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ATTENTION
The slides in this set which contain the
VALUE study logo are unedited slides
from the VALUE study / investigators.
There are additional notes on slides #16,
23 in addition to those from VALUE.
The rest of the slides are ALLHAT
investigators’ slides and not approved
by the VALUE investigators.
VALUE: Primary Hypothesis
In hypertensive patients at high
cardiovascular risk, for the same level of
blood pressure control, valsartan will be
more effective than amlodipine in reducing
cardiac morbidity and mortality
Julius S et al. Lancet. June 2004;363.
VALUE: Primary Endpoint
• Composite cardiac morbidity and mortality
– sudden cardiac death
– fatal/nonfatal MI
– evidence of recent MI on autopsy
– emergency thrombolytic/fibrinolytic treatment
and/or emergency PTCA/CABG to avoid MI
– death during/after PTCA/CABG
– new or chronic CHF requiring hospital
management
– heart failure death
Mann J, Julius S. Blood Press. 1998;7:176–183.
VALUE: Secondary Endpoints and
Pre-specified Analyses
• Secondary Endpoints:
– fatal/non-fatal myocardial infarction
– fatal/non-fatal stroke
– fatal/non-fatal heart failure
• Pre-specified Analyses:
– all-cause mortality
– new-onset diabetes
Julius S et al. Lancet. June 2004;363.
VALUE: Design
Elective titration to target BP (<140/90 mmHg)
Valsartanbased regimen
V 160 mg +
HCTZ 25 mg
V 160 mg +
HCTZ 12.5 mg
V 160 mg +
HCTZ 25 mg + "Free" add-on
V 160 mg
Rollover
from
previous
therapy
(92%)
V 80 mg
A 5 mg
A 10 mg
A 10 mg +
HCTZ 12.5 mg
Amlodipinebased regimen
Month 0.5
0
A 10 mg +
HCTZ 25 mg
A 10 mg +
HCTZ 25 mg + "Free" add-on
1
Screening
Randomisation
2
3
6
*
72
End of treatment adjustment period
*Patient visits every 6 months for months 6–72.
Julius S et al. Lancet. June 2004;363.
4
VALUE: Patient Population
• Treated or untreated hypertensive patients
– entry criteria for untreated hypertension:
160–210 mmHg systolic, 95–105 mmHg
diastolic
• Age ≥50 years, male or female
• High-risk for cardiac events
– one or more defined risk factors or diseases
Mann J, Julius S. Blood Press. 1998;7:176–183.
VALUE: Qualifying Risk Factor
and Disease Algorithm
Age Range
Male Patients
Female Patients
50 to 59 yrs
At least 3 risk
factors or 1 disease
At least 2 risk factors
and 1 disease or at
least 2 diseases
60 to 69 yrs
At least 2 risk
factors or 1 disease
At least 2 risk factors
or 1 disease
≥70 yrs
At least 1 risk factor
or 1 disease
At least 1 risk factor
or 1 disease
Mann J, Julius S. Blood Press. 1998;7:176–183.
VALUE: Qualifying Risk Factors
and Diseases
Risk Factors
Diseases
• Diabetes mellitus
• History of CHD
• Cigarette smoking
• Peripheral vascular
disease
• Hypercholesterolemia
• Left ventricular hypertrophy (LVH) without strain
patterns
• Proteinuria
• Serum creatinine
150–265 µmol/L
Mann J, Julius S. Blood Press. 1998;7:176–183.
• Stroke or transient ischemic
attack
• LVH with ECG documented
strain patterns (ST segment
depression)
VALUE: Exclusion Criteria
• Renal artery stenosis
• Pregnancy
• Acute myocardial infarction
• Percutaneous transluminal coronary angioplasty, or
coronary artery bypass graft within the past 3 months
• Clinically relevant valvular disease
• Cerebrovascular accident in the past 3 months
• Severe hepatic disease
• Severe chronic renal failure (defined as creatinine
>265 mol/L)
• Congestive heart failure requiring ACE inhibitor therapy
• Patients on monotherapy with beta blockers for both
coronary artery disease and hypertension
Mann J, Julius S. Blood Press. 1998;7:176–183.
Valsartan Antihypertensive Long-Term Use Evaluation
15,313 randomised at 942 sites in 31 countries
Average follow up 4.2 years
Julius S et al. Lancet. June 2004;363.
VALUE: Baseline Characteristics
Valsartan
(n = 7649)
Amlodipine
(n = 7596)
Women (%)
Age (y)
3240 (42.4%)
67.2 ± 8.2*
3228 (42.5%)
67.3 ± 8.1
BMI (kg/m2)
HTN previously treated (%)
SBP (mmHg)
DBP (mmHg)
Heart rate (beats/min)
Race (%)
Caucasian
Black
Oriental
Other
28.6 ± 5.1
7088 (92.7%)
154.5 ± 19.0
87.4 ± 10.9
72.3 ± 10.8
28.7 ± 5.0
6989 (92.0%)
154.8 ± 19.0
87.6 ± 10.7
72.5 ± 10.7
6821 (89.2%)
325 (4.3%)
272 (3.6%)
231 (3.0%)
6796 (89.5%)
314 (4.1%)
261 (3.4%)
225 (3.0%)
Variable
*Mean ± SD or % of total.
Julius S et al. Lancet. June 2004;363.
VALUE: Qualifying Risk Factors*
Valsartan
(n = 7649)
Amlodipine
(n = 7596)
Elevated cholesterol
2555 (33.4%)
2522 (33.2%)
Diabetes mellitus
2395 (31.3%)
2428 (31.9%)
Current smoking
1826 (23.9%)
1838 (24.2%)
Proteinuria
1721 (22.5%)
1714 (22.6%)
954 (12.5%)
902 (11.9%)
290 (3.8%)
260 (3.4%)
LVH without strain pattern
Elevated serum creatinine
*Data are shown as numbers of patients (%) or mean (±SD).
Julius S et al. Lancet. June 2004;363.
VALUE: Qualifying Disease Factors*
Valsartan
(n = 7649)
Amlodipine
(n = 7596)
Coronary heart disease
3490 (45.6%)
3491 (46.0%)
Stroke or TIA
1513 (19.8%)
1501 (19.8%)
Peripheral arterial
disease
1052 (13.8%)
1062 (14.0%)
454 (5.9%)
462 (6.1%)
LVH with strain pattern†
*Data are shown as numbers of patients (%) or mean (±SD).
†LVH including left bundle branch block.
Julius S et al. Lancet. June 2004;363.
VALUE: Blood Pressure Changes From
Baseline to the End of the Study
0
mmHg
–5
SBP
DBP
–10
–15
–20
ValsartanBased Therapy
Julius S et al. Lancet. June 2004;363.
AmlodipineBased Therapy
VALUE: Trends in SBP Control
(<140 mmHg)
Before
Randomisation
22%
Study End
Valsartan-Based
Regimen
57%
Noncontrolled
Controlled
22%
Amlodipine-Based
Regimen
63%
Noncontrolled
Controlled
92% of patients were previously treated
with antihypertensive medication(s) at time of entry.
Julius S et al. Lancet. June 2004;363.
BP Levels in Other Clinical Trials
Trial
Publication
Baseline BP
Final BP
HOT
CAPPP
STOP-2
ALLHAT
NORDIL
INSIGHT
LIFE
VALUE
Lancet 1998
Lancet 1999
Lancet 1999
JAMA 2000
Lancet 2000
Lancet 2000
Lancet 2002
Am J Hypertens
175 / 105
161 / 99
194 / 98
145 / 83
173 / 106
173 / 99
174 / 98
154 / 88
142 / 83
150 / 90
159 / 81
136 / 76
151 / 88
138 / 82
145 / 81
138 / 79
William C. Cushman, MD:
The ALLHAT data is not what we want to promote, since it is apparently
from the doxazosin paper – we should add a slide after this giving our “final
BP” (end of study) to be comparable to VALUE end of study BP. Charlie has
data. Also, in notes, it doesn’t compare BP control rates to ALLHAT.
Adapted from S. Kjeldsen 2000 and updated April 2002.
VALUE: Systolic Blood Pressure in Study
Sitting SBP by Time and Treatment Group
mmHg
155
Valsartan
(N= 7649)
150
145
140
135
Baseline
1
2
3
4
6
12 18 24 30 36 42 48 54 60 66
Months
mmHg
Amlodipine
(N = 7596)
5.0
4.0
3.0
2.0
1.0
0
–1.0
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
1
2
3
4
6
Julius S et al. Lancet. June 2004;363.
12 18 24 30 36 42 48 54 60 66
Months
(or final visit)
VALUE: Diastolic Blood Pressure in Study
mmHg
Sitting DBP by Time and Treatment Group
90
Valsartan
(N= 7649)
85
Amlodipine
(N = 7596)
80
75
Baseline
1
2
3
4
6
12 18 24 30 36 42 48 54 60 66
mmHg
Months
5.0
4.0
3.0
2.0
1.0
0
–1.0
(or final visit)
Difference in DBP Between Valsartan and Amlodipine
1
2
3
4
6
Julius S et al. Lancet. June 2004;363.
12 18 24 30 36 42 48 54 60 66
Months
(or final visit)
VALUE: Hazard Ratios
for Pre-specified Analyses
Hazard Ratio
Valsartan/Amlodipine
Primary cardiac composite endpoint
cardiac mortality
cardiac morbidity
All myocardial infarction
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
0.5
1
2
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. June 2004;363.
VALUE: Main Results
Good BP control was achieved with both
treatment regimens, but BP decrease in the
amlodipine group was more pronounced,
particularly early in the trial
Despite BP differences, the primary composite
cardiac endpoint in both groups was not
different
Julius S et al. Lancet. June 2004;363.
VALUE: Other Results
• Incidence of stroke was lower, but not
significantly, in the amlodipine group
• Incidence of non-fatal MI was significantly
lower in the amlodipine group
• There was a positive trend in favour of
valsartan for less heart failure but this did
not reach significance
• There was a highly significant lower rate of
new-onset diabetes in the valsartan group
Julius S et al. Lancet. June 2004;363.
VALUE: Interpretations
• The observed difference in stroke rates
appears to be strongly related to
differences in achieved BPs
• The benefits of valsartan in heart failure
prevention emerged later in the study when
BP differences were smaller, indicating that
there is a potential beneficial effect of
valsartan beyond BP control
Julius S et al. Lancet. June 2004;363.
VALUE: Analysis of Results
Based on Serial Median Matching
Rationale:
Differences in achieved BP levels in VALUE
precluded valid comparisons of drug effects on
outcomes. Therefore, a statistical technique that
adjusts for BP differences was applied post hoc to
create treatment cohorts with closely similar
characteristics
Weber MA et al. Lancet. 2004;363:2047–49.
VALUE: Analysis of Results
Based on Serial Median Matching
Description:
The novel computerised procedure of Serial Median Matching
was applied at 6 months, following the treatment adjustments
intended to achieve BP control.
The programme selected the most median patient (by achieved
systolic BP) in the valsartan group; this patient was paired with
one from the amlodipine group ( 2 mmHg) and was matched
also for age, sex and the presence or absence of prior coronary
disease, stroke and diabetes.
The newly created patient pair was moved to a new database,
and the procedure repeated serially until all possible patient
pairs were matched.
Weber MA et al. Lancet. 2004;363:2047–49.
VALUE: Major Study Endpoints in 5006 Patient Pairs
(N = 10,012) on Valsartan- or Amlodipine-Based
Therapies Using Serial Median Matching
Hazard Ratio
(95% CI)
P
Composite cardiac events
0.90 (0.79–1.03)
0.111
Stroke
1.02 (0.81–1.28)
0.899
Death
0.96 (0.84–1.10)
0.566
Myocardial infarction
0.97 (0.80–1.19)
0.791
Heart failure
0.81 (0.66–0.99)* 0.040
0.6
*P < 0.05.
0.8
Favours valsartan
Weber MA et al. Lancet. 2004;363:2047–49.
1.0
1.2
1.4
Favours amlodipine
VALUE: Analysis of Results
Based on Serial Median Matching
Conclusions:
Serial median matching created valsartanamlodipine patient pairs matched exactly for
systolic BP and demographic and clinical
characteristics excluding the high and low
extremes of achieved BPs.
It allowed us to address the original study
hypothesis, and demonstrated that for the same
achieved BPs, valsartan in an intermediate dose
had effects similar to amlodipine on most CV
endpoints, and was more effective in reducing
heart failure hospitalisations.
Weber MA et al. Lancet. 2004;363:2047–49.
VALUE: Analyses of Results
Based on BP Control
Overall Conclusions:
Blood pressure control, and rapidity of response,
are critical for reducing events in high-risk
hypertension
The significant between-group differences in heart
failure and diabetes suggest that valsartan may
offer benefits beyond BP control
Weber MA et al. Lancet. 2004;363:2047–49.
VALUE Summary
• ARB (valsartan) not more effective than CCB
(amlodipine) in decreasing cardiac mortality
and morbidity
– CCB →lower SBP than ARB (4 mm Hg at 1-2
months, 2 mm Hg at 6 months)
– CCB →significantly lower incidence of MI, higher
incidence of new-onset diabetes
• Serial median matching adjusted for BP Δ
– MI incidence became equivalent for CCB & ARB
– Lower rate of HF with ARB
Julius S, Kjeldsen SE, Weber M, et al. Lancet 2004;363:2022-31
Comments on VALUE Analyses
• Differing odds ratios over time
– Cox regressions assume constant hazard
ratios, but were used in analyses anyway
• Rationale for BP adjustment method?
– Discards thousands of observations.
– Alternatives: Cox model with BP as timedependent covariate or beginning at 6 months
Does Lower Rate of BP Control with ARB
Imply Differences should be Dismissed?
• If a drug does not reduce CVD more because of less
effect on BP, seems like limiting property of drug
ALLHAT VALUE –
diuretic valsartan
BP control
70%
56%
ALLHAT – VALUE amlodipine amlodipine
68%
62%
• RAS-blocker did not have sufficient special
properties to overcome 2 mm Hg SBP disadvantage
• In VALUE, thiazide available for step-up – 25% of
both groups – but did not obviate BP disadvantage
for RAS-blocker
Diabetes Incidence
If CCBs raise incidence of new-onset
diabetes but lower incidence of MI
compared with ARBs, why would an
ARB be preferred?
ARBs & β-blockers may prevent MI less
than thiazide-like diuretics, CCBs, ARBs
1.
In meta-analysis1, β-blockers did not reduce
coronary events as well as low-dose diuretics
2.
No differences in LIFE trial between ARB
(losartan) & β-blocker (atenolol)2
3.
No differences in ALLHAT between
chlorthalidone, lisinopril, and amlodipine for
primary outcome
4.
Taken together, this suggests ARBs and βblockers may reduce CHD less than thiazidetype diuretics, CCBs, or ACEIs.
1Psaty
BM, Smith ML, Siscovick DS, et al. JAMA 1997;277:739-745.
2Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet 2002;359:995-1003.