Bhatt_SIMPLICITY HTN 3

Report
Renal Denervation in Patients with
Uncontrolled Hypertension: Results
of the SYMPLICITY HTN 3 Trial
Deepak L. Bhatt, M.D., M.P.H., David E. Kandzari, M.D.,
William W. O’Neill, M.D., Ralph D'Agostino, Ph.D., John
M. Flack, M.D., M.P.H., Barry T. Katzen, M.D., Martin B.
Leon, M.D., Minglei Liu, Ph.D., Laura Mauri, M.D., M.Sc.,
Manuela Negoita, M.D., Sidney A. Cohen, M.D., Ph.D.,
Suzanne Oparil, M.D., Krishna Rocha-Singh, M.D.,
Raymond R. Townsend, M.D., George L. Bakris, M.D.,
for the SYMPLICITY HTN-3 Investigators
Disclosures for Dr. Bhatt
Advisory Board: Elsevier Practice Update Cardiology, Medscape Cardiology,
Regado Biosciences; Board of Directors: Boston VA Research Institute, Society
of Cardiovascular Patient Care; Chair: American Heart Association Get With The
Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical
Research Institute; Harvard Clinical Research Institute; Mayo Clinic; Population
Health Research Institute (including EnligHTNment); Honoraria: American
College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications
(Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical
trial steering committees), Harvard Clinical Research Institute (clinical trial
steering committee), HMP Communications (Editor in Chief, Journal of Invasive
Cardiology); Population Health Research Institute (clinical trial steering
committee), Slack Publications (Chief Medical Editor, Cardiology Today’s
Intervention), WebMD (CME steering committees); Research Grants: Amarin,
AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic (co-PI of
SYMPLICITY HTN-3, steering committee member of SYMPLICITY HTN-4),
Roche, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo,
PLx Pharma, Takeda.
This presentation discusses off-label and investigational uses of various devices.
The SYMPLICITY HTN-3 trial was funded by Medtronic, Inc.
Background
• Due to aging of the population and greater trends towards
obesity, hypertension is growing in prevalence worldwide.
• Approximately 10% of patients with diagnosed
hypertension have “resistant” hypertension.
• The sympathetic nervous system appears to play an
important role in resistant hypertension.
• Prior non-blinded studies have suggested that catheterbased renal artery denervation reduces blood pressure in
resistant hypertension.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Trial Objectives
• SYMPLICITY HTN-3 is the first prospective, multi-center,
randomized, blinded, sham controlled study to evaluate
both the safety and efficacy of percutaneous renal artery
denervation in patients with severe treatment-resistant
hypertension.
• The trial included 535 patients enrolled by 88 participating
US centers.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
MetroHealth
Participating Sites
Providence
Cleveland, OH
St. Joseph
Mercy Oakland
Pontiac, MI
U of Michigan
St. Joseph
Mercy
Ann Arbor, MI
Southfield, MI
Morristown
Memorial
UH Case
Cleveland, OH
Brigham & Women’s
Morristown, NJ
Harper
Boston, MA
Virginia
Commonweath U
Detroit, MI
Burlington, MA
Fletcher Allen
Richmond, VA
Ypsilanti, MI
Lahey Clinic
South Burlington, VT
U of Virginia
U of Mass
Charlottesville, VA
Worcester, MA
Providence
Spokane, WA
Abbott Northwestern
U of Connecticut
Farmington, CT
Montefiore
Bronx, NY
SUNY
U of Pitt
Minneapolis, MN
VA Boston
West Roxbury, MA
Brooklyn, NY
Pittsburg, PA
Rhode Island
Providence, RI
Stony Brook U
Aurora St. Lukes
St. Mary’s
Stony Brook, NY
Milwaukee, WI
St. Francis
Rochester, MN
Roslyn, NY
Wheaton Franciscan
Mount Sinai
Racine, WI
Stanford
Palo Alto, CA
New York, NY
Mercy Medical
West Des Moines, IA
U of Colorado
Cleveland Clinic
Weill
Cleveland, OH
New York, NY
St. John’s
Aurora, CO
Springfield, IL
Orange, CA
Scripps
MIdwest
Heart
St. Louis, MO
U of Texas
Los Angeles, CA
Lexington, KY
Baptist
Memorial
Plano, TX
Neptune, NJ
Duke
Durham, NC
Vanderbilt
Nashville, TN
Carolinas Medical
Charlotte, NC
Philadelphia, PA
Philadelphia, PA
Lankenau
Wynnewood, PA
Chatanooga, TN
Medical USC
Charleston, SC
Mayo Clinic
Dallas, TX
Jacksonville, FL
Scott & White
Deborah
Heart & Lung
Brown Mills, NJ
Geisinger
Danville, PA
Temple, TX
Shands at UF
Gainesville, FL
Heart Hospital
Austin, TX
U of Penn
Thomas Jefferson U
Dallas VA
Dallas, TX
New York, NY
Jersey Shore
Wake Forest
Winston-Salem, NC
Memorial
Baylor Heart Hospital
Baylor
Columbia University
Columbus, OH
Germantown, TN
Dallas, TX
Cedars-Sinai
U of Kentucky
Barnes Jewish
Chicago, IL
San Diego, CA
Cincinnati, OH
Kansas City, MO
Northwestern
Memorial Oakbrook Terrace, IL
Sharp
Kaiser Permanente
Christ Hospital
St. Luke’s
Chicago, IL
La Jolla, CA
Los Angeles, CA
Langone
New York, NY
Riverside
Methodist
U of Chicago Medical Ctr
St. Joseph
Ohio State
Columbus, OH
Emory
Methodist
Lancaster, PA
U of Maryland
Atlanta, GA
Houston, TX
Lancaster General
Baltimore, MD
Piedmont
Washington
Hospital Center
Atlanta, GA
Washington, DC
Forrest General
Hattiesburg, MS
Princeton
Baptist Medical
Ochsner
New Orleans, LA
Washington, DC
Tampa General
Birmingham, AL
Memorial Hermann
Houston, TX
Howard University
Tampa, FL
U of Miami
Miami, FL
U of Alabama
Baptist Hospital
Birmingham, AL
Miami, FL
George Washington
University
Washington, DC
UNC Memorial
Chapel Hill, NC
SYMPLICITY HTN-3 Committees
Steering Committee
Co-PIs: Deepak L. Bhatt, MD, MPH, and
George L. Bakris, MD
Chair: William O’Neill, MD
Members: Sidney A. Cohen, MD, PhD; Ralph
D'Agostino, PhD; Murray Esler, MBBS, PhD;
John Flack, MD, MPH; David Kandzari, MD;
Barry Katzen, MD; Martin Leon, MD; Laura
Mauri, MD, MSc; Manuela Negoita, MD;
Suzanne Oparil, MD; Krishna Rocha-Singh,
MD; Ray Townsend, MD; Paul Sobotka, MD
Independent Data & Safety Monitoring
Board
Chair: Bernard J. Gersh, MB, ChB, D.Phil
Members: John A. Ambrose, MD; Phyllis
August, MD, MPH; Glenn M. Chertow, MD;
Stuart Pocock, BSc, MSc, PhD
Non-voting member: Joseph Massaro, PhD
Independent Statistical Analysis Validation
Harvard Clinical Research Institute
Independent Clinical Events Committee
Chair: Clive Rosendorff, MD, PhD, DSc Med
Members: Ladan Golestaneh, MD; Steven
Marx, MD; Michele H. Mokrzycki, MD; Joel
Neugarten, MD
Non-voting members: Sorin Brener, MD;
Roxana Mehran, MD
Renal Artery Duplex Core Laboratory
Michael Jaff, DO, VasCore
Angiographic Core Laboratory
Jeffrey J. Popma, MD
Beth Israel Deaconess Medical Center
MRA Core Laboratory
Milind Y. Desai, MD, C5 Research
Blood Core Laboratory
Tania Cochran, Sr. Project Manager
ACM Global Laboratory
Sponsor
Medtronic, Inc.
Key Inclusion Criteria
• Age ≥18 and ≤80 years at time of randomization
• Stable medication regimen including full tolerated doses of
3 or more antihypertensive medications of different classes,
including a diuretic (with no changes for a minimum of 2
weeks prior to screening) and no expected changes for at
least 6 months
• Office SBP ≥160 mm Hg based on an average of 3 blood
pressure readings measured at both an initial and a
confirmatory screening visit
• Written informed consent
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Key Exclusion Criteria
•
ABPM 24 hour average SBP <135 mm Hg
•
eGFR of <45 mL/min/1.73 m2
•
Main renal arteries <4 mm diameter or <20 mm treatable
length
•
Multiple renal arteries where the main renal artery is
estimated to supply <75% of the kidney
•
Renal artery stenosis >50% or aneurysm in either renal
artery
•
History of prior renal artery intervention
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
SYMPLICITY HTN-3 Trial Design
2 weeks
2 weeks
1M
Home BP &
HTN med
confirmation
Screening Visit 1
Screening Visit 2
• Office SBP ≥160
mm Hg
• Office SBP ≥160
mm Hg
• Full doses ≥3
meds
• 24-h ABPM SBP
≥135 mm Hg
• No med changes
in past 2 weeks
• Documented med
adherence
• No planned med
changes for 6 M
3M
Home BP &
HTN med
confirmation
6M
Sham Procedure
Renal
angiogram;
Eligible
subjects
randomized
Renal
Denervation
1M 3M
Primary
endpoint
Home BP &
HTN med
confirmation
2 weeks
6M
• Patients, BP assessors, and study personnel
all blinded to treatment status
• No changes in medications for 6 M
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
12-60 M
Primary Safety Endpoint
• The rate of Major Adverse Events (MAE) in the treatment
group compared with an Objective Performance Criterion
(OPC)
• OPC = 9.8% (derived from historical data)
• MAE was defined as all-cause mortality, end-stage renal
disease, embolic event resulting in end-organ damage,
renal artery or other vascular complication, hypertensive
crisis through 30 days, or new renal artery stenosis within
six months
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Efficacy Endpoints
Primary Effectiveness Endpoint:
• Comparison of office SBP change from baseline to 6 months
in RDN arm compared with change from baseline to 6
months in control arm
Endpoint = (SBPRDN 6 month – SBPRDN Baseline) – (SBPCTL 6 month – SBPCTL Baseline)
• Superiority margin of 5 mm Hg
Powered Secondary Effectiveness Endpoint:
• Comparison of mean 24-hour ambulatory (ABPM) SBP
change from baseline to 6 months in RDN arm compared
with change from baseline to 6 months in control arm
• Superiority margin of 2 mm Hg
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Patient Disposition
1441 subjects assessed for eligibility
Excluded:
• 880 not eligible for randomization
• 26 eligible but not randomized because
randomization cap was reached
535 subjects randomized
364 subjects randomly
allocated to renal
denervation
171 subjects randomly
allocated to sham
control
• 2 subjects died
• 1 subject withdrew
• 11 missed 6-month
visit
350 (96.2%) subjects with
6 month follow-up
• 1 subject died
• 1 missed 6-month visit
169 (98.8%) subjects with
6 month follow-up
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Results: Population Demographics
Characteristic
mean ± SD or %
Renal Denervation Sham Procedure
(N=364)
(N=171 )
P
57.9 ± 10.4
56.2 ± 11.2
0.09
59.1
64.3
0.26
180±16
159±13
34.2 ± 6.5
180±17
160±15
33.9 ±6.4
0.77
0.83
0.56
0.57
24.8
73.0
29.2
69.6
9.3
1.4
25.8
9.9
2.3
31.6
0.88
0.48
0.18
Stroke
Type 2 diabetes
Hospitalization for hypertensive crisis
8.0
47.0
22.8
11.1
40.9
22.2
0.26
0.19
0.91
Hyperlipidemia
69.2
64.9
0.32
Current smoking
9.9
12.3
0.45
Age (years)
Male sex (%)
Office systolic blood pressure (mm Hg)
24 hour mean systolic ABPM (mm Hg)
BMI (kg/m2)
Race* (%)
African American
White
Medical history (%)
Renal insufficiency (eGFR<60 ml/min/1.73m2)
Renal artery stenosis
Obstructive sleep apnea
*Race also includes Asian, Native American, or other
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Baseline Hypertensive Therapy
Characteristic
mean ± SD or %
No. of antihypertensive medications
Angiotensin-converting enzyme inhibitors
% at max tolerated dose
Angiotensin receptor blockers
% at max tolerated dose
Aldosterone antagonists
Alpha-adrenergic blockers
Beta blockers
Calcium channel blockers
% at max tolerated dose
Centrally-acting sympatholytics
Diuretics
% at max tolerated dose
Direct renin inhibitors
Direct-acting vasodilators
Renal Denervation
(N=364)
Sham Procedure
(N=171 )
5.1 ± 1.4
49.2
45.9
50.0
49.5
22.5
11.0
85.2
69.8
57.1
49.2
99.7
96.4
7.1
36.8
5.2 ± 1.4
41.5
37.4
53.2
51.5
28.7
13.5
86.0
73.1
63.7
43.9
100
97.7
7.0
45.0
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Blinding Efficacy
Blinding Procedure:
•
•
•
•
All patients underwent renal angiography
Conscious sedation
Sensory isolation (e.g., blindfold and music)
Lack of familiarity with procedural details and expected
duration
• Assessed by questionnaire at discharge and 6 months
(before unblinding)
Time
Blinding Index*
95% CI
Discharge
0.68
(0.64, 0.72)
6 Months
0.77
(0.74, 0.81)
*The lower boundaries of the confidence intervals of the
blinding index are both > 0.5, indicating sufficient
evidence of blinding.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Primary Safety Endpoint
10%
Major
Adverse
Event
Rate
(MAE)
Performance Goal = 9.8%
8%
6%
P < 0.001
4%
2%
1.4%
0%
MAE
Renal Denervation
(N=364)
1.4% (5/361)
Sham Procedure
(N=171)
0.6% (1/171)
Difference [95% CI]
0.8% [-0.9%, 2.5%]
*comparison of MAE to control group
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
P*
0.67
Safety Event Rate
Safety Measures (%)
Major Adverse Events
To 6 Months
6-Month Composite Safety
Death
Myocardial infarction
New onset ESRD
Serum creatinine elevation >50%
Embolic event resulting in end-organ
damage
Renal artery intervention
Vascular complication requiring treatment
Hypertensive crisis/emergency
Stroke
Hospitalization for new onset heart failure
Hospitalization for atrial fibrillation
New renal artery stenosis >70%
Renal
Sham
Denervation Procedure
(N=364)
(N=171)
Difference
(95% CI)
P
1.4
0.6
0.8 (-0.9, 2.5)
0.67
4.0
0.6
1.7
0
1.4
0.3
5.8
0.6
1.8
0
0.6
0
-1.9 (-6.0, 2.2)
0.0 (-1.4, 1.4)
0.0 (-2.4, 2.3)
0.8 (-0.8, 2.5)
0.3 (-0.3, 0.8)
0.37
1.00
1.00
0.67
1.00
0
0.3
2.6
1.1
2.6
1.4
0.3
0
0
5.3
1.2
1.8
0.6
0
0.3 (-0.3, 0.8)
-2.7 (-6.4, 1.0)
0.0 (-2.0, 1.9)
0.8 (-1.8, 3.4)
0.8 (-0.8, 2.5)
0.3 (-0.3, 0.9)
1.00
0.13
1.00
0.76
0.67
1.00
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Primary Efficacy Endpoint
Δ = -2.39 (95% CI, -6.89 to 2.12)
P=0.26*
Δ = -14.1±23.9
Δ = -11.7±25.9
P<0.001
P<0.001
Office SBP (mm Hg)
200
150
180 mm Hg
180 mm Hg
168 mm Hg
166 mm Hg
Baseline
6 Months
100
50
0
(N=364)
(N=353)
Denervation
*P value for superiority with a 5 mm Hg margin; bars denote standard deviations
(N=171)
(N=171)
Sham
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Powered Secondary Efficacy
Endpoint
Δ = -1.96 (95% CI, -4.97 to 1.06)
P=0.98*
Δ = -6.8±15.1
Δ = -4.8±17.3
P<0.001
P<0.001
150
ABPM (mm Hg)
24-hour mean systolic
180
159 mm Hg
152 mm Hg
160 mm Hg
154 mm Hg
120
Baseline
6 Months
90
60
30
0
(N=360)
(N=329)
Denervation
*P value for superiority with a 2 mm Hg margin; bars denote standard deviations
(N=167)
(N=162)
Sham
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Change in Office SBP by Tertile
of Baseline Office SBP
<170 mm Hg
170 – 184 mm Hg
>184 mm Hg
0
∆ Office SBP (mm Hg)
N=124
N=54
N=107
N=61
N=119
N=54
-4.5
-10
-6.6
-9.8
P=0.57
-13.8
P=0.29
-20
-19.7
Denervation
Control
-30
-25.7
P=0.13
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Results: Prespecified Subgroup
Analyses
*
* P value for superiority with margin of 5 mm Hg
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Potential Limitations
• Drug adherence not measured by blood levels, but
adherence was measured by patient diaries at baseline
and 6 months.
• Medication changes did occur, but results unchanged
even when these patients were censored.
• Duration of primary endpoint may have been too short,
but prior studies had found benefit by 6 months.
• Operator learning curve is always a possibility, but we
found no relationship with procedural volume in the trial.
• Biological confirmation of denervation did not occur, as
there is no accepted measure, but appropriate energy
delivery was confirmed.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Conclusions
• In a prospective, multicenter, randomized, blinded, sham
controlled trial of patients with uncontrolled resistant
hypertension, percutaneous renal denervation was safe
but not associated with significant additional reductions in
office or ambulatory blood pressure.
• These results underscore the importance of blinding and
sham controls in evaluations of new devices.
• Further study in rigorously designed clinical trials will be
necessary to confirm previously reported benefits of renal
denervation in patients with resistant hypertension or to
validate alternate methods of renal denervation.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
For Full Details, Please Go to WWW.NEJM.ORG
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

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