Hypertension Management: Thinking Outside the Protocol

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

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

3. Case: A woman walks into the office 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. 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 patients blood pressure is 145/82. Exam is unremarkable. Her BMI is 29 and BP is 156/91. On re-check, the patients 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. 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. 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. 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? How should you proceed?

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

6. Case: A man walks into the office 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. 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. 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) 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. 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. Labs are significant for creatinine of 1.3 (at baseline), HgbA1c of 8.6, and LDL of 110.

8. ACC Medicine Clinic Protocol Diabetes ACC Medicine Clinic Protocol Diabetes

9. Summary for diabetic patient Summary for diabetic patient If SBP >130, DBP > 80 start 5 mg of enalapril. If SBP >130, DBP > 80 start 5 mg of enalapril. If BP still > 130/80, increase to maximal dose and recheck electrolytes. If BP still > 130/80, increase to 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. 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). Subsequent additions include atenolol, then non-preferred agents (amlodipine, diltiazem, clonidine, doxazosin).

10. The ACCOMPLISH Trial The ACCOMPLISH Trial

11. Study objective 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. 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 Study funding

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

14. Who are the patients? 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. 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 at high risk for cardiac events

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

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

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

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

19. Results: Improved BP Control Results: Improved BP Control Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood pressure control Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood pressure control Amlodipine Amlodipine HCTZ HCTZ Mean SBP Mean SBP 131.6 131.6 132.5 132.5 Mean DBP Mean DBP 73.3 73.3 74.4 74.4 % BP <140/90 % BP <140/90 75.4 75.4 72.4 72.4

20. Results: CV Mortality and Events Results: CV Mortality and Events Benazepril/amlodipine group saw: Benazepril/amlodipine group saw: Decreased primary endpoints at 30 mos. Decreased primary endpoints at 30 mos. Decrease secondary endpoints: death from CV causes, non-fatal MI< stroke 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 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 Kaplan-Meier Curve: Time to First Primary Composite Endpoint

22. Results: Primary Endpoints Results: Primary Endpoints Primary endpoint at 30 months Primary endpoint at 30 months Benazepril/ Benazepril/ Amlodipine (%) Amlodipine (%) Benazepril/ Benazepril/ HCTZ HCTZ (%) (%) ARR ARR (EER-CER) (EER-CER) (%) (%) RRR RRR (ARR/CER) (ARR/CER) (%) (%) All All 9.6 9.6 11.8 11.8 2.2 2.2 19.6 19.6 Male Male 10.6 10.6 13.1 13.1 2.5 2.5 19 19 Female Female 8.1 8.1 9.7 9.7 1.6 1.6 16.4 16.4 Age >65 Age >65 10.1 10.1 12.4 12.4 2.3 2.3 18.5 18.5 Age >70 Age >70 11 11 13.8 13.8 2.8 2.8 20.2 20.2 +DM +DM 8.8 8.8 11 11 2.2 2.2 20 20 - DM - DM 10.8 10.8 12.9 12.9 2.1 2.1 16.2 16.2

23. Hazard Ratios for Primary Outcome and Individual Components Hazard Ratios for Primary Outcome and Individual Components

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

25. Results: Concerns Results: Concerns Study results have application to a subset of patients 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 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) 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) Other medications used to control HTN were not divulged (although % used was)

26. Question #1 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? 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 patients co-morbidities (diabetes, renal insufficiency, CHF, etc) We have said yes in the past based on the patients co-morbidities (diabetes, renal insufficiency, CHF, etc)

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

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

29. Drug Costs Drug Costs Drug name Drug name Cost for 30 day supply Cost for 30 day supply Enalapril 5 mg -20 mg Enalapril 5 mg -20 mg $4 $4 HCTZ 12.5-25 mg HCTZ 12.5-25 mg $4 $4 Atenolol 25 mg- 100 mg Atenolol 25 mg- 100 mg $4 $4 Amlodipine (Norvasc) 5 mg Amlodipine (Norvasc) 5 mg $75 $75 Amlodipine (generic) 5 mg Amlodipine (generic) 5 mg $21 $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? Should the clinic HTN protocol be changed based on the results of this study?

31. Conclusions Conclusions The clinic protocol should stay in tact, especially for non-diabetic patients. 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. 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. Head to head combination therapy trial in similar subset of patients comparing amlodipine to beta-blocker in reducing cardiovascular events and mortality.

32. Conclusions 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. 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. Costs of amlodipine continue to drop making it more accessible to this clinic population. It is likely that many of the clinics patients who are similar to the study subjects, requiring 3 or more agents, are already on amlodipine! It is likely that many of the clinics patients who are similar to the study subjects, requiring 3 or more agents, are already on amlodipine!

33. Thanks for your attention and input! Thanks for your attention and input!