Transcript Heart Failure Findings: Are They Real?

ALLHAT
Heart Failure (HF) Findings:
Are They Real?
Stanley S. Franklin, MD, FACP, FACC
Clinical Professor of Medicine
University of California at Irvine
Associate Medical Director
UCI Heart Disease Prevention Program
Irvine, California
Presenter Disclosure Information
Stanley S. Franklin, MD, FACP, FACC, FAHA, FASN
DISCLOSURE INFORMATION:
The following relationships exist related to this presentation:
Speakers bureau for: Boehringer Ingelheim, Bristol-Myers
Squibb, Merck.
Consultant for: AtCor Medical, Bristol-Myers Squibb, and
Merck
ALLHAT
HF Objectives
 Characterize HF in ALLHAT by its antecedent risk factors
and underlying conditions.
 Examine occurrence of HF by treatment groups overall, in
subgroups, and over time.
 Examine post-HF mortality overall and by treatment
group.
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
Decision to Stop
Doxazosin Arm
 Futility of finding a significant difference
for primary outcome compared to
chlorthalidone
 Statistically significant 25 percent higher
rate of major cardiovascular events,
including near twofold higher rate of HF
(hospitalized, treated out-of-hospital, or
fatal)
ALLHAT
Blood Pressure Trial
Design
• Randomized, practice –based
• Double-blind (not PROBE)
• Diagnoses assigned by clinic investigators
guided by protocol-defined diagnostic criteria
• Randomization stratified by clinic
• Exclude: h/o symptomatic HF (stage C)
and/or known LVEF <35%
ALLHAT
Baseline Characteristics
Hospitalized/Fatal HF During Trial
Yes
No
Difference
p
N
1,773
31,584
Age (mean)
70.3
66.7
+3.6
<0.001
Men, %
55.2%
53.0%
+2.2%
0.008
Pre-RZ Treatment, %
93.1%
90.0%
+3.1%
0.004
SBP (mean mm Hg)
148.2
146.2
+2.0
<0.001
DBP (mean mm Hg)
81.8
84.1
-2.3
<0.001
Pulse (mean bpm)
74.6
73.5
+1.1
<0.001
18.3%
22.1%
-3.8
<0.001
49.4
35.4
+14.0%
<0.001
LVH by ECG, %
18.4%
16.3%
+2.1%
<0.001
History of CHD, %
37.6%
24.7%
+12.9
<0.001
30.3
29.7
+0.6
<0.001
Cigarette smoking, %
Diabetes, %
BMI (mean)
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
Cumulative Event Rate
.1
.08
Hospitalized/ Fatal HF by ALLHAT
Treatment Group
RR
95% CI
A-C
1.35
1.21-1.50
L-C
1.11
0.99-1.24
A-L
1.23
1.09 – 1.38
Chlorthalidone
Amlodipine
Lisinopril
.06
.04
.02
0
0
1
2
3
4
Years
Davis BH, et al. Circulation 2006;113:2201-10
5
6
7
ALLHAT
HF Before and After 1 Year
• A test of the proportional hazards
assumption for Cox regression revealed
that RRs were not constant over time.
Therefore, a Cox regression that used a
time-dependent indicator variable (<=1
year versus >1 year) was utilized.
Davis BH, et al. Circulation 2006;113:2201-10
Hospitalized/ Fatal HF by ALLHAT Treatment
Group Within 1 Year and >1 Year
ALLHAT
Cumulative Hosp/Fatal HF Rate
Baseline to Year 1
.02
RR
95% CI
A-C
2.22
1.69 – 2.91
L-C
2.08
1.58 – 2.74
A-L
1.07
0.82 – 1.38
> Year 1
.1
Chlorthalidone
Amlodipine
Lisinopril
RR
95% CI
A-C
1.22
1.08 – 1.38
L-C
0.96
0.85 – 1.10
A-L
1.27
1.10 – 1.46
.08
.06
.01
.04
.02
00
0
0
.5
Years to Hosp/Fatal HF
1
1
2
3
4
5
Years to Hosp/Fatal HF
6
7
Hospitalized/fatal HF in Subgroups Amlodipine / Chlorthalidone Relative Risks
from Baseline to 1 Year of Follow-up
ALLHAT
Relative Risk
(95% CI)
Total
2.22 (1.69 - 2.91)
Age < 65
2.89 (1.62 - 5.17)
Age ≥ 65
2.06 (1.51 - 2.80)
Non-Black
2.12 (1.49 - 3.01)
Black
2.37 (1.55 - 3.63)
Men
2.27 (1.56 - 3.30)
Women
2.17 (1.46 - 3.21)
Diabetic
2.71 (1.83 - 4.02)
Non-Diabetic
1.83 (1.25 - 2.67)
Favors
Favors
Amlodipine Chlorthalidone
0.50
1
2
3
4 5 6
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
Hospitalized/fatal HF in Subgroups Amlodipine / Chlorthalidone Relative Risks
After 1 Year of Follow-up
Relative Risk
(95% CI)
Total
1.22 (1.08 - 1.38)
Age < 65
1.38 (1.10 - 1.73)
Age ≥ 65
1.17 (1.02 - 1.35)
Non-Black
1.20 (1.04 - 1.39)
Black
1.28 (1.03 - 1.58)
Men
1.28 (1.09 - 1.50)
Women
1.16 (0.97 - 1.39)
Diabetic
1.23 (1.04 - 1.46)
Non-Diabetic
1.21 (1.02 - 1.43)
Favors
Favors
Amlodipine Chlorthalidone
0.50
1
2
3 4 5 6
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
Hospitalized/fatal HF in Subgroups Lisinopril / Chlorthalidone Relative Risks
from Baseline to 1 Year of Follow-up
Relative Risk
(95% CI)
Total
2.08 (1.58 - 2.74)
Age < 65
2.53 (1.39 - 4.59)
Age ≥ 65
1.98 (1.45 - 2.70)
Non-Black
2.04 (1.43 - 2.90)
Black
2.15 (1.39 - 3.33)
Men
1.80 (1.22 - 2.67)
Women
2.40 (1.63 - 3.54)
Diabetic
1.99 (1.31 - 3.05)
Non-Diabetic
2.16 (1.50 - 3.10)
Favors
Lisinopril
0.50
Favors
Chlorthalidone
1
2
3
4 5
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
Hospitalized/fatal HF in Subgroups Lisinopril / Chlorthalidone Relative Risks
After 1 Year of Follow-up
Relative Risk
(95% CI)
Total
0.96 (0.85 - 1.10)
Age < 65
0.95 (0.74 - 1.23)
Age ≥ 65
0.97 (0.84 - 1.13)
Non-Black
0.90 (0.77 - 1.06)
Black
1.10 (0.88 - 1.37)
Men
1.02 (0.86 - 1.21)
Women
0.89 (0.73 - 1.09)
Diabetic
1.01 (0.84 - 1.22)
Non-Diabetic
0.93 (0.77 - 1.12)
Favors
Lisinopril
0.50
Favors
Chlorthalidone
1
2
Davis BH, et al. Circulation 2006;113:2201-10
ALLHAT
4 Unanswered Questions
1. Can the early divergence of HF
curves in the treatment arms be
explained by the preferential
discontinuation of diuretics
upon entry into ALLHAT?
ALLHAT
Potential Confounders
• Confounders by indication: why was
the patient placed on a specific class of
drug prior to participation in the study?
• Missing data: approximately one third of
HF cases lacked information on specific
drugs used prior to entry into ALLHAT
Grimm R, et al J Am Cardiol Coll 2007;49:350A
ALLHAT
Baseline Characteristics of Participants with HF
within First Year Following Randomization
With Prior
BP Med Data
Without
Prior BP
Med Data
P Value
Hx of CHD, %
40.7
33.7
NS
Hx of cor. revasc., %
20.7
18.0
NS
Hx of diabetes, %
45.8
48.3
NS
Cigarette smoker,%
20.4
14.6
NS
LVH on ECG, %
24.4
22.5
NS
Tchol., mean, mg/dL
216.0
212.4
NS
Fast. trig.,mean, mg/dL
180.8
161.8
NS
Grimm R, et al J Am Cardiol Coll 2007;49:350A
ALLHAT
Validation of Case-Only
Analyses
• A technique know as case-only analyses was used
to examine if there was interaction between prior
drugs and treatment effects.
• Does “any prior meds (yes/no)” have the same
interaction effect with treatment on outcomes in a
“cases and non-cases” analysis versus a “case only
analysis” ?
Grimm R, et al J Am Cardiol Coll 2007;49:350A
Interaction OR between prior use of
ALLHAT diuretic and treatment effects in HF
• Prior use of antihypertensive agents:
39% diuretics
37% ACEIs
47% CCBs
• Prior use of diuretic on “A” effect for new HF:
A vs C: OR 1.08 (0.53-2.21, p=0.83)
• Prior use of diuretic on “L” effect for new HF:
vs C: OR 1.33 (0.65-2.74, p=0.44)
Grimm R, et al J Am Cardiol Coll 2007;49:350A
L
ALLHAT
Summary
• Patients on any prior BP med (vs. none) were at
higher risk of developing HF.
• No evidence for any statistically significant interaction
between prior drug type (e.g., diuretic) and treatment
effect for HF, overall or during the first year
• These findings suggest that the type of BP drug at
entry is not a major determinant of the HF results.
Grimm R, et al J Am Cardiol Coll 2007;49:350A
ALLHAT
2. How accurate is
the diagnosis of
HF?
ALLHAT
Origin of the HF Validation Study
 HF endpoint defined as treated in hospital or out-
of-hospital or fatal
 A component of combined CVD (CHD, stroke, HF,
PAD) – pre-specified secondary outcome
 Systematic central review of hospitalized HF
events initiated in 2001, on advice of the DSMB
Einhorn PT, et al. Am Heart J 2007;153:42-53
ALLHAT
HF Validation Study Objectives
 Evaluate ALLHAT site physician-assigned diagnoses
 Evaluate treatment effects reported in December
2002 (JAMA. 2002;288:2981-2997)

Compare RRs of validated HF between randomized
treatment groups with RRs reported in 2002
 Evaluate incidence of validated HF and examine
subsequent mortality rates as indicators of clinical
significance of HF
Einhorn PT, et al. Am Heart J 2007;153:42-53
ALLHAT
HF Validation Study

2850 hospital records for 1987 patients received.

2778 records of 1935 patients suitable for review.




Centrally abstracted by cardiology fellow blinded to
treatment assignment.
Each record independently reviewed by two reviewers.
For algorithmic criteria (ALLHAT and Framingham),
diagnoses were assigned by computer.
Reviewers’ clinical judgment entered as yes, no, don’t
know.
Einhorn PT, et al. Am Heart J 2007;153:42-53.
ALLHAT
HF Validation Study
ACEI versus diuretic
Definition, Relative Risk and 95% Confidence Intervals
HF*
1.19 (1.07 - 1.31)
Hosp/Fatal HF
1.10 (0.98 - 1.23)
1st Documented
1.13 (1.00 - 1.28)
ALLHAT 1
1.18 (1.02 - 1.36)
ALLHAT 3 (CXR)
1.21 (1.04 - 1.40)
Framingham 1
1.13 (0.99 - 1.30)
Framingham 2
1.12 (0.99 - 1.31)
Reviewers agree
1.15 (1.01 - 1.32)
0.50
Favors Lisinopril
1
2
Favors Chlorthalidone
* Pre-specified endpoint of treated in hospital or as outpatient or fatal
% agreement
ALLHAT
Percent agreement with investigatorassigned diagnosis of HF
100
90
80
70
60
50
40
30
20
10
0
Einhorn PT, et al. Am Heart J 2007;153:42-53.
ALLHAT
HF Outcome Verified
Clinically Significant
 ALLHAT site physician diagnoses confirmed in most patients
 Treatment differences based on site physician reports
corroborated when applying validation criteria sets
• RRs approximating these for the HF prespecified endpoint
 6-year incidence rates of validated HF events comparable to
those of stroke (5.6%) and to about half of non-fatal MI+CHD
deaths (11.4%)
 High mortality rates subsequent to validated hospitalized HF
(55% at 5 years)
Einhorn PT, et al. Am Heart J 2007;153:42-53.
ALLHAT
3. How important are the blood
pressure differences in the
three treatment arms?
BP Results by Treatment Group
ALLHAT
Amlodipine
Lisinopril
150
90
145
85
mm Hg BP
mm Hg BP
Chlorthalidone
140
80
135
75
130
70
0
1
2
3
Years
4
5
6
0
1
2
3
Years
4
5
Compared to chlorthalidone:
Compared to chlorthalidone:
SBP significantly higher in the
amlodipine group (~1 mm Hg) and
the lisinopril group (~2 mm Hg,
and in blacks ~4 mm Hg)
DBP significantly lower in the
amlodipine group (~1 mm Hg).
6
ALLHAT

BP Differences
Adjustment for follow-up SBP as timedependent covariates in a Cox regression
model only slightly modified the relative risks
–
Amlodipine/chlorthalidone 2.22  2.16 first
year, 1.22  1.18 after 1 year
–
Lisinopril/chlorthalidone 2.08  2.01 first year,
0.96  0.93 after 1 year
Davis BH, et al. Circulation 2006;113:2201-10
Exposure to different rates of BP Reduction

Early, inadequate blood pressure responses are
never fully corrected (ALLHAT, Syst-Eur, SCOPE,
ASCOT, VALUE)

The comparator was never able to catch up to the
active drug after short differences in initial BP
despite attempts to increase therapy.
Benefit-Differences Persists Over Time
Time
ALLHAT
•
What we don’t and never will know!
24 hour blood pressure ?
• Night time blood pressure ?
• Central blood pressure ?
ALLHAT
4. How can differences in
secondary endpoints
be termed significant
when primary endpoints
are equal in all three
treatment arms?
ALLHAT
Drug comparisons for HF
• Chlorthalidone vs Amlodipine:
RR 1.35 (95% CI 1.21-1.50, p<0.0013)
and consistent with external data:
Meta-analysis: RR 1.30 (1.21-1.47) in favor of
Diuretics/ß blocker over CCBs for preventing HF.
(BPLTT Collaboration Lancet, 2003;362:1527)
Yusuf SY, Circulation 2006;113:2166
ALLHAT
Drug comparisons for HF
• Chlorthalidone vs lisinopril:
HF RR 1.19 (95% CI 1.07-1.31), p<0.001
―Pre-specified endpoint of treated in hospital
or as outpatient or fatal
(Einhorn PT, et al. Am Heart J 2007;153:42-53)
and consistent with external data:
Network meta–analysis: RR 0.88 (0.80-0.96) p<0.01 in
favor of a diuretic over ACEI for preventing HF.
(Psaty BM, et al. JAMA 2003;289:2534-2544)
ALLHAT
Final Conclusions
 Chlorthalidone was superior to amlodipine in
both time periods in preventing HF in the
aggregate and in all subgroups: age, race, sex,
diabetic history.
 Chlorthalidone was superior to lisinopril in
preventing HF during the first year of
treatment; thereafter, the 2 drugs were equally
effective in preventing HF.
 The ALLHAT studies confirmed that thiazide-
type diuretics should be a preferred first-step
drug treatment for prevention of HF in high-risk
patients with hypertension and/or post MI.
Postscript:
What constitutes
optimal treatment of
ACC/AHA stage A or B
HF to prevent progression
to stage C—overt
symptomatic HF?
Heart Failure: Causal Mechanisms
Smoking
Dyslipidemia
Diabetes
MI
Systolic
Dysfunction
Hypertension
Obesity
Diabetes
Normal LV Structure
and Function
HF
LVH
LV Remodeling
ACC/AHA Stage A
Vasan RS and Levy D. Archives Int Med 1996
Stage B
Diastolic
Dysfunction
Subclinical LV
Dysfunction
Overt Heart
Failure
Stage C
Current ACC/AHA Guidelines: Management
of HF as Applied to ALLHAT Patients
• ALLHAT patients were divided between stage A
and B categories (Stage C patients were excluded).
• For the stage A patients (high risk without structural
abnormalities), ACEIs and diuretics are recommended
for treatment of HTN.
• For the stage B patients (structural heart disease), ACEIs
and diuretics are recommended for treatment of HTN;
ACEIs and BBs are recommended for post MI, LVH,
and reduced LVEF.
• Therefore, poly-pharmacy will be necessary in the majority
of patients for optimal control of HTN (Stage A and B) and
for treatment of structural heart disease (Stage B).
Hunt. et al. Circulation 2005;112:1825-1852
JNC-7 Guidelines for HF Treatment
• “HF is a ‘compelling indication’ for the use of ACEI.
Abundant evidence exists to justify their use with all stages
of HF.”
• “Blood pressure targets in HF have not been firmly
established. In most successful trials SBP were lowered to
the range of 110-130 mm Hg.”
• Therefore, ACEI (or ARB)/diuretic combinations, rather
than single agents, are necessary in the majority of patients
for achieving ‘optimal control’ of HTN, preventing and/or
reversing structural heart damage, and preventing
progression to overt HF.
JNC- 7 Report. JAMA 2003;289:2560-72.