1. Hypertension Management: Thinking Outside the Protocol Seuli Bose Brill, MD ACC Ambulatory Conference January 7, 2009 Review of the ACCOMPLISH trial and its application to clinical practice

2. Objectives  Review current clinic protocols for management of hypertension  Review study design and results of ACCOMPLISH trial  Discuss barriers to HTN control  Discuss how results of ACCOMPLISH trial might affect current clinic protocols

3. Case: A woman walks into the office A 54 year old Caucasian female presents to your office to “establish care.” She has not been to the doctor in the last 25 years because she “has nothing wrong” with her. She denies any past or present medication use. Her BMI is 29 and BP is 156/91. On re-check, the patient’s blood pressure is 145/82. Exam is unremarkable. She is counseled on diet and weight reduction, and is scheduled for BP re-check in 2 weeks.

4. A woman walks into the office, again. Her blood pressure is 161/88. On repeat, using manual large cuff, 156/84. Labs from her last visit show normal creatinine, normal K+ normal serum glucose and A1c, and normal lipids. How should you proceed?

5. Non-diabetic protocol Initial agent: HCTZ 2 nd agent: Enalapril 3 rd agent: Atenolol vs. amlodipine

6. Case: A man walks into the office You are seeing a 78 year old male in clinic for the first time. He recently moved from Ohio to be near his daughter. He has his medical records for you to review. He has a history of HTN and hyperlipidemia, as well as diabetes, diagnosed 14 years ago, controlled with insulin. He has never had an MI, but has CHF with diastolic dysfunction. He had been on furosemide 20 mg daily, atenolol 50 mg daily, and enalapril 20 mg daily, but was taken off atenolol due to recurrent pre-syncopal episodes. He is also on ASA and simvastatin.

7. Case: A man walks into the office (continued) On exam, the patient has a BMI of 32, BP 145/87 initially, and 146/86 on recheck. Labs are significant for creatinine of 1.3 (at baseline), HgbA1c of 8.6, and LDL of 110.

8. ACC Medicine Clinic Protocol Diabetes

9. Summary for diabetic patient  If SBP >130, DBP > 80 start 5 mg of enalapril.  If BP still > 130/80, increase to ½ maximal dose and recheck electrolytes.  If BP still > 130/80 and no CAD, initiate HCTZ at 12.5mg daily. May increase to 25 mg daily.  Subsequent additions include atenolol, then non-preferred agents (amlodipine, diltiazem, clonidine, doxazosin).

10. The ACCOMPLISH Trial

11. Study objective Comparison of cardiovascular events between group treated with combination benazepril-HCTZ versus combination benazepril-amlodipine, with hypothesis that benazepril-amlodipine would be superior in reducing cardiovascular events. HCTZ

12. Study funding

13. Study design  Total 11,506 patients recruited for study  Multi-center  Randomized, double-blind trial  Similar patient demographic and co- morbidities in each group  Intention to treat model

14. Who are the patients? This study has a high predominance of patients who are elderly, obese, Caucasian, have multiple co-morbidities (including diabetes, dyslipidemia, and CAD), and difficult to control HTN, requiring multiple agents. “at high risk for cardiac events”

15. Who are the patients?  38% Receiving 3 or more drugs at enrolment  Only 37% had BP <140/70  60% had diabetes  Average age 68yrs (fairly geriatric)

16. Study procedures  Patients started in one of treatment groups immediately after entering the study  No washout period  Addition of other anti-hypertensives permitted to achieve adequate BP control  Follow-up at 1 month, 3 months, then at 6 month intervals

17. Study procedures (cont’d) Algorithm outlined by study for optimization of blood pressure control

18. Study Endpoints Primary endpoint  Time to first event  One event per patient  Composite of a cardiovascular event and death from cardiovascular causes Secondary endpoints  Multiple events counted for a patient  Including composite of cardiovascular events, hospitalization from heart failure, death from any cause

19. Results: Improved BP Control  Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood pressure control AmlodipineHCTZ Mean SBP 131.6132.5 Mean DBP 73.374.4 % BP <140/90 75.472.4

20. Results: CV Mortality and Events Benazepril/amlodipine group saw:  Decreased primary endpoints at 30 mos.  Decrease secondary endpoints: death from CV causes, non-fatal MI< stroke  Early cessation of study by safety & monitoring committee when pre-specified thresholds for termination seen in Ace/CCB arm d/t efficacy

21. Kaplan-Meier Curve: Time to First Primary Composite Endpoint

22. Results: Primary Endpoints Primary endpoint at 30 months Benazepril/ Amlodipine (%) Benazepril/HCTZ(%)ARR(EER-CER)(%)RRR(ARR/CER)(%) All9.611.82.219.6 Male10.613.12.519 Female8.19.71.616.4 Age >65 10.112.42.318.5 Age >70 1113.82.820.2 +DM8.8112.220 - DM 10.812.92.116.2

23. Hazard Ratios for Primary Outcome and Individual Components

24. Results: Attrition  8.8% patients discontinued treatment (8.5 B/A vs 9.1 B/H)  15.3% withdrawal (15.1B/A vs 15.4 B/H)

25. Results: Concerns  Study results have application to a subset of patients  Complete stratified analysis not done (looking at CAD, LVH, CHF), making results difficult to apply to individual patient  HCTZ group at disadvantage due to higher rates of treatment discontinuation (increasing Type 1 error)  Other medications used to control HTN were not divulged (although % used was)

26. Question #1  Is the “how to” of hypertension control as important as the “how well” of hypertension control in patients requiring more than one anti-hypertensive agent?  We have said yes in the past based on the patient’s co-morbidities (diabetes, renal insufficiency, CHF, etc)

27. Question #2  Is there synergy between certain anti- hypertensive medication combinations that outweigh benefits of the individual medications?

28. Barriers to HTN control  Cost  Medication side effects  Lack of gratifying response to therapy (patient does not feel better)  Need for lifestyle changes  Titration- requiring multiple visits and close monitoring on the part of physician and patient

29. Drug Costs Drug name Cost for 30 day supply Enalapril 5 mg -20 mg $4 HCTZ 12.5-25 mg $4 Atenolol 25 mg- 100 mg $4 Amlodipine (Norvasc) 5 mg $75 Amlodipine (generic) 5 mg $21 Adapted from Blue Cross Blue Shield of North Carolina and WalMart $4 pharmacy list 90 supply available from Drugstore.com for $18

30. Should the clinic HTN protocol be changed based on the results of this study?

31. Conclusions  The clinic protocol should stay in tact, especially for non-diabetic patients.  More information is needed from stratified analysis, especially in patients with limited cardiac risk factors.  Head to head combination therapy trial in similar subset of patients comparing amlodipine to beta-blocker in reducing cardiovascular events and mortality.

32. Conclusions  However, need to consider amlodipine as a very viable option in BP control, especially in patients requiring more than 2 agents to achieve control.  Costs of amlodipine continue to drop making it more accessible to this clinic population.  It is likely that many of the clinic’s patients who are similar to the study subjects, requiring 3 or more agents, are already on amlodipine!

33. Thanks for your attention and input!