BHS Live 3 Management of High Risk Hypertensive Patients Royal College of Physicians London Wednesday 23rd June 2004

1. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004

2. Chairman�s Welcome & IntroductionProfessor Bryan Williams

3. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004

4. Professor Bryan Williams, LeicesterProfessor Morris Brown, CambridgeProfessor Gordon McInnes, GlasgowProfessor Neil Poulter, LondonDr Mark Davis, Leeds

5. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004

6. Background to the VALUE trialProfessor Morris BrownUniversity of Cambridge & Addenbrookes Hospital

7. Association of hypertension with absolute and relative risk of stroke and MI

8. Meta-analysis of older outcome trials suggests short-fall in prevention of CHD by diuretics & ? blockade NEEDS LEGEND FOR Y AXIS (NO. OF EVENTS) FALSE SHOULD BE FATAL I THINK X AXIS COULD BE SIMPLIFIED - ? OMIT SD. SHOW P VALUES AS P� , NOT 2P� The combined results of 5 randomised trials of antihypertensive treatment in the elderly were assessed. The effects of blood pressure reduction on stroke, coronary heart disease, vascular death, and nonvascular death in a total of 12,483 elderly (>60 years) patients (systolic blood pressure difference of 12-14 mm Hg and diastolic blood pressure difference of 5-6 mm Hg),were recorded with 5 years' follow-up. Treated patients had a 34% reduction in the incidence of stroke & 19% reduction in the incidence of coronary heart disease. Reductions in fatal & nonfatal strokes and in fatal CHD and nonfatal MI were also seen in treated patients. A 23% reduction in total vascular deaths & a 29% reduction in total vascular events were observed. The proportional reduction in strokes is greater than that in coronary events, and that (despite this) the number of strokes remains a higher proportion of all cardiovascular events than in the normotensive population. The absolute benefits seen in older patients treated for hypertension are twice as great as those in younger patients. MacMahon S, et al. The effects of blood pressure reduction in older patients: An overview of five randomized controlled trials in elderly hypertensives. Clin Exp Hypertens 1993;15:967-978.NEEDS LEGEND FOR Y AXIS (NO. OF EVENTS) FALSE SHOULD BE FATAL I THINK X AXIS COULD BE SIMPLIFIED - ? OMIT SD. SHOW P VALUES AS P� , NOT 2P� The combined results of 5 randomised trials of antihypertensive treatment in the elderly were assessed. The effects of blood pressure reduction on stroke, coronary heart disease, vascular death, and nonvascular death in a total of 12,483 elderly (>60 years) patients (systolic blood pressure difference of 12-14 mm Hg and diastolic blood pressure difference of 5-6 mm Hg),were recorded with 5 years' follow-up. Treated patients had a 34% reduction in the incidence of stroke & 19% reduction in the incidence of coronary heart disease. Reductions in fatal & nonfatal strokes and in fatal CHD and nonfatal MI were also seen in treated patients. A 23% reduction in total vascular deaths & a 29% reduction in total vascular events were observed. The proportional reduction in strokes is greater than that in coronary events, and that (despite this) the number of strokes remains a higher proportion of all cardiovascular events than in the normotensive population. The absolute benefits seen in older patients treated for hypertension are twice as great as those in younger patients. MacMahon S, et al. The effects of blood pressure reduction in older patients: An overview of five randomized controlled trials in elderly hypertensives. Clin Exp Hypertens 1993;15:967-978.

9. Hypothesis of newer, active-controlled outcome trials �Newer� drugs more effective than �older� Cause-specific benefits i.e. drug classes differ in success at preventing major complications of hypertension: CHD Stroke Heart Failure

10. High-renin patients are at increased risk of myocardial infarction

11. Blood Pressure Lowering Treatment Trialists� CollaborationSecond cycle of overview analyses

12. ACE inhibitor vs. calcium antagonist

13. STROKEComparisons of active treatments and control

14. STROKEComparisons of different active treatments

15. CORONARY HEART DISEASEComparisons of active treatments and control

16. CORONARY HEART DISEASEComparisons of different active treatments

17. HEART FAILUREComparisons of active treatments and control

18. HEART FAILUREComparisons of different active treatments

19. MAJOR CARDIOVASCULAR EVENTS Comparisons of different active treatments

20. Benefits of antihypertensive treatment is proportional to reduction in blood pressure

21. Coronary Heart Disease

22. Two types of drugs for hypertension: 1Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120.

23. Two types of drugs for hypertension: 2Brown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120.

24. ACEi vs ARB: Consequences of the negative feedback on renin

26. ARBs block AT1 but stimulate AT2 receptors

27. The presence of AT1 and AT2 receptors in various tissues has been documented. The function of the AT2 receptors is currently under investigation; however, angiotensin II stimulation of the AT2 receptor is believed to counterbalance deleterious effects of AT1 receptor stimulation on the blood vessels, kidneys, and the adrenal glands.1 Effects of AT1 receptor stimulation include vasoconstriction, cell growth and proliferation, angiogenesis, renal sodium reabsorption, secretion of aldosterone and vasopressin, and sympathetic activation.2 Effects of AT2 receptor stimulation include vasodilation, antiproliferation, apoptosis, differentiation, and regeneration.2 1. Siragy HM. The role of the AT2 receptor in hypertension. Am J Hypertens. 2000;13:62S�67S. 2. Siragy H. Angiotensin II receptor blockers: review of the binding characteristics. Am J Cardiol. 1999;84:3S�8S. The presence of AT1 and AT2 receptors in various tissues has been documented. The function of the AT2 receptors is currently under investigation; however, angiotensin II stimulation of the AT2 receptor is believed to counterbalance deleterious effects of AT1 receptor stimulation on the blood vessels, kidneys, and the adrenal glands.1 Effects of AT1 receptor stimulation include vasoconstriction, cell growth and proliferation, angiogenesis, renal sodium reabsorption, secretion of aldosterone and vasopressin, and sympathetic activation.2 Effects of AT2 receptor stimulation include vasodilation, antiproliferation, apoptosis, differentiation, and regeneration.2 1. Siragy HM. The role of the AT2 receptor in hypertension. Am J Hypertens. 2000;13:62S�67S. 2. Siragy H. Angiotensin II receptor blockers: review of the binding characteristics. Am J Cardiol. 1999;84:3S�8S.

28. Meta-analysis of outcome on ARBs vs. other antihypertensive drugs

30. Dose response curve for blood pressure reduction in systolic BP by valsartan

31. Dose response curve for blood pressure reduction in diastolic BP by valsartan

33. Distribution of best drugs in younger patients (& 24 h BP readings on these)

36. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004

37. The Results of VALUEProfessor Gordon McInnes

38. The main hypothesis of VALUE was that, for an equivalent decrease in blood pressure, valsartan would be more effective than amlodipine in decreasing cardiac mortality and morbidity in a group of high-risk hypertensive patients.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. The main hypothesis of VALUE was that, for an equivalent decrease in blood pressure, valsartan would be more effective than amlodipine in decreasing cardiac mortality and morbidity in a group of high-risk hypertensive patients.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.

39. The primary endpoint in VALUE is the effect of valsartan vs amlodipine on the composite measure of cardiac morbidity and mortality.1 In VALUE, cardiac morbidity and mortality is defined as sudden cardiac death, fatal/nonfatal myocardial infarction (MI), evidence of recent MI on autopsy, emergency thrombolytic or fibrinolytic treatment and/or emergency PTCA or CABG, death during or following PTCA or CABG, a new or chronic incidence of heart failure that requires hospitalisation, or heart failure death.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.The primary endpoint in VALUE is the effect of valsartan vs amlodipine on the composite measure of cardiac morbidity and mortality.1 In VALUE, cardiac morbidity and mortality is defined as sudden cardiac death, fatal/nonfatal myocardial infarction (MI), evidence of recent MI on autopsy, emergency thrombolytic or fibrinolytic treatment and/or emergency PTCA or CABG, death during or following PTCA or CABG, a new or chronic incidence of heart failure that requires hospitalisation, or heart failure death.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.

40. VALUE was designed as a randomised, double-blind, active-controlled, parallel, 2-arm comparison with a response-dependent dosage titration scheme.1 Patients aged 50 years and over, with a high-risk cardiovascular profile and essential systolic and/or diastolic hypertension, were randomised to stepwise titrations of valsartan or amlodipine, with HCTZ and later free add-on of other antihypertensive agents excepting ACE inhibitors, calcium channel blockers, ARBs, or diuretics other than HCTZ (except that patients with impaired renal function or congestive heart failure were allowed to substitute loop diuretics for the thiazide).1 Patients were initially randomised to valsartan 80 mg or amlodipine 5 mg QD for the first month (Step 1). Depending on the blood pressure response, the dosage was titrated to valsartan 160 mg or amlodipine 10 mg QD for month 2 (Step 2), followed by the addition of HCTZ 12.5 mg (month 3) and 25 mg (month 4) as necessary (Steps 3 and 4). Step 5 allowed for the free addition of other antihypertensive agents from month 5 until the end of follow-up.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. VALUE was designed as a randomised, double-blind, active-controlled, parallel, 2-arm comparison with a response-dependent dosage titration scheme.1 Patients aged 50 years and over, with a high-risk cardiovascular profile and essential systolic and/or diastolic hypertension, were randomised to stepwise titrations of valsartan or amlodipine, with HCTZ and later free add-on of other antihypertensive agents excepting ACE inhibitors, calcium channel blockers, ARBs, or diuretics other than HCTZ (except that patients with impaired renal function or congestive heart failure were allowed to substitute loop diuretics for the thiazide).1 Patients were initially randomised to valsartan 80 mg or amlodipine 5 mg QD for the first month (Step 1). Depending on the blood pressure response, the dosage was titrated to valsartan 160 mg or amlodipine 10 mg QD for month 2 (Step 2), followed by the addition of HCTZ 12.5 mg (month 3) and 25 mg (month 4) as necessary (Steps 3 and 4). Step 5 allowed for the free addition of other antihypertensive agents from month 5 until the end of follow-up.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.

41. During enrolment, more men than women were randomised during every month of the inclusion period, resulting in a total of 57.6% men (n = 8816) in the trial.1 The valsartan and amlodipine arms were well balanced for gender, age, body mass index (BMI), severity of hypertension, antihypertensive therapy prior to enrolment, heart rate, and race.2 1. Kjeldsen SE, Julius S, Brunner H, et al. Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE trial. The Valsartan Antihypertensive Long-term Use Evaluation. Blood Press. 2001;10:83-91 2. 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;363.During enrolment, more men than women were randomised during every month of the inclusion period, resulting in a total of 57.6% men (n = 8816) in the trial.1 The valsartan and amlodipine arms were well balanced for gender, age, body mass index (BMI), severity of hypertension, antihypertensive therapy prior to enrolment, heart rate, and race.2 1. Kjeldsen SE, Julius S, Brunner H, et al. Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE trial. The Valsartan Antihypertensive Long-term Use Evaluation. Blood Press. 2001;10:83-91 2. 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;363.

42. VALUE: Qualifying Disease Factors* As described previously, the primary endpoint in VALUE was time to first cardiac morbidity or mortality event. Cardiac mortality was defined as sudden cardiac death, fatal myocardial infarction, death during or after revascularization, death due to congestive heart failure, and evidence of recent acute myocardial infarction on autopsy. Cardiac morbidity was defined as an incident of heart failure requiring hospitalisation, non-fatal myocardial infarction, or interventional procedure performed to prevent a full-blown myocardial infarction.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.As described previously, the primary endpoint in VALUE was time to first cardiac morbidity or mortality event. Cardiac mortality was defined as sudden cardiac death, fatal myocardial infarction, death during or after revascularization, death due to congestive heart failure, and evidence of recent acute myocardial infarction on autopsy. Cardiac morbidity was defined as an incident of heart failure requiring hospitalisation, non-fatal myocardial infarction, or interventional procedure performed to prevent a full-blown myocardial infarction.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.

43. VALUE: Qualifying Disease Factors* Most patients (>92%) were taking antihypertensive medication at the time of randomisation and were transferred to blinded study drugs without washout.1 In both the valsartan-based and amlodipine-based treatment groups, approximately equal percentages of patients had been receiving ACE inhibitors, ARBs, alpha blockers, calcium channel blockers, and diuretics, both as monotherapy and in fixed-dose combinations.2 Coexisting cardiovascular conditions, the qualifying disease factors, were equally prevalent in both treatment groups.1 1. Kjeldsen SE, Julius S, Brunner H, et al. Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE trial. The Valsartan Antihypertensive Long-term Use Evaluation. Blood Press. 2001;10:83-91 2. 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;363. Most patients (>92%) were taking antihypertensive medication at the time of randomisation and were transferred to blinded study drugs without washout.1 In both the valsartan-based and amlodipine-based treatment groups, approximately equal percentages of patients had been receiving ACE inhibitors, ARBs, alpha blockers, calcium channel blockers, and diuretics, both as monotherapy and in fixed-dose combinations.2 Coexisting cardiovascular conditions, the qualifying disease factors, were equally prevalent in both treatment groups.1 1. Kjeldsen SE, Julius S, Brunner H, et al. Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE trial. The Valsartan Antihypertensive Long-term Use Evaluation. Blood Press. 2001;10:83-91 2. 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;363.

44. At study end (72 months) or final visit, SBP averaged 139.3?17.6 mmHg with valsartan-based regimens and 137.5?15.0 mmHg with amlodipine-based regimens. The reduction in SBP from baseline until study end was 15.2 mmHg and 17.3 mmHg in the valsartan and amlodipine groups, respectively. The difference between groups was substantial at 1 month (4.0 mmHg) but decreased to approximately 2.1 mmHg at 6 months and averaged 2.0 mmHg thereafter. SBP decreased in both treatment groups from 6 months until end of study, by 3.3 mmHg in the valsartan group and 3.0 mmHg in the amlodipine group. Control of SBP (<140 mmHg) was achieved in 58% of the valsartan group and 64% of the amlodipine group by the end of the trial.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;363.At study end (72 months) or final visit, SBP averaged 139.3?17.6 mmHg with valsartan-based regimens and 137.5?15.0 mmHg with amlodipine-based regimens. The reduction in SBP from baseline until study end was 15.2 mmHg and 17.3 mmHg in the valsartan and amlodipine groups, respectively. The difference between groups was substantial at 1 month (4.0 mmHg) but decreased to approximately 2.1 mmHg at 6 months and averaged 2.0 mmHg thereafter. SBP decreased in both treatment groups from 6 months until end of study, by 3.3 mmHg in the valsartan group and 3.0 mmHg in the amlodipine group. Control of SBP (<140 mmHg) was achieved in 58% of the valsartan group and 64% of the amlodipine group by the end of the trial.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;363.

45. At study end or final visit, DBP averaged 79.6?9.8 mmHg in the valsartan group and 15.0?9.0 mmHg in the amlodipine group. The reduction in DBP from baseline until study end was 8.2 mmHg and 9.9 mmHg in the valsartan and amlodipine groups, respectively. As with SBP, the difference in DBP between groups was substantial at 1 month (2.1 mmHg) but decreased to 1.6 mmHg at 6 months and remained relatively constant thereafter. Also as with SBP, DBP decreased in both treatment groups from 6 months until end of study, by 2.6 mmHg in the valsartan group and 2.5 mmHg in the amlodipine group. Control of DBP (<90 mmHg) was achieved in 88% of the valsartan group and 92% of the amlodipine group. Target BP of <140 mmHg SBP and <90 mmHg DBP was achieved in 56% of the valsartan group and 62% of the amlodipine group.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;363.At study end or final visit, DBP averaged 79.6?9.8 mmHg in the valsartan group and 15.0?9.0 mmHg in the amlodipine group. The reduction in DBP from baseline until study end was 8.2 mmHg and 9.9 mmHg in the valsartan and amlodipine groups, respectively. As with SBP, the difference in DBP between groups was substantial at 1 month (2.1 mmHg) but decreased to 1.6 mmHg at 6 months and remained relatively constant thereafter. Also as with SBP, DBP decreased in both treatment groups from 6 months until end of study, by 2.6 mmHg in the valsartan group and 2.5 mmHg in the amlodipine group. Control of DBP (<90 mmHg) was achieved in 88% of the valsartan group and 92% of the amlodipine group. Target BP of <140 mmHg SBP and <90 mmHg DBP was achieved in 56% of the valsartan group and 62% of the amlodipine group.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;363.

46. The primary composite endpoint, a cardiac morbidity or mortality event, occurred in 810 patients in the valsartan group and 789 patients in the amlodipine group (10.6% vs 10.4%, P=0.49).1 There was no significant difference in cardiac morbidity or mortality in these high-risk patients treated with valsartan- or amlodipine-based regimens. The Kaplan-Meier curves separated during the first 6 months, but then started to converge and ultimately overlapped towards the end of the study.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;363.The primary composite endpoint, a cardiac morbidity or mortality event, occurred in 810 patients in the valsartan group and 789 patients in the amlodipine group (10.6% vs 10.4%, P=0.49).1 There was no significant difference in cardiac morbidity or mortality in these high-risk patients treated with valsartan- or amlodipine-based regimens. The Kaplan-Meier curves separated during the first 6 months, but then started to converge and ultimately overlapped towards the end of the study.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;363.

47. Of the secondary endpoints, fatal or non-fatal myocardial infarction occurred in 369 patients in the valsartan group and 313 patients in the amlodipine group (HR=1.19 [95% CI 1.02�1.38], P=0.02).1 The Kaplan-Meier curves separated during the first 6 months and remained separated in favor of amlodipine throughout the study. 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;363.Of the secondary endpoints, fatal or non-fatal myocardial infarction occurred in 369 patients in the valsartan group and 313 patients in the amlodipine group (HR=1.19 [95% CI 1.02�1.38], P=0.02).1 The Kaplan-Meier curves separated during the first 6 months and remained separated in favor of amlodipine throughout the study. 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;363.

48. VALUE: Hazard Ratios for Fatal and Non-fatal Myocardial Infarction In VALUE, the risk ratio for combined fatal and non-fatal myocardial infarction favours amlodipine. However, the risk for fatal myocardial infarction is identical in the two treatment groups, indicating that the risk ratio favours amlodipine only in non-fatal myocardial infarction.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;363. In VALUE, the risk ratio for combined fatal and non-fatal myocardial infarction favours amlodipine. However, the risk for fatal myocardial infarction is identical in the two treatment groups, indicating that the risk ratio favours amlodipine only in non-fatal myocardial infarction.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;363.

49. VALUE: Heart Failure A total of 354 patients in the valsartan group were hospitalised for heart failure, compared to 400 patients in the amlodipine group (HR=0.89 [95% CI 0.77 - 1.03], P=0.12).1 Thus there was a trend towards fewer heart failure hospitalisations in the valsartan group. The Kaplan-Meier curves separated after 36 months and the trend in favor of valsartan that became more pronounced as the study progressed. 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;363.A total of 354 patients in the valsartan group were hospitalised for heart failure, compared to 400 patients in the amlodipine group (HR=0.89 [95% CI 0.77 - 1.03], P=0.12).1 Thus there was a trend towards fewer heart failure hospitalisations in the valsartan group. The Kaplan-Meier curves separated after 36 months and the trend in favor of valsartan that became more pronounced as the study progressed. 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;363.

50. VALUE: Fatal and Non-fatal Stroke There was a trend towards fewer fatal or non-fatal strokes in the amlodipine group, 322 vs 281 in the valsartan and amlodipine groups, respectively (HR=1.15 [95% CI 0.98 - 1.36], P=0.08).1 The Kaplan-Meier curves separated early in favor of amlodipine, and the slopes subsequently became parallel for the remainder of the study.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;363.There was a trend towards fewer fatal or non-fatal strokes in the amlodipine group, 322 vs 281 in the valsartan and amlodipine groups, respectively (HR=1.15 [95% CI 0.98 - 1.36], P=0.08).1 The Kaplan-Meier curves separated early in favor of amlodipine, and the slopes subsequently became parallel for the remainder of the study.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;363.

51. VALUE: All-cause Death All-cause mortality was not significantly different between groups. A total of 841 patients in the valsartan group died from any cause compared to 818 in the amlodipine group (HR=1.04 [95% CI 0.94�1.14], P=0.45).1 The Kaplan-Meier curves for total mortality separated early but converged later in the trial.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;363.All-cause mortality was not significantly different between groups. A total of 841 patients in the valsartan group died from any cause compared to 818 in the amlodipine group (HR=1.04 [95% CI 0.94�1.14], P=0.45).1 The Kaplan-Meier curves for total mortality separated early but converged later in the trial.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;363.

52. VALUE was the first trial to demonstrate a significant decrease in new-onset diabetes with an angiotensin receptor blocker when compared with a calcium channel blocker. Therapy with the valsartan-based regimen reduced the incidence of new-onset diabetes by 23% compared to the amlodipine-based regimen (690 vs 845 patients, P<0.0001).1 As diabetes mellitus is a significant risk factor for cardiovascular outcomes, this significant result provides support for use of valsartan in patients who are at risk for developing diabetes. 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;363. VALUE was the first trial to demonstrate a significant decrease in new-onset diabetes with an angiotensin receptor blocker when compared with a calcium channel blocker. Therapy with the valsartan-based regimen reduced the incidence of new-onset diabetes by 23% compared to the amlodipine-based regimen (690 vs 845 patients, P<0.0001).1 As diabetes mellitus is a significant risk factor for cardiovascular outcomes, this significant result provides support for use of valsartan in patients who are at risk for developing diabetes. 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;363.

53. Both the valsartan-based regimens and the amlodipine-based regimens were well-tolerated with few severe adverse events. However, the most frequent adverse event, oedema (including peripheral oedema) was more than twice as common in the amlodipine group (32.9% vs 14.9%, P<0.001). Dizziness, headache, and fatigue were more common in the valsartan group, though the frequency of these events was low.1 A total of 911 patients (11.9%) of patients in the valsartan group discontinued therapy because of adverse events, compared to 983 patients (12.9%) in the amlodipine group.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;363.Both the valsartan-based regimens and the amlodipine-based regimens were well-tolerated with few severe adverse events. However, the most frequent adverse event, oedema (including peripheral oedema) was more than twice as common in the amlodipine group (32.9% vs 14.9%, P<0.001). Dizziness, headache, and fatigue were more common in the valsartan group, though the frequency of these events was low.1 A total of 911 patients (11.9%) of patients in the valsartan group discontinued therapy because of adverse events, compared to 983 patients (12.9%) in the amlodipine group.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;363.

54. VALUE: Main Results No difference in composite primary endpoint despite blood pressure differences Significantly lower incidence of myocardial infarction (non-fatal) in amlopidine group Trend in favour of valsartan for heart failure and in favour of amlodipine for stroke No difference in all cause mortality Significantly lower incidence of new-onset diabetes in the valsartan group Exclusion criteria for VALUE included patients with renal artery stenosis, pregnant patients, patients with acute myocardial infarction, specific coronary procedures or cerebrovascular accident in the last 3 months, clinically relevant valvular disease, hepatic disease, heart failure requiring ACE inhibitor therapy, and patients on monotherapy with beta blockers for both hypertension and coronary artery disease.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. Exclusion criteria for VALUE included patients with renal artery stenosis, pregnant patients, patients with acute myocardial infarction, specific coronary procedures or cerebrovascular accident in the last 3 months, clinically relevant valvular disease, hepatic disease, heart failure requiring ACE inhibitor therapy, and patients on monotherapy with beta blockers for both hypertension and coronary artery disease.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.

55. For the primary composite endpoint, higher odds ratios in favor of amlodipine were seen during the first 6 months of the trial when differences in BP control were greatest. In the following months, as the difference in SBP decreased, there was an attenuation in these odds ratios; in the last 2 years of the study the odds ratio for the primary endpoint was lower than unity.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;363. For the primary composite endpoint, higher odds ratios in favor of amlodipine were seen during the first 6 months of the trial when differences in BP control were greatest. In the following months, as the difference in SBP decreased, there was an attenuation in these odds ratios; in the last 2 years of the study the odds ratio for the primary endpoint was lower than unity.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;363.

56. The novel technique of serial median matching was used to create a unique database of patient pairs, which allows for testing of the VALUE study hypothesis. This technique created a cohort of 5006 matched patient pairs (10012 patients) and excludes patients at the extremes of achieved blood pressures.1 1. Weber MA et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical values in the VALUE trial. Lancet. 2004;363:2047-49.The novel technique of serial median matching was used to create a unique database of patient pairs, which allows for testing of the VALUE study hypothesis. This technique created a cohort of 5006 matched patient pairs (10012 patients) and excludes patients at the extremes of achieved blood pressures.1 1. Weber MA et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical values in the VALUE trial. Lancet. 2004;363:2047-49.

57. VALUE: Major Study Endpoints in 5006 Patient Pairs(N = 10,012) on Valsartan- or Amlodipine-Based Therapies Using Serial Median Matching Using the patient cohort established by serial median matching, patient outcomes, including combined cardiac events, were closely similar for the valsartan-based and amlodipine-based regimens.1 Significantly fewer hospitalisations for heart failure occurred in the group given the valsartan-based regimen, supporting the hypothesis that a mechanism other than blood pressure provides benefits in those taking valsartan.1 1. Weber MA et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical values in the VALUE trial. Lancet. 2004;363:2047-49. Using the patient cohort established by serial median matching, patient outcomes, including combined cardiac events, were closely similar for the valsartan-based and amlodipine-based regimens.1 Significantly fewer hospitalisations for heart failure occurred in the group given the valsartan-based regimen, supporting the hypothesis that a mechanism other than blood pressure provides benefits in those taking valsartan.1 1. Weber MA et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical values in the VALUE trial. Lancet. 2004;363:2047-49.

58. VALUE: Overall conclusions Blood pressure control and rapidity of response are critical for reducing events in high-risk hypertension Valsartan-based therapy may offer benefits beyond blood pressure reduction Valsartan-based therapy reduces the incidence of new-onset diabetes A total of 14,400 patients, equally allocated to each of the 2 treatment arms, was required for this trial. This calculation assumed 2 years of patient accrual and total trial length of 6 years.1 Unless completed early because of statistically significant interim analysis, the trial was planned to continue until 1450 patients reached the primary endpoint.1 The expected enrolment period was 2 years and the expected follow-up period was 4 to 6 years, for a total expected trial duration of 6 years.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. A total of 14,400 patients, equally allocated to each of the 2 treatment arms, was required for this trial. This calculation assumed 2 years of patient accrual and total trial length of 6 years.1 Unless completed early because of statistically significant interim analysis, the trial was planned to continue until 1450 patients reached the primary endpoint.1 The expected enrolment period was 2 years and the expected follow-up period was 4 to 6 years, for a total expected trial duration of 6 years.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.

59. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004

60. Interpretation of the evidenceinto clinical practice

61. BHS Live! 3Management of High RiskHypertensive PatientsRoyal College of PhysiciansLondonWednesday 23rd June 2004