Transcript Popular Links - UNC School of Medicine

Hypertension Management:
Thinking Outside the
Protocol
Review of the ACCOMPLISH trial and its application to clinical practice
Seuli Bose Brill, MD
ACC Ambulatory Conference
January 7, 2009
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
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.
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?
Non-diabetic protocol
Initial agent: HCTZ
2nd agent: Enalapril
3rd agent: Atenolol vs.
amlodipine
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.
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.
ACC Medicine Clinic Protocol
Diabetes
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).
The ACCOMPLISH Trial
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
Study funding
Study design
 Total
11,506 patients recruited for study
 Multi-center
 Randomized, double-blind trial
 Similar patient demographic and comorbidities in each group
 Intention to treat model
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”
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)
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
Patient randomized
Study procedures
(cont’d)
20 mg benazepril
5 mg amlodipine
20 mg benazepril
12.5 mg HCTZ
Algorithm outlined by study for
optimization of blood pressure
control
One month
40 mg benazepril
5 mg amlodipine
40 mg benazepril
12.5 mg HCTZ
Three months
BP > 140/90 without diabetes
OR
BP > 130/80 with diabetes
No
Yes
Continue current
regimen
BP > 140/90 without diabetes
OR
BP > 130/80 with diabetes
Yes
40 mg benazepril
10 mg amlodipine
BP > 140/90 without diabetes
OR
BP > 130/80 with diabetes
40 mg benazepril
25 mg HCTZ
Six
months
BP > 140/90 without diabetes
OR
BP > 130/80 with diabetes
Add other agents
Eg beta blocker, alpha blocker,
clonidine, spironolactone
No
Continue current
regimen
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
Results: Improved BP Control
 Both
benazepril/ amlodipine and
benazepril/ HCTZ combination therapy
improved blood pressure control
Amlodipine
HCTZ
Mean SBP
131.6
132.5
Mean DBP
73.3
74.4
% BP <140/90
75.4
72.4
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
Kaplan-Meier Curve:
Time to First Primary Composite Endpoint
Results: Primary Endpoints
Primary
endpoint at
30 months
Benazepril/
Amlodipine
(%)
Benazepril/
HCTZ
(%)
ARR
(EER-CER)
(%)
RRR
(ARR/CER)
(%)
All
9.6
11.8
2.2
19.6
Male
10.6
13.1
2.5
19
Female
8.1
9.7
1.6
16.4
Age >65
10.1
12.4
2.3
18.5
Age >70
11
13.8
2.8
20.2
+DM
8.8
11
2.2
20
- DM
10.8
12.9
2.1
16.2
Hazard Ratios for Primary Outcome
and Individual Components
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)
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)
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)
Question #2
 Is
there synergy between certain antihypertensive medication combinations that
outweigh benefits of the individual
medications?
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
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
Should the clinic HTN protocol be changed
based on the results of this study?
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.
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!
Thanks for your attention and input!