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Clinical Trials in Hypertension and Renal Diseases
Placebo + Other Antihypertensive Therapy (excluding ACEI, AIIA) Maintain prior antihypertensive therapy (excluding ACEI, AIIA) Los 100 mg + Other Antihypertensive Therapy Los 100 mg Goal BP < 140/90 mmHg n = 1520 Los 50 mg Placebo NIDDM Patients with proteinuria Clinical Trials in Hypertension and Renal Diseases Clinical Trials in Hypertension and Renal Diseases Hypertension and renal parenchymal disease are closely interrelated. Primary renal diseases eventually disrupt sodium and volume control to produce clinical hypertension. Activation of the renin-angiotensin system, adrenergic nervous system and endothelin can enhance vasoconstriction and mediate tissue injury by the promotion of inflammatory cytokines and interstitial fibrosis. Arterial hypertension accelerates renal disease and hastens the progression to end stage renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of many forms of renal parenchymal injury, particularly those characterized by massive proteinuria. Damage to the heart and cardiovascular system from prolonged hypertension represents the major cause of morbidity and mortality for patients with end stage renal disease.
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The Dual Significance of Proteinuria
Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is associated with progressive kidney disease In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albuminuria) is associated with increased cardiovascular risk The Dual Significance of Proteinuria In patients with proteinuric renal diseases the rate of progression of renal insufficiency is determined by the level of blood pressure and proteinuria. The reduction of blood pressure and proteinuria has a beneficial impact on renal risk. Observational studies have also demonstrated that proteinuria is a marker for systemic vascular injury. It is hoped that efforts to reduce proteinuria and control blood pressure will improve cardiovascular risk and reduce mortality. In this belief, the National Kidney Foundation and the American Diabetes Association have revised their recommendations for management of high-risk patients for tighter blood pressure control to <130/80. References: Agarwal R. Treatment of hypertension in patients with diabetes: lessons from recent trials. Cardiol Rev. 2001;9(1):36-44. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3): Bianchi S, Bigazzi R, Campese VM. Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis. 1999;34(6): Keane WF. Proteinuria: its clinical importance and role in progressive renal disease. Am J Kidney Dis. 2000;35(4suppl1):S97-S105. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):
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Renal Disease and Hypertension Core Concepts of Treatment
Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and consequence of hypertension Reduction of blood pressure reduces cardiovascular risk and renal risk Reduction of proteinuria (albuminuria) may lower both cardiovascular risk and renal risk Renal Disease and Hypertension Core Concepts of Treatment Blood pressure levels are reliable predictors of renal outcome. Both absolute systolic and diastolic blood pressures correlate with the risk of renal damage. African Americans may be at greater risk compared to other racial/ethnic groups. In patients with renal disease, blood pressure reduction clearly effects renal outcome. In both diabetic and non-diabetic patients blood pressure reduction provides greater protection of renal function. The absolute level of blood pressure reduction is important. The initial stages of effective blood pressure control can produce a relative hypoperfusion of the kidneys and a transient increase in serum creatinine. But, clinicians can become alarmed by this rise in serum creatinine and inappropriately withdraw anti-hypertensive therapy rather than waiting several weeks for the serum creatinine to stabilize and/or decline. References: Agarwal R. Treatment of hypertension in patients with diabetes: lessons from recent trials. Cardiol Rev. 2001;9(1):36-44. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3): Bianchi S, Bigazzi R, Campese VM. Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis. 1999;34(6): Keane WF. Proteinuria: its clinical importance and role in progressive renal disease. Am J Kidney Dis. 2000;35(4suppl1):S97-S105. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):
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Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics 95 98 101 104 107 110 113 116 119 r = 0.69; P < 0.05 MAP (mmHg) GFR (mL/min/year) 130/85 140/90 Untreated HTN -2 -4 -6 -8 -10 -12 -14 Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics Hypertension and renal parenchymal disease are closely interrelated. Arterial hypertension accelerates renal disease and hastens the progression to end stage renal failure. Recent studies have firmly established the importance of blood pressure reduction as a means to slow the progression of different forms of renal parenchymal injury. For diabetic or non-diabetic nephropathy, the higher the blood pressure the greater the renal risk. The beneficial impact from achieved control of mean arterial pressure (MAP) is demonstrated in this slide, which shows a meta-analysis of the 9 major clinical trials in diabetic and non-diabetic renal diseases. The GISEN Group, Klahr, and Moschio studies are those in non-diabetic subjects. The higher the MAP the faster the GFR declines; the better the control of MAP the slower the GFR declines. References: Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blocker on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29(3): Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): Herbert LA, Bain RP, Verme D, Cattran D, Whittier FC, Tolchin N, Rohde RD, Lewis EJ. Remission of nephrotic range proteinuria in type 1 diabetes. Collaborative Study Group. Kidney Int. 1994;46(6): Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure. N Eng J Med. 1994;330(13): Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM:Role of baseline albuminuria. Kidney Int Suppl. 1994;Suppl 45: Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ. 1989;299(6698): Viberti G, Morgensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994;271(4): Parving HH, et al. Br Med J Moschio G, et al. N Engl J Med Viberti GC, et al. JAMA Bakris GL, et al. Kidney Int Klahr S, et al. N Eng J. Med Bakris GL. Hypertension Hebert L, et al. Kidney Int The GISEN Group. Lancet Lebovitz H, et al. Kidney Int Bakris GL, et al. Am J Kidney Dis. 2000;36(3): Reprinted by permission from WB Saunders.
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Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics SBP (mmHg) 130 134 138 142 146 150 154 170 180 -2 r = 0.69; P < .05 -4 -6 GFR (mL/min/year) Untreated HTN -8 -10 Meta Analysis: Lower Systolic BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics Like control of mean arterial blood pressure, lower systolic blood pressure results in slower rates of decline in glomerular filtration rate (GFR) in patients with diabetic and non-diabetic renal disease. The beneficial impact from achieved control of systolic blood pressure (SBP) is demonstrated in this slide, which shows a meta-analysis of the 9 major clinical trials in diabetic and non-diabetic renal diseases. The GISEN Group, Klahr, and Moschio studies are those in non-diabetic subjects. The higher the SBP, the faster the GFR declines; the better the control of SBP, the slower the GFR declines. References: Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blocker on the progression of diabetic nephropathy in African Americans. Hypertension. 1997;29(3): Bakris GL, Siomos M, Richardson D, et al. Comparative effects of an ACE inhibitor and an angiotensin receptor blocker on potassium homeostasis in high risk patients. Kidney Int. (in press). Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3): Herbert LA, Bain RP, Verme D, Cattran D, Whittier FC, Tolchin N, Rohde RD, Lewis EJ. Remission of nephrotic range proteinuria in type 1 diabetes. Collaborative Study Group. Kidney Int. 1994;46(6): Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal failure. N Eng J Med. 1994;330(13): Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM:Role of baseline albuminuria. Kidney Int Suppl. 1994;Suppl 45: Parving HH, Hommel E, Damkjaer Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ. 1989;299(6698): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): Viberti G, Morgensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994;271(4): -12 -14 Parving HH, et al. Br Med J Moschio G, et al. N Engl J Med Viberti GC, et al. JAMA Bakris GL, et al. Kidney Int Klahr S, et al. N Eng J Med Bakris GL. Hypertension Hebert L, et al. Kidney Int The GISEN Group. Lancet Lebovitz H, et al. Kidney Int Bakris GL, et al. Am J Kidney Dis. 2000;36(3):
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Goal BP Recommendations for Patients with DM or Renal Disease
Organization Year Systolic BP Diastolic BP American Diabetes Association 2001 <130 <80 National Kidney Foundation 2000 Canadian Hypertension Society 1999 British Hypertension Society <140 WHO & International Society of Hypertension <85 Joint National Committee (JNC VI) 1997 Goal BP Recommendations for Patients with DM or Renal Disease Since 1997, 6 international organizations have revised their recommendations for goal blood pressures in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 140/80 down to 125/75 mmHg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to <130/80 mmHg. References: American Diabetes Association: Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2001;24(suppl1):33-66. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3): Ramsay L, Williams B, Johnston G, MacGregor G, Poston L, Potter J, Poulter N, Russell G. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens. 1999;13(9): Feldman RD, Campbell N, Larochelle P, Bolli P, Burgess ED, Carruthers SG, Floras JS, Haynes RB, Honos G, Leenen FH, Leiter LA, Logan AG, Myers MG, Spence JD, Zarnke KB Canadian recommendations for the management of hypertension. Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension. CMAJ 1999;161(suppl12):S1-17. Chalmers J, MacMahon S, Mancia G, Whitworth J, Beilin L, Hansson L et al World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee of the World Health Organization. Clin Exp Hypertens. 1999;21(5-6): The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157(21):
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JNC-VI General Goals for BP Control
Pre-existing condition % achieved BP goals (mmHg) Essential Hypertension 27% <140/90 Diabetes 11% <130/85 Renal Disease and proteinuria >1.0 gram/24 h <10% <125/75 JNC-VI General Goals for BP Control In the 1997 Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, a stratification scheme for management of hypertensive patients was recommended. In particular, patients with diabetes mellitus, renal insufficiency and heart failure received special attention. These three categories of hypertensive subjects were recommended for drug therapy when BP was ≥130/85 mmHg. Since the JNC-VI report, Coresh et al have reported that only a small percentage of these patients have achieved goal blood pressures. References: Coresh J, Wei GL, McQuillan G, Brancati FL, Levey AS, Jones C, Klag MJ. Prevalence of high blood pressure and elevated serum creatinine levels in the United States: findings from the third National Health and Nutrition Examination Survey ( ). Arch Intern Med. 2001;161(9): The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997; 157(21): Coresh J, et al. Arch Intern Med. 2001;161(9):
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Frequency of Proteinuria (Albuminuria) in the United States
Adults With Proteinuria Quantitation Total adults (in millions) % of adults in US Increased urine ratio albumin/creatinine (>30 mg/gm) 20.2 11.7 Proteinuria (>300mg/24h) 18.3 10.6 Microalbuminuria ( mg/24h) 1.9 1.1 Frequency of Proteinuria (Albuminuria) in the United States Microalbuminuria, proteinuria, and increased urine albumin to creatinine ratio are defined in this slide. Approximately 1% of the US population is estimated to have microalbuminuria, but 10-11% is believed to have proteinuria or an elevated urine albumin to creatinine ratio. Thus, a substantial portion of the US population is at risk of developing advanced renal disease. References: Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis. 1999;33(5): Keane WF, Eknoyan G. Am J Kidney Dis. 1999;33(5):
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Impact of Blood Pressure Reduction on Mortality in Diabetes
Trial Conventional care Intensive Risk reduction P-value UKPDS 154/87 144/82 32% 0.019 HOT 144/85 140/81 66% 0.016 Impact of Blood Pressure Reduction on Mortality in Diabetes Additional support for CV risk reduction in diabetes related to lower ranges of blood pressure values comes from two recent prospective trials. The Hypertension Optimal Treatment (HOT) trial was the first to show the benefit of a lower blood pressure goal in reducing CV events in the subgroup of people with diabetes. In this study, 1,501 diabetic patients were randomized to one of three diastolic blood pressure targets: <90 mmHg, <85 mmHg, or <80 mmHg. Initial anti-hypertensive therapy in this group was with the calcium channel blocker, felodipine; however, 73% of the people randomized to the lowest blood pressure group required approximately 2.7 different antihypertensive medications, and most participants in this group also received an ACE inhibitor. Those who achieved the lowest blood pressure goal experienced the lowest rate of CV events. The United Kingdom Prospective Diabetes Study (UKPDS) was the second study to show the long-term benefit of a lower-than-usual blood pressure goal for people with diabetes. In this study, 1,148 type 2 diabetics were randomized to one of two goal blood pressures [<150/85 mmHg (intensively treated group) or <180/105 mmHg (conventional group)]. Average blood pressures for both groups are shown on this slide. The differences were 5 mmHg in diastolic pressure and 10 mmHg in systolic pressure. Follow-up was an average of 8.4 years. Those randomized to the intensively treated group had 32% fewer deaths, 44% fewer strokes, 24% fewer diabetes-related endpoints (including amputations), and 37% fewer microvascular complications (including retinal hemorrhages). In the HOT trial, there was also a 4-mmHg difference in the achieved diastolic blood pressure between the intensively treated group and other target groups (84.6 versus 81 mmHg). However, these small reductions in blood pressure in both trials resulted in a significantly lower CV event rate and a greater preservation of renal function. References: Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351(9118): Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317(7160): Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160): Mortality endpoints are: UK Prospective Diabetes Study (UKPDS) – “diabetes related deaths” Hypertension Optimal Treatment (HOT) Study – “cardiovascular deaths” in diabetics Turner RC, et al. BMJ. 1998;317: Hansson L, et al. Lancet. 1998;351:1755–1762.
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Better blood pressure control reduces…
UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions Better blood pressure control reduces… Strokes by > one third Serious deterioration of vision by > one third Death related to diabetes by one third Better glucose control reduces… Early kidney damage by one third Major diabetic eye disease by one fourth UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions The United Kingdom Prospective Diabetes Study (UKPDS) included an evaluation of baseline risk factors for macrovascular and microvascular complications in patients with type 2 diabetes mellitus. A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are: increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycemia, and smoking. The control of elevated blood pressure and elevated glucose can reduce, by up to a third, the risk for complications from diabetes. The specific end-organ benefits of blood pressure control and glucose control are shown on this slide. References: Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316(7134): Turner RC, et al. BMJ. 1998;317:
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Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS
Stroke Any Diabetic Endpoint DM Deaths Microvascular Complications 5% 10% -10 12% -20 24% % Reduction In Relative Risk * -30 32% 32% Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS A comparison of tight glucose control, HbA1c=7% (achieved was 8.2%) vs tight blood pressure control <150/85 mmHg (achieved 144/82 mmHg) revealed that blood pressure reduction contributed to a greater extent to the relative reduction of cardiovascular events. References: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160): Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160): * 37% *P <0.05 compared to tight glucose control * -40 44% Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL) Tight BP Control (Average 144/82 mmHg) * -50 Bakris GL, et al. Am J Kidney Dis. 2000;36(3): Reprinted by permission from WB Saunders.
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UKPDS: Relationship Between BP Control And Diabetes-Related Deaths
17% decrease per 10 mmHg decrement in BP p<0.0001 . 5 1 2 3 4 6 7 Hazard ratio UKPDS: Relationship Between BP Control And Diabetes-Related Deaths In patients with type 2 diabetes, the risk of diabetic complications is strongly associated with raised blood pressure. UKPDS determined the relationship over time between systolic blood pressure and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. This was a prospective observational study in 23 hospital-based clinics in England, Scotland, and Northern Ireland. There were 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients included in analyses of incidence and 3642 were included in analyses of relative risk. The primary predefined aggregate clinical outcome was any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes were myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Risk reduction associated with a 10 mmHg decrease in updated mean systolic blood pressure adjusted for specific confounders. The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mmHg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 17% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure <120 mmHg. Reference: Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000; 321(7258): Mean systolic blood pressure (mmHg) Adler AI, et al. BMJ. 2000;321: Reprinted by permission, BMJ Publishing Group.
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HOT Trial: BP Control Reduces Cardiovascular Events in Diabetics
30 25 20 15 10 5 P < .005 24.4 18.6 11.9 Diabetes Subgroup Target Diastolic BP (mmHg) Number of Patients Achieved† Systolic BP Diastolic 90 501 143.7 85.2 85 141.4 83.2 80 499 139.7 81.1 † Achieved = Mean of all BPs from 6 months of follow-up to end of study Major CV events* 1000 patient-yrs HOT Trial: BP Control Reduces Cardiovascular Events in Diabetics The Hypertension Optimal Treatment (HOT) trial demonstrated fewer cardiovascular events with tighter control of diastolic blood pressure in patients with diabetes. Target goals and achieved levels of diastolic blood pressure are depicted on the right portion of the slide. One objective of the HOT trial was to assess the optimum target diastolic blood pressure in the treatment of hypertension. In the subgroup of patients with diabetes there was a 51% reduction in major cardiovascular events in target group <80 mmHg compared with target group <90 mmHg (P=.005). Reference: Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118): *includes all myocardial infarction, all strokes, and all other CV deaths Hansson L, et al. Lancet. 1998;351:1755–1762.
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Landmark ACE Inhibitor Trials in Diabetics
Study Drug N Dosing Study years Endpoint P-value Lewis Captopril 409 25 mg tid ~ 3 Doubling of serum creatinine P=0.007 Lebovitz Enalapril 165 5-40 mg qd Correlation of MAP w/ rate of change in GFR P=0.026 ABCD Trial 470 5 24-hr creatinine clearance NS Landmark ACE Inhibitor Trials in Diabetics Until recently, reductions in proteinuria had not been clearly associated with renal benefit. There are now numerous long-term clinical trials in patients who have lost >35% of their renal function, with or without diabetes, demonstrating that reductions in proteinuria of >30% below baseline correlate with marked reductions in renal disease progression. The 3 landmark trials in diabetes are shown on this slide. References: Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338(10): Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl2):B54-64. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): Lebovitz HE, Wiegmann TB, Cnaan A, Shahinfar S, Sica DA, Broadstone V, Schwartz SL, Mengel MC, Segal R, Versaggi JA, et al. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int Suppl. 1994;45:S150-S155. ABCD = Appropriate Blood Pressure Control in Diabetes Trial Lewis EJ, et al. N Engl J Med. 1993;329(20): Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155. Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.
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ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes
100 75 50 25 Baseline creatinine >1.5 mg/dL % with doubling of baseline creatinine Placebo n=202 P<.001 ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes In this landmark trial by Lewis et al, the study design was a randomized, controlled trial in patients with type 1 diabetes who were treated with captopril (n=207) or placebo (n=202). Those assigned to captopril received 25 mg tid, and those assigned to the control group received placebo tid. Entry criteria included urinary protein excretion of >500 mg/day and serum creatinine <2.5 mg/dL. Blood-pressure goals were defined to achieve control during a median follow-up of three years. The recommended dietary protein intake was 1 g/kg of body weight per day. The primary end point was a doubling of the base-line serum creatinine concentration. As shown, the number of patients who experienced a doubling of baseline serum creatinine was reduced significantly (p<0.001) with captopril. Reference: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): Captopril n=207 1 2 3 4 Years of follow-up Lewis EJ, et al. N Engl J Med. 1993;329(20): Copyright © 1993 Massachusetts Medical Society. Adapted with permission.
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ACE-I Is More Renoprotective than Conventional Therapy in Type 1 Diabetes
40 20 -20 -40 -60 2 -4 -6 -8 P<.001 Decrease in mean arterial pressure (mmHg) % change in proteinuria ACE-I Is More Renoprotective than Conventional Therapy in Type 1 Diabetes In this landmark trial by Lewis et al, the study design was a randomized, controlled trial in patients with type 1 diabetes who were treated with captopril (n=207) or placebo (n=202). Those assigned to captopril received 25 mg tid, and those assigned to the control group received placebo tid. Entry criteria included urinary protein excretion of >500 mg/day and serum creatinine <2.5 mg/dL. Blood-pressure goals were defined to achieve control during a median follow-up of three years. The recommended dietary protein intake was 1 g/kg of body weight per day. The primary end point was a doubling of the base-line serum creatinine concentration. The number of patients who experienced a doubling of baseline serum creatinine was reduced significantly (p<0.001) with captopril. As shown on this slide, this benefit was accompanied by a similar improvement in proteinuria. But, the average blood pressure reductions for both captopril and placebo were nearly identical. Thus, the benefit from captopril treatment is not related solely to the reduction in blood pressure; inhibition of the renin-angiotensin system and reduction of proteinuria play an important role. Reference: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): NS Placebo Captopril Placebo Captopril Lewis EJ, et al. N Engl J Med. 1993;329(20):
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# patients with final proteinuria
Relationship of Achieved Mean Arterial Pressure to Parameters of Renal Function in Type 1 Diabetes Mean arterial pressure (mmHg)* n Final total proteinuria(mg/24h) Serum creatinine (mg/dL) GFR (mL/min) # patients with final proteinuria <500 mg/24h < 92 47 1, ,535† (418) +0.14† -5.2† 27 92.1–99.9 41 1, ,701 (1,798) +0.38 -6.2 11 100–107 32 4, ,754 (2,659) -11.6 2 107.1 6 4, ,878 (5,825) +0.92 -11.0 Relationship of Achieved Mean Arterial Pressure to Parameters of Renal Function in Type 1 Diabetes One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy, who had previously participated in the ACE-I in Diabetic Nephropathy Study (Lewis EJ et al. N Engl J Med. 1993; 329: ), and had a serum creatinine level <4.0 mg/dL, participated in this study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving ACE inhibitor (ramipril). Patients were randomly assigned to a goal of mean arterial blood pressure (MAP) ≤92 mm Hg (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary anti-hypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). As shown in columns 5 and 6 on this data slide, 32% of 126 patients achieved a final total protein excretion <500 mg/24 hrs. The patient subgroup that achieved MAP ≤92 mmHg had the greatest frequency of total protein excretion <500 mg/24 hrs and lowest rate of decline in GFR. Reference: Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ.Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group. Am J Kidney Dis. 1999;34(5): Note: Values expressed as mean + SD. Data based on achieved blood pressures, not randomized blood pressure goals. *Mean of all pressure readings observed during the trial for each patient. † P < 0.05 when < 92 group is compared with these patients with MAP >92.1 mmHg. Reprinted from Lewis JB, et al. Am J Kidney Dis. 1999;34(5): with permission from National Kidney Foundation.
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Impact of ACE-I on BP and GFR: Acute and Chronic Effects
* GFR ml/min/1.73m2 * * * * Impact of ACE-I on BP and GFR: Acute and Chronic Effects In this study, patients with diabetic nephropathy given the ACEI lisinopril had from a 1% to 9% fall in GFR at 1 month following treatment initiation. Between 1 month and 5 years, the GFR remained stable without further decline. The range of mean arterial pressure achieved in this study was 99 to 105 mmHg. After an average of 5 years of ACEI therapy, patients were withdrawn from the ACEI treatment, and clonidine was substituted to maintain blood pressure control. The GFR returned to levels not different from baseline within 1 month of ACEI termination, despite similar blood pressure control. This study further supports the concept that while GFR may be reduced acutely, one can markedly blunt the rate of progression of renal disease with ACEIs. Also, these initial ACEI associated declines in GFR are reversible and partially independent of systemic arterial pressure. Reference: Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160(5): *P<0.05 compared to baseline Bakris GL, Weir MR. Arch Intern Med. 2000;160(5): ©American Medical Association
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Urinary Albumin Excretion
ARB (Losartan) Reduces Urinary Albumin and TGF-1 in Type 2 Diabetes with Microalbuminuria 160 100 24-hour Systolic BP P<0.01 vs baseline Urinary Albumin Excretion P<0.01 vs baseline 90 140 80 mcg/min mmHg 70 130 60 120 50 90 6 24-hour Diastolic BP P<0.03 vs baseline TGF- P<0.005 vs baseline 5 80 ARB (Losartan) Reduces Urinary Albumin and TGF-1 in Type 2 Diabetes with Microalbuminuria In this study of type 2 diabetes with microalbuminuria, systolic and diastolic blood pressure fell equivalently with losartan following 4 and 8 weeks of treatment, as did urine albumin excretion and plasma levels of TGF-β, the profibrotic cytokine. Reference: Esmatjes E, Flores L, Inigo P, Lario S, Ruilope LM, Campistol JM. Effect of losartan on TGF-beta1 and urinary albumin excretion in patients with type 2 diabetes mellitus and microalbuminuria. Nephrol Dial Transplant. 2001; 16(suppl1):90-93. ng/mL 4 mmHg 3 70 2 1 60 Baseline 4 Weeks 8 Weeks Baseline 4 Weeks 8 Weeks Esmatjes E, et al. Nephrol Dial Transplant. 2001;16(Suppl1):90-93.
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Endpoint significance
Landmark Trials in Diabetics and Non-Diabetics with ESRD/Death as an Endpoint Trial Year Endpoint significance Achieved BP Captopril 1993 P=0.007 141/82 AIPRI 1996 P<0.001 139/82 REIN 1997 P=0.03 142/84 RENAAL 2001 P=0.01 142/77 IDNT results pending Landmark Trials in Diabetics and Non-Diabetics with ESRD/Death as an Endpoint Lewis et al showed that patients with type I diabetes and nephrotic range proteinuria had their renal function stabilized after prolonged treatment with ACE inhibitors, which also resulted in proteinuria dropping into subclinical ranges. In the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study (AIPRI), the risk of doubling the serum creatinine concentration in these 583 non-diabetic patients was lowered by using benazepril to achieve better blood pressure control as compared with using conventional anti-hypertensive therapy. The Ramipril Efficacy in Nephropathy (REIN) study randomized 352 non-diabetic patients with chronic proteinuric nephropathies to ACE inhibition or conventional therapy with the aim of achieving a comparable blood pressure control in the two groups. Results showed that in patients who had rapid progression of renal disease, and proteinuria >3 grams/24 hours at baseline, ACE inhibition safely lowered the rate of decline in GFR and reduced by half the combined risk of doubling serum creatinine or progressing to end stage renal disease. These effects were accompanied by a substantial lowering of the urinary protein excretion rate, which exceeded what can be expected from the degree of blood pressure reduction. In addition, the REIN follow-up study showed that GFR became almost stable in patients who actively stayed on the drug more than 3 years. Results from two pivotal clinical trials - Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Receptor Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT) - with 2 angiotensin II receptor antagonists (Losartan and Irbesartan, respectively) are just emerging, as yet without their first peer reviewed publications, to demonstrate similar renal benefits for type 2 diabetics. References: Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000;35(6): Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334(15): Hannedouche TP, Natov S, Boitard C, Lacour B, Grunfeld JP. Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal dysfunction in type 1 diabetes. Nephrol Dial Transplant. 1996;11(4): Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): Lewis EJ, et al. N Engl J Med. 1993;329(20): Maschio G, et al. N Engl J Med. 1996;334(15): The GISEN Group. Lancet. 1997;349:1857–1863.
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Landmark Renal Trials in Non-Diabetics with ACE Inhibitors
Study Drug Dosing Survival Benefit Study Duration AIPRI Benazepril 10-20 mg qd P<0.001 ~3.0 years REIN Ramipril 5-10 P=0.03 ~ 3.5 years Landmark Renal Trials in Non-Diabetics with ACE Inhibitors In the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study (AIPRI) the risk of doubling the serum creatinine concentration in these 583 patients was lowered by using benazepril to achieve better blood pressure control as compared with using conventional anti-hypertensive therapy. The Ramipril Efficacy in Nephropathy (REIN) study randomized 352 non-diabetic patients with chronic proteinuric nephropathies to ACE inhibition or conventional therapy with the aim of achieving a comparable blood pressure control in the two groups. Results showed that in patients who had rapid progression of renal disease and proteinuria >3 grams/24 hours at baseline, ACE inhibition safely lowered the rate of decline in GFR, and reduced by half the combined risk of doubling serum creatinine or progressing to end stage renal disease. These effects were accompanied by a substantial lowering of the urinary protein excretion rate, which exceeded what can be expected from the degree of blood pressure reduction. In addition, the REIN follow-up study showed that GFR became almost stable in patients who actively stayed on the drug more than 3 years. References: Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334(15): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): AIPRI = ACE Inhibition in Progressive Renal Insufficiency Study REIN = Ramipril Efficacy In Nephropathy Study Maschio G, et al. N Engl J Med. 1996;334(15): The GISEN Group. Lancet. 1997;349:
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24-Hr Urine Protein Excretion
AIPRI: Baseline Prognostic Factors and Reduction of Risk for Progressive Renal Insufficiency with ACE-I Creatinine Clearance 24-Hr Urine Protein Excretion >45 ml/min ≤45 ml/min ≤1gm >1 to <3gm ≥3gm 31% 46% AIPRI: Baseline Prognostic Factors and Reduction of Risk for Progressive Renal Insufficiency with ACE-I In the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency Study (AIPRI), Benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases. Drugs that inhibit ACE had been shown to slow the progression of renal insufficiency in patients with diabetic nephropathy. AIPRI was the first study to confirm that these drugs have a similar action in patients with other renal diseases. In a three-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (n=192), interstitial nephritis (n=105), nephrosclerosis (n=97), polycystic kidney disease (n=64), diabetic nephropathy (n=21), and miscellaneous or unknown disorders (n=104). The severity of renal insufficiency was classified according to the base-line creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, mL/min), and 356 had moderate insufficiency (creatinine clearance, mL/min). The primary end point was a doubling of the baseline serum creatinine concentration or the need for dialysis. At three years, 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P<0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53% overall with 71% among the patients with mild renal insufficiency, and 46% among those with moderate renal insufficiency. The reduction in risk was greatest among the male patients; those with glomerular diseases, diabetic nephropathy, or miscellaneous or unknown causes of renal disease; and those with baseline urinary protein excretion >1 g per 24 hours. Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5 to 5.0 mmHg in the benazepril group and increased by 0.2 to 1.5 mmHg in the placebo group. Reference: Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334(15): 53% 66% 71% Maschio G, et al. N Engl J Med. 1996;334(15):
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REIN Study: ACE Inhibition in Proteinuric Non-Diabetic Nephropathy
100 80 60 40 20 Ramipril % of patients without combined endpoint* P=0.02 Placebo REIN Study: ACE Inhibition in Proteinuric Non-Diabetic Nephropathy The Ramipril Efficacy In Nephropathy (REIN) study is the second clinical trial to confirm that ACE inhibitors have a similar action in patients with chronic non-diabetic nephropathies. In chronic nephropathies with proteinuria of ≥3 grams/24 hrs, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood pressure lowering. In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1-3 grams/24-hrs; stratum 2: ≥3 grams/24-hrs), and randomly assigned ramipril or placebo plus conventional anti-hypertensive therapy targeted at achieving diastolic blood pressure <90 mmHg. The primary end point of intent-to-treat analysis was the rate of GFR decline. At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p=0.001). The Independent Adjudicating Panel therefore decided to open the randomization code and do the final analysis in this stratum (stratum 1 continued in the trial). Data analysis for 56 ramipril-assigned patients and 61 placebo-assigned patients showed the decline in GFR per month was significantly lower in the ramipril group than the placebo group (0.53 vs 0.88 mL/min, p=0.03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with decline in GFR (p=0.035) and predicted the reduction in risk of doubling of baseline creatinine or end stage renal failure (18 ramipril vs 40 placebo, p=0.04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p=0.04) and diastolic (p=0.04) blood pressure, but not after adjustment for changes in proteinuria. Blood pressure control and the overall number of cardiovascular events were similar in the two treatment groups. Reference: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): 6 12 18 24 30 36 Baseline SBP ∆ SBP Baseline DBP ∆ DBP Ramipril 149.8 -5.8 mmHg 92.4 -4.2 mmHg Placebo 148.0 -3.4 mmHg 91.3 *Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.
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REIN Study: ACE Inhibition in Proteinuric Non-Diabetic Nephropathy
Mean rate of GFR decline (mL/min/month) 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Baseline urinary protein excretion (g/24 h) n = 61 3–4.5 n = 36 4.5–7.0 n = 20 7.0 of baseline Cr or ESRD % pts with doubling 70 60 50 40 30 20 10 Baseline urinary protein excretion (g/24 h) n = 87 3–4.5 n = 48 4.5–7.0 n = 31 7.0 Placebo Ramipril REIN Study: ACE Inhibition in Proteinuric Non-Diabetic Nephropathy In the Ramipril Efficacy In Nephropathy (REIN) study, early (1 month after randomization) percentage reduction in urinary protein excretion from baseline was inversely correlated with long-term (≥6 months after randomization) rate of GFR decline in the ramipril treatment group. A higher rate of baseline urinary protein excretion was associated with a more rapid mean GFR decline in the placebo than in the ramipril group, and with a larger difference in the mean rate of GFR decline between the two treatment groups. References: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354(9176): Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000;35(6): Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.
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REIN Study: Ramipril Group Median Change in Urinary Protein Excretion
Months % change in urinary protein excretion REIN Study: Ramipril Group Median Change in Urinary Protein Excretion In the Ramipril Efficacy In Nephropathy (REIN) study, urinary protein excretion significantly decreased (p<0.01) by month 1 in the ramipril group, and remained lower than baseline throughout the study period. Compared with baseline, median percentage changes in urinary protein excretion were -23%, -35%, -23%, -33%, -50%, and -55% at 1, 3, 6, 12, 24, and 36 months, respectively. Urinary protein excretion did not change significantly in the placebo group. The change in urinary protein excretion rate after randomization differed significantly between the two treatment groups (p=0.002). References: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069): Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354(9176): Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000;35(6): The GISEN Group. Lancet. 1997;349:1857–1863.
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ACE inhibitors (ACE-I)
ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy Study Year Conclusions about ACE inhibitors (ACE-I) Bjork et al 1992 ACE-I reduced both the rate of decline in GFR and the amount of albuminuria. Lewis et al 1993 In Type I diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. REIN 1997 In non-diabetics, ACE-I reduced proteinuria, risk of doubling serum creatinine, and risk of ESRD+Death. But, ESRD alone was not reduced. MicroHOPE 2000 ACE-I reduced progression of proteinuria from normoalbuminuria to microalbuminuria and from microalbuminuria to macroalbuminuria. AASK 2001 ACE-I was superior to amlodipine in reducing proteinuria among non-diabetic African Americans with hypertension and kidney disease. ACE-I Provides Greater Renoprotection Than Non-ACE-I in Patients with Diabetic and Non-Diabetic Nephropathy With respect to renoprotection, both diabetic and non-diabetic patients benefit when the actions of angiotensin II are inhibited. ACE inhibition reduces the risk of doubling of serum creatinine and the combined endpoint of end stage renal disease (ESRD) and death. There is also decreased progression of proteinuria from normoalbuminuria to microalbuminuria, and from microalbuminuria to macroalbuminuria. Furthermore, it appears that the ability to prescribe drugs that inhibit the actions of angiotensin II yields superior outcomes compared to other drugs that act through calcium channel blockade or through beta blockade. References: Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001; 285(21): Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M. Renal protective effect of enalapril in diabetic nephropathy. BMJ. 1992;304(6823): Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet Jan 22;355(9200):253-9. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal failure in proteinuric, non-diabetic nephropathy. The GISEN group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):
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AASK: The African American Study of Kidney Disease and Hypertension
The AASK trial enrolled 1,094 African American patients with renal disease at 21 US centers, and randomized them to receive one of 3 study drugs: Ramipril – ACEI or Amlodipine – CCB or Metoprolol – Beta-blocker Results After adjustments for covariates, the risk reduction for ramipril vs amlodipine groups in the clinical composite outcomes (GFR, dialysis, or death) was 38% (p=0.005) AASK: The African American Study of Kidney Disease and Hypertension African Americans are a high risk group for renal failure. They comprise 12% of the total population, but 33% of all dialysis patients. Almost 1 in every 3 African Americans has high blood pressure, and when compared to whites, they are 7 times more likely to develop kidney disease. The burden of kidney failure caused by hypertension in African Americans is striking, with a rate 20 times higher among African Americans age years than among whites in the same age group. In an attempt to address these issues, the AASK trial enrolled 1,094 African American patients with renal disease at 21 US centers, and randomized them to receive an ACE inhibitor (ramipril), the dihydropyridine antagonist, amlodipine, or a beta-blocker (metoprolol). AASK is the first major study of kidney disease in this population. Interim results show a 1.6 fold relative risk with amlodipine vs ramipril for the combined event (decrease in GFR, dialysis, or death). Reference: Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA. 2001; 285(21): Agodoa L, et al. JAMA. 2001;285(21):
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HOPE TRIAL: Independent Predictive Variables for Combined Endpoints of CV Death, MI, and Stroke
Hazard Ratio Microalbuminuria 1.59 Creatinine > 1.4 mg/dL 1.40 CAD 1.51 PVD 1.49 Diabetes Mellitus 1.42 Male 1.20 Age 1.03 Waist-Hip Ratio 1.13 HOPE TRIAL: Independent Predictive Variables for Combined Endpoints of CV Death, MI, and Stroke A post hoc analysis was performed on data from the Heart Outcomes and Prevention Evaluation (HOPE) Study, a randomized, double-blind, multinational trial involving 267 study centers. Prior to the HOPE Study, cardiovascular risk associated with early renal insufficiency was unknown. Furthermore, clinicians have often been reluctant to use ACE inhibitors in patients with renal insufficiency. To determine whether mild renal insufficiency increases cardiovascular risk, and whether ramipril decreases that risk, 980 patients with mild renal insufficiency (serum creatinine ≥1.4 mg/dL) were compared to 8,307 patients with normal renal function (serum creatinine <1.4 mg/dL). Patients with a baseline serum creatinine >2.3 mg/dL were excluded. The primary outcome measure was incidence of cardiovascular death, myocardial infarction, or stroke. Cumulative incidence of the primary outcome was higher in patients with renal insufficiency than in those without (22.2% vs 15.1%; P< 0.001), and increased with serum creatinine. Patients with renal insufficiency had a substantially increased risk for cardiovascular death (11.4% vs 6.6%, P< 0.001) and total mortality (17.8% vs. 10.6%, P< 0.001). Ramipril reduced the incidence of the primary outcome in patients with, and those without, renal insufficiency (hazard ratio, 0.80 vs 0.79; P > 0.2 for the difference). Using multivariate analysis, an elevated serum creatinine concentration and microalbuminuria were highly significant, independent renal risk factors for the aggregate primary outcome of cardiovascular death, myocardial infarction, or stroke (HR, 1.40 (P< 0.001) and 1.59 (P< 0.001), respectively). In patients who had preexisting vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril reduced cardiovascular risk without increasing adverse effects, including worsening renal function. Reference: Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134(8): Mann JFE, et al. Ann Intern Med. 2001;134(8):
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HOPE Trial: Main Outcomes and Serum Creatinine
All Patients Placebo Ramipril *p=<0.001 Primary Outcome* Myocardial Infarction* <1.4 mg/dL >1.4 mg/dL <1.4 mg/dL >1.4 mg/dL Events per 1000 Person-Years, n Cardiovascular Death* All Death* HOPE Trial: Main Outcomes and Serum Creatinine A post hoc analysis was performed on data from the Heart Outcomes and Prevention Evaluation (HOPE) Study, a randomized, double-blind, multinational trial involving 267 study centers. In patients with pre-existing vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Ramipril significantly reduced the high cardiovascular risk associated with renal insufficiency. The risk reduction was at least as great in patients with renal insufficiency as in those without. For cardiovascular mortality, all-cause mortality, and heart failure-related hospitalization, the risk reduction was greater in patients with renal insufficiency than in those without. These observations did not change when calculated creatinine clearance was analyzed instead of serum creatinine. Reference: Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134(8): <1.4 mg/dL >1.4 mg/dL <1.4 mg/dL >1.4 mg/dL Mann JFE, et al. Ann Intern Med. 2001;134(8): Reprinted by permission, ACP-ASIM.
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HOPE Trial: Primary Outcomes and Serum Creatinine
Placebo Ramipril Diabetic Patients Hypertensive Patients Events per 1000 Person-Years, n <1.4 mg/dL >1.4 mg/dL <1.4 mg/dL >1.4 mg/dL Non-Diabetic Patients Normotensive Patients HOPE Trial: Primary Outcomes and Serum Creatinine A post hoc analysis was performed on data from the Heart Outcomes and Prevention Evaluation (HOPE) Study, a randomized, double-blind, multinational trial involving 267 study centers. In patients with pre-existing vascular disease or diabetes combined with an additional cardiovascular risk factor, mild renal insufficiency significantly increased the risk for subsequent cardiovascular events. Hypertension and diabetes mellitus are important confounders when the effects of renal insufficiency are analyzed. However, the impact of renal insufficiency on primary and secondary outcomes was similar among non-diabetic and normotensive subgroups compared with the diabetic and hypertensive subgroups. Only primary outcomes data are shown. Hazard ratios favoring ramipril treatment for prevention of the primary outcome in subgroups with, and those without, renal insufficiency did not differ regardless of whether patients had a history of diabetes or hypertension. These hazard ratios ranged between 0.48 for diabetic patients with renal insufficiency, and 0.82 for normotensive patients without renal insufficiency. Reference: Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134(8): <1.4 mg/dL >1.4 mg/dL <1.4 mg/dL >1.4 mg/dL Mann JFE, et al. Ann Intern Med. 2001;134(8): Reprinted by permission, ACP-ASIM.
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Comparison of Anti-Hypertensive Regimens on Proteinuria
With similar reductions of blood pressure… Dihydropyridine calcium channel blockers (DHPCCB) increase proteinuria Ref: Mimran A, et al. Diabetes Care. 1988;11: Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113: Ref: Agodoa L, et al. JAMA. 2001;285(21): Non-DHPCCB reduces proteinuria when a DHPCCB produces no change or increase in proteinuria Ref: Smith AC, et al. Kidney Int. 1998;54: Ref: Kloke H, et al. Kidney Int. 1998; 53: Comparison of Anti-Hypertensive Regimens on Proteinuria Calcium channel blockers (CCBs) are effective anti-hypertensive drugs, but their safety in patients with proteinuric renal diseases and renal insufficiency may be questioned because of reported untoward effects on urinary protein excretion. CCBs are known to have differential effects on both changes in proteinuria as well as progression of diabetic nephropathy. For patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria despite a reduction of blood pressure. Studies on the effects on the course of renal function are limited, however, the available data do suggest that this class of CCBs may be less advantageous than other antihypertensive drugs, thus arguing against the use of these agents as first-line drugs in patients with proteinuric renal diseases. Information on the effects of the non-dihydropyridine CCBs is limited. Data support the hypothesis that CCBs that provide sustained reductions in proteinuria do so, in part, by improving glomerular size permselectivity. Although the data suggest that these classes of CCBs might be more beneficial, more studies are needed, particularly in patients with non-diabetic renal diseases. References: Mimran A, Insua A, Ribstein J, Bringer J, Monnier L. Comparative effect of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. Diabetes Care. 1988;11(10): Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med ;113(12): Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney Int. 1998;54(3):
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Mean Changes in Albuminuria and Mean Arterial Pressure (MAP) in Studies of Patients with HTN and Proteinuria Other Dihydropyridine CCBs Diltiazem & Verapamil CCBs All ACE Inhibitors Nifedipine N=173 N=121 N=111 N=723 Mean Changes in Albuminuria and Mean Arterial Pressure (MAP) in Studies of Patients with HTN and Proteinuria It has been demonstrated that strict blood pressure control with angiotensin converting enzyme (ACE) inhibitors or beta-blockers, aimed at reaching values of <130/80 mm Hg, attenuates the deterioration of renal function. The beneficial effects of these drugs are reflected in a parallel lowering of proteinuria. Calcium channel blockers are effective anti-hypertensive drugs. But, their safety in patients with proteinuric renal diseases and renal insufficiency has been questioned because of reported untoward effects on urinary protein excretion. This review and analysis of published data demonstrates the potential benefits and risks of calcium channel blockers (CCBs) in the treatment of patients with renal diseases. In patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria despite a reduction of blood pressure. Studies on the effects on the course of renal function are limited, however, the available data do suggest that this class of CCBs may be less advantageous than other antihypertensive drugs, thus arguing against the use of these agents as first-line drugs in patients with proteinuric renal diseases. Information on the effects of the non-dihydropyridine CCBs is limited to a small number of studies in patients with diabetic renal disease. Although the data suggest that these classes of CCBs might be more beneficial, more studies are needed, particularly in patients with non-diabetic renal diseases, before founded conclusions can be reached. Reference: Kloke HJ, Branten AJ, Huysmans FT, Wetzels JF. Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers? Kidney Int. 1998; 53(6): Kloke H, et al. Kidney Int. 1998;53:
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ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 Year
Trandolapril (5.5 mg/d) Verapamil (315 mg/d) Trandolapril (2.9 mg/d) + Verapamil (219 mg/d) n=12 n=11 n=14 -27% -33% Percent reduction ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 Year The degree of proteinuria in patients with diabetes correlates strongly with both an increase in progression of nephropathy as well as cardiovascular events. Moreover, post hoc analyses of recent clinical trials support the concept that reductions of blood pressure and proteinuria correlate with a slowed progression of nephropathy. Both angiotensin converting enzyme (ACE) inhibitors and the non-dihydropyridine calcium antagonists (non-DHPCAs) reduce arterial pressure and proteinuria in those with diabetic nephropathy. The present randomized, open label, parallel group designed study tests the hypothesis that, at similar levels of blood pressure, the combination of an ACE inhibitor, trandolapril (T), with the non-DHPCA, verapamil (V), produces a greater reduction in proteinuria over either agent alone at one year. Thirty-seven participants, mean age /- 5.8 years, with nephropathy (baseline creatinine 1.4 +/- 0.3 mg/dl and proteinuria of /- 284 mg/dl) secondary to type 2 diabetes completed the study. Doses of drug were titrated in each group over 8 weeks to achieve a goal blood pressure of < 140/90 mmHg. All participants were counseled to ingest a sodium diet of < 120 mEq/day. Proteinuria reduction from baseline was significantly greater in the T+V group compared to either T alone (-33 +/- 8%, T vs -62 +/- 10%, T+V; P < 0.001) or V alone (-27 +/- 8%, V vs /- 10%, T+V; P < 0.001). No significant differences in either glomerular filtration rate, arterial pressure, fasting blood glucose or urinary sodium excretion were noted at one year. The mean daily dose of the individual components of T+V (2.9 +/- 0.8 mg, T/219 +/ mg V) was significantly lower than the dose of either T alone 5.5 +/- 1.1 mg/day (P < 0.01) or V alone / mg, given in two divided doses (P < 0.01). These data support the concept that the combination of an ACE inhibitor with a non-DHPCA reduce proteinuria to a greater extent than either agent alone. This added anti-proteinuric effect occurs at lower doses of each drug, and is independent of further reductions in arterial pressure. These findings could have ramifications for slowing renal disease progression in patients with nephropathy from type 2 diabetes. Reference: Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int. 1998; 54(4): -62% * *p <0.001 combination vs either monotherapy Bakris GL, et al. Kidney Int. 1998;54: Reprinted by permission, Blackwell Science, Inc.
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