Transcript Did Type of Prior Antihypertensive Therapy Influence the Heart

ALLHAT
Did Type of Prior Antihypertensive
Therapy Influence the Heart Failure
Results in ALLHAT?
Richard Grimm, Barry Davis, Linda Piller,
Karen Margolis, Joshua Barzilay, Richard
Dart, James Graumlich, Robert Murden,
Otelio Randall, Katrina Sawyer, for the
ALLHAT Collaborative Research Group
Randomized Design
of ALLHAT
ALLHAT
High-risk
hypertensive
patients ≥ 55
years
Consent /
Randomize
(42,418)
Eligible for lipidlowering
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Not eligible for
lipid-lowering
Consent / Randomize (10,355)
Pravastatin
Usual care
Follow for CHD and other outcomes until death or end of study (up to 8 yr).
ALLHAT
Secondary Outcomes
• All-cause mortality
• Stroke
• Combined CHD – nonfatal MI, CHD death,
coronary revascularization, hospitalized angina
• Combined CVD – combined CHD, stroke, lower
extremity revascularization, treated angina, fatal /
hospitalized / treated CHF
• All components of CVD – prespecified
ALLHAT
ALLHAT Criteria for
HF Evaluation*
Must have one from each category:
Category “A”
Category “B”
Paroxysmal nocturnal dyspnea
Rales
Dyspnea at rest
Ankle edema
NYHA Classification III
Tachycardia
Orthopnea
Cardiomegaly by CXR
CXR characteristic of CHF
S3 gallop
Jugular venous distention
*ALLHAT Manual of Operations, 5.3.4
ALLHAT
Heart Failure Data
Collection
• Hospitalized nonfatal – discharge summary
• Hospitalized fatal – death certificate,
discharge summary
• Nonhospitalized fatal – death certificate
• Nonhospitalized nonfatal (treated) –
checkbox
• 100% review of discharge summaries and
death certificates by CTC Medical Reviewer
--Queries to clinics if diagnosis questionable
ALLHAT
Background: Hospitalized
and Fatal Heart Failure
HR
P value
95% CI
A vs. C*
1.35
< 0.001
1.21-1.50
L vs. C*
1.10
0.11
0.98-1.23
D vs. C†
1.66
< 0.001
1.46-1.89
*JAMA 2002;288:2981-2997
†Hypertension
2003;42:239-246
Cumulative Event Rates for
Hospitalized/Fatal Heart Failure by
Treatment Group
ALLHAT
Cumulative Event Rate
.1
.08
RR
95% CI
A-C
1.35
1.21-1.50
L-C
1.10
0.98-1.23
Chlorthalidone
Amlodipine
Lisinopril
.06
.04
.02
0
0
1
2
3
Years
4
5
6
7
Cumulative Event Rates for Hospitalized/
Fatal Heart Failure by Treatment Group
Cumulative Fatal+Hosp HF Event Rate
ALLHAT
.12
D/C
RR (95% CI)
p value
1.66 (1.46-1.89)
<0.001
.09
Doxazosin
.06
.03
Chlorthalidone
0
0
1
2
3
Years to Fatal or Hosp HF
4
5
ALLHAT
Question to be Addressed
by these Analyses
Kaplan-Meier curves for the HF outcome
show an early divergence of the curves for
chlorthalidone vs. amlodipine, lisinopril, or
doxazosin.
Question: Can the heart failure
findings in part be explained by
discontinuing antihypertensive
medications such as diuretics and
ACE-inhibitors upon entry into
ALLHAT?
ALLHAT
HF Validation Study – BP
Meds at Entry
• 2091 pts w/ 3032 hosp/fatal HF cases centrally
reviewed
• Criteria – ALLHAT, Framingham, reviewer
judgment
• 70-84% confirmed on central review (similar
across Rx groups; Rx group effects larger in
confirmed cases)
• Requested information about pts’ BP drug use at
trial entry just before end of study
• Received information for 1418 pts (~ 2/3 total) 
population for this study
ALLHAT
ALLHAT
Received
ALLHAT BLOOD PRESSURE MEDICATION AT STUDY ENTRY
ALLHAT
Baseline Characteristics
HF Ppts with BP
Med Data
Total HF Ppts
Number
1418
2091
Age, mean, yr
70.3
70.1
Female, %
43.9
43.3
White, %
62.4
61.1
Black, %
33.2
34.8
RX at baseline, %
93.6
93.5
BP, mean, mg Hg
148.5 / 82.0
148.5 / 81.9
Ethnicity
ALLHAT
Baseline Characteristics
HF Ppts with
BP Med Data
Total HF Ppts
Hx of CHD, %
38.4
37.2
Hx of coro. revasc., %
23.1
21.5
Hx of diabetes, %
47.5
49.4
Cigarette smoker,%
15.3
19.1
LVH on ECG, %
18.0
18.8
T-chol, mean, mg/dL
217.8
216.9
Fast. trig., mean, mg/dL
181.4
182.2
ALLHAT
Source of Entry Drug
Information
Source of information
ALLHAT RZ records
Distribution
66.2%
Other medical chart
53.7%
Asked patient
1.6%
Other
4.1%
Note: More than one source was used for some patients.
ALLHAT
Heart Failure During ALLHAT: Percent
of Patients on Prior BP Meds
Prior BP Med
C
A
L
D
Total
Diuretics
36
41
37
42
39
CCB
46
47
45
49
47
ACE-I
38
39
35
34
37
Beta Blockers
17
14
22
16
17
Total # of ppts*†
460
369 285 304 1418
*Participants may have been on one, multiple, or no prior BP meds.
†Refers to participants with HF during ALLHAT and for whom prior medication
data is available.
ALLHAT
Heart Failure Within the First Year
Following Randomization: Percent
of Patients on Prior BP Meds
Prior BP Med
C
A
L
D
Total
Diuretics
45
47
52
49
48
CCB
35
44
51
46
45
ACE-I
43
42
36
40
40
Beta Blockers
10
11
24
10
14
Total # of ppts*†
49
79
75
99
302
*Participants may have been on one, multiple, or no prior BP meds.
†Refers to participants with HF during first year following randomization and for
whom prior medication data is available.
Cumulative Event Rates for Heart
ALLHAT
Failure by Prior Meds Status
Cumulative HF Rate
Y/N
RR (95% CI)
p value
1.48 (1.25-1.75)
<.001
.09
Prior Meds
.06
.03
No Prior Meds
0
0
1
2
3
4
Years to HF
5
6
7
ALLHAT
Case-Only Analyses
• Cannot do analyses on entire
population since pre-ALLHAT BP meds
data was only collected for HF cases.
• A technique know as case-only
analyses will allow us to examine if
there was interaction.
• Do “full” analyses and case-only
analyses provide comparable results?
ALLHAT
Interactions of Step 1 Treatment
and Use of ANY Prior BP Meds for
Occurrence of HF*
Full logistic
Year 1
A vs C
L vs C
D vs C
+ OR
OR
1.81+
3.52
1.70
P
0.29
0.07
0.30
Case-only
OR
1.83
3.49
1.69
P
0.28
0.07
0.30
(A vs. C) = 2.32 (1.75, 3.08) for those on meds;
1.28 (.44, 3.71) for those not on meds
* All hospitalized/fatal heart failure cases
ALLHAT
Prior BP Meds
Interaction of Treatment (L vs. C)
and Specific Prior BP Meds
for Occurrence of HF
Univariate
OR
95% CI
Multivariate*
OR
95% CI
Diuretic
1.33
0.65-2.74
1.57
0.73-3.38
ACE-I
0.75
0.36-1.57
1.03
0.47-2.29
CCB
1.93
0.92-4.06
2.51
1.13-5.60
Beta blocker
2.78
0.96-8.07
3.30
1.08-10.07
* Controlled for use of other classes of BP drugs
ALLHAT
Interaction of Treatment (A vs. C)
and Specific Prior BP Meds
for Occurrence of HF
Univariate
OR
95% CI
Multivariate*
OR
95% CI
Prior BP Meds
Diuretic
1.08
0.53-2.21
1.17
0.55-2.47
ACE-I
0.96
0.47-1.97
1.06
0.49-2.28
CCB
1.50
0.72-3.13
1.68
0.77-3.68
Beta blocker
1.13
0.36-3.60
1.42
0.43-4.72
* Controlled for use of other classes of BP drugs
ALLHAT
Potential Confounders
• Confounders by indication: why was the patient
placed on a specific class of drug prior to
participation in the study?
• Use of additional meds during the study: what
conditions developed that caused the patient to be
placed on additional meds?
• Possibility of misclassification of drugs used prior
to study entry
• Missing data: approximately one third of heart
failure cases lacked information on specific drugs
used prior to entry into ALLHAT
ALLHAT
Conclusions
• Among the HF cases, CCB’s were the most used
BP drug prior to entry into ALLHAT, followed by
diuretics and ACE inhibitors.
• Pts on any prior BP med (vs. none) were at higher
risk of developing HF.
• These findings are noteworthy for those on CCB’s
and BB’s at entry (confounding by indication?).
• These findings suggest that the type of BP drug at
entry is not a major determinant of the HF results.