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
VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) is a prospective, multinational, multicenter, double-blind, randomized, active-controlled trial that compared cardiovascular outcomes in high-risk hypertensive patients receiving valsartan or amlodipine, both with or without the addition of hydrochlorothiazide (HCTZ).1 VALUE is the largest reported trial with an angiotensin receptor blocker (ARB).
1. Julius S, Kjeldsen SE, Brunner H, et al. VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk. Am J Hypertens. 2003;16:

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
The main hypothesis of VALUE is that, for the same level of blood pressure control, valsartan will be more effective than amlodipine in decreasing cardiac mortality and morbidity in hypertensive patients at high cardiovascular risk.1
1. Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Press. 1998;7:
Julius S et al. Lancet. June 2004;363.

3. VALUE: Blood Pressure Changes From Baseline to the End of the Study–5
SBP
DBP
mmHg
–10
–15
–20
Valsartan- Based Regimen
Amlodipine- Based Regimen
Julius S et al. Lancet. June 2004;363.

4. VALUE: Trends in SBP Control (<140 mmHg)
Before Randomisation
Study End
22%
Valsartan-Based Regimen
Non-controlled
57%
Controlled
22%
Amlodipine-Based Regimen
Non-controlled
Systolic blood pressure control was significantly increased in patients receiving both valsartan-based and amlodipine-based treatment regimens throughout the VALUE trial. At baseline, only 22% of patients had controlled hypertension despite previous treatment in 92% of patients. At the end of the study, 58% of patients on the valsartan-based regimen and 63% of patients on the amlodipine-based regimen had controlled systolic blood pressure.1
1. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, a randomised trial. Lancet [in press].
63%
Controlled
92% of patients were previously treated
with antihypertensive medication(s) at time of entry.
Julius S et al. Lancet. June 2004;363.

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 mg mg
Dose minimum/maximum
(0–160 mg)
(0–10 mg)
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 2004;363.

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
Baseline 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66
Months
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
5.0
4.0
3.0
mmHg
2.0
1.0 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66
–1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004;363.

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 2 3 4 6 12 18 24 30 36 42 48 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 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66
–1.0
Months
(or final visit)
Julius S et al. Lancet. June 2004;363.

8. VALUE: Primary Endpoint Result

9. VALUE: Primary Composite Cardiac Endpoint14 12 10 8 6 4 2
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event (%)
HR = 1.03; 95% CI = 0.94–1.14; P = 0.49
Time (months)
Number at risk
Valsartan
7649
7459
7407
7250
7085
6906
6732
6536
6349
5911
3765
1474
Amlodipine
7596
7469
7424
7267
7117
6955
6772
6576
6391
5959
3725
1474
Julius S et al. Lancet. June 2004;363.

10. VALUE: Total Mortality Result

11. VALUE: All-cause Death Proportion of Patients With First Event (%)16 14 12 10 8 6 4 2
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event (%)
HR = 1.04; 95% CI = 0.94–1.14; P = 0.45
Time (months)
Number at risk
Valsartan
7649
7527
7496
7383
7267
7136
6994
6843
6682
6273
3981
1563
Amlodipine
7596
7520
7484
7385
7276
7155
7025
6874
6729
6312
3961
1582
Julius S et al. Lancet. June 2004;363.

12. VALUE: Secondary Endpoint Results

13. VALUE: Fatal and Non-Fatal Myocardial Infarction7 6 5 4 3 2 1
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event (%)
HR = 1.19; 95% CI = 1.02–1.38; P = 0.02
Time (months)
Number at risk
Valsartan
7649
7499
7458
7319
7177
7016
6853
6680
6504
6078
3864
1520
Amlodipine
7596
7497
7458
7332
7205
7065
6905
6727
6562
6141
3840
1532
Julius S et al. Lancet. June 2004;363.

14. Myocardial Infarction
VALUE: Outcome and SBP Differences at Specific Time Periods: Myocardial Infarction
Time Interval D
SBP
Myocardial Infarction
Odds Ratios and 95% CIs
(months)
(mmHg)
Overall study
2.2
0–3
3.8
3–6
2.3
6–12
2.0
12–24
1.8
24–36
1.6
36–48
1.4
Study end
1.7
0.25
0.5
1.0
2.0
4.0
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. June 2004;363.

15. VALUE: Hazard Ratios for Fatal and Non-fatal Myocardial Infarction
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 2004;363.

16. VALUE: Fatal and Non-fatal Stroke6 5 4 3 2 1
Valsartan-based regimen
Amlodipine-based regimen
HR = 1.15; 95% CI = 0.98–1.35; P = 0.08
Proportion of Patients With First Event (%)
Time (months)
Number at risk
Valsartan
7649
7494
7448
7312
7170
7022
6877
6692
6515
6093
3859
1516
Amlodipine
7596
7499
7455
7334
7195
7055
6918
6744
6587
6163
3846
1532
Julius S et al. Lancet. June 2004;363.

17. VALUE: Outcome and SBP Differences at Specific Time Periods: Stroke
Time Interval
 SBP
STROKE
(months)
(mmHg)
Odds Ratios and 95% CIs
Overall study
2.2
0–3
3.8
3–6
2.3
6–12
2.0
12–24
1.8
24–36
1.6
36–48
1.4
Study end
1.7
0.25
0.5
1.0
2.0
4.0
Favours valsartan Favours amlodipine
Julius S et al. Lancet. June 2004;363.

18. Proportion of Patients With First Event (%)
VALUE: Heart Failure
Hospitalisation for HF or Death From HF 9 8 7 6 5 4 3 2 1
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event (%)
HR = 0.89; 95% CI = 0.77–1.03; P = 0.12
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
7012
6852
6671
6498
6072
3860
1513
Amlodipine
7596
7486
7444
7312
7176
7033
6874
6702
6534
6100
3823
1511
Julius S et al. Lancet. June 2004;363.

19. VALUE: Outcome and SBP Differences at Specific Time Periods: Heart Failure
Time interval
 SBP
Heart Failure
Odds Ratios and 95% CIs
(months)
(mmHg)
Overall study
2.2
0–3
3.8
3–6
2.3
6–12
2.0
12–24
1.8
24–36
1.6
36–48
1.4
Study end
1.7
0.25
0.5
1.0
2.0
4.0
Favours valsartan
Favours amlodipine
Heart Failure: Hospitalisation for HF or death from HF.
Julius S et al. Lancet. June 2004;363.

20. VALUE: Incidence of New-onset Diabetes
23% Risk Reduction With Valsartan 18 16
P < 14 12
New-Onset Diabetes (% of patients in treatment group) 10
16.4% 8
13.1% 6 4 2
Valsartan-based Regimen
(n = 5094)
Amlodipine-based Regimen
(n = 5074)
Julius S et al. Lancet. June 2004;363.

21. CV Events in Treated Hypertensive Diabetic Patients
100 90
No diabetes 80
New-onset diabetes
Probability of Event-Free Survival (%) 70
Previously known diabetes 60 50 40 30 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. 2004;43:963–969.

22. for Pre-specified Analyses Valsartan/Amlodipine
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.

23. VALUE: Tolerability Valsartan Amlodipine (%) (%) P Value
Discontinuations due to AE
13.4
14.5
0.045
Prespecified adverse events
Peripheral Oedema
14.9
32.9
<0.0001
Dizziness
16.5
14.3
<0.0001
Headache
15.2
12.9
<0.0001
Additional common adverse events
Diarrhoea*
8.8
6.8
<0.0001
Angina Pectoris*
9.3
6.4
<0.0001
Angina Pectoris†
4.4
3.1
<0.0001
Oedema Other*
3.2
6.1
<0.0001
Hypokalaemia*
3.5
6.2
<0.0001
Atrial Fibrillation†
2.4
2.0
0.1197
Syncope†
1.7
1.0
<0.0001
*With an incidence >3% and a difference between treatment groups >1%.
†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 2004;363.

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 2004;363.

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 2004;363.

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 2004;363.

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 analysis of data at time-specific intervals over the course of a trial
Julius S et al. Lancet. June 2004;363.

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 2004;363.