NO-BAV p
None 26.8% (37/138)
Post BAV: 5/37
26.5% (18/68)
Post BAV: 2/18
27.1% (19/70)
Post BAV: 3/19
0.67
Mild 65.2% (90/138)
Post BAV: 19/90
63.2% (43/68)
Post BAV: 6/43
67.1% (47/70)
Post BAV: 13/47
Moderate 7.2% (10/138)
Post BAV: 4/10
8.8% (6/68)
Post BAV: 2/6
5.7% (4/70)
Post BAV:2/4
Severe 0.7% (1/138)
Post BAV: 1/1
1.5% (1/68)
Post BAV: 1/1
0% (0/70)
PARAVALVULAR REGURGITATION
PVL definition:
ALL CAUSE MORTALITY
(30 days-1 year)
Total BAV NO-BAV p
2.3% (3/130) 3.2% (2/62) 1.5% (1/68) 0.47
1. Death from chest infection 172 days
2. Death from gastrointestinal bleeding (ca stomach and triple therapy) on 53 days
3. Death from pulmonary embolism and cancer at 173 days
STROKE
(30 days-1 year)
Total BAV NO-BAV
0.8% (1/130) 1.6% (1/62) 0% (0/68)
On day 185 under dual antiplatelet therapy
90% carotid artery stenosis
TAVI RCTsComparison
DIRECT COREVALVE US SURTAVI PARTNER 2
All cause Mortality
30 day 0% 3.3% 2.2% 3.9%
1 year 2.3% 14.2% 6.7% 12.3%
Stroke
30 day 0.7% 4.9% 3.4% 5.5%
1 year 1.4% 8.8% 5.4% 8%
Pacemaker 31.8% 19.8% 25.9% 8.5%
PVL (moderate+severe) 7.9% 7.8% 3.4% 3.8%
Multicenter Randomized Trials in Greece
• Background - Questions
• Feasible
• Sponsorship
