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Disclosures for Dr. Bhatt

Renal Denervation in Patients with Uncontrolled Hypertension: Results of the SYMPLICITY HTN 3 Trial.

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Disclosures for Dr. Bhatt

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  1. 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

  2. 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, PLxPharma, Takeda. This presentation discusses off-label and investigational uses of various devices. The SYMPLICITY HTN-3 trial was funded by Medtronic, Inc.

  3. 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 catheter-based 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

  4. 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

  5. Participating Sites MetroHealth Cleveland, OH Morristown Memorial Morristown, NJ St. Joseph Mercy Oakland Pontiac, MI UH Case Cleveland, OH Brigham & Women’s Boston, MA U of Michigan Ann Arbor, MI Harper Detroit, MI Providence Southfield, MI Virginia Commonweath U Richmond, VA Lahey Clinic Burlington, MA St. Joseph Mercy Ypsilanti, MI VA Boston West Roxbury, MA Fletcher Allen South Burlington, VT U of Connecticut Farmington, CT U of Virginia Charlottesville, VA U of Mass Worcester, MA Montefiore Bronx, NY Providence Spokane, WA SUNY Brooklyn, NY Abbott Northwestern Minneapolis, MN U of Pitt Pittsburg, PA Rhode Island Providence, RI Stony Brook U Stony Brook, NY Aurora St. Lukes Milwaukee, WI St. Mary’s Rochester, MN St. Francis Roslyn, NY Wheaton Franciscan Racine, WI Mount Sinai New York, NY Stanford Palo Alto, CA Mercy Medical West Des Moines, IA Weill New York, NY Cleveland Clinic Cleveland, OH U of Colorado Aurora, CO Ohio State Columbus, OH St. John’s Springfield, IL Langone New York, NY Riverside Methodist Columbus, OH Columbia University New York, NY U of Chicago Medical Ctr Chicago, IL Jersey Shore Neptune, NJ Christ Hospital Cincinnati, OH St. Luke’s Kansas City, MO Wake Forest Winston-Salem, NC St. Joseph Orange, CA U of Penn Philadelphia, PA Duke Durham, NC MIdwest Heart Oakbrook Terrace, IL Northwestern Memorial Chicago, IL U of Kentucky Lexington, KY Barnes Jewish St. Louis, MO Vanderbilt Nashville, TN Thomas Jefferson U Philadelphia, PA Scripps La Jolla, CA Baptist Memorial Germantown, TN Carolinas Medical Charlotte, NC Lankenau Wynnewood, PA U of Texas Dallas, TX Memorial Hospital Chatanooga, TN Sharp San Diego, CA Baylor Heart Plano, TX Deborah Heart & Lung Brown Mills, NJ Medical USC Charleston, SC Baylor Dallas, TX Dallas VA Dallas, TX Cedars-Sinai Los Angeles, CA Mayo Clinic Jacksonville, FL Geisinger Danville, PA Scott & White Temple, TX Shandsat UF Gainesville, FL Lancaster General Lancaster, PA Kaiser Permanente Los Angeles, CA Heart Hospital Austin, TX Emory Atlanta, GA U of Maryland Baltimore, MD Methodist Houston, TX Piedmont Atlanta, GA WashingtonHospital Center Washington, DC Howard University Washington, DC Princeton Baptist Medical Birmingham, AL Tampa General Tampa, FL Forrest General Hattiesburg, MS U of Miami Miami, FL George WashingtonUniversity Washington, DC Memorial Hermann Houston, TX Baptist Hospital Miami, FL U of Alabama Birmingham, AL Ochsner New Orleans, LA UNC Memorial Chapel Hill, NC

  6. SYMPLICITY HTN-3 Committees • Independent Clinical Events Committee • Chair: Clive Rosendorff, MD, PhD, DSc Med • Members: LadanGolestaneh, MD; Steven Marx, MD;Michele H. Mokrzycki, MD; Joel Neugarten, MD • Non-voting members: SorinBrener, 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 LaboratoryMilindY. Desai, MD, C5 Research • Blood Core Laboratory • Tania Cochran, Sr. Project Manager • ACM Global Laboratory • SponsorMedtronic, Inc. 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

  7. 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

  8. 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

  9. SYMPLICITY HTN-3 Trial Design 2 weeks 2 weeks 1 M 3 M 6 M Home BP & HTN med confirmation Home BP & HTN med confirmation Sham Procedure Renal angiogram; Eligible subjects randomized Primary endpoint Screening Visit 1 Screening Visit 2 • Office SBP ≥160 mm Hg • Full doses ≥3 meds • No med changes in past 2 weeks • No planned med changes for 6 M • Office SBP ≥160 mm Hg • 24-h ABPM SBP≥135 mm Hg • Documented med adherence Renal Denervation Home BP & HTN med confirmation 6 M 1 M 3 M 12-60 M 2 weeks • 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

  10. 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

  11. 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 = (SBPRDN6 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

  12. 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 171 subjects randomly allocated to sham control 364 subjects randomly allocated to renal denervation • 2 subjects died • 1 subject withdrew • 11 missed 6-month visit • 1 subject died • 1 missed 6-month visit 350 (96.2%) subjects with 6 month follow-up 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

  13. Results: Population Demographics *Race also includes Asian, Native American, or other Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

  14. Baseline Hypertensive Therapy Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

  15. 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) *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

  16. Primary Safety Endpoint Performance Goal = 9.8% Major Adverse Event Rate (MAE) P < 0.001 *comparison of MAE to control group Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

  17. Safety Event Rate Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

  18. Primary Efficacy Endpoint Δ = -2.39 (95% CI, -6.89 to 2.12) P=0.26* Δ = -14.1±23.9 P<0.001 Δ = -11.7±25.9 P<0.001 180 mm Hg 180 mm Hg 168 mm Hg 166 mm Hg Office SBP (mm Hg) (N=364) (N=353) (N=171) (N=171) Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014 *P value for superiority with a 5 mm Hg margin; bars denote standard deviations

  19. Powered Secondary Efficacy Endpoint Δ = -1.96 (95% CI, -4.97 to 1.06) P=0.98* Δ = -6.8±15.1 P<0.001 Δ = -4.8±17.3 P<0.001 159 mm Hg 160 mm Hg 154 mm Hg 152 mm Hg 24-hour mean systolic ABPM (mm Hg) (N=329) (N=360) (N=167) (N=162) Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014 *P value for superiority with a 2 mm Hg margin; bars denote standard deviations

  20. Change in Office SBP by Tertile of Baseline Office SBP <170 mm Hg 170 – 184 mm Hg >184 mm Hg -4.5 -6.6 -9.8 P=0.57 ∆ Office SBP (mm Hg) -13.8 P=0.29 -19.7 -25.7 P=0.13 Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

  21. Results: Prespecified Subgroup Analyses * Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014 * P value for superiority with margin of 5 mm Hg

  22. 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

  23. 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

  24. 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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