Letters and Corrections
Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request. Mild Hypertension and Cardiovascular Risks To the Editor: It is very unfortunate that the TAIM (Trial of Antihypertensive Interventions and Management) study lasted only 6 months (1). It has been well known for some time that thiazide diuretics initially increase both total and low-density lipoprotein (LDL) cholesterol. The lipid changes probably peak at 6 to 9 months, and cholesterol declines to or below baseline thereafter (2). Such a relatively transient increase in cholesterol would not be expected to have any long-term effect on coronary risk. The TAIM study thus assessed chlorthalidone at the worst possible time for evaluating the long-term effect of thiazides on cardiovascular risk status. In clinical trials comparing thiazides with placebo, no evidence has been found of an increase in coronary deaths; indeed, an overall trend toward the reduction of such deaths is evident (3). Moreover, in three major trials comparing thiazides with beta-adrenergic antagonists, no overall difference has been observed in the effect of these agents on coronary death rates (4). Thus, any conclusion that thiazides relatively increase coronary risk because of their short-term effects on serum lipids is premature at best. James F. Burris, MD Georgetown University Medical Center Washington, D.C. 20007 References 1. Oberman A, Wassertheil-Smoller S, Langford HG, et al. Pharmacologic and nutritional treatment of mild hypertension: changes in cardiovascular risk status. Ann Intern Med. 1990;112:89-95. 2. Freis ED. The cardiovascular risks of thiazide diuretics. Clin Pharmacol Ther. 1986;39:239-44. 3. Cutler JA, MacMahon SW, Furberg CD. Controlled clinical trials of drug treatment for hypertension—a review. Hypertension. 1989; 13(Suppl I):I36-44. 4. Furberg C, Cutler JA. Diuretic agents versus beta-blockers—comparison of effects on mortality, stroke, and coronary events. Hypertension. 1989;13(Suppl I):I57-61.
In response: Few studies have been properly designed to evaluate drug-induced changes in blood lipid levels which occur with different antihypertensive treatment regimens. In our study (1), the data were used to quantify the overall effect of antihypertensive treatment on composite coronary heart dis-
ease risk. The effect on total cholesterol was but one of several factors considered. Although the study is continuing, our article (1) dealt with findings at 6 months and not with the longterm effect of thiazide diuretics. Whether the influence of diuretics on lipid levels is transient or sustained has not been resolved (2, 3). Concurrent population decreases in lipid levels, use of multiple drugs, alteration in diet and exercise habits, and inappropriate study designs make the interpretation of lipid changes difficult. Nevertheless, clinical trials (3, 4) with more useful lipid data and of at least 12 months duration have shown a persistent increase of 5% or more in total cholesterol when hypertensive patients are treated with diuretics (3, 4). No clinical trials comparing thiazides with placebo have shown an increase in coronary deaths in the diuretic-treated groups excepting the MRFIT (Multiple Risk Factor Intervention Trial) subgroup with electrocardiographic abnormalities (5). Also, it is not known whether thiazide-induced cholesterol elevation has the same prognostic importance as naturally occurring elevations. However, the lack of a strong effect on coronary heart disease in previous trials has been attributed in part to adverse lipid changes caused by diuretic therapy. Regardless of the duration and extent of the lipid changes, the important and often neglected point is the efficacy of weight reduction in conjunction with antihypertensive therapy in negating the lipid-raising effect of diuretic therapy. Adding weight reduction to chlorthalidone therapy resulted in a significantly lowered risk for coronary heart disease (1). Long-term, the benefits could be even more pronounced. In our view, the finding that weight reduction in conjunction with chlorthalidone monotherapy decreases composite coronary heart disease risk while limiting potential adverse metabolic changes is one of the major results of our trial. Albert Oberman, MD University of Alabama at Birmingham Birmingham, AL 35294 For the TAIM Research Group
References 1. Oberman A, Wassertheil-Smoller S, Langford HG, et al. Pharmacologic and nutritional treatment of mild hypertension: changes in cardiovascular risk status. Ann Intern Med. 1990;112:89-95. 2. The 1988 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, Maryland: U.S. Department of Health and Human Services: 1988. NIH publication no. 88-1088. 3. Johnson BF, Danylchuk MA. The relevance of plasma lipid changes with cardiovascular drug therapy. Med Clin North Am. 1989;73: 449-73. 4. Ames R. Effects of diuretic drugs on the lipid profile. Drugs. 1988; 36:33-40. 5. Multiple Risk Factor Intervention Trial Research Group. Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol. 1985;55:1-15.
Enalapril and Vulvovaginal Pruritis To the Editor: Enalapril is an angiotensin-converting enzyme inhibitor that has proved to be effective in treating hypertension. Inhibition of converting enzyme may decrease the degradation of bradykinin, and elevated levels of bradykinin may result in increased production of prostaglandin E 2 (1). Side
1 June 1990 • Annals of Internal Medicine Downloaded from https://annals.org by Karolinska Institute user on 01/15/2019
• Volume 112 • Number 11
879
effects of enalapril include cough (2, 3), bronchospasm (4), and flushing (5), which have been hypothesized to be bradykininor prostaglandin-mediated (1). Vulvovaginal pruritis and dysuria have not, to our knowledge, been reported in association with the use of enalapril. An 80-year-old woman with essential hypertension was begun on enalapril (Vasotec, Merck Sharp & Dohme, West Point, Pennsylvania), 2.5 mg/d. Within 48 hours she developed symptoms of vulvovaginal pruritis and burning at the end of urination, without frequency, urgency, or vaginal discharge. She denied having had any symptoms of cough, flushing, or generalized pruritis. Because of a misunderstanding about her medications, she discontinued therapy with enalapril, and during the next 24 hours her vulvovaginal pruritis and terminal dysuria resolved. Because of continuing uncontrolled hypertension, enalapril was reinstituted, and she again developed vulvar and vaginal itching with dysuria. A physical examination showed normal vulvar skin and vaginal mucosa, without evidence of erythema or discharge. A urinalysis, urine culture, and Papanicolaou smear were all unremarkable. Enalapril was withdrawn, and she was started on nifedipine (Procardia, Pfizer, New York, New York) for control of her hypertension. Within 24 hours of discontinuing enalapril therapy, the urethral and vulvovaginal symptoms resolved. Vulvovaginal pruritis and dysuria have not been reported in association with enalapril use and are not listed among the adverse reactions to enalapril in the Physicians' Desk Reference. However, on two occasions, our patient had onset of these symptoms within 48 hours of taking enalapril and relief of these symptoms within 24 hours of discontinuing it. Thus, it appears that her symptoms were attributable to enalapril. Although the mechanism remains speculative, enalapril-induced elevations of bradykinin and prostaglandin E 2 may stimulate nociceptive fibers in the vulvovaginal mucosa, resulting in pruritis and urethral pain. Similarly, kinin- or prostaglandin-mediated stimulation of irritant receptors of the pharynx are hypothesized to be responsible for the cough and "tickling" sensation of the throat described in up to 10% of patients taking enalapril (3). It is intriguing that enalapril-induced cough appears to be significantly commoner in women than in men (2, 3), suggesting an unexplained predisposition of women to the bradykinin- or prostaglandin-mediated side effects of the drug. Because older women may not voluntarily report vulvovaginal symptoms, women taking enalapril for hypertension should be questioned about vulvar or vaginal pruritis, and withdrawal of the medication should be considered for women who develop these symptoms while taking enalapril. Paul S. Heckerling, MD University of Illinois Chicago, IL 60680
References 1. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med. 1988;319:1517-25. 2. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. Br Med J. 1987;294:1521-3. 3. Gibson GR. Enalapril-induced cough. Arch Intern Med. 1989;149: 2701-3. 4. Semple PF, Herd GW. Cough and wheeze caused by inhibitors of angiotensin-converting enzyme. N Engl J Med. 1986;314:61. 5. Cohen KR. Flushing induced by angiotensin converting enzyme inhibitor therapy. Am J Med. 1989,86:358.
Hemoccult Screening and Colorectal Neoplasms To the Editor: Allison and associates (1) evaluated the sensitivity of fecal occult blood tests in detecting colorectal neoplasms. The 50% sensitivity they found at 1 year was lower than previous estimates and, as these authors point out, may limit the effectiveness of the fecal occult blood test in colorectal cancer screening programs. The authors also speculate on the likelihood of finding a significant colorectal adenoma in patients with a negative fecal occult blood test. The implication that significant adenomas are unusual (
Letters submitted for possible publication must be identified as such and submitted with a signed transfer-of-copyright form (see Table of Contents for location). Text length must not exceed 400 words. No more than five references may be used; reference format must be that specified in "Information for Readers and Authors." Letters must have no more than three authors. All parts of letters must be typed double-spaced, including references. Letters not typed double-spaced will not be considered for publication. Tables and figures will not be published. Acceptance of letters for publication depends on several factors: newness of information, relevance to current topics and recent content of this journal, clarity of statement, distribution of topics within this section, conformity to acceptable formats, and space available; only about half of the letters submitted can be published. The Editor reserves the right to shorten letters and make changes to our style. Authors of letters to be published will be notified of their acceptance. Unpublished letters are returned only on request. Mild Hypertension and Cardiovascular Risks To the Editor: It is very unfortunate that the TAIM (Trial of Antihypertensive Interventions and Management) study lasted only 6 months (1). It has been well known for some time that thiazide diuretics initially increase both total and low-density lipoprotein (LDL) cholesterol. The lipid changes probably peak at 6 to 9 months, and cholesterol declines to or below baseline thereafter (2). Such a relatively transient increase in cholesterol would not be expected to have any long-term effect on coronary risk. The TAIM study thus assessed chlorthalidone at the worst possible time for evaluating the long-term effect of thiazides on cardiovascular risk status. In clinical trials comparing thiazides with placebo, no evidence has been found of an increase in coronary deaths; indeed, an overall trend toward the reduction of such deaths is evident (3). Moreover, in three major trials comparing thiazides with beta-adrenergic antagonists, no overall difference has been observed in the effect of these agents on coronary death rates (4). Thus, any conclusion that thiazides relatively increase coronary risk because of their short-term effects on serum lipids is premature at best. James F. Burris, MD Georgetown University Medical Center Washington, D.C. 20007 References 1. Oberman A, Wassertheil-Smoller S, Langford HG, et al. Pharmacologic and nutritional treatment of mild hypertension: changes in cardiovascular risk status. Ann Intern Med. 1990;112:89-95. 2. Freis ED. The cardiovascular risks of thiazide diuretics. Clin Pharmacol Ther. 1986;39:239-44. 3. Cutler JA, MacMahon SW, Furberg CD. Controlled clinical trials of drug treatment for hypertension—a review. Hypertension. 1989; 13(Suppl I):I36-44. 4. Furberg C, Cutler JA. Diuretic agents versus beta-blockers—comparison of effects on mortality, stroke, and coronary events. Hypertension. 1989;13(Suppl I):I57-61.
In response: Few studies have been properly designed to evaluate drug-induced changes in blood lipid levels which occur with different antihypertensive treatment regimens. In our study (1), the data were used to quantify the overall effect of antihypertensive treatment on composite coronary heart dis-
ease risk. The effect on total cholesterol was but one of several factors considered. Although the study is continuing, our article (1) dealt with findings at 6 months and not with the longterm effect of thiazide diuretics. Whether the influence of diuretics on lipid levels is transient or sustained has not been resolved (2, 3). Concurrent population decreases in lipid levels, use of multiple drugs, alteration in diet and exercise habits, and inappropriate study designs make the interpretation of lipid changes difficult. Nevertheless, clinical trials (3, 4) with more useful lipid data and of at least 12 months duration have shown a persistent increase of 5% or more in total cholesterol when hypertensive patients are treated with diuretics (3, 4). No clinical trials comparing thiazides with placebo have shown an increase in coronary deaths in the diuretic-treated groups excepting the MRFIT (Multiple Risk Factor Intervention Trial) subgroup with electrocardiographic abnormalities (5). Also, it is not known whether thiazide-induced cholesterol elevation has the same prognostic importance as naturally occurring elevations. However, the lack of a strong effect on coronary heart disease in previous trials has been attributed in part to adverse lipid changes caused by diuretic therapy. Regardless of the duration and extent of the lipid changes, the important and often neglected point is the efficacy of weight reduction in conjunction with antihypertensive therapy in negating the lipid-raising effect of diuretic therapy. Adding weight reduction to chlorthalidone therapy resulted in a significantly lowered risk for coronary heart disease (1). Long-term, the benefits could be even more pronounced. In our view, the finding that weight reduction in conjunction with chlorthalidone monotherapy decreases composite coronary heart disease risk while limiting potential adverse metabolic changes is one of the major results of our trial. Albert Oberman, MD University of Alabama at Birmingham Birmingham, AL 35294 For the TAIM Research Group
References 1. Oberman A, Wassertheil-Smoller S, Langford HG, et al. Pharmacologic and nutritional treatment of mild hypertension: changes in cardiovascular risk status. Ann Intern Med. 1990;112:89-95. 2. The 1988 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Bethesda, Maryland: U.S. Department of Health and Human Services: 1988. NIH publication no. 88-1088. 3. Johnson BF, Danylchuk MA. The relevance of plasma lipid changes with cardiovascular drug therapy. Med Clin North Am. 1989;73: 449-73. 4. Ames R. Effects of diuretic drugs on the lipid profile. Drugs. 1988; 36:33-40. 5. Multiple Risk Factor Intervention Trial Research Group. Baseline rest electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol. 1985;55:1-15.
Enalapril and Vulvovaginal Pruritis To the Editor: Enalapril is an angiotensin-converting enzyme inhibitor that has proved to be effective in treating hypertension. Inhibition of converting enzyme may decrease the degradation of bradykinin, and elevated levels of bradykinin may result in increased production of prostaglandin E 2 (1). Side
1 June 1990 • Annals of Internal Medicine Downloaded from https://annals.org by Karolinska Institute user on 01/15/2019
• Volume 112 • Number 11
879
effects of enalapril include cough (2, 3), bronchospasm (4), and flushing (5), which have been hypothesized to be bradykininor prostaglandin-mediated (1). Vulvovaginal pruritis and dysuria have not, to our knowledge, been reported in association with the use of enalapril. An 80-year-old woman with essential hypertension was begun on enalapril (Vasotec, Merck Sharp & Dohme, West Point, Pennsylvania), 2.5 mg/d. Within 48 hours she developed symptoms of vulvovaginal pruritis and burning at the end of urination, without frequency, urgency, or vaginal discharge. She denied having had any symptoms of cough, flushing, or generalized pruritis. Because of a misunderstanding about her medications, she discontinued therapy with enalapril, and during the next 24 hours her vulvovaginal pruritis and terminal dysuria resolved. Because of continuing uncontrolled hypertension, enalapril was reinstituted, and she again developed vulvar and vaginal itching with dysuria. A physical examination showed normal vulvar skin and vaginal mucosa, without evidence of erythema or discharge. A urinalysis, urine culture, and Papanicolaou smear were all unremarkable. Enalapril was withdrawn, and she was started on nifedipine (Procardia, Pfizer, New York, New York) for control of her hypertension. Within 24 hours of discontinuing enalapril therapy, the urethral and vulvovaginal symptoms resolved. Vulvovaginal pruritis and dysuria have not been reported in association with enalapril use and are not listed among the adverse reactions to enalapril in the Physicians' Desk Reference. However, on two occasions, our patient had onset of these symptoms within 48 hours of taking enalapril and relief of these symptoms within 24 hours of discontinuing it. Thus, it appears that her symptoms were attributable to enalapril. Although the mechanism remains speculative, enalapril-induced elevations of bradykinin and prostaglandin E 2 may stimulate nociceptive fibers in the vulvovaginal mucosa, resulting in pruritis and urethral pain. Similarly, kinin- or prostaglandin-mediated stimulation of irritant receptors of the pharynx are hypothesized to be responsible for the cough and "tickling" sensation of the throat described in up to 10% of patients taking enalapril (3). It is intriguing that enalapril-induced cough appears to be significantly commoner in women than in men (2, 3), suggesting an unexplained predisposition of women to the bradykinin- or prostaglandin-mediated side effects of the drug. Because older women may not voluntarily report vulvovaginal symptoms, women taking enalapril for hypertension should be questioned about vulvar or vaginal pruritis, and withdrawal of the medication should be considered for women who develop these symptoms while taking enalapril. Paul S. Heckerling, MD University of Illinois Chicago, IL 60680
References 1. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. N Engl J Med. 1988;319:1517-25. 2. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. Br Med J. 1987;294:1521-3. 3. Gibson GR. Enalapril-induced cough. Arch Intern Med. 1989;149: 2701-3. 4. Semple PF, Herd GW. Cough and wheeze caused by inhibitors of angiotensin-converting enzyme. N Engl J Med. 1986;314:61. 5. Cohen KR. Flushing induced by angiotensin converting enzyme inhibitor therapy. Am J Med. 1989,86:358.
Hemoccult Screening and Colorectal Neoplasms To the Editor: Allison and associates (1) evaluated the sensitivity of fecal occult blood tests in detecting colorectal neoplasms. The 50% sensitivity they found at 1 year was lower than previous estimates and, as these authors point out, may limit the effectiveness of the fecal occult blood test in colorectal cancer screening programs. The authors also speculate on the likelihood of finding a significant colorectal adenoma in patients with a negative fecal occult blood test. The implication that significant adenomas are unusual (
