Valsartan Antihypertensive Long-Term Use Evaluation Results

1
Valsartan Antihypertensive Long-Term Use
Evaluation Results

• Stevo Julius, MD, ScD
• Professor of Medicine and Physiology
• Frederick G. Huetwell Professor of Hypertension
• University of Michigan Health System
• Ann Arbor, Michigan, USA

2
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 2004363.
3
VALUE Blood Pressure Changes From Baseline to
the End of the Study
0
5
SBP DBP
mmHg
10
15
20
Valsartan-Based Regimen
Amlodipine-Based Regimen
Julius S et al. Lancet. June 2004363.
4
VALUE Trends in SBP Control (lt140 mmHg)
Before Randomisation
Study End
22
Valsartan-Based Regimen
Non-controlled
57
Controlled
Amlodipine-Based Regimen
22
Non-controlled
63
Controlled
92 of patients were previously treated with
antihypertensive medication(s) at time of entry.
Julius S et al. Lancet. June 2004363.
5
VALUE Antihypertensive Medications in the Study
Valsartan (n 7649) Amlodipine (n 7596)
Valsartan 80 mg or amlodipine 5 mg 1213 (15.9) 1583 (20.8)
Valsartan 160 mg or amlodipine 10 mg 852 (11.1) 1105 (14.5)
Valsartan 80 mg or amlodipine 5 mg HCTZ 159 (2.1) 329 (4.3)
Valsartan 160 mg or amlodipine 10 mg HCTZ 1719 (22.5) 1481 (19.5)
Other combinations or add-ons 1758 (23.0) 1279 (16.8)
No study therapy 1948 (25.5) 1819 (23.9)
Median dose 151.7 mg 8.5
mg
(0160 mg)
(010 mg)
Dose minimum/maximum
Number () of patients on study medication at
primary endpoint, including stroke or at final
visit for patients without event, (ITT
population).
Julius S et al. Lancet. June 2004363.
6
VALUE Systolic Blood Pressure in Study
Sitting SBP by Time and Treatment Group
155
Valsartan (N 7649)
Amlodipine (N 7596)
150
mmHg
145
140
135
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Baseline
Months
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
2.0
mmHg
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004363.
7
VALUE Diastolic Blood Pressure in Study
Sitting DBP by Time and Treatment Group
90
Valsartan (N 7649)
Amlodipine (N 7596)
mmHg
85
80
75
Baseline
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
Months
(or final visit)
Difference in DBP Between Valsartan and Amlodipine
5.0
4.0
3.0
mmHg
2.0
1.0
0
1
24
48
2
3
4
6
12
18
30
36
42
54
60
66
1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004363.
8
VALUE Primary Endpoint Result
9
VALUE Primary Composite Cardiac Endpoint
14 12 10 8 6 4 2 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.03 95 CI 0.941.14 P 0.49
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
7649
7459
7407
7250
7085
6732
6906
6536
5911
3765
1474
6349
Valsartan
Amlodipine
7596
7469
7424
7267
7117
6772
6955
6576
5959
3725
1474
6391
Julius S et al. Lancet. June 2004363.
10
VALUE Total Mortality Result
11
VALUE All-cause Death
16 14 12 10 8 6 4 2 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.04 95 CI 0.941.14 P 0.45
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7527
7496
7383
7267
6994
7136
6843
6273
3981
1563
6682
Amlodipine
7596
7520
7484
7385
7276
7025
7155
6874
6312
3961
1582
6729
Julius S et al. Lancet. June 2004363.
12
VALUESecondary Endpoint Results
13
VALUE Fatal and Non-FatalMyocardial Infarction
7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 1.19 95 CI 1.021.38 P 0.02
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7499
7458
7319
7177
6853
7016
6680
6078
3864
1520
6504
Amlodipine
7596
7497
7458
7332
7205
6905
7065
6727
6141
3840
1532
6562
Julius S et al. Lancet. June 2004363.
14
VALUE Outcome and SBP Differencesat Specific
Time Periods Myocardial Infarction
Time Interval
Myocardial Infarction Odds Ratios and 95 CIs
D
SBP
(months)
(mmHg)
Overall study
2.2
3.8
03
2.3
36
2.0
612
1.8
1224
1.6
2436
1.4
3648
Study end
1.7
4.0
1.0
2.0
0.5
0.25
Favours amlodipine
Favours valsartan
Julius S et al. Lancet. June 2004363.
15
VALUE Hazard Ratios for Fatal and Non-fatal
Myocardial Infarction
Hazard Ratio Valsartan/Amlodipine
Myocardial Infarction
Fatal and non-fatal Fatal Non-fatal
0.5
1
2
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. June 2004363.
16
VALUE Fatal and Non-fatal Stroke
6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7494
7448
7312
7170
6877
7022
6692
6093
3859
1516
6515
7596
Amlodipine
7499
7455
7334
7195
6918
7055
6744
6163
3846
1532
6587
Julius S et al. Lancet. June 2004363.
17
VALUE Outcome and SBP Differencesat Specific
Time Periods Stroke
STROKE
Time Interval
? SBP
Odds Ratios and 95 CIs
(months)
(mmHg)
Overall study
2.2
03
3.8
36
2.3
612
2.0
1224
1.8
2436
1.6
3648
1.4
Study end
1.7
1.0
2.0
0.5
0.25
4.0
Favours valsartan Favours amlodipine
Julius S et al. Lancet. June 2004363.
18
VALUE Heart Failure
Hospitalisation for HF or Death From HF
9 8 7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 0.89 95 CI 0.771.03 P 0.12
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
6852
7012
6671
6072
3860
1513
6498
Amlodipine
7596
7486
7444
7312
7176
6874
7033
6702
6100
3823
1511
6534
Julius S et al. Lancet. June 2004363.
19
VALUE Outcome and SBP Differencesat Specific
Time Periods Heart Failure
Time interval
Heart Failure Odds Ratios and 95 CIs
? SBP
(months)
(mmHg)
Overall study
2.2
3.8
03
2.3
36
2.0
612
1.8
1224
1.6
2436
1.4
3648
Study end
1.7
1.0
2.0
0.5
0.25
4.0
Favours amlodipine
Favours valsartan
Heart Failure Hospitalisation for HF or death
from HF.
Julius S et al. Lancet. June 2004363.
20
VALUE Incidence of New-onset Diabetes
23 Risk Reduction With Valsartan
18
P lt 0.0001
16
14
12
10
New-Onset Diabetes ( of patients in treatment
group)
16.4
8
13.1
6
4
2
0
Valsartan-based Regimen (n 5094)
Amlodipine-based Regimen (n 5074)
Julius S et al. Lancet. June 2004363.
21
CV Events in TreatedHypertensive Diabetic
Patients
100
90
No diabetes
80
New-onset diabetes
70
Probability of Event-Free Survival ()
Previously known diabetes
60
50
40
30
0
3
6
9
12
15
Time to Event (years)
Patients with new or prior diabetes were ?
3-times more likely to have a CV event than those
without diabetes.
Verdecchia P et al. Hypertension. 200443963969.
22
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 2004363.
23
VALUE Tolerability
Amlodipine
Valsartan
P Value
()
()
Discontinuations due to AE
0.045
14.5
13.4
Prespecified adverse events
lt0.0001
32.9
14.9
Peripheral Oedema
lt0.0001
14.3
16.5
Dizziness
lt0.0001
12.9
15.2
Headache
Additional common adverse events
lt0.0001
6.8
8.8
Diarrhoea
6.4
9.3
Angina Pectoris
lt0.0001
3.1
4.4
Angina Pectoris
lt0.0001
lt0.0001
6.1
3.2
Oedema Other
lt0.0001
6.2
3.5
Hypokalaemia
0.1197
2.0
2.4
Atrial Fibrillation
lt0.0001
1.0
1.7
Syncope
With an incidence gt3 and a difference between
treatment groups gt1. Reported as serious.
Data on file. Novartis Pharmaceuticals.
24
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 blood pressure differences, the
primary composite cardiac endpoint was not
different between the treatment groups
Julius S et al. Lancet. June 2004363.
25
VALUE Other Results

• There was no difference in all cause death
  between the two groups
• Incidence of non-fatal MI was significantly lower
  in the amlodipine group
• Incidence of stroke was lower, but not
  significantly, 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 2004363.
26
VALUE Interpretations

• VALUE is the first trial to show a lower rate of
  new-onset diabetes when an ARB (valsartan) was
  compared to a CCB (amlodipine)
• Long-term implications and mechanisms of this
  important finding deserve further investigation

Julius S et al. Lancet. June 2004363.
27
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 2004363.
28
VALUE Implications

• Our results provide an important lesson about the
  design, conduct, and analysis of future trials in
  hypertension
• VALUE shows the importance of analysisof data at
  time-specific intervals over the course of a
  trial

Julius S et al. Lancet. June 2004363.
29
VALUE Conclusions

• Prompt BP control in hypertensive patients at
  high cardiovascular risk is very important
• The between-group differences in heart failure
  and diabetes suggest that valsartan may offer
  benefits beyond BP control

Julius S et al. Lancet. June 2004363.