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Presenter Disclosure Information
FINANCIAL DISCLOSURE:DSMB’s: Merck, Takeda
Barry R. Davis, MD, PhDClinical Outcomes in Participants with Dysmetabolic Syndrome in ALLHAT
UNLABELED / UNAPPROVED USES DISCLOSURE:None
2
Clinical Outcomes in Participants with Dysmetabolic
Syndrome in ALLHATBarry R. Davis, MD, PhD & Henry R. Black, MD for the ALLHAT Collaborative Research Group
Presented at the
American Heart Association Meeting
November 8, 2004
ALLHATALLHAT
3
Randomized Designof ALLHAT
High-risk hypertensive patients
Consent / Randomize
(42,418)
Amlodipine
Chlorthalidone
Doxazosin
Lisinopril
Eligible for lipid-lowering
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
4
Dysmetabolic SyndromeDysmetabolic Syndrome
ALLHAT reported overall superiority of ALLHAT reported overall superiority of thiazide-type treatment for first-step therapy thiazide-type treatment for first-step therapy of hypertensionof hypertension
Patients with dysmetabolic syndrome (DS) Patients with dysmetabolic syndrome (DS) are at especially high risk for many are at especially high risk for many hypertensive complicationshypertensive complications
Post hoc analyses from ALLHAT regarding Post hoc analyses from ALLHAT regarding treatment of hypertension in patients with treatment of hypertension in patients with and without DS are of interestand without DS are of interest
Definitions of DS vary (WHO, ATP III, etc.)Definitions of DS vary (WHO, ATP III, etc.)
ALLHATALLHAT
5
Dysmetabolic Syndrome (DS)
Any 3 or more of the following items:
• Glycemic disorder – History of diabetes– Baseline glucose
• BMI ≥30• Fasting triglycerides 150+ • HDL cholesterol <40 in men, <50 in women• High BP (“yes” for all ALLHAT participants)
• DS missing: # yes <3 and # yes + # missing ≥ 3
ALLHATALLHAT
6
Glycemic DisorderALLHATALLHAT
Fasting Glucose Nonfasting glucose
Missing
glucose<100 ≥100 <100 100-199 ≥200
Hx of diabetes
Yes Yes Yes Yes Yes Yes
No hx of diabetes
No Yes No Missing Yes Missing
7
Definitions ofDysmetabolic Syndrome
ALLHAT ATP III WHO AACE
Insulin resistance (any of following):
Fasting glucose ≥100 ≥110 IFG 110 - 126
Nonfasting glucose
≥200
History of diabetes Yes Yes
OGTT NA IGT
2-hr post-glucose >140
Obesity (any of following):
Abdominal obesity WC: >40” M, >35” F
W/H: >.9M >.85W
BMI ≥30 >30 ≥25
ALLHATALLHAT
ATP III – National Cholesterol Education Program’s Adult Treatment Panel III ReportWHO – World Health OrganizationAACE – American Association of Clinical Endocrinologists
IFG = Impaired fasting glucoseIGT = Impaired glucose toleranceWC = Waist circumferenceW/H = Waist / hip ratio
8
Definitions of Dysmetabolic Syndrome (continued)
ALLHATALLHAT
ALLHAT ATP III WHO AACE
Lipids (any of following):
Fasting TRIGs ≥150 ≥150 ≥150 ≥150
HDL <40 M <50 F <40 M <50 F <35M <39F <40 M <50 F
Blood pressure:
↑BP Yes ≥130/ ≥85 ≥140/ ≥90 ≥130/ ≥85
AHT medications Yes Yes
Other:
UA* Exr ≥20 or A/C** ≥30
Many+
* UA = Urinary albumin excretion rate** A/C = Albumin:creatinine ratio+ Family history of type 2 diabetes, hypertension or CVD; polycystic ovary syndrome; sedentary lifestyle; advancing age; ethnic groups having high risk for type 2 diabetes or CVD
9
Dysmetabolic Syndrome –Classification & Missing Values
DS No DS Missing Total
Chlor 8,315 54.5% 5,155 33.8% 1,785 11.7% 15,255
Amlod 4,915 54.3% 3,030 33.5% 1,103 12.2% 9,048
Lisin 4,953 54.7% 2,995 33.1% 1,106 12.2% 9,054
Total 18,183 54.5% 11,180 33.5% 3,994 12.0% 33,357
ALLHATALLHAT
10
Baseline Characteristics - Participants* With and Without DS
DS No DS
N 18,183 11,180Age – mean 66.1 68.0 **Women (%) 49.8 42.0 **Black (%) 28.4 34.6 **SBP – mean 146.1 146.6 **DBP – mean 83.8 84.4 **Current smokers (%) 17.8 27.4 **ASCVD (%) 46.5 58.4 **
*Randomized to chlorthalidone, amlodipine, or lisinopril.** p<.05
ALLHATALLHAT
11
Baseline Characteristics - Participants* With and Without DS
DS No DS
N 18,183 11,180
Fasting gluc - mean (sd) 135.2 (61.3) 102.6 (41.5) **
History of diabetes % 31.7 6.3 **
BMI – mean (sd) 32.0 (6.2) 26.5 (4.4) **
Fasting trig - mean (sd) 205.1 (148.4) 122.1 (84.6) **
HDL chol – mean (sd) 42.3 (12.2) 53.9 (15.5) **
*Randomized to chlorthalidone, amlodipine, or lisinopril.** p<.05
ALLHATALLHAT
12
Blood Pressure at 5 Yearsby Baseline DS Status
Chlor Amlod Lisin
SBP mean (sd)
DS 134 (15) 135 (15) 136 (18)*
No DS 133 (15) 134 (15) 136 (18)*
DBP mean (sd)
DS 75 (10) 74 (10)* 75 (10)
No DS 76 (10) 75 (10)* 76 (11)
SBP/DBP difference compared with chlorthalidone
DS --- +0.6 / +0.2* +1.9* / 0.0
No DS --- +0.9 / -1.0* +2.1* / 0.0
* p<0.05 compared with chlorthalidone
ALLHATALLHAT
13
Biochemical Measures at 4 Yearsin Participants with Dysmetabolic Syndrome
Chlor Amlod Lisin
TChol mg/dL
Mean
N
196.3
4,736
195.6
2,752
194.7
2,629
Fasting Glucose mg/dL
Mean
% 126+
N
137.5
43.1
2,809
134.7
41.8
1,674
131.1*
37.6*
1,523
Potassium mmol/L
Mean
N
4.1
4572
4.4*
2658
4.6*
2523
* p<0.05 compared with chlorthalidone
ALLHATALLHAT
14
Biochemical Measures at 4 Yearsin Participants without Dysmetabolic Syndrome
Chlor Amlod Lisin
TChol mg/dL
Mean
N
197.4
2,924
194.6*
1,765
194.9*
1,606
Fasting Glucose mg/dL
Mean
% 126+
N
108.6
16.7
1,793
106.6
13.1*
1,057
107.7
16.4
989
Potassium mmol/L
Mean
N
4.1
2,849
4.4*
1,720
4.5*
1,570
* p<0.05 compared with chlorthalidone
ALLHATALLHAT
15
CHD by Treatment Group In Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
2
4
6
08
10
12
14
Cu
mu
lati
ve C
HD
Eve
nt
Rat
e, %
0 1 2 3 4 5 6
Years to CHD
HR (95% CI) p value
A/C 0.95 (0.84 – 1.07) 0.37
L/C 1.01 (0.90 – 1.13) 0.86
16
CHD by Treatment GroupIn Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
2
4
6
8
10
12
14
Cu
mu
lati
ve C
HD
Eve
nt
Rat
e, %
0 1 2 3 4 5 6
Years to CHD
HR (95% CI) p value
A/C 1.05 (0.90 – 1.22) 0.53
L/C 1.02 (0.88 – 1.20) 0.78
17
CHD
All-cause mortality
Stroke
Heart Failure
Combined CVD
ESRD
FavorsChlorthalidone
FavorsAmlodipine
FavorsChlorthalidone
WithDysmetabolic Syndrome
WithoutDysmetabolic Syndrome
FavorsAmlodipine
0.50 1 2
0.81 (0.51 - 1.26)
1.05 (0.96 - 1.15)
1.45 (1.20 - 1.75)
1.04 (0.83 - 1.29)
0.93 (0.83 - 1.04)
1.05 (0.90 - 1.22)
0.50 1 2
1.27 (0.96 - 1.68)
1.05 (0.98 - 1.12)
1.32 (1.15 - 1.51)
0.87 (0.74 - 1.04)
0.97 (0.88 - 1.06)
0.95 (0.84 - 1.07)
Amlodipine/ChlorthalidoneRelative Risk and 95% Confidence IntervalsALLHAT
18
CHD
All-cause mortality
Stroke
Heart Failure
Combined CVD
ESRD
FavorsChlorthalidone
FavorsLisinopril
FavorsChlorthalidone
FavorsLisinopril
0.50 1 2
1.22 (0.92 - 1.63)
1.14 (1.06 - 1.21)
1.28 (1.12 - 1.47)
1.09 (0.93 - 1.28)
1.01 (0.93 - 1.12)
1.01 (0.90 - 1.13)
0.50 1 2
0.76 (0.48 - 1.21)
1.07 (0.98 - 1.17)
1.02 (0.83 - 1.25)
1.20 (0.97 - 1.48)
1.02 (0.91 - 1.14)
1.02 (0.88 - 1.20)
ALLHAT Lisinopril/ChlorthalidoneRelative Risk and 95% Confidence Intervals
WithDysmetabolic Syndrome
WithoutDysmetabolic Syndrome
19
Results by Baseline Dysmetabolic Syndrome -
Conclusions• Treatment group comparison results were
similar in participants with and without DS at baseline (i.e., there were no significant interactions)
• For both DS and non-DS participants, neither the CCB nor ACEI arms were superior to the diuretic arm
– For HF, diuretic was superior to CCB
• Results were similar with DS definition similar to ATP III
ALLHAT
20
Results - Overall
• Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy in patients with and without dysmetabolic syndrome.
ALLHAT
21
Additional Slides
(Not presented at AHA)
ALLHAT
22
BP Results by Treatment Group and Baseline DS
DS-Chlor DS–Amlod DS–Lisin
No DS–Chlor No DS–Amlod No DS–Lisin
ALLHATALLHAT
23
DS-Chlor DS–Amlod
No DS–Chlor No DS–Amlod
ALLHATALLHAT BP Results by Treatment Group and Baseline DS
Amlodipine vs Chlorthalidone
24
ALLHATALLHAT BP Results by Treatment Group and Baseline DS
Lisinopril vs Chlorthalidone
DS-Chlor DS–Lisin
No DS–Chlor No DS–Lisin
25
Outcomes in Participants with DS –Amlodipine Compared With Chlorthalidone
6-Year Rates per 100 (se)
# Events
RR (95% CI)
p
Chlor Aml Aml/Chl
CHD 11.5 (0.4)
771
10.9 (0.5)
434
0.95 (0.84 – 1.07)
0.37
Mortality 15.6 (0.5)
1,126
15.1 (0.6)
644
0.97 (0.88 – 1.06)
0.49
Stroke 5.7 (0.3)
386
5.2 (0.4)
201
0.87 (0.74 – 1.04)
0.12
Heart Failure 8.0 (0.4)
526
10.5 (0.5)
403
1.32 (1.15 – 1.51)
<0.001
Combined CVD
20.6 (0.5)
1,447
21.2 (0.7)
863
1.05 (0.98 – 1.12)
0.15
ESRD 1.8 (0.2)
135
2.4 (0.3)
97
1.27 (0.96 – 1.68)
0.09
ALLHAT
26
Outcomes in Participants with DS –Lisinopril Compared with Chlorthalidone
6-Year Rates per 100 (se)
# Events
RR (95% CI)
p
Chlor Lisin Lisin/Chl
CHD 11.5 (0.4)
771
11.4 (0.5)
457
1.01 (0.90 – 1.13)
0.86
Mortality 15.6 (0.5)
1,126
15.7 (0.6)
678
1.01 (0.93 – 1.12)
0.70
Stroke 5.7 (0.3)
386
6.1 (0.4)
248
1.09 (0.93 – 1.28)
0.27
Heart Failure 8.0 (0.4)
526
9.7 (0.5)
395
1.28 (1.12 – 1.47)
<0.001
Combined CVD
20.6 (0.5)
1,447
21.4 (0.7)
883
1.14 (1.06 – 1.21)
<0.001
ESRD 1.8 (0.2)
135
2.3 (0.3)
92
1.22 (0.92 – 1.63)
0.16
ALLHAT
27
Outcomes in Participants without DS –Amlodipine Compared with Chlorthalidone
6-Year Rates per 100 (se)
RR (95% CI)
p
Chlor Aml Aml/Chl
CHD 10.4 (0.5)
429
10.9 (0.7)
269
1.05 (0.90 – 1.22)
0.53
Mortality 17.6 (0.6)
795
17.0 (0.8)
441
0.93 (0.83 – 1.04)
0.23
Stroke 5.0 (0.4)
208
5.1 (0.5)
129
1.04 (0.83 – 1.29)
0.73
Heart Failure 6.8 (0.5)
258
8.6 (0.6)
215
1.45 (1.20 – 1.75)
<0.001
Combined CVD
17.6 (0.7)
732
17.3 (0.8)
448
1.05 (0.96 – 1.15)
0.28
ESRD 1.5 (0.2)
26
1.1 (0.2)
17
0.81 (0.51 – 1.26)
0.35
ALLHAT
28
Outcomes in Participants without DS –Lisinopril Compared with Chlorthalidone
6-Year Rates per 100 (se)
RR (95% CI)
p
Chlor Lisin Lisin/Chl
CHD 10.4 (0.5)
429
10.4 (0.7)
256
1.02 (0.88 – 1.20)
0.78
Mortality 17.6 (0.6)
795
18.3 (0.8)
476
1.02 (0.91-1.14)
0.72
Stroke 5.0 (0.4)
208
5.8 (0.5)
145
1.20 (0.97 – 1.48)
0.09
Heart Failure
6.8 (0.5)
258
6.6 (0.6)
153
1.02 (0.83 – 1.25)
0.84
Combined CVD
17.6 (0.7)
732
18.2 (0.9)
455
1.07 (0.98 – 1.17)
0.15
ESRD 1.5 (0.2)
26
1.0 (0.2)
16
0.76 (0.48 – 1.21)
0.26
ALLHAT
29
All-Cause Mortalityby Treatment Group
In Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
4
8
12
16
20
Cu
mu
lati
ve D
eath
Eve
nt
Rat
e, %
0 1 2 3 4 5 6
Years to Death
HR (95% CI) p value
A/C 0.97 (0.88 – 1.06) 0.49
L/C 1.01 (0.93 – 1.12) 0.70
30
All-Cause Mortalityby Treatment Group
In Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
4
8
12
16
20
Cu
mu
lati
ve D
eath
Eve
nt
Rat
e, %
0 1 2 3 4 5 6
Years to Death
HR (95% CI) p value
A/C 0.93 (0.83 – 1.04) 0.23
L/C 1.02 (0.91-1.14) 0.72
31
Stroke by Treatment GroupIn Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
1
2
3
4
5
6
7
Cu
mu
lati
ve S
tro
ke E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to Stroke
HR (95% CI) p value
A/C 0.87 (0.74 – 1.04) 0.12
L/C 1.09 (0.93 – 1.28) 0.27
32
Stroke by Treatment GroupIn Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
1
2
3
4
5
6
7
Cu
mu
lati
ve S
tro
ke E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to Stroke
HR (95% CI) p value
A/C 1.04 (0.83 – 1.29) 0.73
L/C 1.20 (0.97 – 1.48) 0.09
33
Heart Failure by Treatment GroupIn Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
2
4
6
8
10
12
Cu
mu
lati
ve H
F E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to HF
OR (95% CI) p value
A/C 1.32 (1.15 – 1.51) <0.001
L/C 1.28 (1.12 – 1.47) <0.001
34
Heart Failure by Treatment GroupIn Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
2
4
6
8
10
12
Cu
mu
lati
ve H
F E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to HF
OR (95% CI) p value
A/C 1.45 (1.20 – 1.75) <0.001
L/C 1.02 (0.83 – 1.25) 0.84
35
Combined CVD by Treatment GroupIn Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
5
10
15
20
25
30
35
Cu
mu
lati
ve C
CV
D E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to CCVD
HR (95% CI) p value
A/C 1.05 (0.98 – 1.12) 0.15
L/C 1.14 (1.06 – 1.21) <0.001
36
Combined CVD by Treatment GroupIn Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
5
10
15
20
25
30
35
Cu
mu
lati
ve C
CV
D E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to CCVD
HR (95% CI) p value
A/C 1.05 (0.96 – 1.15) 0.28
L/C 1.07 (0.98 – 1.17) 0.15
37
End Stage Renal Diseaseby Treatment Group
In Participants With DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
1
2
3
Cu
mu
lati
ve E
SR
D E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to ESRD
HR (95% CI) p value
A/C 1.27 (0.96 – 1.68) 0.09
L/C 1.22 (0.92 – 1.63) 0.16
38
End Stage Renal Diseaseby Treatment Group
In Participants Without DS at Baseline
ChlorthalidoneAmlodipineLisinopril
ALLHAT
0
1
2
3
Cu
mu
lati
ve E
SR
D E
ven
t R
ate,
%
0 1 2 3 4 5 6
Years to ESRD
HR (95% CI) p value
A/C 0.81 (0.51 – 1.26) 0.35
L/C 0.76 (0.48 – 1.21) 0.26
39
CHD
All-cause mortality
Stroke
Heart Failure
Combined CVD
ESRD
Favors Amlodipine0.50 1 2
1.27 (0.96 - 1.68)
1.05 (0.98 - 1.12)
1.32 (1.15 - 1.51)
0.87 (0.74 - 1.04)
0.97 (0.88 - 1.06)
0.95 (0.84 - 1.07)
Favors Chlorthalidone
ALLHATAmlodipine/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Outcomes in Participants With Dysmetabolic Syndrome-
40
CHD
All-cause mortality
Stroke
Heart Failure
Combined CVD
ESRD
Favors Amlodipine0.50 1 2
0.81 (0.51 - 1.26)
1.05 (0.96 - 1.15)
1.45 (1.20 - 1.75)
1.04 (0.83 - 1.29)
0.93 (0.83 - 1.04)
1.05 (0.90 - 1.22)
Favors Chlorthalidone
ALLHATAmlodipine/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Outcomes in Participants Without Dysmetabolic Syndrome
41
ESRD
Combined CVD
Heart Failure
Stroke
All-cause mortality
CHD
Favors Lisinopril
0.50 1 2
1.22 (0.92 - 1.63)
1.14 (1.06 - 1.21)
1.28 (1.12 - 1.47)
1.09 (0.93 - 1.28)
1.01 (0.93 - 1.12)
1.01 (0.90 - 1.13)
Favors Chlorthalidone
ALLHATLisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals
Outcomes in Participants With Dysmetabolic Syndrome
42
CHD
All-cause mortality
Stroke
Heart Failure
Combined CVD
ESRD
Favors Lisinopril0.50 1 2
0.76 (0.48 - 1.21)
1.07 (0.98 - 1.17)
1.02 (0.83 - 1.25)
1.20 (0.97 - 1.48)
1.02 (0.91 - 1.14)
1.02 (0.88 - 1.20)
Favors Chlorthalidone
ALLHATOutcomes in Participants Without
Dysmetabolic SyndromeLisinopril/Chlorthalidone
Relative Risk and 95% Confidence Intervals