Evidence for the Reaffirmation of the U.S. Preventive Services Task Force Recommendation on Screening for High Blood Pressure

Hypertension is usually defined in adults as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher (1). Data from NHANES III (Third National Health and Nutrition Examination Survey) suggest that an estimated 43 million U.S. adults older than 25 years have hypertension and that hypertension is more common in African American and elderly persons than in other groups. In the United States, hypertension is responsible for 35% of myocardial infarctions and strokes, 49% of episodes of heart failure, and 24% of premature deaths. Additional complications of hypertension include end-stage renal disease, retinopathy, and aortic aneurysm (24). In 2006, the U.S. Preventive Services Task Force (USPSTF) decided to reexamine the evidence in order to reaffirm its 2003 recommendation on screening for high blood pressure (or hypertension). The Task Force issues a reaffirmation update for a topic that the USPSTF decides to keep current because the topic is one of its priorities, is within its scope, and is a topic for which there is a compelling reason to make a recommendation. Topics in this category are well-established evidence-based standards of current medical practice. The USPSTF decided to perform a reaffirmation update because the evidence base on hypertension is strong and only large, high-quality studies would overturn such a recommendation. Such recommendations would previously have been an A or D recommendation. Therefore, we performed a literature search for new, substantial evidence that would be sufficient to change the 2003 recommendation. Methods The USPSTF developed 2 key questions to be addressed: 1) What are the benefits of screening for high blood pressure in adults? 2) What are the harms of screening and/or early treatment of high blood pressure? To determine whether the benefits of screening for hypertension continue to outweigh the harms, the USPSTF included new information on the adverse effects of drug therapy for early hypertension as part of the question on harms. Data Sources and Searches We performed nonsystematic literature searches of PubMed and the Cochrane Library. We used the following search terms: hypertension, mass screening, adverse effects, and false positive results. We limited the searches to English-language studies of adult humans (age >18 years) that were published in core clinical journals between 1 October 2001 and 31 March 2006. Core clinical journals are a subset of 120 English-language journals defined by the National Library of Medicine; it was previously known as the Abridged Index Medicus. We also checked reference lists of systematic reviews and other studies for possibly relevant studies. Study Selection We included studies on benefits and harms of screening and treatment of early hypertension. We understood early hypertension to be blood pressure elevation that screening could reasonably identify. We defined early hypertension as prehypertension (systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg), hypertension detected through screening, or untreated or newly diagnosed mild to moderate hypertension (systolic blood pressure of 140 to 180 mm Hg or diastolic blood pressure of 90 to 110 mm Hg, when information was not given about how hypertension was detected). We excluded studies in very high-risk or special populations, including patients with preexisting cardiovascular disease. We included studies of nonpregnant adults older than 18 years. We included studies from the United States and from countries with patient populations that are generalizable to the United States. For the literature on benefits, we included meta-analyses; systematic reviews; and randomized, controlled trials. For harms, we included meta-analyses; systematic reviews; randomized, controlled trials; cohorts; casecontrol studies; and case series of large, multisite databases. We excluded editorials, case reports, nonsystematic reviews, and guideline reports. Data Extraction No studies were included for data abstraction on the benefits or harms of screening. For harms of early treatment, 2 reviewers abstracted information on sample size, entry criteria, demographic characteristics, comorbid conditions, study design, treatment group allocation, reports of adverse effects of drug therapy, and quality-of-life outcomes. Data Synthesis and Analysis Data from the included studies were synthesized qualitatively in tabular and narrative formats. Role of the Funding Source The work of the USPSTF is supported by the Agency for Healthcare Research and Quality. No separate funding was used specifically for this study. Results The search returned 378 potentially relevant titles, which we entered into a reference database. A total of 341 studies were excluded after title review, 19 studies were excluded after abstract review, and 13 were excluded after full article review. We excluded 253 studies that were not on hypertension, 62 that included a high-risk population, 31 that did not meet study design criteria, 12 that were not from a U.S. population, 8 that were not done in adults, and 7 that had no relevant outcomes. No new studies on the benefits or harms of screening for high blood pressure met our inclusion criteria. Five studies evaluated the harms of early treatment of hypertension and met our inclusion criteria (Table); these are discussed below. Table. Studies on the Harms of Early Treatment of High Blood Pressure Three studies presented data on adverse effects related to antihypertensive drugs. These studies compared outcomes from treatment of one type of drug versus another type of drug or placebo. In general, they were multicenter studies in the United States, Canada, and United Kingdom; included a predominantly white, male patient sample; and excluded persons with multiple comorbid conditions or manifest cardiovascular disease. In addition, 2 studies examined the effects of antihypertensive medications on quality of life. In these 2 studies, participants with untreated hypertension were randomly allocated to different treatment regimens (the second study also included a placebo group) and followed for effects on quality of life: sexual dysfunction in one study, and symptom distress in the other study. The study on sexual dysfunction included men 40 to 49 years of age, and the study on symptom distress included men and women 50 years of age or older. In 1 study that gathered data on adverse effects, White and colleagues studied the effect of bedtime dosing on early-morning blood pressure in 261 persons who were randomly allocated to 10 weeks of extended-release diltiazem or ramipril (5). Adverse effects were reported in 50% of the diltiazem group and 40% of the ramipril group. Serious adverse effects were uncommon, and 2 of the 3 reported events were probably not related to the drug: 1 event occurred during placebo run-in, and 1 was associated with infection. The most common reasons for withdrawal from the study were lower-extremity edema associated with diltiazem (3%) and cough associated with ramipril (2%). Headache was commonly reported in both groups. The main finding of the study was that diltiazem at bedtime reduced early-morning blood pressure to a greater extent than ramipril. Julius and colleagues compared candesartan with placebo in participants with systolic blood pressure of 130 to 139 mm Hg and diastolic blood pressure of 89 mm Hg or less (6). Serious adverse effects were uncommon, occurring in 3.5% of candesartan recipients and 5.9% of placebo recipients. However, other, less serious adverse effects were very common, occurring in approximately 89% of participants in both the candesartan and placebo groups. Commonly reported adverse effects in the candesartan group were headache (22%), upper respiratory infection (14%), nasopharyngitis (10%), and dizziness (10%). A third study evaluated the effectiveness in reducing clinic-measured and ambulatory blood pressure of 4 antihypertensive agents (doxazosin, amlodipine, enalapril, and bendrofluazide) in 204 persons with diastolic blood pressure of 95 to 110 mm Hg (7). The authors reported that clinic-measured and ambulatory blood pressure decreased in all groups, with no significant differences among them; the authors did not report data that allowed us to determine the statistical significance of this comparison. Adverse effects were very common and did not statistically significantly differ among treatment groups (overall rate, 74% [range among groups, 68% to 81%]). Serious adverse effects were uncommon (overall rate, 11% [range, 6% to 14%]), and the rate of withdrawals due to adverse events was 11%. The most commonly reported adverse effect was headache (overall rate, 20% [range, 16% to 25%]). In 1 study with quality-of-life outcomes, Fogari and colleagues followed 160 married men 40 to 49 years of age with newly diagnosed hypertension (diastolic blood pressure of 95 to 110 mm Hg) who had never been treated for hypertension and had no symptoms of sexual dysfunction (8). One hundred twenty men were randomly assigned to receive an angiotensin II receptor antagonist (valsartan) or a -blocker (carvedilol) for 16 weeks, and, after a placebo washout period, were crossed over to the alternative regimen for another 16 weeks; 40 men were randomly assigned to receive placebo. Results indicated that carvedilol caused a decline in sexual function (the rate of sexual intercourse decreased by 50%, and 13.5% of patients experienced sexual dysfunction). Valsartan produced a temporary and nonstatistically significant decline in sexual function, and function improved with ongoing treatment: By 16 weeks, the rate of sexual intercourse had increased by 19%. The 2 drugs did not differ in control of blood pressure. The other study with quality-of-life outcomes evaluated symptom distress associated with a calcium-channel blocker (amlodipine) and an aldosterone receptor antagonist (eplerenone)

H ypertension is usually defined in adults as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher (1). Data from NHANES III (Third National Health and Nutrition Examination Survey) suggest that an estimated 43 million U.S. adults older than 25 years have hypertension and that hypertension is more common in African American and elderly persons than in other groups. In the United States, hypertension is responsible for 35% of myocardial infarctions and strokes, 49% of episodes of heart failure, and 24% of premature deaths. Additional complications of hypertension include end-stage renal disease, retinopathy, and aortic aneurysm (2)(3)(4).
In 2006, the U.S. Preventive Services Task Force (USPSTF) decided to reexamine the evidence in order to reaffirm its 2003 recommendation on screening for high blood pressure (or hypertension). The Task Force issues a reaffirmation update for a topic that the USPSTF decides to keep current because the topic is one of its priorities, is within its scope, and is a topic for which there is a compelling reason to make a recommendation. Topics in this category are well-established evidence-based standards of current medical practice. The USPSTF decided to perform a reaffirmation update because the evidence base on hypertension is strong and only large, high-quality studies would overturn such a recommendation. Such recommendations would previously have been an A or D recommendation. Therefore, we performed a literature search for new, substantial evidence that would be sufficient to change the 2003 recommendation.

METHODS
The USPSTF developed 2 key questions to be addressed: 1) What are the benefits of screening for high blood pressure in adults? 2) What are the harms of screening and/or early treatment of high blood pressure? To determine whether the benefits of screening for hypertension continue to outweigh the harms, the USPSTF included new information on the adverse effects of drug therapy for "early hypertension" as part of the question on harms.

Data Sources and Searches
We performed nonsystematic literature searches of PubMed and the Cochrane Library. We used the following search terms: hypertension, mass screening, adverse effects, and false positive results. We limited the searches to Englishlanguage studies of adult humans (age Ͼ18 years) that were published in core clinical journals between 1 October 2001 and 31 March 2006. "Core clinical journals" are a subset of 120 English-language journals defined by the Na-

Clinical Guidelines
Screening for High Blood Pressure www.annals.org tional Library of Medicine; it was previously known as the Abridged Index Medicus. We also checked reference lists of systematic reviews and other studies for possibly relevant studies.

Study Selection
We included studies on benefits and harms of screening and treatment of "early hypertension." We understood "early hypertension" to be blood pressure elevation that screening could reasonably identify. We defined "early hypertension" as prehypertension (systolic blood pressure of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg), hypertension detected through screening, or untreated or newly diagnosed mild to moderate hypertension (systolic blood pressure of 140 to 180 mm Hg or diastolic blood pressure of 90 to 110 mm Hg, when information was not given about how hypertension was detected). We excluded studies in very high-risk or special populations, including patients with preexisting cardiovascular disease.
We included studies of nonpregnant adults older than 18 years. We included studies from the United States and from countries with patient populations that are generalizable to the United States. For the literature on benefits, we included meta-analyses; systematic reviews; and randomized, controlled trials. For harms, we included meta-analyses; systematic reviews; randomized, controlled trials; cohorts; case-control studies; and case series of large, multisite databases. We excluded editorials, case reports, nonsystematic reviews, and guideline reports.

Data Extraction
No studies were included for data abstraction on the benefits or harms of screening. For harms of early treatment, 2 reviewers abstracted information on sample size, entry criteria, demographic characteristics, comorbid conditions, study design, treatment group allocation, reports of adverse effects of drug therapy, and quality-of-life outcomes.

Data Synthesis and Analysis
Data from the included studies were synthesized qualitatively in tabular and narrative formats.

Role of the Funding Source
The work of the USPSTF is supported by the Agency for Healthcare Research and Quality. No separate funding was used specifically for this study.

RESULTS
The search returned 378 potentially relevant titles, which we entered into a reference database. A total of 341 studies were excluded after title review, 19 studies were excluded after abstract review, and 13 were excluded after full article review. We excluded 253 studies that were not on hypertension, 62 that included a high-risk population, 31 that did not meet study design criteria, 12 that were not from a U.S. population, 8 that were not done in adults, and 7 that had no relevant outcomes.
No new studies on the benefits or harms of screening for high blood pressure met our inclusion criteria. Five studies evaluated the harms of early treatment of hypertension and met our inclusion criteria (Table); these are discussed below.
Three studies presented data on adverse effects related to antihypertensive drugs. These studies compared outcomes from treatment of one type of drug versus another type of drug or placebo. In general, they were multicenter studies in the United States, Canada, and United Kingdom; included a predominantly white, male patient sample; and excluded persons with multiple comorbid conditions or manifest cardiovascular disease. In addition, 2 studies examined the effects of antihypertensive medications on quality of life. In these 2 studies, participants with untreated hypertension were randomly allocated to different treatment regimens (the second study also included a placebo group) and followed for effects on quality of life: sexual dysfunction in one study, and "symptom distress" in the other study. The study on sexual dysfunction included men 40 to 49 years of age, and the study on symptom distress included men and women 50 years of age or older.
In 1 study that gathered data on adverse effects, White and colleagues studied the effect of bedtime dosing on early-morning blood pressure in 261 persons who were randomly allocated to 10 weeks of extended-release diltiazem or ramipril (5). Adverse effects were reported in 50% of the diltiazem group and 40% of the ramipril group. Serious adverse effects were uncommon, and 2 of the 3 reported events were probably not related to the drug: 1 event occurred during placebo run-in, and 1 was associated with infection. The most common reasons for withdrawal from the study were lower-extremity edema associated with diltiazem (3%) and cough associated with ramipril (2%). Headache was commonly reported in both groups. The main finding of the study was that diltiazem at bedtime reduced early-morning blood pressure to a greater extent than ramipril.
Julius and colleagues compared candesartan with placebo in participants with systolic blood pressure of 130 to 139 mm Hg and diastolic blood pressure of 89 mm Hg or less (6). Serious adverse effects were uncommon, occurring in 3.5% of candesartan recipients and 5.9% of placebo recipients. However, other, less serious adverse effects were very common, occurring in approximately 89% of participants in both the candesartan and placebo groups. Commonly reported adverse effects in the candesartan group were headache (22%), upper respiratory infection (14%), nasopharyngitis (10%), and dizziness (10%).
A third study evaluated the effectiveness in reducing clinic-measured and ambulatory blood pressure of 4 antihypertensive agents (doxazosin, amlodipine, enalapril, and bendrofluazide) in 204 persons with diastolic blood pressure of 95 to 110 mm Hg (7). The authors reported that clinic-measured and ambulatory blood pressure decreased Clinical Guidelines Screening for High Blood Pressure in all groups, with no significant differences among them; the authors did not report data that allowed us to determine the statistical significance of this comparison. Adverse effects were very common and did not statistically significantly differ among treatment groups (overall rate, 74% [range among groups, 68% to 81%]). Serious adverse effects were uncommon (overall rate, 11% [range, 6% to 14%]), and the rate of withdrawals due to adverse events was 11%. The most commonly reported adverse effect was headache (overall rate, 20% [range, 16% to 25%]).
In 1 study with quality-of-life outcomes, Fogari and colleagues followed 160 married men 40 to 49 years of age with newly diagnosed hypertension (diastolic blood pressure of 95 to 110 mm Hg) who had never been treated for hypertension and had no symptoms of sexual dysfunction (8). One hundred twenty men were randomly assigned to receive an angiotensin II receptor antagonist (valsartan) or a ␤-blocker (carvedilol) for 16 weeks, and, after a placebo washout period, were crossed over to the alternative regimen for another 16 weeks; 40 men were randomly assigned to receive placebo. Results indicated that carvedilol caused a decline in sexual function (the rate of sexual intercourse decreased by 50%, and 13.5% of patients experienced sexual dysfunction). Valsartan produced a temporary and non-statistically significant decline in sexual function, and function improved with ongoing treatment: By 16 weeks, the rate of sexual intercourse had increased by 19%. The 2 drugs did not differ in control of blood pressure.
The other study with quality-of-life outcomes evaluated symptom distress associated with a calcium-channel blocker (amlodipine) and an aldosterone receptor antagonist (eplerenone) (9). A total of 269 men and women 50 years of age or older with untreated seated systolic blood pressure of 140 to 190 mm Hg were randomly assigned to receive 1 of the study drugs after a placebo run-in period. On average, participants were approximately 68 years of age, and 89% were white. Participants were followed for 24 weeks; quality-of-life measures were collected at randomization, 14 weeks, and 24 weeks. At 24 weeks, the groups did not statistically significantly differ in blood pressure control or scores on the Short Form-36 Health Survey. However, there was a statistically significant difference among treatment groups on a summary measure of symptom distress in favor of eplerenone (P ϭ 0.03). The amlodipine group experienced symptoms commonly associated with the drug, including ankle swelling, headache, facial flushing, and constipation. Twenty-five percent of amlodipine recipients and 5% of eplerenone recipients experienced edema. Other adverse events were hyperkalemia in 2 eplerenone recipients and 1 amlodipine recipient, and hypokalemia in 2 amlodipine recipients. Erectile dysfunction was reported by 2 of 61 eplerenone recipients and no amlodipine recipients.

CONCLUSION
In summary, there is no new evidence on the benefits of screening for high blood pressure. New evidence on the harms of treatment of early hypertension shows that pharmacologic therapy is associated with common side effects; serious adverse events are uncommon.
From the Agency for Healthcare Research and Quality, Rockville, Maryland.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Financial Support: The USPSTF is an independent, voluntary body, The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.