Hypertension Management: Hypertension Management:

Thinking Outside the Thinking Outside the ProtocolProtocol

Seuli Bose Brill, MDSeuli Bose Brill, MD

ACC Ambulatory ConferenceACC Ambulatory Conference

January 7, 2009January 7, 2009

Review of the ACCOMPLISH trial and its application to clinical practice

ObjectivesObjectives

Review current clinic protocols for Review current clinic protocols for management of hypertensionmanagement of hypertension

Review study design and results of Review study design and results of ACCOMPLISH trialACCOMPLISH trial

Discuss barriers to HTN controlDiscuss barriers to HTN control Discuss how results of ACCOMPLISH trial Discuss how results of ACCOMPLISH trial

might affect current clinic protocolsmight affect current clinic protocols

Case: A woman walks into the officeCase: A woman walks into the office

A 54 year old Caucasian female presents to your office to A 54 year old Caucasian female presents to your office to “establish care.” She has not been to the doctor in the last 25 “establish care.” She has not been to the doctor in the last 25 years because she “has nothing wrong” with her. She denies years because she “has nothing wrong” with her. She denies any past or present medication use. any past or present medication use.

Her BMI is 29 and BP is 156/91. On re-check, the patient’s blood Her BMI is 29 and BP is 156/91. On re-check, the patient’s blood pressure is 145/82. Exam is unremarkable.pressure is 145/82. Exam is unremarkable.

She is counseled on diet and weight reduction, and is scheduled She is counseled on diet and weight reduction, and is scheduled for BP re-check in 2 weeks. for BP re-check in 2 weeks.

A woman walks into the office, again.A woman walks into the office, again.

Her blood pressure is 161/88. On repeat, using Her blood pressure is 161/88. On repeat, using manual large cuff, 156/84. Labs from her last manual large cuff, 156/84. Labs from her last visit show normal creatinine, normal K+ normal visit show normal creatinine, normal K+ normal serum glucose and A1c, and normal lipids. serum glucose and A1c, and normal lipids.

How should you proceed?How should you proceed?

Non-diabetic protocol Non-diabetic protocol

Initial agent: HCTZInitial agent: HCTZ

22ndnd agent: Enalapril agent: Enalapril

33rdrd agent: Atenolol vs. agent: Atenolol vs. amlodipineamlodipine

Case: A man walks into the officeCase: A man walks into the office

You are seeing a 78 year old male in clinic for the first time. He 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 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 medical records for you to review. He has a history of HTN and hyperlipidemia, as well as diabetes, diagnosed 14 years ago, hyperlipidemia, as well as diabetes, diagnosed 14 years ago, controlled with insulin. He has never had an MI, but has CHF with controlled with insulin. He has never had an MI, but has CHF with diastolic dysfunction.diastolic dysfunction.

He had been on furosemide 20 mg daily, atenolol 50 mg daily, and 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 enalapril 20 mg daily, but was taken off atenolol due to recurrent pre-syncopal episodes. He is also on ASA and simvastatin. pre-syncopal episodes. He is also on ASA and simvastatin.

Case: A man walks into the office Case: A man walks into the office (continued)(continued)

On exam, the patient has a BMI of 32, BP 145/87 On exam, the patient has a BMI of 32, BP 145/87 initially, and 146/86 on recheck.initially, and 146/86 on recheck.

Labs are significant for creatinine of 1.3 (at Labs are significant for creatinine of 1.3 (at baseline), HgbA1c of 8.6, and LDL of 110.baseline), HgbA1c of 8.6, and LDL of 110.

ACC Medicine Clinic ProtocolACC Medicine Clinic ProtocolDiabetesDiabetes

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 ½ maximal dose If BP still > 130/80, increase to ½ maximal dose

and recheck electrolytes.and recheck electrolytes. If BP still > 130/80 and no CAD, initiate HCTZ at If BP still > 130/80 and no CAD, initiate HCTZ at

12.5mg daily. May increase to 25 mg daily. 12.5mg daily. May increase to 25 mg daily. Subsequent additions include atenolol, then Subsequent additions include atenolol, then

non-preferred agents (amlodipine, diltiazem, non-preferred agents (amlodipine, diltiazem, clonidine, doxazosin).clonidine, doxazosin).

The ACCOMPLISH TrialThe ACCOMPLISH Trial

Study objectiveStudy objective

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

HCTZ

Study fundingStudy funding

Study designStudy design

Total 11,506 patients recruited for studyTotal 11,506 patients recruited for study Multi-center Multi-center Randomized, double-blind trialRandomized, double-blind trial Similar patient demographic and co-Similar patient demographic and co-

morbidities in each groupmorbidities in each group Intention to treat modelIntention to treat model

Who are the patients?Who are the patients?

This study has a high This study has a high predominance of patients predominance of patients who are elderly, obese, who are elderly, obese, Caucasian, have multiple Caucasian, have multiple co-morbidities (including co-morbidities (including diabetes, dyslipidemia, diabetes, dyslipidemia, and CAD), and difficult to and CAD), and difficult to control HTN, requiring control HTN, requiring multiple agents. multiple agents.

““at high risk for cardiac events”at high risk for cardiac events”

Who are the patients?Who are the patients?

38% Receiving 3 or more drugs at 38% Receiving 3 or more drugs at enrolmentenrolment

Only 37% had BP <140/70Only 37% had BP <140/70 60% had diabetes60% had diabetes Average age 68yrs (fairly geriatric)Average age 68yrs (fairly geriatric)

Study proceduresStudy procedures

Patients started in one of treatment groups Patients started in one of treatment groups immediately after entering the studyimmediately after entering the study

No washout periodNo washout period Addition of other anti-hypertensives Addition of other anti-hypertensives

permitted to achieve adequate BP control permitted to achieve adequate BP control Follow-up at 1 month, 3 months, then at 6 Follow-up at 1 month, 3 months, then at 6

month intervalsmonth intervals

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

Patient randomized

20 mg benazepril 5 mg amlodipine

20 mg benazepril 12.5 mg HCTZ

One month

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

40 mg benazepril 5 mg amlodipine

40 mg benazepril 12.5 mg HCTZ

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

Yes Yes No No

Continue current regimen

Continue current regimen

40 mg benazepril 10 mg amlodipine

40 mg benazepril 25 mg HCTZ

Three months

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

Six months

Add other agents Eg beta blocker, alpha blocker,

clonidine, spironolactone

Study EndpointsStudy Endpoints

Primary endpointPrimary endpoint Time to first eventTime to first event One event per patientOne event per patient Composite of a Composite of a

cardiovascular event cardiovascular event and death from and death from cardiovascular cardiovascular causes causes

Secondary endpointsSecondary endpoints Multiple events Multiple events

counted for a patientcounted for a patient Including composite Including composite

of cardiovascular of cardiovascular events, hospitalization events, hospitalization from heart failure, from heart failure, death from any causedeath from any cause

Results: Improved BP ControlResults: Improved BP Control

Both benazepril/ amlodipine and Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy benazepril/ HCTZ combination therapy improved blood pressure controlimproved blood pressure control

AmlodipineAmlodipine HCTZHCTZ

Mean SBPMean SBP 131.6131.6 132.5132.5

Mean DBPMean DBP 73.373.3 74.474.4

% BP <140/90% BP <140/90 75.475.4 72.472.4

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 Decrease secondary endpoints: death

from CV causes, non-fatal MI< strokefrom CV causes, non-fatal MI< stroke Early cessation of study by safety & Early cessation of study by safety &

monitoring committee when pre-specified monitoring committee when pre-specified thresholds for termination seen in thresholds for termination seen in Ace/CCB arm d/t efficacyAce/CCB arm d/t efficacy

Kaplan-Meier Curve:Kaplan-Meier Curve:Time to First Primary Composite EndpointTime to First Primary Composite Endpoint

Results: Primary EndpointsResults: Primary Endpoints

Primary Primary endpoint at endpoint at 30 months30 months

Benazepril/Benazepril/Amlodipine Amlodipine (%)(%)

Benazepril/Benazepril/HCTZHCTZ(%)(%)

ARRARR(EER-CER)(EER-CER)(%)(%)

RRRRRR(ARR/CER)(ARR/CER)(%)(%)

AllAll 9.69.6 11.811.8 2.22.2 19.619.6

MaleMale 10.610.6 13.113.1 2.52.5 1919

FemaleFemale 8.18.1 9.79.7 1.61.6 16.416.4

Age >65Age >65 10.110.1 12.412.4 2.32.3 18.518.5

Age >70Age >70 1111 13.813.8 2.82.8 20.220.2

+DM+DM 8.88.8 1111 2.22.2 2020

- DM- DM 10.810.8 12.912.9 2.12.1 16.216.2

Hazard Ratios for Primary Outcome Hazard Ratios for Primary Outcome and Individual Componentsand Individual Components

Results: AttritionResults: Attrition

8.8% patients discontinued treatment (8.5 8.8% patients discontinued treatment (8.5 B/A vs 9.1 B/H)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)

Results: Concerns Results: Concerns

Study results have application to a subset of Study results have application to a subset of patients patients

Complete stratified analysis not done (looking at Complete stratified analysis not done (looking at CAD, LVH, CHF), making results difficult to CAD, LVH, CHF), making results difficult to apply to individual patientapply to individual patient

HCTZ group at disadvantage due to higher rates HCTZ group at disadvantage due to higher rates of treatment discontinuation (increasing Type 1 of treatment discontinuation (increasing Type 1 error)error)

Other medications used to control HTN were not Other medications used to control HTN were not divulged (although % used was)divulged (although % used was)

Question #1Question #1

Is the “how to” of hypertension control as Is the “how to” of hypertension control as important as the “how well” of important as the “how well” of hypertension control in patients requiring hypertension control in patients requiring more than one anti-hypertensive agent?more than one anti-hypertensive agent?

We have said yes in the past based on the We have said yes in the past based on the patient’s co-morbidities (diabetes, renal patient’s co-morbidities (diabetes, renal insufficiency, CHF, etc) insufficiency, CHF, etc)

Question #2Question #2

Is there synergy between certain anti-Is there synergy between certain anti-hypertensive medication combinations that hypertensive medication combinations that outweigh benefits of the individual outweigh benefits of the individual medications?medications?

Barriers to HTN controlBarriers to HTN control

CostCost Medication side effectsMedication side effects Lack of gratifying response to therapy Lack of gratifying response to therapy

(patient does not feel better)(patient does not feel better) Need for lifestyle changesNeed for lifestyle changes Titration- requiring multiple visits and close Titration- requiring multiple visits and close

monitoring on the part of physician and monitoring on the part of physician and patient patient

Drug Costs Drug Costs

Drug nameDrug name Cost for 30 day supplyCost for 30 day supply

Enalapril 5 mg -20 mgEnalapril 5 mg -20 mg $4$4

HCTZ 12.5-25 mgHCTZ 12.5-25 mg $4$4

Atenolol 25 mg- 100 mgAtenolol 25 mg- 100 mg $4$4

Amlodipine (Norvasc) 5 mgAmlodipine (Norvasc) 5 mg $75$75

Amlodipine (generic) 5 mgAmlodipine (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

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

ConclusionsConclusions

The clinic protocol should stay in tact, The clinic protocol should stay in tact, especially for non-diabetic patients.especially for non-diabetic patients.

More information is needed from stratified More information is needed from stratified analysis, especially in patients with limited analysis, especially in patients with limited cardiac risk factors.cardiac risk factors.

Head to head combination therapy trial in Head to head combination therapy trial in similar subset of patients comparing similar subset of patients comparing amlodipine to beta-blocker in reducing amlodipine to beta-blocker in reducing cardiovascular events and mortality.cardiovascular events and mortality.

ConclusionsConclusions

However, need to consider amlodipine as a very However, need to consider amlodipine as a very viable option in BP control, especially in patients viable option in BP control, especially in patients requiring more than 2 agents to achieve control.requiring more than 2 agents to achieve control.

Costs of amlodipine continue to drop making it Costs of amlodipine continue to drop making it more accessible to this clinic population.more accessible to this clinic population.

It is likely that many of the clinic’s patients who It is likely that many of the clinic’s patients who are similar to the study subjects, requiring 3 or are similar to the study subjects, requiring 3 or more agents, are already on amlodipine!more agents, are already on amlodipine!

Thanks for your attention and input!Thanks for your attention and input!