Valsartan Antihypertensive Long-Term Use Evaluation Results

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Presentation transcript:

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;16:544-548.

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;7:176-183. Julius S et al. Lancet. June 2004;363.

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.

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. 2004. [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.

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 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.

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.

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.

VALUE: Primary Endpoint Result

VALUE: Primary Composite Cardiac Endpoint 14 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 0 6 12 18 24 30 36 42 48 54 60 66 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.

VALUE: Total Mortality Result

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 0 6 12 18 24 30 36 42 48 54 60 66 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.

VALUE: Secondary Endpoint Results

VALUE: Fatal and Non-Fatal Myocardial Infarction 7 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 0 6 12 18 24 30 36 42 48 54 60 66 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.

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.

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.

VALUE: Fatal and Non-fatal Stroke 6 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 (%) 0 6 12 18 24 30 36 42 48 54 60 66 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.

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.

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 0 6 12 18 24 30 36 42 48 54 60 66 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.

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.

VALUE: Incidence of New-onset Diabetes 23% Risk Reduction With Valsartan 18 16 P < 0.0001 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.

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.

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.

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.

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.

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.

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.

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: 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.

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.