Prof. Sverre E. Kjeldsen, MD, PhD Past-President European Society of Hypertension

1. The 4th International Conference FIXED COMBINATION, Paris, December 3, 2011 Accomplish Update: Fixed Dose RAAS Blocker and CCB in Prevention of Endpoints in the Treatment of Hypertension Prof. Sverre E. Kjeldsen, MD, PhD Past-President European Society of Hypertension Department of Cardiology, Ullevaal University Hospital, Oslo, Norway, and Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, U.S.A.

2. ACCOMPLISH Organizational Structure Executive Committee Operations Committee DSMB Henry R. Black, Chair Lloyd Fisher, Ph.D., Statistician Suzanne Oparil, M.D., Member Stevo Julius, M.D., Sc.D., Member Lars H. Lindholm, Member Kenneth Jamerson Eric Velazquez Victor Shi, Novartis JitendraGupte, Novartis Kenneth Jamerson, Chair George L. Bakris Björn Dahlöf Bertram Pitt Eric Velazquez Michael A. Weber Novartis Trial Team Steering Committee Endpoint Coordinating Center Sverre Kjeldsen Jan Östergren JaakkoTuomilehto Hans Ibsen William C. Cushman Richard Devereux Brent Egan Barry M. Massie Shawna D. Nesbitt Elizabeth Ofili VasiliosPapademetriou Matthew R. Weir Jackson T. Wright, Jr. Endpoint Committee Independent Statistician Marc A. Pfeffer Scott D. Solomon Kenneth Mahaffey Novartis Vendors Central Clinical Labs Duke Clinical Research Institute/Brigham and Women’s Hospital Tom Greene Investigational Sites

3. ACCOMPLISH: Design Free add-on antihypertensive agents* Amlodipine 10 +benazepril 40 mg Amlodipine 5 mg +benazepril 40 mg Amlodipine 5 mg +benazepril 20 mg Screening Randomization Benazepril 20 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 25 mg Titrated to achieve BP<140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency Free add-on antihypertensive agents* 14 Days Day 1 Month 1 Month 2 Month 3 Year 5 *Beta blockers; alpha blockers; clonidine; (loop diuretics). Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A

4. Targeted Population for Recruitment into the ACCOMPLISH Study Men or women age ≥ 55 years SBP ≥ 160 mmHg or currently on antihypertensive therapy Evidence of cardiovascular or renal disease or target organ damage Accomplish randomized 3333 Nordic patients, 8067 American including 1361 African American patients, 6921 patients with diabetes (60%) and 680 patients with Chronic Renal Disease

5. Systolic Blood Pressure Over Time ACEI / HCTZ N=5733 CCB / ACEI N=5713 mm Hg 130mmHg Difference of 0.7 mmHg p<0.05* 129.3 mmHg Month 5731 5387 5206 4999 4804 4285 2520 1045 5709 5377 5154 4980 4831 4286 2594 1075 Patients *Mean values are taken at 30 months F/U visit DBP: 71.1 DBP: 72.8

6. ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 90 81.7 78.5 80 70 60 Control rate (%) 50 40 Baseline Control Rates 37.9 37.2 30 20 10 ACEI / HCTZ N=5733 CCB / ACEI N=5713 P<0.001 at 30 months follow-up Control defined as <140/90 mmHg

7. Kaplan Meier for Primary Endpoint 20% Risk Reduction ACEI / HCTZ 650 CCB / ACEI 526 Cumulative event rate HR (95% CI): 0.80 (0.72, 0.90) p = 0 .0 0 02 Time to 1st CV morbidity/mortality (days) Jamerson K et al. New Engl J Med 2008; 359: 2417-28.

8. Primary Endpoint and Components Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008 (Intent-to-treat population) Risk Ratio(95%) Composite CV mortality/morbidity Cardiovascular mortality Non-fatal MI Non-fatal stroke Hospitalization for unstable angina Coronary revascularization procedure Resuscitated sudden death 0.80 (0.72–0.90) 0.81 (0.62-1.06) 0.81 (0.63-1.05) 0.87 (0.67-1.13) 0.74 (0.49-1.11) 0.85 (0.74-0.99) 1.75 (0.73-4.17) 2.0 0.5 1.0 Favors CCB / ACEI Favors ACEI / HCTZ Jamerson K et al. New Engl J Med 2008; 359: 2417-28.

9. 24-Hour Mean Ambulatory SBP at Year 2 145 140 135 130 125 120 115 110 Benazepril/amlodipineN=288 Benazepril/HCTZN=285 Mean difference 1.6 mmHg p=0.128 10 AM Mean ambulatory SBP (mmHg) (Mean difference in 24 hour DBP = 0.3 mmHg, p=0.7) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hour Jamerson K et al. Hypertension 2011; 57: 174-179.

10. ACCOMPLISH: Progression of chronic kidney disease (doubling of se-creatinine or ESRD) for the ITT population Bakris GL et.al. Lancet 2010, Feb 18th

11. Changes in blood pressure throughout the trial in patients with chronic kidney disease N=680 Bakris GL et.al. Lancet 2010, Feb 18th

12. Blood Pressure in Pts. With and Without Diabetes Weber M, Bakris G, Kjeldsen SE et al. JACC 2010; 56: 77-85.

13. Weber M, Bakris G, Kjeldsen SE et al. JACC 2010; 56: 77-85.

14. Primary Event in Pts. With and Without Diabetes Weber M, Bakris G, Kjeldsen SE et al. JACC 2010; 56: 77-85.

15. ACCOMPLISH Main Findings • Fixed-dose forced titration of two drug combinations (ACEI/CCB or ACEI/HCTZ) achieved BP control in 80% of participants – the highest control rate ever seen in a large outcome trial in hypertension • ACEI/CCB combination reduced primary CV endpoint by 20% • The ambulatory BP substudy confirmed same BP control in ACEI/CCB and ACEI/HCTZ arms • Treatment with ACEI/CCB reduced the secondary renal endpoint (doubling of se-creatinine or ESRD) • Benefits of ACEI/CCB combination was homogenous through main subgroups of non-diabetics, diabetics and high-risk diabetics