Clinical Review Evidence based management of hypertension

What to do when blood pressure is difficult to control

BMJ 2001; 322 doi: (Published 19 May 2001) Cite this as: BMJ 2001;322:1229
  1. Jane E O'Rorke, assistant professor (ororke{at},
  2. W Scott Richardson, assistant professor
  1. This is the last in a series of five articles Division of General Internal Medicine, University of Texas at San Antonio, San Antonio, TX 78249, USA
  1. Correspondence to: J E O'Rorke

    There is no universally accepted definition of blood pressure that is difficult to control, uncontrolled, resistant, or refractory. One consensus based US national guideline defines resistant hypertension as blood pressure that cannot be reduced below 140/90 mm Hg (below 160 mm Hg for isolated systolic hypertension) in patients who are complying with adequate triple drug regimens in appropriate dosage.1 This definition covers many hypertensive patients but not those for whom the target is an even lower pressure.

    Summary points

    Consider the following causes for apparently resistant blood pressure: inaccurate measurement, antagonising substances such as non-steroidal anti-inflammatory drugs, aggravating conditions such as obesity or sleep apnoea, suboptimal treatment regimens, non-compliance

    When apparent resistance remains unexplained or when there are clues suggesting white coat hypertension, consider this and arrange for multiple measurements by self monitoring, visits to or by nurses or health visitors, or ambulatory monitoring

    If hypertension is still unexplained, or for patients who fit specific patterns of higher risk, consider a selective, sequential evaluation for secondary causes of hypertension, starting with relatively common conditions, such as renovascular causes and renal parenchymal disease

    Work closely with patients to identify preferred and feasible solutions for correcting any cause that is found

    Consider referral of patients with severe or persistently resistant hypertension to a centre specialising in its diagnosis and treatment

    Both clinical experience and research surveys suggest that resistant blood pressure is common in everyday practice. For example, population and clinic surveys in North America, Europe, and Australia show that in as many as 50% to 75% of people being treated for hypertension target blood pressure levels are not achieved.2 Fifty per cent of the 19 196 participants in one recent trial had uncontrolled blood pressure levels when enrolled despite already being treated for hypertension; 59% of these uncontrolled patients were being treated with a single drug, and 41% with two drugs. During the trial, 72% of patients needed more than one drug to reduce their diastolic blood pressures to 80 mm Hg.3 In another large trial in hypertensive diabetic patients, 60% of the participants needed two or more drugs to achieve blood pressure levels of less than 150/85 mm Hg, and 33% needed three or more drugs.4 These findings confirm that, even when patients are closely followed, blood pressure can be difficult to control.

    Assessing cause and incidence of resistant blood pressure

    The categories of causes of resistant hypertension are

    • Inaccurate blood pressure measurement

    • White coat hypertension

    • Disease progression

    • suboptimal treatment

    • Non-compliance with prescribed treatments

    • Antagonising substances

    • Coexisting conditions

    Embedded Image

    Measurements of blood pressure taken in the patient's home can be combined with those obtained in the doctor's office to create a fuller picture of blood pressure control

    • Secondary hypertension.

    • Two or more of these categories may be relevant in one patient.

    • There is little evidence as to how often these eight categories are found to be responsible for difficulty in controlling blood pressure, but a small descriptive survey from a referral clinic gave the following relative proportions: suboptimal treatment, 40%; non-adherence to prescribed treatment, 10% to 50%; white coat hypertension, 2% to 4%; and secondary causes, 10%.5 The figures could be quite different in primary care, with lower rates of secondary causes, but there is little direct evidence on the point.

    Inaccurate blood pressure measurement

    The accuracy of blood pressure readings depends on the use of proper technique and on the conditions under which the measurements are made. Before you conclude that a patient has resistant hypertension, blood pressure measurements should be repeated under good conditions and with as near to ideal technique as possible.

    White coat hypertension

    Some patients have acceptably controlled blood pressure while they are at home but have higher readings when examined by the clinician, who may be misled to think that the patient's blood pressure is poorly controlled. To exclude this possibility, arrange for multiple measurements of the patient's blood pressure by, for example, visits to or from nurses or other healthcare workers, self monitoring with a home sphygmomanometer, or ambulatory blood pressure monitoring.

    If good technique is used with well calibrated equipment, these measurements can be combined with those in the doctor's office to create a fuller picture of blood pressure control. If these external readings are also persistently raised, one can conclude that the blood pressure is not yet satisfactorily controlled.

    Disease progression

    With time, the blood pressure in adults with hypertension will gradually increase.6 There is no recent, rigorous evidence as to how often disease progression is the sole cause of resistant hypertension, but without firm evidence to the contrary it seems unwise to accept it as such until other causes have been excluded.

    suboptimal treatment

    The regimens prescribed for patients may not be optimally individualised for many reasons. Many patients require aggressive treatment with several drugs to achieve target blood pressure levels. To detect suboptimal treatment, review all the drugs a patient is taking, as well as the patient's dietary habits and exercise pattern. Consider whether the dosage of each drug prescribed conforms in all respects with recommendations for its rational use and with what is known about the patient's unique health status and preferences.

    Hypervolaemia resulting from a high intake of dietary sodium frequently plays an important part in resistant hypertension, and better use of diuretics is often the answer when a patient's blood pressure is difficult to control.79 Clinicians should review regimens regularly to see if the patients' treatment plans are optimal.

    Antagonists that can increase blood pressure

    • Adrenal steroids (especially mineralocorticoids)

    • Alcohol

    • Amphetamines—for example, appetite suppressants

    • Anaesthetics, local and general

    • Antidiuretic hormone and angiotensin

    • Caffeine

    • Cocaine

    • Cyclosporin

    • Disulfiram

    • Erythropoietin

    • Licorice and carbenoxolone

    • Monoamine oxidase inhibitors, combined with foods containing tyramine or with amphetamine

    • Medications containing sodium—for example, antacids or parenteral antibiotics

    • Non-steroidal anti-inflammatory drugs

    • Oral contraceptives

    • Sympathomimetic agents—for example, nasal decongestants or bronchodilators

    • Withdrawal of antihypertensive agents—for example, β blockers or clonidine


    No matter what treatments are prescribed, they will have no effect if drugs are not taken. For any number of reasons, patients may not take their drugs as prescribed or may not take them at all. Direct and non-judgmental questioning at routine clinic visits is the best way of detecting non-compliance. A systematic review of the discriminatory power of such simple questioning estimated its sensitivity to be 55% and its specificity to be 87%.10

    Antagonising substances

    Patients may be taking many prescription and non-prescription drugs and dietary and other substances that can increase blood pressure or oppose the actions of antihypertensive drugs (see box). No rigorous studies have evaluated the frequency or magnitude of effects of such substances on blood pressure.

    Non-steroidal anti-inflammatory drugs (NSAIDs) account for 5% to 10% of all prescriptions in developed countries. 11 12 If they do raise blood pressure or oppose the effects of antihypertensive drugs, then they could, because of the extent to which they are taken, have a considerable impact on blood pressure control.


    A commonsense approach to evaluating resistant hypertension

    Two systematic reviews have examined the effect of non-steroidal anti-inflammatory drugs on blood pressure. One summary of findings from 54 trials found that treatment with non-steroidal anti-inflammatory drugs increased mean arterial blood pressure by 1.1 mm Hg in normotensive patients and by 3.3 mm Hg in patients with hypertension.13 Most of these trials were short (less than six weeks), and none included elderly patients. Among the non-steroidal anti-inflammatory drugs, indometacin had the largest effect on blood pressure and aspirin the least. Another systematic review summarised 50 trials and estimated that non-steroidal anti-inflammatory drugs increased mean supine blood pressure by 5 mm Hg.14

    Coexisting conditions

    While usually not considered as causes of secondary hypertension, several disorders may coexist in patients with hypertension and either increase blood pressure or interfere with its treatment. These include

    • Alcohol use, more than 12–14 g of absolute alcohol per day

    • Anxiety disorders, including hyperventilation or panic attacks

    • Delirium, with agitation and autonomic excess

    • Hyperinsulinism with insulin resistance

    • Obesity

    • Pain, acute or chronic

    • Pregnancy

    • Sleep apnoea

    • Smoking

    Both clinical experience and research suggest that some of these conditions commonly coexist with hypertension. For example, population surveys have repeatedly shown that up to 40% of people with hypertension are obese.15 Obesity can interfere with accurate blood pressure measurement, can truly increase blood pressure, and can interfere with the effectiveness of antihypertensive drugs. Recognising the coexistence of such disorders makes it possible to treat them and so, potentially, improve control of blood pressure, although to what extent is not clear.

    Secondary hypertension

    By definition, patients with secondary hypertension have an underlying disorder believed to be a direct cause of their hypertension. Detecting such a disorder offers the prospect of giving specific treatment that will lower the blood pressure to normal without the need for specific antihypertensive treatment.

    The prevalence of secondary hypertension in primary care is uncertain but it is probably an uncommon form of hypertension. Studies of secondary hypertension and the relative proportions of its causes have had several methodological limitations, including selection of patients from referral settings, differing diagnostic criteria, and differing evaluations.1620 For example, a study from a referral clinic in the 1960s reported the prevalence of renovascular disease as 4.4%, of phaeochromocytoma as 0.2%, and of hyperaldosteronism as 0.4%.16 At another referral clinic in the early 1970s, the prevalence of renovascular disease was 0.18%, while that of phaeochromocytoma was 0.04% and that of hyperaldosteronism was 0.01%.16 Such rates observed at referral centres are probably much higher than those seen in primary care today. Given this evidence, renovascular and renal parenchymal disorders are the most likely causes of such secondary hypertension seen in primary care practice.

    The overall rarity of disorders causing secondary hypertension presents a diagnostic challenge. Experts recommend investigation of patients who seem to be at above average risk on such epidemiological grounds as age and sex or on the presence of symptoms or signs of specific disorders. With the exception of renal artery stenosis,2123 we could not find evidence of how often presenting patterns thought to be associated with specific secondary causes occur among all patients with high blood pressure in primary care settings. Furthermore, we found relatively little evidence about how powerfully these features discriminate between those who do and those who do not have secondary hypertension.

    Determining the cause(s) of hypertension and adjusting treatment plans

    Ideally we would like to recommend a coherent strategy for evaluating and managing patients whose blood pressure is difficult to control, made up of well studied elements aggregated into a systematic approach itself shown to do more good than harm. Unfortunately, there is little or no evidence beyond expert opinion to guide clinicians, so, as a result, our recommendations, shown in the figure, are tentative. Although the recommendations are presented sequentially, we recommend that clinicians consider many of the options simultaneously and use their own judgment as to the appropriate order of queries.


    • Funding None.

    • Competing interests None declared.

    • Embedded Image The book Evidence-Based Hypertension, edited by Cynthia D Mulrow, can be purchased through the BMJ Bookshop (


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