Hypertension

1. Hypertension

6. why we treat(1st Vet Admin Study) 1964 73 volunteers dBP 115-129 thiaside/hydralizine/reserpine lowering of fatal incidents by 2190% in 18/12

11. ULTIMATE GOAL OF ANTIHYPERTENSIVE THERAPY The ultimate goal in treating hypertension is to make patients to live longer and feel better. This is achieved by controlling blood pressure and preventing complications. The choice of antihypertensive agent plays a major role in achieving this goal of therapy and must offer convenience for physician and patient, consistent efficacy, whilst maintaining a good quality of life for the patient.The ultimate goal in treating hypertension is to make patients to live longer and feel better. This is achieved by controlling blood pressure and preventing complications. The choice of antihypertensive agent plays a major role in achieving this goal of therapy and must offer convenience for physician and patient, consistent efficacy, whilst maintaining a good quality of life for the patient.

12. PROFILE OF AN IDEAL ANTIHYPERTENSIVE SCIENTIFIC RATIONALE AND SELECTIVE MECHANISM OF ACTION SIMPLE PHARMACOKINETIC PROFILE CONSISTENT BLOOD PRESSURE REDUCTION OUTSTANDING SAFETY AND TOLERABILITY SUPERIOR TO EXISTING THERAPIES EASY TO USE IN SPECIAL POPULATIONS EFFECTS BEYOND BLOOD PRESSURE REDUCTION Many classes of antihypertensive agents are available today but older classes do not fulfill the profile of an ideal antihypertensive. This presentation is structured to examine each of these criterion in turn and to present the data available for valsartan for each criterion.Many classes of antihypertensive agents are available today but older classes do not fulfill the profile of an ideal antihypertensive. This presentation is structured to examine each of these criterion in turn and to present the data available for valsartan for each criterion.

13. SCIENTIFIC RATIONALE Angiotensin II has a wide range of effects. Angiotensin II plays a pivotal physiological role in the regulation of blood pressure and also contributes to many effects which are key to cardiovascular homeostasis. Angiotensin II has a wide range of effects. Angiotensin II plays a pivotal physiological role in the regulation of blood pressure and also contributes to many effects which are key to cardiovascular homeostasis.

14. ACE inhibitors not only block the conversion of angiotensin I to angiotensin II but also have other substrates including bradykinin, substance P, neurotensin, enkephalin, LHRH, N-acetyl-Ser-Asp-Lys-Pro. The effects on kinins is suggested to be responsible for the cough associated with ACE inhibitors. ACE inhibitors not only block the conversion of angiotensin I to angiotensin II but also have other substrates including bradykinin, substance P, neurotensin, enkephalin, LHRH, N-acetyl-Ser-Asp-Lys-Pro. The effects on kinins is suggested to be responsible for the cough associated with ACE inhibitors.

15. If ACE is inhibited, an alternative pathway for angiotensin II formation may be activated (chymase). This re-emphasises the importance of selective blockade of the AT1 receptor with the following aims: 1) To block the effect of angiotensin II at the AT1 receptor irrespective of the formation pathway 2) Allowing the potential benefits of stimulation of the AT2 receptor by angiotensin II Based on this rationale, the selective AT1 receptor blocker valsartan, was developed.If ACE is inhibited, an alternative pathway for angiotensin II formation may be activated (chymase). This re-emphasises the importance of selective blockade of the AT1 receptor with the following aims: 1) To block the effect of angiotensin II at the AT1 receptor irrespective of the formation pathway 2) Allowing the potential benefits of stimulation of the AT2 receptor by angiotensin II Based on this rationale, the selective AT1 receptor blocker valsartan, was developed.

16. Angiotensin II, via the AT1 receptor, plays a key role in the pathology of several cardiovascular conditions including hypertension, congestive heart failure, post myocardial infarction and in diabetic nephropathy.Angiotensin II, via the AT1 receptor, plays a key role in the pathology of several cardiovascular conditions including hypertension, congestive heart failure, post myocardial infarction and in diabetic nephropathy.

17. Treatment failures hypertension treatment trials Between one-quarter and one-third of patients failed to achieve target blood pressure (even when clinic blood pressures were considered) during large-scale treatment studies in elderly patients with hypertension (HDFP, 1979; ANBP, 1980; IPPSH, 1985; Wilhelmsen et al, 1987; Amery et al, 1991; SHEP, 1991). The HDFP Cooperative Group. Five-year findings of the Hypertension Detection and Follow-Up Program I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562-2571. Australian National Blood Pressure Management Committee. The Australian therapeutic trial in mild hypertension. Lancet 1980; i: 1261-1267. International Prospective Primary Prevention Study in Hypertension. J Hypertens 1985; 3: 379-392. Wilhelmsen L, Berglund G, Elmfeldt D et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987; 5: 561-572. Amery A, Birkenhäger WH, Bulpitt CJ, Dollery CT (eds). The European Working Party on High Blood Pressure in the Elderly. Proceedings of a symposium held in Rome, 19-20 November 1989. Am J Med 1991; 90 (Suppl 3A): 1-64. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). JAMA 1991; 265: 3255-3264.Between one-quarter and one-third of patients failed to achieve target blood pressure (even when clinic blood pressures were considered) during large-scale treatment studies in elderly patients with hypertension (HDFP, 1979; ANBP, 1980; IPPSH, 1985; Wilhelmsen et al, 1987; Amery et al, 1991; SHEP, 1991). The HDFP Cooperative Group. Five-year findings of the Hypertension Detection and Follow-Up Program I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562-2571. Australian National Blood Pressure Management Committee. The Australian therapeutic trial in mild hypertension. Lancet 1980; i: 1261-1267. International Prospective Primary Prevention Study in Hypertension. J Hypertens 1985; 3: 379-392. Wilhelmsen L, Berglund G, Elmfeldt D et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987; 5: 561-572. Amery A, Birkenhäger WH, Bulpitt CJ, Dollery CT (eds). The European Working Party on High Blood Pressure in the Elderly. Proceedings of a symposium held in Rome, 19-20 November 1989. Am J Med 1991; 90 (Suppl 3A): 1-64. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). JAMA 1991; 265: 3255-3264.

18. Blood pressure and target organ damage Hypertension increases the risk of target organ damage (i.e. cerebrovascular, cardiovascular and renal events). Increased morbidity and mortality associated with these hypertensive complications demonstrates the importance of directing antihypertensive therapy towards the reduction of target organ damage. Several studies have reported a closer relationship between target organ damage and blood pressure when blood pressure was recorded by 24-h ambulatory blood pressure monitoring (ABPM) compared with conventional measurements of blood pressure at the clinic (Mancia, 1990; Devereux et al, 1987). A consistent pattern is seen whether target organ damage is assessed by an overall score, left ventricular mass index (LVMI), left ventricular wall thickness, or retinopathy (Sokolow et al, 1966; Devereux et al, 1983; Parati et al, 1987). Sokolow M, Werdegar D, Kain HK, Hinman AT. Relationship between level of blood pressure measured causally and by portable recorders and severity of complications in essential hypertension. Circulation 1966; 34: 279-298. Devereux RB, Pickering TG, Harshfield GA et al. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983; 68: 470-476. Devereux RB, Pickering TG, Alderman MH, Chiken S, Borer JS, Laragh JH. Left ventricular hypertrophy in hypertension: prevalence and relationship to pathophysiologic variables. Hypertension 1987; 9: (Suppl II): 1153-1160. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987; 5: 93-98. Mancia G. Ambulatory blood pressure monitoring: research and clinical applications. J Hypertens 1990; 8 (Suppl 7): S1-S13. Hypertension increases the risk of target organ damage (i.e. cerebrovascular, cardiovascular and renal events). Increased morbidity and mortality associated with these hypertensive complications demonstrates the importance of directing antihypertensive therapy towards the reduction of target organ damage. Several studies have reported a closer relationship between target organ damage and blood pressure when blood pressure was recorded by 24-h ambulatory blood pressure monitoring (ABPM) compared with conventional measurements of blood pressure at the clinic (Mancia, 1990; Devereux et al, 1987). A consistent pattern is seen whether target organ damage is assessed by an overall score, left ventricular mass index (LVMI), left ventricular wall thickness, or retinopathy (Sokolow et al, 1966; Devereux et al, 1983; Parati et al, 1987). Sokolow M, Werdegar D, Kain HK, Hinman AT. Relationship between level of blood pressure measured causally and by portable recorders and severity of complications in essential hypertension. Circulation 1966; 34: 279-298. Devereux RB, Pickering TG, Harshfield GA et al. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983; 68: 470-476. Devereux RB, Pickering TG, Alderman MH, Chiken S, Borer JS, Laragh JH. Left ventricular hypertrophy in hypertension: prevalence and relationship to pathophysiologic variables. Hypertension 1987; 9: (Suppl II): 1153-1160. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987; 5: 93-98. Mancia G. Ambulatory blood pressure monitoring: research and clinical applications. J Hypertens 1990; 8 (Suppl 7): S1-S13.

23. The “Rule of Halves” Slide 8Slide 8

31. Management of High Risk patients with Hypertension and Type 2 diabetes Program for Irbesartan Mortality and Morbidity Evaluations The Program for Irbesartan Mortality and Morbidity Evaluations (PRIME) is an important research program composed of two ongoing trials. The Irbesartan Diabetic Nephropathy Trial (IDNT) will assess the effects of irbesartan, the calcium channel blocker amlodipine, and placebo (usual care) on cardiovascular morbidity and mortality and on the progression of renal disease in high-risk hypertensive patients with type 2 diabetes and proteinuria. The IRbesartan MicroAlbuminuria (IRMA) II trial will assess the effect of irbesartan or placebo (usual care) on the progression of microalbuminuria to overt nephropathy in hypertensive patients with type 2 diabetes, microalbuminuria, and normal renal function. The results of this program will demonstrate the cardiovascular and renal benefits of irbesartan in high-risk patients with hypertension and type 2 diabetes at both early and late stages of diabetic nephropathy. The Program for Irbesartan Mortality and Morbidity Evaluations (PRIME) is an important research program composed of two ongoing trials. The Irbesartan Diabetic Nephropathy Trial (IDNT) will assess the effects of irbesartan, the calcium channel blocker amlodipine, and placebo (usual care) on cardiovascular morbidity and mortality and on the progression of renal disease in high-risk hypertensive patients with type 2 diabetes and proteinuria. The IRbesartan MicroAlbuminuria (IRMA) II trial will assess the effect of irbesartan or placebo (usual care) on the progression of microalbuminuria to overt nephropathy in hypertensive patients with type 2 diabetes, microalbuminuria, and normal renal function. The results of this program will demonstrate the cardiovascular and renal benefits of irbesartan in high-risk patients with hypertension and type 2 diabetes at both early and late stages of diabetic nephropathy.

32. A review of 24 studies performed since 1983 found country-specific hypertension prevalence rates ranging from 8% in China to a high of about a third of men and a fourth of women in Germany (Marques-Vidal and Tuomilehto, 1997). The lower rates reported in countries like India and China probably reflect underdiagnosis and/or different definitions of hypertension rather than truly low rates. A review of 24 studies performed since 1983 found country-specific hypertension prevalence rates ranging from 8% in China to a high of about a third of men and a fourth of women in Germany (Marques-Vidal and Tuomilehto, 1997). The lower rates reported in countries like India and China probably reflect underdiagnosis and/or different definitions of hypertension rather than truly low rates.

33. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits, the prevalence of diabetes is increasing (Grundy et al, 1999). An estimated 135 million people worldwide have diabetes. That figure is expected to more than double to nearly 300 million by the year 2025 (World Health Organization, 1997). Developing countries are expected to experience the brunt of the increase, with a 200% rise expected. Developed countries can expect to see a rise of 45% in rates of the disease. Type 2 diabetes will continue to account for about 90% of all cases of diabetes.Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits, the prevalence of diabetes is increasing (Grundy et al, 1999). An estimated 135 million people worldwide have diabetes. That figure is expected to more than double to nearly 300 million by the year 2025 (World Health Organization, 1997). Developing countries are expected to experience the brunt of the increase, with a 200% rise expected. Developed countries can expect to see a rise of 45% in rates of the disease. Type 2 diabetes will continue to account for about 90% of all cases of diabetes.

34. 9745/presentation/final/Presv6 The ‘Natural’ Associations With ‘High Risk Hypertensive’ MARKETING One of the first points which we wanted to test was the connotations of “high risk hypertensive’. The underlying intention of describing the population involved in both trials in this way was simply to reinforce the significantly elevated risk that these patient were at. As expected without qualification the “high risk” description generated a significant no. of spontaneous associations. Reassuringly, the population with Type II DM figured prominently and early on amongst all specialties. In order to clarify,and at the same item reinforce the risk the recommendation from the research was to describe the population arising from IDNT as High risk hypertensives with DM MARKETING One of the first points which we wanted to test was the connotations of “high risk hypertensive’. The underlying intention of describing the population involved in both trials in this way was simply to reinforce the significantly elevated risk that these patient were at. As expected without qualification the “high risk” description generated a significant no. of spontaneous associations. Reassuringly, the population with Type II DM figured prominently and early on amongst all specialties. In order to clarify,and at the same item reinforce the risk the recommendation from the research was to describe the population arising from IDNT as High risk hypertensives with DM

35. Coexistence of Hypertension in Diabetes Even at the initial presentation of diabetes, coexisting hypertension is associated with a doubling of the presence of microalbuminuria, left ventricular hypertrophy, electocardiographic signs of myocardial ischemia and a prior history of overt cardiovascular events (Kaplan, 1997). These risks were assessed in a trial of 3,648 newly diagnosed diabetics followed for a median of 4.6 years (The Hypertension in Diabetes Study Group, 1993). Those with hypertension suffered a twofold greater incidence of cardiovascular mortality than did nonhypertensive diabetics (The Hypertension in Diabetes Study Group, 1993). The risk of stroke was increased by fourfold in diabetic hypertensives. In the 26-year follow-up, Framingham data indicated a similar increased risk of cardiovascular disease in hypertensive subjects with glucose intolerance (Kannel et al, 1991).Even at the initial presentation of diabetes, coexisting hypertension is associated with a doubling of the presence of microalbuminuria, left ventricular hypertrophy, electocardiographic signs of myocardial ischemia and a prior history of overt cardiovascular events (Kaplan, 1997). These risks were assessed in a trial of 3,648 newly diagnosed diabetics followed for a median of 4.6 years (The Hypertension in Diabetes Study Group, 1993). Those with hypertension suffered a twofold greater incidence of cardiovascular mortality than did nonhypertensive diabetics (The Hypertension in Diabetes Study Group, 1993). The risk of stroke was increased by fourfold in diabetic hypertensives. In the 26-year follow-up, Framingham data indicated a similar increased risk of cardiovascular disease in hypertensive subjects with glucose intolerance (Kannel et al, 1991).

36. Effect of ACE Inhibition on Diabetic Nephropathy in Patients with Type 1 Diabetes A randomized, controlled trial compared the ACE inhibitor captopril with placebo in 409 patients with type 1 diabetes, diabetic retinopathy, proteinuria ? 500 mg/d, and serum creatinine concentrations ? 2.5 mg/dL. Median follow-up was 3 years. The primary endpoint was a doubling of the baseline serum creatinine concentration. Captopril slowed the progression of diabetic nephropathy, reducing the risk of a doubling of serum creatinine by 48% (p = 0.007). Captopril was also associated with a 50% risk reduction of the combined endpoints of death, need for dialysis, or transplantation. Captopril protected against deterioration in renal function in type 1 diabetic nephropathy to a greater degree than would be expected from blood pressure reduction alone (Lewis et al, 1993). A randomized, controlled trial compared the ACE inhibitor captopril with placebo in 409 patients with type 1 diabetes, diabetic retinopathy, proteinuria ? 500 mg/d, and serum creatinine concentrations ? 2.5 mg/dL. Median follow-up was 3 years. The primary endpoint was a doubling of the baseline serum creatinine concentration. Captopril slowed the progression of diabetic nephropathy, reducing the risk of a doubling of serum creatinine by 48% (p = 0.007). Captopril was also associated with a 50% risk reduction of the combined endpoints of death, need for dialysis, or transplantation. Captopril protected against deterioration in renal function in type 1 diabetic nephropathy to a greater degree than would be expected from blood pressure reduction alone (Lewis et al, 1993).

37. IDNT Pilot Study: Effect of Irbesartan onRenal Function in Type 2 Diabetic Nephropathy At Week 12, irbesartan reduced mean urine protein excretion from baseline by 8.5%, while amlodipine increased mean urine protein excretion by 19.7%. Amlodipine resulted in a slightly greater increase from baseline in serum creatinine level compared with irbesartan. At Week 12, irbesartan increased creatinine clearance (8.6 mL/min/1.73 m2) versus a decrease seen with amlodipine(-14.3 mL/min/1.73 m2, p < 0.01) (Pohl et al, 1997). At Week 12, irbesartan reduced mean urine protein excretion from baseline by 8.5%, while amlodipine increased mean urine protein excretion by 19.7%. Amlodipine resulted in a slightly greater increase from baseline in serum creatinine level compared with irbesartan. At Week 12, irbesartan increased creatinine clearance (8.6 mL/min/1.73 m2) versus a decrease seen with amlodipine(-14.3 mL/min/1.73 m2, p < 0.01) (Pohl et al, 1997).

38. Scope of the PRIME program in relation to the time-course of type 2 diabetes

39. Irbesartan DiabeticNephropathy Trial (IDNT): Objective Comparative trial of the effects of irbesartan, amlodipine, and placebo on renal function, total mortality, and cardiovascular morbidity in patients with hypertension and type 2 diabetic nephropathy Primary comparison of irbesartan with placebo Secondary comparison of irbesartan with amlodipine Independent, unblinded Data Safety Monitoring Committee reviewing safety and efficacy data every 6 months The Collaborative Study Group has initiated a trial to determine the effect of angiotensin II receptor antagonism in reducing the rate of progression of renal disease, total mortality, and cardiovascular events in patients with hypertension and type 2 diabetic nephropathy (Rodby et al, in press). Patients were randomized to receive the angiotensin II receptor antagonist irbesartan, the calcium channel blocker amlodipine, or placebo, with equal blood pressure goals in all 3 arms. Amlodipine was chosen as the comparator in this trial for several reasons. First, calcium channel blockers (CCBs), including amlodipine, have been demonstrated to provide similar protective effects on renal function as ACE inhibitors in patients with diabetic nephropathy (Velussi et al, 1996; Bakris et al, 1996). Second, although the results of 2 relatively small, non-placebo-controlled trials (ABCD and FACET) have raised questions about the use of CCBs in hypertensive patients with type 2 diabetes (Estacio et al, 1998; Tatti et al, 1998), 2 large-scale trials (Syst-Eur and HOT) demonstrated significant reductions in cardiovascular events by treating hypertensive type 2 diabetic patients with CCBs (Tuolmilehto et al, 1999; Hansson et al, 1998); CCBs are frequently used in the treatment of high-risk hypertensive patients for their perceived cardiovascular protective benefits. Third, although ACE inhibition has been demonstrated to reduce the risk of death and of progression of diabetic nephropathy in patients with type 1 diabetic nephropathy (Lewis et al, 1993), such hard endpoint data for patients with type 2 diabetic nephropathy are not currently available for ACE inhibitors or any other class of antihypertensive agents. The majority of research to date has focused on type 1 diabetes, despite the fact that the majority of patients with diabetic nephropathy have type 2 diabetes. IDNT will be the first placebo-controlled trial to directly compare the cardiovascular and renal benefits of 2 different antihypertensive agents, the angiotensin II receptor antagonist irbesartan and the calcium channel blocker amlodipine, in this high-risk hypertensive diabetic population. The primary comparison of IDNT is irbesartan with placebo, while the secondary comparison is irbesartan with amlodipine. An independent Data Safety Monitoring Committee reviews unblinded safety and efficacy data every 6 months.The Collaborative Study Group has initiated a trial to determine the effect of angiotensin II receptor antagonism in reducing the rate of progression of renal disease, total mortality, and cardiovascular events in patients with hypertension and type 2 diabetic nephropathy (Rodby et al, in press). Patients were randomized to receive the angiotensin II receptor antagonist irbesartan, the calcium channel blocker amlodipine, or placebo, with equal blood pressure goals in all 3 arms. Amlodipine was chosen as the comparator in this trial for several reasons. First, calcium channel blockers (CCBs), including amlodipine, have been demonstrated to provide similar protective effects on renal function as ACE inhibitors in patients with diabetic nephropathy (Velussi et al, 1996; Bakris et al, 1996). Second, although the results of 2 relatively small, non-placebo-controlled trials (ABCD and FACET) have raised questions about the use of CCBs in hypertensive patients with type 2 diabetes (Estacio et al, 1998; Tatti et al, 1998), 2 large-scale trials (Syst-Eur and HOT) demonstrated significant reductions in cardiovascular events by treating hypertensive type 2 diabetic patients with CCBs (Tuolmilehto et al, 1999; Hansson et al, 1998); CCBs are frequently used in the treatment of high-risk hypertensive patients for their perceived cardiovascular protective benefits. Third, although ACE inhibition has been demonstrated to reduce the risk of death and of progression of diabetic nephropathy in patients with type 1 diabetic nephropathy (Lewis et al, 1993), such hard endpoint data for patients with type 2 diabetic nephropathy are not currently available for ACE inhibitors or any other class of antihypertensive agents. The majority of research to date has focused on type 1 diabetes, despite the fact that the majority of patients with diabetic nephropathy have type 2 diabetes. IDNT will be the first placebo-controlled trial to directly compare the cardiovascular and renal benefits of 2 different antihypertensive agents, the angiotensin II receptor antagonist irbesartan and the calcium channel blocker amlodipine, in this high-risk hypertensive diabetic population. The primary comparison of IDNT is irbesartan with placebo, while the secondary comparison is irbesartan with amlodipine. An independent Data Safety Monitoring Committee reviews unblinded safety and efficacy data every 6 months.

40. Irbesartan Diabetic NephropathyTrial (IDNT): Study Design Multicenter, randomized, double-blind comparison of irbesartan vs placebo vs amlodipine (N = 1,715) This worldwide, double-blind, placebo-controlled study has enrolled a patient population of 1,715 men and women. Following initial screening for blood pressure (BP) and renal function, antihypertensive treatment with ACE inhibitors, angiotensin II receptor antagonists, and/or calcium channel blockers were discontinued; use of other antihypertensive medication was permitted to maintain BP control. Enrollment then proceeded, with baseline measurements including serum creatinine and blood urea nitrogen or urea, 24-hour urinary protein and albumin excretion, fasting lipid profile, glycosylated hemoglobin (HbA1c) level, and electrocardiography. Patients were randomized in equal numbers to irbesartan 75 mg, amlodipine 2.5 mg, or placebo once daily. The study design calls for the attainment of equal degrees of BP control within all 3 treatment groups: seated systolic BP (SeSBP) ? 135 mm Hg or a reduction of ? 10 mm Hg in SeSBP in patients with SeSBP > 145 mm Hg at screening. Doses of the study medications can be titrated over 8 weeks until target BP goals are reached, up to maximum doses of 300 mg of irbesartan or 10 mg of amlodipine. Adjunctive antihypertensives can be added if monotherapy does not achieve target BP. Dietary recommendations are in keeping with local guidelines. Oral hypoglycemic or insulin therapy for patients enrolled in the study should be managed by the patient’s physician or the study investigator. Treatment will be for a minimum of approximately 2 years, with patients returning for follow-up every 3 months (Rodby et al, in press). This worldwide, double-blind, placebo-controlled study has enrolled a patient population of 1,715 men and women. Following initial screening for blood pressure (BP) and renal function, antihypertensive treatment with ACE inhibitors, angiotensin II receptor antagonists, and/or calcium channel blockers were discontinued; use of other antihypertensive medication was permitted to maintain BP control. Enrollment then proceeded, with baseline measurements including serum creatinine and blood urea nitrogen or urea, 24-hour urinary protein and albumin excretion, fasting lipid profile, glycosylated hemoglobin (HbA1c) level, and electrocardiography. Patients were randomized in equal numbers to irbesartan 75 mg, amlodipine 2.5 mg, or placebo once daily. The study design calls for the attainment of equal degrees of BP control within all 3 treatment groups: seated systolic BP (SeSBP) ? 135 mm Hg or a reduction of ? 10 mm Hg in SeSBP in patients with SeSBP > 145 mm Hg at screening. Doses of the study medications can be titrated over 8 weeks until target BP goals are reached, up to maximum doses of 300 mg of irbesartan or 10 mg of amlodipine. Adjunctive antihypertensives can be added if monotherapy does not achieve target BP. Dietary recommendations are in keeping with local guidelines. Oral hypoglycemic or insulin therapy for patients enrolled in the study should be managed by the patient’s physician or the study investigator. Treatment will be for a minimum of approximately 2 years, with patients returning for follow-up every 3 months (Rodby et al, in press).

41. Irbesartan Diabetic NephropathyTrial (IDNT): Clinical Outcome Measures Primary outcome is time to a composite endpoint consisting of: Doubling of baseline serum creatinine level End-stage renal disease Death (all-cause mortality) Secondary outcome is time to a composite endpoint of fatal or nonfatal cardiovascular events The study will evaluate the efficacy of irbesartan against a series of outcome measures. The primary outcome is the time from randomization until the first occurrence of doubling of baseline serum creatinine level, end-stage renal disease (ie, renal transplantation or the need for dialysis or serum creatinine level ³ 6.0 mg/dL), or death from any cause. The safety and tolerability of irbesartan when administered long-term to patients with hypertension and diabetic nephropathy will also be compared with that of placebo. The secondary outcome measure in these high-risk patients is the time from randomization until the first occurrence of cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation (Rodby et al, in press). The study will evaluate the efficacy of irbesartan against a series of outcome measures. The primary outcome is the time from randomization until the first occurrence of doubling of baseline serum creatinine level, end-stage renal disease (ie, renal transplantation or the need for dialysis or serum creatinine level ³ 6.0 mg/dL), or death from any cause. The safety and tolerability of irbesartan when administered long-term to patients with hypertension and diabetic nephropathy will also be compared with that of placebo. The secondary outcome measure in these high-risk patients is the time from randomization until the first occurrence of cardiovascular death, nonfatal myocardial infarction, hospitalization for heart failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation (Rodby et al, in press).

42. Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA II) Study: Objectives To study patients at an early stage of diabetic nephropathy (normal renal function and microalbuminuria) To determine whether irbesartan can slow the progression from microalbuminuria to overt proteinuria To evaluate renal hemodynamics (substudy) The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA II) study enrolled patients at an earlier stage of diabetic nephropathy (normal renal function and microalbuminuria) compared to the population included in the Irbesartan Diabetic Nephropathy Trial (IDNT). The main study endpoint is time to overt proteinuria to demonstrate the slowed progression of the disease with irbesartan treatment compared to placebo. By examining the effects of 2 doses of irbesartan (150 or 300 mg) versus placebo, the best treatment dose will be defined. A substudy will evaluate renal hemodynamics. The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA II) study enrolled patients at an earlier stage of diabetic nephropathy (normal renal function and microalbuminuria) compared to the population included in the Irbesartan Diabetic Nephropathy Trial (IDNT). The main study endpoint is time to overt proteinuria to demonstrate the slowed progression of the disease with irbesartan treatment compared to placebo. By examining the effects of 2 doses of irbesartan (150 or 300 mg) versus placebo, the best treatment dose will be defined. A substudy will evaluate renal hemodynamics.

43. IRMA II: Design Population: 610 patients with type 2 diabetes, microalbuminuria (albumin excretion rate: 20–200 µg/min), normal renal function, and hypertension

44. Irbesartan Microalbuminuria (IRMA II) Trial in Hypertensive Patients With Type 2 Diabetes: Clinical Outcome Measures Primary outcome: time to occurrence of clinical proteinuria Secondary outcomes: Incidence at 2 years of clinical proteinuria with each treatment Change in overnight urinary albumin excretion rate at each timepoint After 1 and 2 years, change in 24-hour creatinine clearance, clotting factors, and lipid profile After 3 months and 2 years, change in renal function The primary outcome measure of this trial is time to occurrence of clinical proteinuria, which is defined as an overnight urinary albumin excretion rate (AER) exceeding 200 ?g/min and an increase of urinary AER from baseline by at least 30% at 2 successive 3-month evaluations. The secondary outcome measures of IRMA II include incidence at 2 years of clinical proteinuria with each treatment and the change in overnight urinary AER at specified timepoints. After 1 and 2 years, change in 24-hour creatinine clearance, Von Willebrand factor, factor VII, plasminogen activator inhibitor-1, and lipid profile (total cholesterol, triglycerides, high-density cholesterol, low-density cholesterol, and lipoprotein [a]) are to be measured. After 3 months and 2 years, changes in the following renal parameters are to be determined: glomerular filtration rate, renal plasma flow, filtration fraction, and renal vascular resistance. The primary outcome measure of this trial is time to occurrence of clinical proteinuria, which is defined as an overnight urinary albumin excretion rate (AER) exceeding 200 ?g/min and an increase of urinary AER from baseline by at least 30% at 2 successive 3-month evaluations. The secondary outcome measures of IRMA II include incidence at 2 years of clinical proteinuria with each treatment and the change in overnight urinary AER at specified timepoints. After 1 and 2 years, change in 24-hour creatinine clearance, Von Willebrand factor, factor VII, plasminogen activator inhibitor-1, and lipid profile (total cholesterol, triglycerides, high-density cholesterol, low-density cholesterol, and lipoprotein [a]) are to be measured. After 3 months and 2 years, changes in the following renal parameters are to be determined: glomerular filtration rate, renal plasma flow, filtration fraction, and renal vascular resistance.

45. Positive features to highlight... First trial to address the unanswered question of treatment of DN in type 2 patients Definite design helping to address the on-going CCB controversy Similar efficacy to ACEI with improved tolerability Superior within-class efficacy Improved compliance vs all other classes

46. Slide 100. The New Therapeutic Window in Hypertension Most antihypertensive therapies are hampered by the classic profile of increasing side effects with increasing drug doses, which does not necessarily lead to improved rates of hypertension control. This is illustrated by the traditional sigmoid dose curve, indicating that as the dose is increased, efficacy is increased until a plateau is reached; after this point, further increases in efficacy are not apparent with increasing doses, while tolerability may suffer. With the development of AIIRAs, in particular irbesartan, this limitation can be overcome. An extensive clinical trial program has demonstrated that irbesartan is associated with a dose-related efficacy response, without a concomitant dose-response relationship in the rate of adverse events. Comparative trials with other AIIRAs demonstrate that irbesartan therapy lowers BP to a significantly greater degree and that the extent and duration of the antagonistic effects to Ang II challenge are significantly greater with irbesartan. These data may reflect the superior pharmacokinetic profile of irbesartan as compared with other marketed AIIRAs. Furthermore, irbesartan has been demonstrated to reduce BP as effectively as full doses of the leading agents in other antihypertensive classes, with superior tolerability. PRIME will directly compare the clinical benefits of irbesartan, amlodipine, and placebo (usual care) in high-risk patients with hypertension and type 2 diabetes. In summary, irbesartan is a true advance in the clinical management of hypertension, representing the strongest agent in the best tolerated class of antihypertensives. Slide 100. The New Therapeutic Window in Hypertension Most antihypertensive therapies are hampered by the classic profile of increasing side effects with increasing drug doses, which does not necessarily lead to improved rates of hypertension control. This is illustrated by the traditional sigmoid dose curve, indicating that as the dose is increased, efficacy is increased until a plateau is reached; after this point, further increases in efficacy are not apparent with increasing doses, while tolerability may suffer. With the development of AIIRAs, in particular irbesartan, this limitation can be overcome. An extensive clinical trial program has demonstrated that irbesartan is associated with a dose-related efficacy response, without a concomitant dose-response relationship in the rate of adverse events. Comparative trials with other AIIRAs demonstrate that irbesartan therapy lowers BP to a significantly greater degree and that the extent and duration of the antagonistic effects to Ang II challenge are significantly greater with irbesartan. These data may reflect the superior pharmacokinetic profile of irbesartan as compared with other marketed AIIRAs. Furthermore, irbesartan has been demonstrated to reduce BP as effectively as full doses of the leading agents in other antihypertensive classes, with superior tolerability. PRIME will directly compare the clinical benefits of irbesartan, amlodipine, and placebo (usual care) in high-risk patients with hypertension and type 2 diabetes. In summary, irbesartan is a true advance in the clinical management of hypertension, representing the strongest agent in the best tolerated class of antihypertensives.

47. Key point: at 6 months, only 40%?50% of all patients receiving beta blockers, ACE inhibitors, CCBs, or diuretics continued with antihypertensive treatment. A retrospective analysis of patients receiving newly prescribed antihypertensive drugs was conducted from general practice visits in the United Kingdom between October 1992 and September 1993 to evaluate the incidence of discontinuation and changes in treatment [Jones et al, 1995]. Patients with hypertension receiving a beta blocker, calcium channel blocker (CCB), angiotensin-converting enzyme (ACE) inhibitor, or diuretic were identified (N=10,222). Subjects were included if they had been started on a new course of treatment in at least 1 of the 4 therapeutic classes. The main outcome measure was the incidence of patients changing to another treatment or discontinuing a new course of treatment, defined as the absence of a refill prescription for the new drug or another in its category. During a 6-month observation period, low rates of treatment continuation were frequently observed for patients on any of the 4 antihypertensive agents, with continuation rates ranging between 40% and 50% for all 4 classes of drugs at 6 months. Key point: at 6 months, only 40%?50% of all patients receiving beta blockers, ACE inhibitors, CCBs, or diuretics continued with antihypertensive treatment. A retrospective analysis of patients receiving newly prescribed antihypertensive drugs was conducted from general practice visits in the United Kingdom between October 1992 and September 1993 to evaluate the incidence of discontinuation and changes in treatment [Jones et al, 1995]. Patients with hypertension receiving a beta blocker, calcium channel blocker (CCB), angiotensin-converting enzyme (ACE) inhibitor, or diuretic were identified (N=10,222). Subjects were included if they had been started on a new course of treatment in at least 1 of the 4 therapeutic classes. The main outcome measure was the incidence of patients changing to another treatment or discontinuing a new course of treatment, defined as the absence of a refill prescription for the new drug or another in its category. During a 6-month observation period, low rates of treatment continuation were frequently observed for patients on any of the 4 antihypertensive agents, with continuation rates ranging between 40% and 50% for all 4 classes of drugs at 6 months.

48. Key point: the percentage of patients continuing with an angiotensin II receptor antagonist (AIIRA) was found to be higher than the percentage of patients continuing with all other antihypertensive classes. In a retrospective analysis of the prescription refill behavior of patients who had recently started antihypertensive therapy, the percentage of patients continuing with AIIRA therapy was higher than the percentage of patients continuing with other antihypertensive classes [Bloom, 1998]. At 12 months' follow-up, 64% of patients receiving AIIRAs were persistent, compared with 58% of patients receiving angiotensin-converting enzyme (ACE) inhibitors (P<0.01), 50% of patients receiving calcium channel blockers (CCBs), 43% of patients receiving beta blockers, and 38% of patients receiving thiazide diuretics. Key point: the percentage of patients continuing with an angiotensin II receptor antagonist (AIIRA) was found to be higher than the percentage of patients continuing with all other antihypertensive classes. In a retrospective analysis of the prescription refill behavior of patients who had recently started antihypertensive therapy, the percentage of patients continuing with AIIRA therapy was higher than the percentage of patients continuing with other antihypertensive classes [Bloom, 1998]. At 12 months' follow-up, 64% of patients receiving AIIRAs were persistent, compared with 58% of patients receiving angiotensin-converting enzyme (ACE) inhibitors (P<0.01), 50% of patients receiving calcium channel blockers (CCBs), 43% of patients receiving beta blockers, and 38% of patients receiving thiazide diuretics.

49. Key point: in a study of newly diagnosed hypertensive patients, persistence with angiotensin II receptor antagonists (AIIRAs) was consistently higher than persistence with all other antihypertensive classes at all time points. The AIIRA class of antihypertensives has been found to provide similar efficacy to other antihypertensive classes with a placebo-like tolerability profile [Mimran et al, 1998; Larochelle et al, 1997; Stumpe et al, 1998; Lacourcière et al, 1998; Oparil et al, 1996; Pylypchuk, 1998]. As persistence is a measure of patients’ and physicians’ willingness to continue with a prescribed drug treatment regimen, it has been postulated that subjects who receive an agent with favorable efficacy and tolerability profiles, such as an AIIRA, will demonstrate favorable persistence. A study of newly diagnosed patients with essential hypertension from Saskatchewan, Canada, compared initial antihypertensive prescriptions filled between 1995 and 1998 to observe the rate of persistence for each class [Chaput, 2000]. Persistence was measured at 6, 12, 18, and 24 months. The persistence of subjects receiving AIIRAs was statistically superior compared with the persistence of subjects taking all other classes at all time points observed. Further, while persistence remained constant at 70% for patients receiving AIIRAs, persistence declined over time for patients receiving all other antihypertensive classes. Key point: in a study of newly diagnosed hypertensive patients, persistence with angiotensin II receptor antagonists (AIIRAs) was consistently higher than persistence with all other antihypertensive classes at all time points. The AIIRA class of antihypertensives has been found to provide similar efficacy to other antihypertensive classes with a placebo-like tolerability profile [Mimran et al, 1998; Larochelle et al, 1997; Stumpe et al, 1998; Lacourcière et al, 1998; Oparil et al, 1996; Pylypchuk, 1998]. As persistence is a measure of patients’ and physicians’ willingness to continue with a prescribed drug treatment regimen, it has been postulated that subjects who receive an agent with favorable efficacy and tolerability profiles, such as an AIIRA, will demonstrate favorable persistence. A study of newly diagnosed patients with essential hypertension from Saskatchewan, Canada, compared initial antihypertensive prescriptions filled between 1995 and 1998 to observe the rate of persistence for each class [Chaput, 2000]. Persistence was measured at 6, 12, 18, and 24 months. The persistence of subjects receiving AIIRAs was statistically superior compared with the persistence of subjects taking all other classes at all time points observed. Further, while persistence remained constant at 70% for patients receiving AIIRAs, persistence declined over time for patients receiving all other antihypertensive classes.

50. Key point: inadequate blood pressure control and the presence of adverse events are cited by hypertensive patients as the primary reasons for changing antihypertensive therapy. In a German multicenter study, patient persistence during antihypertensive therapy was investigated using patient and physician questionnaires [Düsing et al, 1998]. The most important reason for therapy switch was inadequate blood pressure control (48.4%), followed by adverse effects (30.1%), patient dissatisfaction (20.0%), noncompliance (16.8%), and cost (4.9%). The most frequent side effects noted by physicians were cough (51.9%), edema (36.9%), flushing (36.6%), and dizziness (27.8%). When physician and patient answers were compared, it was discovered that physicians underestimated the extent of patient noncompliance. Key point: inadequate blood pressure control and the presence of adverse events are cited by hypertensive patients as the primary reasons for changing antihypertensive therapy. In a German multicenter study, patient persistence during antihypertensive therapy was investigated using patient and physician questionnaires [Düsing et al, 1998]. The most important reason for therapy switch was inadequate blood pressure control (48.4%), followed by adverse effects (30.1%), patient dissatisfaction (20.0%), noncompliance (16.8%), and cost (4.9%). The most frequent side effects noted by physicians were cough (51.9%), edema (36.9%), flushing (36.6%), and dizziness (27.8%). When physician and patient answers were compared, it was discovered that physicians underestimated the extent of patient noncompliance.

51. Key point: key factors thought to favorably affect persistence are good tolerability, adequate blood pressure control, and a simple drug regimen. Good tolerability and effective blood pressure control are crucial to persistence. A German multicenter study [Düsing et al, 1998] found the most important reason for therapy switch was inadequate blood pressure control (48.4% of patients) followed by adverse effects (30.1% of patients). A simple, easy-to-follow drug protocol is also important. The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study [Lee et al, 1996] found 51% of patients on once-daily treatment with calcium channel blockers (CCBs), beta blockers, or angiotensin-converting enzyme (ACE) inhibitors were not compliant compared with 95% of subjects treated with a twice-daily therapeutic regimen. Key point: key factors thought to favorably affect persistence are good tolerability, adequate blood pressure control, and a simple drug regimen. Good tolerability and effective blood pressure control are crucial to persistence. A German multicenter study [Düsing et al, 1998] found the most important reason for therapy switch was inadequate blood pressure control (48.4% of patients) followed by adverse effects (30.1% of patients). A simple, easy-to-follow drug protocol is also important. The African American Study of Kidney Disease and Hypertension (AASK) Pilot Study [Lee et al, 1996] found 51% of patients on once-daily treatment with calcium channel blockers (CCBs), beta blockers, or angiotensin-converting enzyme (ACE) inhibitors were not compliant compared with 95% of subjects treated with a twice-daily therapeutic regimen.

52. Key point: Patients who drop out of treatment have a 63% higher risk of death and first CV hospitalization. Hypertensive patients who “drop out” of treatment have a 63% higher risk of death and first CV hospitalization compared to patients who continue with follow-up in a tertiary hypertension clinic. “Drop out” status was applied to a patient who failed to return after 3 consecutive calls or letters, generated daily for missed appointments [Elliott, 2000]. The patients who dropped out of treatment also incurred 74% higher annualized charges for medical costs, mostly due to hospitalizations and emergency room visits. Key point: Patients who drop out of treatment have a 63% higher risk of death and first CV hospitalization. Hypertensive patients who “drop out” of treatment have a 63% higher risk of death and first CV hospitalization compared to patients who continue with follow-up in a tertiary hypertension clinic. “Drop out” status was applied to a patient who failed to return after 3 consecutive calls or letters, generated daily for missed appointments [Elliott, 2000]. The patients who dropped out of treatment also incurred 74% higher annualized charges for medical costs, mostly due to hospitalizations and emergency room visits.

53. THE SELECTION OF INITIAL DRUG IN HYPERTENSION Partially restrictive approach Based on evidence Based on economic considerations Unrestrictive

54.  Irbesartan: Dose Response and Tolerability An extensive clinical trials program has demonstrated that irbesartan is associated with a dose-related efficacy response without a concomitant dose-response relationship in the rate of adverse events [Man in’t Veld, 1997]. Total responders included 25% on placebo, 45% on irbesartan 75 mg, 55% on irbesartan 150 mg, and 60% on irbesartan 300 mg. All doses of irbesartan provided tolerability similar to placebo, with no relationship between dose and incidence of adverse events.An extensive clinical trials program has demonstrated that irbesartan is associated with a dose-related efficacy response without a concomitant dose-response relationship in the rate of adverse events [Man in’t Veld, 1997]. Total responders included 25% on placebo, 45% on irbesartan 75 mg, 55% on irbesartan 150 mg, and 60% on irbesartan 300 mg. All doses of irbesartan provided tolerability similar to placebo, with no relationship between dose and incidence of adverse events.

55. Long-Term Efficacy of Irbesartan In a long-term, open-label extension study, 91% of patients achieved normalized blood pressure (SeDBP <90 mm Hg) with an irbesartan-based regimen at 12 months. Irbesartan achieved and maintained normalized blood pressure in 69% of patients with monotherapy at 12 months [Pouleur, 1997].In a long-term, open-label extension study, 91% of patients achieved normalized blood pressure (SeDBP <90 mm Hg) with an irbesartan-based regimen at 12 months. Irbesartan achieved and maintained normalized blood pressure in 69% of patients with monotherapy at 12 months [Pouleur, 1997].

56.  Adverse Drug Events in Placebo-Controlled Trials Pooled data comprising over 2600 patients in nine, placebo-controlled, 4- to 12-week trials with irbesartan monotherapy demonstrate the excellent adverse events profile with irbesartan, which is similar to that of placebo [Pouleur, 1997]. The most commonly reported adverse events for irbesartan and placebo, respectively, were headache (12.3% vs 16.7%, p=0.005), upper respiratory tract infection (8.5% vs 6.2%), musculoskeletal pain (6.6% vs 6.6%), and dizziness (4.9% vs 5.0%). The safety profile was consistent regardless of age, gender, or disease severity.Pooled data comprising over 2600 patients in nine, placebo-controlled, 4- to 12-week trials with irbesartan monotherapy demonstrate the excellent adverse events profile with irbesartan, which is similar to that of placebo [Pouleur, 1997]. The most commonly reported adverse events for irbesartan and placebo, respectively, were headache (12.3% vs 16.7%, p=0.005), upper respiratory tract infection (8.5% vs 6.2%), musculoskeletal pain (6.6% vs 6.6%), and dizziness (4.9% vs 5.0%). The safety profile was consistent regardless of age, gender, or disease severity.

57. AIIRAs: Pharmacologic Comparisons Irbesartan possesses an excellent pharmacologic profile. Unlike losartan and candesartan, irbesartan does not require biotransformation for its pharmacologic activity [Avapro, 1999; Atacand, 1999; Cozaar, 1999; Diovan, 1999; Micardis, 1999; Teveten, 1999]. Compared to the other available AIIRAs, irbesartan has a greater bioavailability (60%-80%), a long half-life (11-15 hours) for 24-hour BP control, and a large volume of distribution (53-93 liters) for reaching AT1 receptors in tissue sites that are not accessible to most other AIIRAs. Further, the pharmacologic profile of irbesartan is not affected by food so that it may be taken with or without meals. Therefore, despite sharing a common mechanism of action, pharmacologic differences do exist that could result in different clinical profiles. AIIRAs: Pharmacologic Comparisons Irbesartan possesses an excellent pharmacologic profile. Unlike losartan and candesartan, irbesartan does not require biotransformation for its pharmacologic activity [Avapro, 1999; Atacand, 1999; Cozaar, 1999; Diovan, 1999; Micardis, 1999; Teveten, 1999]. Compared to the other available AIIRAs, irbesartan has a greater bioavailability (60%-80%), a long half-life (11-15 hours) for 24-hour BP control, and a large volume of distribution (53-93 liters) for reaching AT1 receptors in tissue sites that are not accessible to most other AIIRAs. Further, the pharmacologic profile of irbesartan is not affected by food so that it may be taken with or without meals. Therefore, despite sharing a common mechanism of action, pharmacologic differences do exist that could result in different clinical profiles.

58. Superior Antagonism of Ang II With Irbesartan The first study, designed to compare Ang II antagonistic properties of irbesartan, valsartan, and losartan, indicated that while all three AIIRAs demonstrated clear antagonistic effects to Ang II challenge, the extent and duration of the inhibitory effect with irbesartan was significantly greater than that attained with losartan or valsartan (p<0.05 irbesartan vs valsartan at 24h, irbesartan vs losartan at 4h, 24h, 47h, on Day 1; p<0.05 irbesartan vs valsartan at 36h, irbesartan vs losartan at 4h, 24h, 36h, 47h, on Day 8) [Belz et al, 1999]. These in vivo findings were strongly supported by the radioreceptor assay data. Thus, irbesartan showed the greatest extent and longest duration of Ang II inhibitory effects, with antagonism maintained up to two days following administration.Superior Antagonism of Ang II With Irbesartan The first study, designed to compare Ang II antagonistic properties of irbesartan, valsartan, and losartan, indicated that while all three AIIRAs demonstrated clear antagonistic effects to Ang II challenge, the extent and duration of the inhibitory effect with irbesartan was significantly greater than that attained with losartan or valsartan (p<0.05 irbesartan vs valsartan at 24h, irbesartan vs losartan at 4h, 24h, 47h, on Day 1; p<0.05 irbesartan vs valsartan at 36h, irbesartan vs losartan at 4h, 24h, 36h, 47h, on Day 8) [Belz et al, 1999]. These in vivo findings were strongly supported by the radioreceptor assay data. Thus, irbesartan showed the greatest extent and longest duration of Ang II inhibitory effects, with antagonism maintained up to two days following administration.

59. Five hundred thirty-two patients completed the 8-week, double-blind period [Kassler-Taub et al, 1998]. All active groups reduced blood pressure significantly (p <0.001) versus placebo at all timepoints. A greater antihypertensive effect of irbesartan 300 mg once daily compared with losartan 100 mg once daily was present throughout the study. At Week 8, reductions from baseline in trough SeDBP, the primary endpoint of the trial, were significantly greater with irbesartan 300 mg compared with losartan 100 mg by 3.0 mm Hg (-11.7 vs -8.7 mm Hg) (p <0.01). The difference in SeDBP between these two groups was also statistically significant at Weeks 1 (p <0.01) and 4 (p <0.02). Irbesartan 150 mg produced overall changes in SeDBP comparable to losartan 100 mg.Five hundred thirty-two patients completed the 8-week, double-blind period [Kassler-Taub et al, 1998]. All active groups reduced blood pressure significantly (p <0.001) versus placebo at all timepoints. A greater antihypertensive effect of irbesartan 300 mg once daily compared with losartan 100 mg once daily was present throughout the study. At Week 8, reductions from baseline in trough SeDBP, the primary endpoint of the trial, were significantly greater with irbesartan 300 mg compared with losartan 100 mg by 3.0 mm Hg (-11.7 vs -8.7 mm Hg) (p <0.01). The difference in SeDBP between these two groups was also statistically significant at Weeks 1 (p <0.01) and 4 (p <0.02). Irbesartan 150 mg produced overall changes in SeDBP comparable to losartan 100 mg.

60. Dose Response With Irbesartan/HCTZ Combination Therapy and Components Dose Response With Irbesartan/HCTZ Combination Therapy and Components A 12-week randomized, parallel group, placebo-controlled study of 815 patients with mild-to-moderate hypertension (SeDBP 95-110 mm Hg) found that reductions in seated and standing DBP with an irbesartan/HCTZ combination regimen were superior to placebo and to each of the individual components (left panel) [Weber et al, 1998]. The reduction in SeDBP was increased from -8.2 mm Hg on HCTZ 12.5 mg to -9.7 mm Hg on irbesartan 150 mg, and to -12.0 mm Hg on the combination of irbesartan 150 mg/HCTZ 12.5 mg. The additional reductions in SeDBP with irbesartan/HCTZ combination therapy were significant when compared with either of the components as monotherapy (p<0.01 vs irbesartan or HCTZ monotherapy). In a separate 8-week trial, 683 patients with mild-to-moderate hypertension (SeDBP 95-110 mm Hg) received 16 different doses of the combination of irbesartan (37.5, 100 and 300 mg), HCTZ (6.25, 12.5 and 25 mg) or placebo [Kochar et al, 1999]. At the irbesartan 300 mg/HCTZ 12.5 mg dose, the mean change from baseline in trough SeSBP/SeDBP was -15.9/-15.0 mm Hg, exceeding the BP reductions obtained with either irbesartan or HCTZ monotherapy. A single daily dose of irbesartan/HCTZ combination therapy provides smooth 24-hour BP control with trough:peak ratios of 87% for placebo-adjusted ambulatory SBP (ASBP) and 108% for placebo-adjusted ADBP [Howe et al, 1999].Dose Response With Irbesartan/HCTZ Combination Therapy and Components A 12-week randomized, parallel group, placebo-controlled study of 815 patients with mild-to-moderate hypertension (SeDBP 95-110 mm Hg) found that reductions in seated and standing DBP with an irbesartan/HCTZ combination regimen were superior to placebo and to each of the individual components (left panel) [Weber et al, 1998]. The reduction in SeDBP was increased from -8.2 mm Hg on HCTZ 12.5 mg to -9.7 mm Hg on irbesartan 150 mg, and to -12.0 mm Hg on the combination of irbesartan 150 mg/HCTZ 12.5 mg. The additional reductions in SeDBP with irbesartan/HCTZ combination therapy were significant when compared with either of the components as monotherapy (p<0.01 vs irbesartan or HCTZ monotherapy). In a separate 8-week trial, 683 patients with mild-to-moderate hypertension (SeDBP 95-110 mm Hg) received 16 different doses of the combination of irbesartan (37.5, 100 and 300 mg), HCTZ (6.25, 12.5 and 25 mg) or placebo [Kochar et al, 1999]. At the irbesartan 300 mg/HCTZ 12.5 mg dose, the mean change from baseline in trough SeSBP/SeDBP was -15.9/-15.0 mm Hg, exceeding the BP reductions obtained with either irbesartan or HCTZ monotherapy. A single daily dose of irbesartan/HCTZ combination therapy provides smooth 24-hour BP control with trough:peak ratios of 87% for placebo-adjusted ambulatory SBP (ASBP) and 108% for placebo-adjusted ADBP [Howe et al, 1999].

61. Long-Term Therapeutic Response With Irbesartan/HCTZ-Based Regimens Long-Term Therapeutic Response With Irbesartan/HCTZ-Based Regimens In these same long-term extensions, irbesartan/HCTZ-based regimens resulted in normalization rates (SeDBP <90 mm Hg) of 75% to 85% and total responder rates (SeDBP <90 mm Hg or a reduction from baseline of ?10 mm Hg) of 81% to 91% [Raskin et al, 1999]. At all timepoints, most patients (>87%) were receiving irbesartan/HCTZ alone, without adjunctive therapies. At Month 12, the normalization and responder rates were 83% and 90%, respectively. Less than 1% of all patients were discontinued from the study due to poor BP control. Long-Term Therapeutic Response With Irbesartan/HCTZ-Based Regimens In these same long-term extensions, irbesartan/HCTZ-based regimens resulted in normalization rates (SeDBP <90 mm Hg) of 75% to 85% and total responder rates (SeDBP <90 mm Hg or a reduction from baseline of ?10 mm Hg) of 81% to 91% [Raskin et al, 1999]. At all timepoints, most patients (>87%) were receiving irbesartan/HCTZ alone, without adjunctive therapies. At Month 12, the normalization and responder rates were 83% and 90%, respectively. Less than 1% of all patients were discontinued from the study due to poor BP control.

62. Long-Term Therapeutic Response With Irbesartan- and Irbesartan/HCTZ-Based Regimens Long-Term Therapeutic Response With Irbesartan- and Irbesartan/HCTZ-Based Regimens The excellent long-term therapeutic response of irbesartan monotherapy and combination therapy based regimens was also documented in pooled data from 5 randomized, double-blind trials of irbesartan in 1006 patients with SeDBP 95-110 mm Hg [Littlejohn et al, 1999]. In these trials, open-label therapy began with irbesartan 75 mg monotherapy and was titrated to 300 mg at 2- to 4-week intervals. Adjunctive therapy, beginning with HCTZ, was added to achieve target BP (<140/<90 mm Hg). At Month 12, the mean reduction in SeSBP/SeDBP was -21.0/-15.8 mm Hg. The total responder (SeDBP <90 mm Hg or a reduction from baseline of ?10 mm Hg) and normalization rates (SeDBP <90 mm Hg) were 90% and 83%, respectively. Sixty-two percent of all patients were receiving irbesartan monotherapy. Only 9% of patients required adjunctive therapy with atenolol, amlodipine, or nifedipine. The BP response seen at 12 months was maintained for an additional 12 months of follow-up. Only 0.6% of patients were discontinued from the study due to poor BP control. Long-Term Therapeutic Response With Irbesartan- and Irbesartan/HCTZ-Based Regimens The excellent long-term therapeutic response of irbesartan monotherapy and combination therapy based regimens was also documented in pooled data from 5 randomized, double-blind trials of irbesartan in 1006 patients with SeDBP 95-110 mm Hg [Littlejohn et al, 1999]. In these trials, open-label therapy began with irbesartan 75 mg monotherapy and was titrated to 300 mg at 2- to 4-week intervals. Adjunctive therapy, beginning with HCTZ, was added to achieve target BP (<140/<90 mm Hg). At Month 12, the mean reduction in SeSBP/SeDBP was -21.0/-15.8 mm Hg. The total responder (SeDBP <90 mm Hg or a reduction from baseline of ?10 mm Hg) and normalization rates (SeDBP <90 mm Hg) were 90% and 83%, respectively. Sixty-two percent of all patients were receiving irbesartan monotherapy. Only 9% of patients required adjunctive therapy with atenolol, amlodipine, or nifedipine. The BP response seen at 12 months was maintained for an additional 12 months of follow-up. Only 0.6% of patients were discontinued from the study due to poor BP control.

65. ACE inhibitors improve survival in heart failure, but morbidity and mortality remain high Disadvantages of ACE inhibitors Incomplete inhibition of angiotensin II Significant incidence of cough Potential advantages of angiotensin II receptor antagonists Complete blockade of the renin angiotensin system at the receptor level Well tolerated ACE Inhibitors vs AIIRAs ACE inhibitors substantially improve exercise tolerance, symptoms, and survival of patients with heart failure; however, morbidity and mortality of heart failure remain unacceptably high [Cody, 1994; Garg et al, 1995]. The efficacy of ACE inhibitors may be limited by the production of Ang II by non-ACE pathways [Sweet et al, 1994; Wolny et al, 1997]. In some patients, the utility of ACE inhibitors may be limited by side effects (eg, cough) related to altered metabolism of bradykinin, prostaglandins, or substance P [Skidgel et al, 1987; Fogari et al, 1992]. Selective antagonism of AT1 receptors by AIIRAs should completely block the effects of Ang II independent of its pathway of production, and avoid some of the side effects of ACE inhibitors [Dickstein et al, 1995].ACE inhibitors substantially improve exercise tolerance, symptoms, and survival of patients with heart failure; however, morbidity and mortality of heart failure remain unacceptably high [Cody, 1994; Garg et al, 1995]. The efficacy of ACE inhibitors may be limited by the production of Ang II by non-ACE pathways [Sweet et al, 1994; Wolny et al, 1997]. In some patients, the utility of ACE inhibitors may be limited by side effects (eg, cough) related to altered metabolism of bradykinin, prostaglandins, or substance P [Skidgel et al, 1987; Fogari et al, 1992]. Selective antagonism of AT1 receptors by AIIRAs should completely block the effects of Ang II independent of its pathway of production, and avoid some of the side effects of ACE inhibitors [Dickstein et al, 1995].

66. In patients with mild-to-moderate heart failure, irbesartan added to conventional therapy, including ACE inhibitor, for 12 weeks: Tended to improve ETT, LVEF and heart size Reduced blood pressure without reflex tachycardia Reduced the need for supplemental diuretic Was well tolerated Addition of Irbesartan to ACE Inhibitor in Heart Failure: Conclusions In patients with mild-to-moderate heart failure, once-daily irbesartan added to conventional therapy for 12 weeks, including ACE inhibitors, tended to improve ETT, LV ejection fraction, and heart size, reduce blood pressure without reflex tachycardia, and reduce the need for supplemental diuretics [Tonkon M et al. Int J Clin Pract. 2000; 54: 11-18]. Irbesartan was well tolerated when added to an ACE inhibitor.In patients with mild-to-moderate heart failure, once-daily irbesartan added to conventional therapy for 12 weeks, including ACE inhibitors, tended to improve ETT, LV ejection fraction, and heart size, reduce blood pressure without reflex tachycardia, and reduce the need for supplemental diuretics [Tonkon M et al. Int J Clin Pract. 2000; 54: 11-18]. Irbesartan was well tolerated when added to an ACE inhibitor.

67. Management of High-Risk Patients With Hypertension and Type 2 Diabetes: Conclusions Hypertensive patients with type 2 diabetes and renal disease at very high risk for renal and CV complications Diabetic patients require lower thresholds for initiation of antihypertensive therapy and lower BP targets Various antihypertensive regimens shown to reduce CV events and slow the decline in renal function in hypertensive patients with diabetes Agents blocking the RAS may be most beneficial, although definitive proof lacking PRIME will demonstrate the CV and renal benefits of irbesartan in high-risk hypertensive patients with type 2 diabetes Relative importance of BP reduction vs unique benefits of AT1 blockade with irbesartan will be evaluated Management of High-Risk Patients With Hypertension and Type 2 Diabetes: Conclusions Patients with hypertension and type 2 diabetes are at very high risk for cardiovascular morbidity and mortality, and for the development of end-stage kidney disease [Epstein et al, 1992; Hypertension in Diabetes Study Group, 1993b]. The most common cause of death among hypertensive patients with diabetic nephropathy is from cardiovascular disease [Grundy et al, 1999]. All major hypertension guidelines stratify diabetic patients into the highest risk groups, and recommend lower thresholds for initiating antihypertensive therapy and lower BP goals (<130/85 mm Hg in JNC VI and WHO-ISH guidelines) [Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 1997; WHO-ISH Guidelines, 1999]. Large-scale clinical trials using different antihypertensive regimens (including diuretics, calcium channel blockers, and ACE inhibitors) have demonstrated significant reductions in cardiovascular morbidity and mortality in hypertensive diabetics and other high-risk populations, with tighter BP control providing better risk reductions [Curb et al, 1996; Hansson et al, 1998; UK Prospective Diabetes Study 38, 1998; Tuomilehto et al, 1999; Hansson et al, 1999; HOPE Study Investigators, 2000]. Antihypertensive therapy also slows the rate of declining renal function in hypertensive patients with diabetic nephropathy (Lewis et al, 1993; Parving et al, 1993; Kasiske et al, 1993; Ismail et al, 1999). Data suggest that agents blocking the RAS may provide the greatest renal and cardiovascular protection in hypertensive diabetic patients, although definitive proof as to which is most important, BP reduction or the class of antihypertensive agent used, is currently lacking. Due to the consistency of the data with ACE inhibitors, current hypertension guidelines recommend RAS blockade as important first-line therapy for the management of the hypertensive diabetic patient [Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 1997]. Irbesartan is a once-daily AIIRA that provides antihypertensive efficacy comparable to ACE inhibitors, with superior tolerability [Larochelle et al, 1997; Mimran et al, 1998]. PRIME, an important morbidity and mortality program encompassing the IDNT and IRMA II study, is expected to demonstrate the beneficial effects of irbesartan in reducing cardiovascular events and slowing the progression of renal disease in high-risk hypertensive patients with type 2 diabetes [Rodby et al. Nephrol Dial Transplant. 2000; 15:487-497]. PRIME will provide the first hard endpoint data in patients with type 2 diabetic nephropathy, and will directly investigate whether irbesartan provides a greater reduction in cardiovascular risk, for the same reduction in BP, than other classes of antihypertensive agents. Management of High-Risk Patients With Hypertension and Type 2 Diabetes: Conclusions Patients with hypertension and type 2 diabetes are at very high risk for cardiovascular morbidity and mortality, and for the development of end-stage kidney disease [Epstein et al, 1992; Hypertension in Diabetes Study Group, 1993b]. The most common cause of death among hypertensive patients with diabetic nephropathy is from cardiovascular disease [Grundy et al, 1999]. All major hypertension guidelines stratify diabetic patients into the highest risk groups, and recommend lower thresholds for initiating antihypertensive therapy and lower BP goals (<130/85 mm Hg in JNC VI and WHO-ISH guidelines) [Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 1997; WHO-ISH Guidelines, 1999]. Large-scale clinical trials using different antihypertensive regimens (including diuretics, calcium channel blockers, and ACE inhibitors) have demonstrated significant reductions in cardiovascular morbidity and mortality in hypertensive diabetics and other high-risk populations, with tighter BP control providing better risk reductions [Curb et al, 1996; Hansson et al, 1998; UK Prospective Diabetes Study 38, 1998; Tuomilehto et al, 1999; Hansson et al, 1999; HOPE Study Investigators, 2000]. Antihypertensive therapy also slows the rate of declining renal function in hypertensive patients with diabetic nephropathy (Lewis et al, 1993; Parving et al, 1993; Kasiske et al, 1993; Ismail et al, 1999). Data suggest that agents blocking the RAS may provide the greatest renal and cardiovascular protection in hypertensive diabetic patients, although definitive proof as to which is most important, BP reduction or the class of antihypertensive agent used, is currently lacking. Due to the consistency of the data with ACE inhibitors, current hypertension guidelines recommend RAS blockade as important first-line therapy for the management of the hypertensive diabetic patient [Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, 1997]. Irbesartan is a once-daily AIIRA that provides antihypertensive efficacy comparable to ACE inhibitors, with superior tolerability [Larochelle et al, 1997; Mimran et al, 1998]. PRIME, an important morbidity and mortality program encompassing the IDNT and IRMA II study, is expected to demonstrate the beneficial effects of irbesartan in reducing cardiovascular events and slowing the progression of renal disease in high-risk hypertensive patients with type 2 diabetes [Rodby et al. Nephrol Dial Transplant. 2000; 15:487-497]. PRIME will provide the first hard endpoint data in patients with type 2 diabetic nephropathy, and will directly investigate whether irbesartan provides a greater reduction in cardiovascular risk, for the same reduction in BP, than other classes of antihypertensive agents.

68. Defining the problem… HRT is one of the most prevalent and powerful contributors to cardiovascular disease (affects about 20% of adults) there’s no evidence of a decline in the prevalence of HRT HRT clusters with dyslipidemia, insulin resistance, glucose intolerance, and obesity (in isolation in less than 20%) Kannel WB JAMA 275;24 May 1996

69. Antihypertensive treatment for the future Duration of action which is appropriate for once-daily administration High trough:peak ratio which is consistent over the recommended dosage range Maintenance of control of blood pressure fully and consistently throughout 24 h Maintenance of control of blood pressure beyond 24 h despite poor compliance with treatment No increases in blood pressure variability Based on the results of recent studies, an optimal approach to the treatment of hypertension should include an agent that: has a long duration of action, appropriate for once-daily administration; maintains control of blood pressure fully and consistently throughout a 24-h period; maintains control of blood pressure beyond 24 h despite poor compliance with treatment; produces smooth antihypertensive activity with reduced blood pressure variability in order to minimise target organ damage (Meredith et al, 1995). Meredith PA, Perloff D, Mancia G, Pickering T. Blood pressure variability and its implications for antihypertensive therapy. Blood pressure 1995; 4: 5-11. Based on the results of recent studies, an optimal approach to the treatment of hypertension should include an agent that: has a long duration of action, appropriate for once-daily administration; maintains control of blood pressure fully and consistently throughout a 24-h period; maintains control of blood pressure beyond 24 h despite poor compliance with treatment; produces smooth antihypertensive activity with reduced blood pressure variability in order to minimise target organ damage (Meredith et al, 1995). Meredith PA, Perloff D, Mancia G, Pickering T. Blood pressure variability and its implications for antihypertensive therapy. Blood pressure 1995; 4: 5-11.

70. Antihypertensive treatment for the future Additional benefit may be offered by a profile of pharmacological activity which can augment the benefits of blood pressure reduction interference with the early stages of the atherosclerotic process ‘protection’ against renal damage Once optimal blood pressure has been achieved it may then be possible to discern the additional benefit offered by a hypertensive agent that has a pharmacological profile that can augment the benefits of blood pressure reduction including: interference with the early stages of the atherosclerotic process; protection against renal damage.Once optimal blood pressure has been achieved it may then be possible to discern the additional benefit offered by a hypertensive agent that has a pharmacological profile that can augment the benefits of blood pressure reduction including: interference with the early stages of the atherosclerotic process; protection against renal damage.