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What is the best treatment for slowing the progression to end-stage renal disease (ESRD) in African Americans with hypertensive nephropathy?
BACKGROUND: Deaths in African Americans from hypertensive renal disease have risen in recent years. The effects of various antihypertensives on mortality are unknown, since studies have included few African Americans.
POPULATION STUDIED: This study included 1094 African Americans between the ages of 18 and 70 years with hypertensive renal disease, defined as a glomerular filtration rate (GFR) of 20 to 65 mL per minute. The patients included in this study had no other identified causes of renal disease, and were excluded if they had diabetes mellitus, malignant hypertension, secondary hypertension, or congestive heart failure. The average age of the participants was 54 years, and they had a history of hypertension for a mean of 14 years. Nearly half were women with a mean arterial pressure (MAP) of 115. Patients with more than 2.5 g per day of urinary protein excretion were excluded; however, approximately one third of the study participants had proteinuria greater than 300 mg per day, with the average being 600 mg per day. Half of the subjects had a history of heart disease. At enrollment, 40% were taking an angiotensin-converting enzyme (ACE) inhibitor, 27% a b-blocker, 60% a calcium channel blocker (CCB), and 45% a dihydropyridine calcium channel blocker (DHP-CCB).
STUDY DESIGN AND VALIDITY: The patients were randomized to 1 of 3 antihypertensive medications: the ACE inhibitor ramipril 2.5 to 10 mg per day, the sustained-release b-blocker metoprolol 50 to 200 mg per day, or the DHP-CCB amlodipine 5 to 10 mg per day. Each of these groups was further divided into 2 target blood pressure groups: “usual” (MAP) goal of 102 or a “low” MAP goal of 92. Blood pressures were checked and medications adjusted monthly to achieve target MAPs, and GFR was evaluated at baseline and every 3 months. Data were analyzed using an intention-to-treat approach. This is an interim analysis of the African American Study of Kidney Disease and Hypertension (AASK) trial, a multicentered and double-blinded study. Allocation concealment was maintained for study drug assignments but not for the blood pressure goals. Because interim analysis showed large differences between the ramipril and metoprolol groups compared with the amlodipine group, the amlodipine arm was terminated. Follow-up of patients in the remaining arms is ongoing and will be reported at a later time.
OUTCOMES MEASURED: The primary outcome measured was the effect of the study drugs on the long-term rate of decline of GFR. Secondary outcomes were “GFR events” (a decrease of GFR greater than 50%), progression to ESRD, death, and combinations of these.
RESULTS: Baseline characteristics were similar between the amlodipine and ramipril groups, and the average follow-up was 3 years. Overall, the rate of decline in GFR was 36% slower in the ramipril group compared with the amlodipine group (P=.002). This slowed decline in GFR was more pronounced in the subgroup of participants with proteinuria and in the subgroup that had a baseline GFR of less than 40 mL per minute.
Although African Americans have traditionally been thought to be less responsive to ACE inhibitors, in this study ramipril (2.5-10 mg/day) was useful in the treatment of already established hypertensive nephropathy in this population. Ramipril slowed progression to ESRD, especially in those patients with preexisting proteinuria and in those with more advanced renal failure (GFR less than 40 mg/minute). Interestingly, amlodipine was inferior to both ramipril and metoprolol in the treatment of hypertensive renal disease. The question of which is better, ramipril or metoprolol, is currently under study.
BACKGROUND: Deaths in African Americans from hypertensive renal disease have risen in recent years. The effects of various antihypertensives on mortality are unknown, since studies have included few African Americans.
POPULATION STUDIED: This study included 1094 African Americans between the ages of 18 and 70 years with hypertensive renal disease, defined as a glomerular filtration rate (GFR) of 20 to 65 mL per minute. The patients included in this study had no other identified causes of renal disease, and were excluded if they had diabetes mellitus, malignant hypertension, secondary hypertension, or congestive heart failure. The average age of the participants was 54 years, and they had a history of hypertension for a mean of 14 years. Nearly half were women with a mean arterial pressure (MAP) of 115. Patients with more than 2.5 g per day of urinary protein excretion were excluded; however, approximately one third of the study participants had proteinuria greater than 300 mg per day, with the average being 600 mg per day. Half of the subjects had a history of heart disease. At enrollment, 40% were taking an angiotensin-converting enzyme (ACE) inhibitor, 27% a b-blocker, 60% a calcium channel blocker (CCB), and 45% a dihydropyridine calcium channel blocker (DHP-CCB).
STUDY DESIGN AND VALIDITY: The patients were randomized to 1 of 3 antihypertensive medications: the ACE inhibitor ramipril 2.5 to 10 mg per day, the sustained-release b-blocker metoprolol 50 to 200 mg per day, or the DHP-CCB amlodipine 5 to 10 mg per day. Each of these groups was further divided into 2 target blood pressure groups: “usual” (MAP) goal of 102 or a “low” MAP goal of 92. Blood pressures were checked and medications adjusted monthly to achieve target MAPs, and GFR was evaluated at baseline and every 3 months. Data were analyzed using an intention-to-treat approach. This is an interim analysis of the African American Study of Kidney Disease and Hypertension (AASK) trial, a multicentered and double-blinded study. Allocation concealment was maintained for study drug assignments but not for the blood pressure goals. Because interim analysis showed large differences between the ramipril and metoprolol groups compared with the amlodipine group, the amlodipine arm was terminated. Follow-up of patients in the remaining arms is ongoing and will be reported at a later time.
OUTCOMES MEASURED: The primary outcome measured was the effect of the study drugs on the long-term rate of decline of GFR. Secondary outcomes were “GFR events” (a decrease of GFR greater than 50%), progression to ESRD, death, and combinations of these.
RESULTS: Baseline characteristics were similar between the amlodipine and ramipril groups, and the average follow-up was 3 years. Overall, the rate of decline in GFR was 36% slower in the ramipril group compared with the amlodipine group (P=.002). This slowed decline in GFR was more pronounced in the subgroup of participants with proteinuria and in the subgroup that had a baseline GFR of less than 40 mL per minute.
Although African Americans have traditionally been thought to be less responsive to ACE inhibitors, in this study ramipril (2.5-10 mg/day) was useful in the treatment of already established hypertensive nephropathy in this population. Ramipril slowed progression to ESRD, especially in those patients with preexisting proteinuria and in those with more advanced renal failure (GFR less than 40 mg/minute). Interestingly, amlodipine was inferior to both ramipril and metoprolol in the treatment of hypertensive renal disease. The question of which is better, ramipril or metoprolol, is currently under study.
BACKGROUND: Deaths in African Americans from hypertensive renal disease have risen in recent years. The effects of various antihypertensives on mortality are unknown, since studies have included few African Americans.
POPULATION STUDIED: This study included 1094 African Americans between the ages of 18 and 70 years with hypertensive renal disease, defined as a glomerular filtration rate (GFR) of 20 to 65 mL per minute. The patients included in this study had no other identified causes of renal disease, and were excluded if they had diabetes mellitus, malignant hypertension, secondary hypertension, or congestive heart failure. The average age of the participants was 54 years, and they had a history of hypertension for a mean of 14 years. Nearly half were women with a mean arterial pressure (MAP) of 115. Patients with more than 2.5 g per day of urinary protein excretion were excluded; however, approximately one third of the study participants had proteinuria greater than 300 mg per day, with the average being 600 mg per day. Half of the subjects had a history of heart disease. At enrollment, 40% were taking an angiotensin-converting enzyme (ACE) inhibitor, 27% a b-blocker, 60% a calcium channel blocker (CCB), and 45% a dihydropyridine calcium channel blocker (DHP-CCB).
STUDY DESIGN AND VALIDITY: The patients were randomized to 1 of 3 antihypertensive medications: the ACE inhibitor ramipril 2.5 to 10 mg per day, the sustained-release b-blocker metoprolol 50 to 200 mg per day, or the DHP-CCB amlodipine 5 to 10 mg per day. Each of these groups was further divided into 2 target blood pressure groups: “usual” (MAP) goal of 102 or a “low” MAP goal of 92. Blood pressures were checked and medications adjusted monthly to achieve target MAPs, and GFR was evaluated at baseline and every 3 months. Data were analyzed using an intention-to-treat approach. This is an interim analysis of the African American Study of Kidney Disease and Hypertension (AASK) trial, a multicentered and double-blinded study. Allocation concealment was maintained for study drug assignments but not for the blood pressure goals. Because interim analysis showed large differences between the ramipril and metoprolol groups compared with the amlodipine group, the amlodipine arm was terminated. Follow-up of patients in the remaining arms is ongoing and will be reported at a later time.
OUTCOMES MEASURED: The primary outcome measured was the effect of the study drugs on the long-term rate of decline of GFR. Secondary outcomes were “GFR events” (a decrease of GFR greater than 50%), progression to ESRD, death, and combinations of these.
RESULTS: Baseline characteristics were similar between the amlodipine and ramipril groups, and the average follow-up was 3 years. Overall, the rate of decline in GFR was 36% slower in the ramipril group compared with the amlodipine group (P=.002). This slowed decline in GFR was more pronounced in the subgroup of participants with proteinuria and in the subgroup that had a baseline GFR of less than 40 mL per minute.
Although African Americans have traditionally been thought to be less responsive to ACE inhibitors, in this study ramipril (2.5-10 mg/day) was useful in the treatment of already established hypertensive nephropathy in this population. Ramipril slowed progression to ESRD, especially in those patients with preexisting proteinuria and in those with more advanced renal failure (GFR less than 40 mg/minute). Interestingly, amlodipine was inferior to both ramipril and metoprolol in the treatment of hypertensive renal disease. The question of which is better, ramipril or metoprolol, is currently under study.
What is the best approach to the evaluation and treatment of chronic cough?
Potentially cough-inducing agents, such as tobacco products and angiotensin-converting enzyme (ACE) inhibitors, should be eliminated first. Evaluation and treatment for postnasal drip syndrome (PNDS), asthma, and gastroesophageal reflux disease (GERD) should remedy symptoms in the vast majority of patients (grade of recommendation: C, based on case series at referral centers).
Evidence summary
By definition, chronic cough persists past 3 to 8 weeks.1 Irwin proposed an algorithm to evaluate chronic cough in 19812 that has successfully diagnosed and treated chronic cough 82% to 100% of the time in referral centers.2-6 Among patients in this setting who are not using tobacco or ACE inhibitors (assuming a normal or stable chest x-ray), most have PNDS, asthma, GERD, or a combination of these diagnoses.2-5 The protocol evaluates for these 3 conditions. The key weakness of the protocol is that a positive diagnostic test result does not mean that treatment for that condition will relieve the cough.5 Recently, empiric treatment before diagnostic testing has been recommended for primary care.1
An important unanswered clinical question is whether empiric treatment trials or diagnostic testing–directed trials are the best approach.7 Initial empiric treatment for PNDS appears reasonable, since it is the most common single cause of chronic cough,2,4-6 and symptoms and signs and diagnostic tests for PNDS are unreliable.3,6 One prospective study using empiric PNDS treatment as a first step decreased the number of tests required and the mean time to diagnosis compared with previously published studies.6 No studies were found evaluating empiric treatment for asthma before diagnosis. Multiple studies report a 100% negative predictive value for the methacholine challenge test,3-5 but this carries some risk and is not universally available. Empiric treatment of GERD with omeprazole before diagnostic testing with a 24-hour pH probe was evaluated in 1 study. Cough resolved with treatment in only 6 of 17 patients with a positive 24-hour pH probe.8 In another study, 5 of 5 patients with cough due to GERD responded to an H2-blocker.6 The negative predictive value of a 24-hour pH probe is between 90% and 100%,3-6 but this may also be reserved for those who fail initial empiric therapy.
The best timing of the chest x-ray is also unclear. The diagnostic protocol has been historically evaluated in patients with a normal or stable chest x-ray.2-5 One study used a protocol that delayed the chest x-ray for 2 weeks, until after empiric treatment for PNDS and evaluation for asthma. These authors eliminated half of the x-rays and achieved results equivalent to previous studies.6
A recommended approach based on available literature is outlined in the Table 1. Keep in mind that all studies have been done in referral centers.
Recommendations from others
The American College of Chest Physicians recommends the following order of interventions: stop ACE inhibitors, obtain chest x-ray, avoid irritants (such as tobacco), evaluate for PNDS, evaluate for asthma, evaluate for GERD, consider special studies, and reconsider adequacy oftreatments.9
Sang-Ick Chang, MD
San Francisco, California
Chronic cough is an extremely common and vexing problem in primary care. The approach recommended above is helpful and sensible, and I offer a few comments. Given the 3- to 8-week minimum definition of chronic cough, many patients who present with “chronic” cough to their primary care provider will have a postviral cough that will go away on its own. This includes patients taking ACE inhibitors, and how long they are allowed to cough before you stop the ACE inhibitor is a difficult question. Also, before blaming a new “chronic” cough on tobacco use, remember that smokers get reflux, postnasal drip, and asthma at least as often as nonsmokers, not to mention lung cancer. Finally, methacholine challenge testing and pH probe testing are not readily available in my public institution, but even where they are available, I think empiric treatment is more cost-effective and more acceptable to patients.
1. Lawler R. An office approach to the diagnosis of chronic cough. Am Fam Physician 1998;58:2015-22.
2. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcomes of specific therapy. Am Review Respir Dis 1981;123:413-17.
3. McGarvey LP, Heaney LG, Lawson JT, et al. Evaluation and outcomes of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998;53:738-43.
4. Smyrnios NA, Irwin RS, Curley FJ, French CL. From a prospective study of chronic cough: diagnostic and therapeutic aspects in older adults. Arch Intern Med 1998;158:1222-28.
5. Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes and key components of the diagnostic evaluation and outcomes of specific therapy. Am Rev Respir Dis 1990;141:640-47.
6. Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic approach to chronic cough. Ann Intern Med 1993;119:977-83.
7. Irwin RS, Madison JM. Symptom research on chronic cough: a historical perspective. Ann Intern Med 2001;134:809-14.
8. Ours TM, Kavauru MS, Schultz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999;94:3131-38.
9. American College of Chest Physicians. Managing cough as a defense mechanism and as a symptom. Figures accessed at:www.chestnet.org/health.science.policy/quick.reference.guides/coughqrg.figures.html.
Potentially cough-inducing agents, such as tobacco products and angiotensin-converting enzyme (ACE) inhibitors, should be eliminated first. Evaluation and treatment for postnasal drip syndrome (PNDS), asthma, and gastroesophageal reflux disease (GERD) should remedy symptoms in the vast majority of patients (grade of recommendation: C, based on case series at referral centers).
Evidence summary
By definition, chronic cough persists past 3 to 8 weeks.1 Irwin proposed an algorithm to evaluate chronic cough in 19812 that has successfully diagnosed and treated chronic cough 82% to 100% of the time in referral centers.2-6 Among patients in this setting who are not using tobacco or ACE inhibitors (assuming a normal or stable chest x-ray), most have PNDS, asthma, GERD, or a combination of these diagnoses.2-5 The protocol evaluates for these 3 conditions. The key weakness of the protocol is that a positive diagnostic test result does not mean that treatment for that condition will relieve the cough.5 Recently, empiric treatment before diagnostic testing has been recommended for primary care.1
An important unanswered clinical question is whether empiric treatment trials or diagnostic testing–directed trials are the best approach.7 Initial empiric treatment for PNDS appears reasonable, since it is the most common single cause of chronic cough,2,4-6 and symptoms and signs and diagnostic tests for PNDS are unreliable.3,6 One prospective study using empiric PNDS treatment as a first step decreased the number of tests required and the mean time to diagnosis compared with previously published studies.6 No studies were found evaluating empiric treatment for asthma before diagnosis. Multiple studies report a 100% negative predictive value for the methacholine challenge test,3-5 but this carries some risk and is not universally available. Empiric treatment of GERD with omeprazole before diagnostic testing with a 24-hour pH probe was evaluated in 1 study. Cough resolved with treatment in only 6 of 17 patients with a positive 24-hour pH probe.8 In another study, 5 of 5 patients with cough due to GERD responded to an H2-blocker.6 The negative predictive value of a 24-hour pH probe is between 90% and 100%,3-6 but this may also be reserved for those who fail initial empiric therapy.
The best timing of the chest x-ray is also unclear. The diagnostic protocol has been historically evaluated in patients with a normal or stable chest x-ray.2-5 One study used a protocol that delayed the chest x-ray for 2 weeks, until after empiric treatment for PNDS and evaluation for asthma. These authors eliminated half of the x-rays and achieved results equivalent to previous studies.6
A recommended approach based on available literature is outlined in the Table 1. Keep in mind that all studies have been done in referral centers.
Recommendations from others
The American College of Chest Physicians recommends the following order of interventions: stop ACE inhibitors, obtain chest x-ray, avoid irritants (such as tobacco), evaluate for PNDS, evaluate for asthma, evaluate for GERD, consider special studies, and reconsider adequacy oftreatments.9
Sang-Ick Chang, MD
San Francisco, California
Chronic cough is an extremely common and vexing problem in primary care. The approach recommended above is helpful and sensible, and I offer a few comments. Given the 3- to 8-week minimum definition of chronic cough, many patients who present with “chronic” cough to their primary care provider will have a postviral cough that will go away on its own. This includes patients taking ACE inhibitors, and how long they are allowed to cough before you stop the ACE inhibitor is a difficult question. Also, before blaming a new “chronic” cough on tobacco use, remember that smokers get reflux, postnasal drip, and asthma at least as often as nonsmokers, not to mention lung cancer. Finally, methacholine challenge testing and pH probe testing are not readily available in my public institution, but even where they are available, I think empiric treatment is more cost-effective and more acceptable to patients.
Potentially cough-inducing agents, such as tobacco products and angiotensin-converting enzyme (ACE) inhibitors, should be eliminated first. Evaluation and treatment for postnasal drip syndrome (PNDS), asthma, and gastroesophageal reflux disease (GERD) should remedy symptoms in the vast majority of patients (grade of recommendation: C, based on case series at referral centers).
Evidence summary
By definition, chronic cough persists past 3 to 8 weeks.1 Irwin proposed an algorithm to evaluate chronic cough in 19812 that has successfully diagnosed and treated chronic cough 82% to 100% of the time in referral centers.2-6 Among patients in this setting who are not using tobacco or ACE inhibitors (assuming a normal or stable chest x-ray), most have PNDS, asthma, GERD, or a combination of these diagnoses.2-5 The protocol evaluates for these 3 conditions. The key weakness of the protocol is that a positive diagnostic test result does not mean that treatment for that condition will relieve the cough.5 Recently, empiric treatment before diagnostic testing has been recommended for primary care.1
An important unanswered clinical question is whether empiric treatment trials or diagnostic testing–directed trials are the best approach.7 Initial empiric treatment for PNDS appears reasonable, since it is the most common single cause of chronic cough,2,4-6 and symptoms and signs and diagnostic tests for PNDS are unreliable.3,6 One prospective study using empiric PNDS treatment as a first step decreased the number of tests required and the mean time to diagnosis compared with previously published studies.6 No studies were found evaluating empiric treatment for asthma before diagnosis. Multiple studies report a 100% negative predictive value for the methacholine challenge test,3-5 but this carries some risk and is not universally available. Empiric treatment of GERD with omeprazole before diagnostic testing with a 24-hour pH probe was evaluated in 1 study. Cough resolved with treatment in only 6 of 17 patients with a positive 24-hour pH probe.8 In another study, 5 of 5 patients with cough due to GERD responded to an H2-blocker.6 The negative predictive value of a 24-hour pH probe is between 90% and 100%,3-6 but this may also be reserved for those who fail initial empiric therapy.
The best timing of the chest x-ray is also unclear. The diagnostic protocol has been historically evaluated in patients with a normal or stable chest x-ray.2-5 One study used a protocol that delayed the chest x-ray for 2 weeks, until after empiric treatment for PNDS and evaluation for asthma. These authors eliminated half of the x-rays and achieved results equivalent to previous studies.6
A recommended approach based on available literature is outlined in the Table 1. Keep in mind that all studies have been done in referral centers.
Recommendations from others
The American College of Chest Physicians recommends the following order of interventions: stop ACE inhibitors, obtain chest x-ray, avoid irritants (such as tobacco), evaluate for PNDS, evaluate for asthma, evaluate for GERD, consider special studies, and reconsider adequacy oftreatments.9
Sang-Ick Chang, MD
San Francisco, California
Chronic cough is an extremely common and vexing problem in primary care. The approach recommended above is helpful and sensible, and I offer a few comments. Given the 3- to 8-week minimum definition of chronic cough, many patients who present with “chronic” cough to their primary care provider will have a postviral cough that will go away on its own. This includes patients taking ACE inhibitors, and how long they are allowed to cough before you stop the ACE inhibitor is a difficult question. Also, before blaming a new “chronic” cough on tobacco use, remember that smokers get reflux, postnasal drip, and asthma at least as often as nonsmokers, not to mention lung cancer. Finally, methacholine challenge testing and pH probe testing are not readily available in my public institution, but even where they are available, I think empiric treatment is more cost-effective and more acceptable to patients.
1. Lawler R. An office approach to the diagnosis of chronic cough. Am Fam Physician 1998;58:2015-22.
2. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcomes of specific therapy. Am Review Respir Dis 1981;123:413-17.
3. McGarvey LP, Heaney LG, Lawson JT, et al. Evaluation and outcomes of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998;53:738-43.
4. Smyrnios NA, Irwin RS, Curley FJ, French CL. From a prospective study of chronic cough: diagnostic and therapeutic aspects in older adults. Arch Intern Med 1998;158:1222-28.
5. Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes and key components of the diagnostic evaluation and outcomes of specific therapy. Am Rev Respir Dis 1990;141:640-47.
6. Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic approach to chronic cough. Ann Intern Med 1993;119:977-83.
7. Irwin RS, Madison JM. Symptom research on chronic cough: a historical perspective. Ann Intern Med 2001;134:809-14.
8. Ours TM, Kavauru MS, Schultz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999;94:3131-38.
9. American College of Chest Physicians. Managing cough as a defense mechanism and as a symptom. Figures accessed at:www.chestnet.org/health.science.policy/quick.reference.guides/coughqrg.figures.html.
1. Lawler R. An office approach to the diagnosis of chronic cough. Am Fam Physician 1998;58:2015-22.
2. Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcomes of specific therapy. Am Review Respir Dis 1981;123:413-17.
3. McGarvey LP, Heaney LG, Lawson JT, et al. Evaluation and outcomes of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998;53:738-43.
4. Smyrnios NA, Irwin RS, Curley FJ, French CL. From a prospective study of chronic cough: diagnostic and therapeutic aspects in older adults. Arch Intern Med 1998;158:1222-28.
5. Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes and key components of the diagnostic evaluation and outcomes of specific therapy. Am Rev Respir Dis 1990;141:640-47.
6. Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic approach to chronic cough. Ann Intern Med 1993;119:977-83.
7. Irwin RS, Madison JM. Symptom research on chronic cough: a historical perspective. Ann Intern Med 2001;134:809-14.
8. Ours TM, Kavauru MS, Schultz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol 1999;94:3131-38.
9. American College of Chest Physicians. Managing cough as a defense mechanism and as a symptom. Figures accessed at:www.chestnet.org/health.science.policy/quick.reference.guides/coughqrg.figures.html.
Evidence-based answers from the Family Physicians Inquiries Network