Tracy Wolff, MD, MPH; Therese Miller, DrPH
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.
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Reprints are available from the USPSTF Web site (http://www.preventiveservices.ahrq.gov).
Current Author Addresses: Drs. Wolff and Miller: U.S. Preventive Services Task Force Program, Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850.
Wolff T., Miller T.; Evidence for the Reaffirmation of the U.S. Preventive Services Task Force Recommendation on Screening for High Blood Pressure. Ann Intern Med. 2007;147:787-791. doi: 10.7326/0003-4819-147-11-200712040-00010
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Published: Ann Intern Med. 2007;147(11):787-791.
High blood pressure is common, and screening is a well-established evidence-based standard of current medical practice.
To perform a literature search for new, substantial evidence on screening for high blood pressure that would inform the reaffirmation of the U.S. Preventive Services Task Force recommendation on screening for high blood pressure.
The PubMed and Cochrane databases were searched. The searches were limited to English-language articles on studies of adult humans (age >18 years) that were published between 1 October 2001 and 31 March 2006 in core clinical journals.
For the literature on benefits, meta-analyses; systematic reviews; and randomized, controlled trials were included. For harms, meta-analyses; systematic reviews; randomized, controlled trials; cohort studies; caseâ€“control studies; and case series of large, multisite databases were included. Two reviewers independently reviewed titles, abstracts, and full articles for inclusion.
No new evidence was found on benefits or harms of screening. Two reviewers extracted data from studies on the harms of early treatment, including adverse effects of drug therapy and adverse quality-of-life outcomes.
No new evidence was found for 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.
The nonsystematic search may have missed some smaller studies on the benefits and harms of screening and treatment for high blood pressure.
No new evidence was found on the benefits of screening. Pharmacotherapy for early hypertension is associated with common side effects.
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 (2–4).
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.
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.
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.
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.
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 from the included studies were synthesized qualitatively in tabular and narrative formats.
The work of the USPSTF is supported by the Agency for Healthcare Research and Quality. No separate funding was used specifically for this study.
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 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 β-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 = 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.
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.
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Franz H. Messerli
St. Luke's-Roosevelt Hospital Center
January 19, 2008
Early BP Screening and Treatment Absolutely Necessary
In their Clinical Guideline article Drs. Wolff and Miller concluded that, while there was no new evidence on the benefits of screening for high blood pressure (BP), there was new evidence on the harms of treatment of early hypertension in that "pharmacologic therapy is associated with common side effects"(1). We take issue with this statement and submit that their conclusions stem from a highly selective, if not to say biased, interpretation of the literature. When discussing the TROPHY study (2), Drs. Wolff and Miller extensively list all the adverse events with a (non significantly) higher rate with candesartan than with placebo. However, they conveniently forget to list the adverse events that occurred at a (non significantly) higher rate with placebo than with candesartan. Thus, arthralgia, back pain, sinusitis, bronchitis, depression, nausea and angioedema were more common in the placebo group than in the candesartan group. Overall, candesartan was as well or even better tolerated than placebo in this study as is documented by the fact that there were 14 (3.5%) patients in the candesartan group who had a serious adverse event as opposed to 23 (5.9%) in the placebo group. Regardless of whether the incidence of adverse events is 5% or 50% it should not be quantified as more or less "common" as long as it does not significantly differ from placebo.
Hypertension by and large is an asymptomatic disease and should remain so while under therapy. Apart from nuisance side effects such as pedal edema with calcium antagonists and cough with ACE inhibitors, modern antihypertensive therapy is exceedingly well-tolerated and adverse events are, in general, not distinguishable from placebo. A meta-analysis of 94 randomized placebo-controlled trials (17,641 participants) of 4 different classes of blood pressure"“lowering drugs (thiazides, ÃŸ-blockers, ACE inhibitors, and angiotensin II receptor antagonists) showed that the prevalence of headache was reduced (P<0.001) with each of the 4 drug strategies(3). Similarly, in a meta-analysis of 7 randomized, double- blind, placebo-controlled trials with more than 2000 patients, the use of an angiotensin receptor blocker was associated with a significant reduction in the incidence of headache (p=0.003) when compared to placebo(4). These data suggest that the incidence of headaches occurring with untreated hypertension can be reduced by antihypertensive therapy. Moreover, the Hypertension Optimal Treatment (HOT) Study (5) found that intensive BP lowering was associated with improved quality of life. Despite the aggressive use of antihypertensive agents, a substudy of patients participating in the HOT Study (n=610) demonstrated that intensive BP lowering improved quality of life and 2 self-administered questionnaires"”the Psychological General Well-Being Index and the Subjective Symptoms Assessment Profile"”indicated that the lower the diastolic BP achieved, the greater the improvement in well-being reported by patients(6). It is studies like these that deserve to be emphasized, given that in the United States still about two-thirds of patients with hypertension do not have their BP under control. By indiscriminately disparaging antihypertensive therapy as being fraught with side effects, Drs. Wolff and Miller have provided a disservice to patients and physicians alike.
Franz H. Messerli, MD, Kelly C. Hanretta, DO, Division of Cardiology St.Luke's-Roosevelt Hospital Columbia University College of Physicians and Surgeons 1000 Tenth Avenue New York, NY 10019
1. Wolff T, Miller T. Evidence for the reaffirmation of the U.S. Preventive Services Task Force recommendation on screening for high blood pressure. Ann Intern Med 2007;147:787-91.
2. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, Black HR, Grimm RH Jr, Messerli FH, Oparil S, Schork MA; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006 Apr 20;354(16):1685-97.
3. Law M, Morris JK, Jordan R, Wald N. Headaches and the treatment of blood pressure: results from a meta-analysis of 94 randomized placebo- controlled trials with 24,000 participants. Circulation. 2005 Oct 11;112(15):2301-6.
4. Hansson L, Smith DH, Reeves R, Lapuerta P. Headache in mild-to- moderate hypertension and its reduction by irbesartan therapy. Arch Intern Med. 2000 Jun 12;160(11):1654-8.
5. Wiklund I, Halling K, RydÃ©n-Bergsten T, Fletcher A. Does lowering the blood pressure improve the mood? Quality-of-life results from the Hypertension Optimal Treatment (HOT) study. Blood Press. 1997 Nov;6(6):357 -64.
6. Hansson L, Zanchetti A, Carruthers SG, DahlÃ¶f B, Elmfeldt D, Julius S, MÃ©nard 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 Jun 13;351(9118):1755-62.
Dr. Messerli is ad hoc consultant/speaker for the following organizations: GSK, Novartis, Pfizer, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Forest, Daiichi Sankyo, Sanofi, Merck, Jerini, King Pharmaceuticals and Mars.
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