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ACC 2012 RDN Final

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ACC 2012 RDN Final

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ACC 2012 RDN Final

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  1. UC201206031EE Symplicity HTN-1 and HTN-2 Data Presented at ACC 2012

  2. Introduction UC201206031EE • Hello and welcome to the ACC 2012 Symplicity™ RDN Data eLearning module. • This course will describe the data and the results of the Symplicity HTN-1 and HTN-2 clinical trials as presented at the 2012 American College of Cardiology (ACC) meeting. • The new data presents a prime opportunity for Medtronic RDN to position the Symplicity brand for long-term market share growth and maintenance.

  3. Learning Objectives UC201206031EE After completing this module, you will be able to: • Articulate key messages from the latest Symplicity™ RDN data • Describe the sustained results seen in Symplicity HTN-1 at 3 years • Explain the superior results achieved in the Symplicity HTN-2 clinical study

  4. Section 1: The Key Message UC201206031EE Only the Symplicity™ RDN system has proven… SAFE SUPERIOR SUSTAINED …reductions in blood pressure

  5. Safety Established UC201206031EE • Over 4000 patients treated • First use: June 2007 • No serious device or procedure related events • No evidence of vascular injury/stenosis at a treatment site via imaging at 6 months • No orthostatic or electrolyte disturbances • Sustained renal function (eGFR and creatinine) • No indication of late procedure-related safety events out to 3 years Data from: Symplicity HTN-1 and Symplicity HTN-2 SAFE SUPERIOR SUSTAINED

  6. Common Objections on Safety UC201206031EE • Delivering RF to the vessel will damage it. How do you know there will not be any late safety issues? • Ultrasound, Drug Delivery, Bipolar, etc. ... may cause less damage to the vessel, I’ll just wait for that.

  7. Handling Objections: Safety UC201206031EE Objection: Delivering RF to the vessel will damage it, how do you know there will not be any late safety issues? Talking Points: • The Symplicity™ RDN system has a very positive safety record and has been used in 4000+ patients • Generator features numerous shut-off and adjustment proprietary algorithms with the ability to respond to changes in the artery within 1 millisecond • Published preclinical work reveals no sign of inflammatory cells at 6 months. • Clinical follow-up from HTN-1 and HTN-2 reveals NO significant treatment-related events and no significant changes in kidney function.

  8. Handling Objections: Safety UC201206031EE Objection: Ultrasound, Drug Delivery, Bipolar, etc. …may cause less damage to the vessel. I’ll just wait for that. Talking Points: • NO long term human data on these experimental approaches • Amount, depth and type of denervation caused by the Symplicity™ system is very specific – not transferrable. • The long-term safety and efficacy of the Symplicity system has been established through careful studies, starting in June of 2007. • Any new technology will need to prove itself in well-controlled, long-term studies as well.

  9. Superiority Proven UC201206031EE Symplicity HTN-2 SAFE SUPERIOR ∆ from Baseline to 6 Months (mmHg) Systolic Diastolic The randomised controlled study showed a superior reduction in BP of the RDN group vs. the Control group at 6 months. SUSTAINED Diastolic p <0.01 for difference between RDN and Control Systolic

  10. Common Objections on Superiority UC201206031EE • What causes non-responders (or slow responders)? • All RF energy delivery is the same. I expect this other device will have the same effect as the Symplicity™ system? • RDN only affects white coat hypertension. ABPM response is not significant.

  11. Handling Objections: Superiority UC201206031EE Objection: What causes non-responders (or slow responders)? Talking Points: • There are a variety of hypotheses for slow response, but we don’t currently know why therapy response may take different amounts of time for different patients. • What is encouraging is that we have seen a trend towards improved response time. Recently, results from the Symplicity HTN-1 trial suggested that 100% of patients who had reached 3 year follow up had showed at least 10 mmHg reduction by that point.

  12. Handling Objections: Superiority UC201206031EE Objection: All RF energy delivery is the same. I expect this other device will have the same effect as the Symplicity™ system. Talking Points: • I understand this idea and, at first, I had a similar thought. When I looked into this further, I found that the depth and characteristics of the lesion created vary quite significantly based on seemingly small differences between products. For example, changing the electrode size (keeping all else the same) can dramatically increase the injury zone, potentially affecting adjacent tissues, etc. (Examples can be seen on the ESC and HRS websites). These differences could impact the prognosis for long term safety and efficacy. For this reason, it will be important to carefully evaluate any new system in a well-controlled clinical study before adoption more broadly. • (http://www.hrsonline.org/education/selfstudy/onlinecourses/ablation.cfm)

  13. Handling Objections: Superiority UC201206031EE Objection: RDN only affects white coat hypertension. ABPM response is not significant. Talking Points: • There were only 20 patients who had >70% of paired ambulatory blood pressure measurements readable and hence, allowed into study data. • Of these patients, their office and home SBP was also lower, so maybe there was a selection bias. • However, ambulatory blood pressure measurements are always lower because it takes into account night time measurements, when blood pressure is already lower (dipping), so a reduction in SBP is also lower. • In fact, according to JNC-7, the criteria for uncontrolled BP in home measurements is 135/85 mmHg; 24-hour ambulatory BP includes an overnight threshold of 120/75 mmHg

  14. Sustained Effect UC201206031EE • The Symplicity HTN-1 non-randomised study shows significant reduction in BP relative to baseline at all timepoints out to 3 years SAFE Symplicity HTN-1 SUPERIOR SUSTAINED

  15. Common Objections on Sustainability UC201206031EE • Nerves can grow back. How do you know that the effect is sustained? • Why does it take 3 years for the response?

  16. Handling Objections: Sustainability UC201206031EE Objection: Nerves can grow back. How do you know that the effect is sustained? Talking Points: • Although nerve fibers might grow to transplanted organs, recovery of renal sympathetic function in man has not been shown. • Furthermore, renal afferent fibers might never reestablish function as suggested by the absence of angina following cardiac transplantation. • In Symplicity HTN-1, no loss of antihypertensive response was evident with follow-up now to three years (ACC 2012).

  17. Handling Objections: Sustainability UC201206031EE Objection: Why does it take 3 years for the response? Talking Points: • In Symplicity HTN-1over 70% of patients had ≥10 mmHg response within 1 month. • What is encouraging is that we have seen a trend toward improved response over time. Recently, results from the Symplicity HTN-1 trial suggested that 100% of patients who had reached 3 year follow up had showed ≥10 mmHg reduction by that point. • There are a variety of hypotheses for this pattern, but we don’t currently know why therapy response may take different amounts of time for different patients.

  18. The Bonus “S” – SpecificNot all Ablation is the Same UC201206031EE • Different catheter designs may impact the consistency of ablation depth and safety • Electrode Size/Shape • Ablation Power/Waveform • Time of Exposure • Type of Energy Different Catheter Different Results More information is available from the European Society of Cardiology (www.escardio.org) and Heart Rhythm Society (www.hrsonline.org)

  19. Summary Section 1: The Key Message UC201206031EE The Symplicity RDN System has proven: SAFE - Strong safety record in over 4000 patients SUPERIOR - Proven superiority in a randomised study SUSTAINED - Sustained results to 3 years SPECIFIC - Not all catheters are the same

  20. Section 2: Symplicity HTN-1 UC201206031EE This section will describe the following about the Symplicity HTN-1 Trial: • The STUDY • The PATIENTS • The PROCEDURE • The RESULTS • The SAFETY RECORD • The RESPONSE OVER TIME

  21. Symplicity HTN-1: The STUDY The Symplicity HTN-1 Trial involved a groundbreaking series of non-randomised studies UC201206031EE • Initial First-in-Man Cohort: • 45 patients, EU, Australia • Non-Randomised • First patient enrolled: June, 2007 • 12-month initial report in The Lancet, 2009 • Expanded Cohort* (this report): • 153 patients, EU, Australia, USA • Non-Randomised • 36-month follow-up Key Inclusion Criteria • Office SBP ≥160 mmHg • Stable drug regimen of 3+ more anti-HTN medications • eGFR ≥45 mL/min/1.73m2 *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  22. Symplicity HTN-1: The PATIENTS UC201206031EE Patient population reflects severe treatment-resistant hypertension Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  23. Symplicity HTN-1: The PROCEDURE The Symplicity HTN-1 Trial involved a brief procedure with a low complication rate UC201206031EE • 38-minute median time from first to last ablation • Average of 4 ablations per artery • Intravenous narcotics and sedatives used to manage pain during delivery of RF energy • No catheter or generator malfunctions • No major complications • Minor complications 4/153 • 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae • 3 access site complications, treated without further sequelae Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  24. Symplicity HTN-1: The RESULTS Patients experienced significant, sustained blood pressure reductions out to at least 3 years UC201206031EE p <0.01 for  from baseline for all time points Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  25. Symplicity HTN-1: The SAFETY RECORD An impressive safety record continues in long-term follow-up UC201206031EE • 81 patients with 6-month renal CTA, MRA or duplex • No vascular abnormalities at any site of RF delivery • One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae) • One new moderate stenosis which was not hemodynamically relevant and not treated • 3 deaths within the follow-up period; all unrelated to the device or therapy • No hypotensive events that required hospitalisation • There were no observed changes in mean electrolytes or eGFR Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  26. Symplicity HTN-1: The RESPONSE OVER TIME The percentage of responders increased over time UC201206031EE Responder was defined as an office SBP reduction ≥10 mmHg (n=130) (n=59) (n=143) (n=148) (n=144) (n=107) (n=24) (n=24) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  27. Summary Section 2: Symplicity HTN-1 The STUDY - The Expanded Cohort was a non-randomised study of 153 patients over 36 months UC201206031EE The PATIENTS - Baseline BP and number of anti-HTN meds indicates severe treatment-resistant hypertension The PROCEDURE - 38-minute procedure using intravenous narcotics/ sedatives to manage pain, low complication rate The RESULTS - Sustained blood pressure reductions to at least 3 years The SAFETY RECORD - Impressive record throughout long term follow-up The RESPONSE OVER TIME - Percentage of responders increased over time

  28. Check Your Understanding Section 2: Symplicity HTN-1 Please note down your answers to the following questions. UC201206031EE • True/False:Patients with a stable regimen of 2 or more anti-HTN medications were included in the Expanded Cohort. ________ • Fill in the blank: The Expanded Cohort studied patients for ____ months. • Fill in the blank: During the procedure, there was an average of ____ ablations per artery. • True/False: Four out of the 153 patients in the study experienced catheter or generator malfunctions. ________ • Fill in the blank: The systolic change in blood pressure at the 3 year mark was - ____. • Fill in the blank: For patients that completed the 3-year follow-up, ____% have been classified as responders.

  29. Check Your Understanding Section 2: Symplicity HTN-1 How did you do? Compare your answers to those below. UC201206031EE • True/False:Patients with a stable regimen of 2 or more anti-HTN medications were included in the Expanded Cohort. ________ • Fill in the blank: The Expanded Cohort studied patients for ____ months. • Fill in the blank: During the procedure, there was an average of ____ ablations per artery. • True/False: Four out of the 153 patients in the study experienced catheter or generator malfunctions. ________ • Fill in the blank: The systolic change in blood pressure at the 3 year mark was - ____. • Fill in the blank: For patients that completed the 3-year follow-up, ____% have been classified as responders. False. Key inclusion criteria for anti-HTN meds was 3+ 36 4 False. There were no catheter or generator malfunctions. -33 100%

  30. Section 3: Symplicity HTN-2 UC201206031EE This section will describe the following about the Symplicity HTN-2 Trial: • The STUDY • The PATIENT DISPOSITION • The PROCEDURAL SAFETY • The RESULTS • The IMPACT ON MEDICATION • The SAFETY RECORD

  31. Symplicity HTN-2: The STUDY The Symplicity HTN-2 Trial was a randomised controlled trial UC201206031EE • Patients: 106 patients randomised 1:1 to treatment with RDN vs. control • Clinical sites: 24 centres in Europe, Australia and New Zealand Key Inclusion/Exclusion Criteria • Inclusion: • Office SBP ≥160 mmHg (≥150 mmHg with type 2 diabetes mellitus) • Stable drug regimen of 3+ more anti-HTN medications • Age 18–85 years • Exclusion: • Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention • eGFR <45 mL/min/1.73m2 (MDRD formula) • Type 1 diabetes mellitus • Contraindication to MRI • Stenotic valvular heart disease for which reduction of BP would be hazardous • MI, unstable angina or CVA in the past 6 months *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  32. Symplicity HTN-2: The PATIENT DISPOSITION Assessed for Eligibility (n=190) UC201206031EE Screening • Excluded During Screening, • Prior to Randomisation (n=84) • BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) • Ineligible anatomy (n=30; 16%) • Declined participation (n=10; 5%) • Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106)

  33. Symplicity HTN-2: The PATIENT DISPOSITION Assessed for Eligibility (n=190) UC201206031EE Screening • Excluded During Screening, • Prior to Randomisation (n=84) • BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) • Ineligible anatomy (n=30; 16%) • Declined participation (n=10; 5%) • Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106) 6-month Primary End-Point Allocated to RDN n=52 Treated n=49 Analysable Allocated to Control n=54 Control n=51 Analysable * Crossed-over with ineligible BP (<160 mmHg)

  34. Symplicity HTN-2: The PATIENT DISPOSITION Assessed for Eligibility (n=190) UC201206031EE Screening • Excluded During Screening, • Prior to Randomisation (n=84) • BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) • Ineligible anatomy (n=30; 16%) • Declined participation (n=10; 5%) • Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106) 6-month Primary End-Point Allocated to RDN n=52 Treated n=49 Analysable Allocated to Control n=54 Control n=51 Analysable 12-month Post- Randomisation 12-month post-RDN n=47 * Crossed-over with ineligible BP (<160 mmHg)

  35. Symplicity HTN-2: The PATIENT DISPOSITION Assessed for Eligibility (n=190) UC201206031EE Screening • Excluded During Screening, • Prior to Randomisation (n=84) • BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) • Ineligible anatomy (n=30; 16%) • Declined participation (n=10; 5%) • Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106) 6-month Primary End-Point Allocated to RDN n=52 Treated n=49 Analysable Allocated to Control n=54 Control n=51 Analysable Crossover n=46 12-month Post- Randomisation 2 LTFU Per protocol, 6-mo Post-RDN (Crossover) n=35 Not-per-protocol*, 6-mo Post-RDN (Crossover) n=9 12-month post-RDN n=47 * Crossed-over with ineligible BP (<160 mmHg)

  36. Symplicity HTN-2: The PATIENT DISPOSITION The RDN and Control populations were well-matched severe treatment-resistant hypertensives UC201206031EE * n = 42 for RDN and n = 43 for Control. Wilcoxon rank-sum test for two independent samples used for between-group comparisons of UACR. † n = 39 for RDN and n = 42 for Control. Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

  37. Symplicity HTN-2: The PROCEDURAL SAFETY There was impressive procedural safety in the Expanded Cohort of treated patients UC201206031EE • One renal artery dissection from injection of contrast into renal artery wall during dye angiography. The lesion was stented without further consequences. • One hospitalisationprolonged in a crossover patient due to hypotension following the RDN procedure. IV fluids administered, anti-hypertensive medications decreased and patient discharge without further incident. • No radiofrequency-related renal artery stenosis or aneurysm occurred in either randomised group. • Minor adverse events (full cohort) • 1 femoral artery pseudoaneurysm treated with manual compression • 1 post procedural drop in BP resulting in a reduction in medication • 1 urinary tract infection • 1 prolonged hospitalisation for evaluation of paraesthesias • 1 back pain treated with pain medications and resolved after 1 month Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

  38. Symplicity HTN-2: The RESULTS RDN is superior to medical management UC201206031EE Latest Follow-up (12M post Randomisation) Primary Endpoint (6M post Randomisation) RDN (n= 47) ∆ from Baseline to 6 Months (mmHg) ∆ from Baseline to 12 Months (mmHg) Systolic Diastolic Diastolic Diastolic p <0.01 for difference between RDN and Control Systolic Reductions sustained to 12M Systolic p <0.01 for  from baseline • Primary Endpoint: • 84% of RDN patients had ≥10 mmHg reduction in SBP • 10% of RDN patients had no reduction in SBP • Latest Follow-up: • Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

  39. Symplicity HTN-2: The SAFETY RECORD No Significant Changes in Renal Function Observed in Either Arm UC201206031EE RDN n=47 Treated at Randomisation Treated after 6-mo follow-up Crossover n=35 Symplicity HTN-2 Investigators. The Lancet. 2010.

  40. Summary Section 3: Symplicity HTN-2 Nicole, Insert coach character The STUDY - The HTN-2 Trial was a randomised controlled trial of 106 patients (1:1 treatment) UC201206031EE The PATIENTS - The RDN and control populations were well-matched, severe treatment-resistant hypertensives The PROCEDURAL SAFETY - There was impressive procedural safety in the expanded cohort of treated patients The RESULTS - RDN is superior to medical management with reductions sustained to 12 months The IMPACT ON MEDICATION - Post-renal denervation showed medication changes at 6 and 12 months The SAFETY RECORD - The safety record continues to be strong in expanded results

  41. Check Your Understanding Section 3: Symplicity HTN-2 Please jot down your answers to the following questions. UC201206031EE • True/False:Patients with diabetes mellitus were excluded from the HTN-2 Trial. ________ • Multiple Choice: There were [no / minor / major] adverse events during the HTN-2 Trial procedure. • Fill in the blank: When following up after 12 months, the systolic change in BP of the RDN group was -_____ . • True/False: The RDN patient population had a much higher baseline BP than the control population. ________ • Multiple Choice: There was a[n] [increase / decrease] in the number of, or dose of, medications at 12 months post-RDN. • True/False: The eGFR and Cystatin C tests show that the safety record for Symplicity™ RDN continues to be ________ in expanded results.

  42. Check Your Understanding Section 3: Symplicity HTN-2 How did you do? Compare your answers to those below. UC201206031EE • True/False:Patients with diabetes mellitus were excluded from the HTN-2 Trial. ________ • Multiple Choice: There were [no / minor / major] adverse events during the HTN-2 Trial procedure. • Fill in the blank: When following up after 12 months, the systolic change in BP of the RDN group was -_____ . • True/False: The RDN patient population had a much higher baseline BP than the control population. ________ • Multiple Choice: There was a[n] [increase / decrease] in the number of, or dose of, medications at 12 months post-RDN. • True/False: The eGFR and Cystatin C tests show that the safety record for Symplicity™ RDN continues to be ________ in expanded results. True minor -28 False. Baseline BPs were well-matched in both populations. decrease strong

  43. Course Recap The Symplicity HTN-1 Trial showed sustained blood pressure reductions out to three years UC201206031EE • Three-year reporting shows no diminishment of effect and impressive long-term safety • For patients that completed the three-year follow-up, 100% have been classified as responders (>10 mmHg reduction), while at 6 months 71% of patients were classified as responders The Symplicity HTN-2 Trial confirmed superior results with a randomised study • The Symplicity HTN-2 treatment population showed a sustained treatment effect at a 12-month follow-up • Control cross-over patients also showed significant blood pressure reduction

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