Hypertension Criterion for Stroke Prevention—to Strengthen the Principle of Individualization in Guidelines

Abstract

The diagnosis of hypertension, as recommended by most guidelines, is determined by systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. A threshold‐based definition of hypertension, however, ignores sex and age, pathophysiology, and disparities in patient‐specific conditions. Moreover, the harmful effects of hypertension‐induced target organ damage cannot be ignored. Although the principle of individualization for hypertension management is recommended, especially for stroke prevention, how to practice it in a clinical setting has not been clearly elaborated. Therefore, we put forward a proposal for individualized hypertension management incorporating target organ damage, the main harmful effect of hypertension. We propose that hypertension should be diagnosed when an individual's blood pressure exceeds some difference from their own baseline in young adulthood, accompanied by any hypertension‐induced target organ damage, confirmed by various detection methods. Application of this proposal to stroke prevention will hopefully strengthen the principle of individualized hypertension management.

The 2014 guideline for the prevention of stroke in patients with stroke and transient ischemic attack (TIA) from the American Heart Association/American Stroke Association (AHA/ASA) confirms that antihypertension treatment is possibly the most important secondary prevention for ischemic stroke and suggests that initiation and resumption of therapy as well as optimal therapeutic target should be individualized.1 On December 18, 2013, the Eighth Joint National Committee (JNC 8) released online for the first time the 2014 Evidence‐Based Guideline for the Management of High Blood Pressure in Adults2 and updated the previous edition of JNC 7. Simultaneously (December 17, 2013), the American Society of Hypertension (ASH) and the International Society of Hypertension (ISH) published their new article “Clinical Practice Guidelines for the Management of Hypertension in the Community.”3 In 2013, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) practice guideline for the management of arterial hypertension was also renewed.4 The JNC 8 guideline has drawn attention with its recommendation to raise the therapeutic target for blood pressure (BP) for hypertensive individuals 60 years and older to <150/90 mm Hg (<140/90 mm Hg for younger adults), a sizeable variation from the JNC 7 target of <140/90 mm Hg. Until recently, no agreement was reached on hypertension diagnostic criteria and treatment goals, particularly regarding ischemic stroke, despite years of debate. Additionally, the principle of individualization for hypertension management has been emphasized in stroke guidelines, but without elaboration. Because hypertension can cause target organ damage, we propose to incorporate target organ damage into hypertension management and accordingly optimize hypertension therapy for primary and secondary stroke prevention, hoping to strengthen the concept of individualization.

Challenges in Defining Hypertension

Changing Hypertension Definitions

Hypertension diagnostic criteria have undergone several changes (Table 1), although most guidelines recommend systolic BP (SBP)/diastolic BP (DBP) ≥140/90 mm Hg as the demarcation. Historically, more emphasis was placed on DBP than SBP. Before 1993 (JNC 5), DBP ≥90 mm Hg alone was the threshold in JNC guidelines, even though the World Health Organization's (WHO's) guideline early in 1978 incorporated SBP into its hypertension definition. With SBP added, the threshold was ≥160 mm Hg before 1993, and was then reduced to ≥140 mm Hg. Recently, age was taken into account. The 2013 ASH/ISH guideline recommends SBP and/or DBP ≥150/90 mm Hg as the diagnostic criterion for patients 80 years and older. In the JNC 8 guidelines, an age divide of 60 was adopted. Age stratification in hypertension diagnosis is moving forward, but inconsistencies and constant revision bring into question the current one‐size‐fits‐all definition.

Table 1.

Evolution of Diagnostic Criteria for Adult Hypertension

Guidelines	Year Published	Basis for Hypertension	Diagnostic Criteria
			BP, mm Hg	Age, y
WHO	1978	SBP or DBP	≥160/95
WHO	1994	SBP and/or DBP	≥140/90
WHO/ISH	1993/1999/2003	SBP and/or DBP	≥140/90
		ISH	≥140/<90
JNC 1	1976	DBP	>90
JNC 2	1980	DBP	>90
JNC 3	1984	DBP	≥90
		IsoSH	≥160/<90
JNC 4	1988	DBP	≥90
		IsoSH	≥160/<90
JNC 5	1993	SBP and/or DBP	≥140/90
JNC 6	1997	SBP and/or DBP	≥140/90
JNC 7	2003	SBP and/or DBP	≥140/90
JNC 8	2014	SBP and/or DBP	≥150/90	≥60
			≥140/90	<60
ESH/ESC	2003/2007/2009/2013	SBP and/or DBP	≥140/90
		IsoSH	≥140/<90
ASH/ISH	2013	SBP and/or DBP	≥140/90	18–79
			≥150/90	≥80
ACCF/AHA	2011	SBP and/or DBP	≥140/90	65–79
			≥145/90	≥80

Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; ASH, American Society of Hypertension; BP, blood pressure; DBP, diastolic blood pressure; ESC, European Society of Cardiology; ESH, European Society of Hypertension; IsoSH, isolated systolic hypertension; JNC, Joint National Committee; SBP, systolic blood pressure; WHO, World Health Organization.

Continuous BP Distribution in the General Population

The SBP and DBP unimodal distribution in the general population makes any hypertension definition involving choosing a cutoff value arbitrary.5 In 1996, the WHO expert committee confirmed that population BP levels are continuously distributed, like the normal/bell curve, and no absolute demarcation line exists between normotension and hypertension. Therefore, to distinguish hypertension from normotension requires an operative method, ie, determining a cutoff value where the advantages of detection and treatment outweigh the disadvantages.6 The 2013 ESH/ESC Task Force for the management of arterial hypertension shares a similar opinion: “In practice, cutoff BP values are universally used, both to simplify the diagnostic approach and to facilitate the decision about treatment.”

Sex and Age Disparities in BP

A fixed threshold–based hypertension definition also includes an arbitrary element, because BP values are not uniform among individual patients, especially those of different age and sex. The 1993 WHO/ISH subcommittee7 was keenly aware of marked differences among individual patients with similar hypertension levels and that these differences have important implications for treatment decisions.

Sex and age disparities in BP have been confirmed.8, 9 SBP is lower in young women than in men, and DBP tends to be lower at all ages. Women's BP catches up with men's after the sixth decade and then becomes slightly higher.8 Hypertension results in a lower morbidity rate in young women than in young men. However, hypertension prevalence increases more rapidly after age 50 in women; hence, it is more common among women older than 60 years.9 Given the sex distinction of BP among different ages, Atalar and colleagues10 investigated the 5th to 95th percentile reference ranges for SBP, DBP, and mean arterial pressure (MAP) in 640 healthy young women (aged 18–35 years) and proposed using the 95th percentile of SBP (115 mm Hg), DBP (72 mm Hg), and MAP (85 mm Hg) as cutoff values for hypertension in young women.

Whether hypertension thresholds should differ according to sex or age is controversial. A recent study found that hypertension thresholds stratified for sex and age were nonsignificant and supported a single BP threshold applied indiscriminately in current guidelines.11 However, the baseline BP of women was lower than that of men in young adulthood;8 therefore, a larger gap between baseline BP and hypertensive threshold exists in women. Cumulative BP has been reported to predict cardiovascular disease (CVD) among adults,12, 13 and long‐term exposure to BP levels in the prehypertension range or higher was a strong risk predictor for CVD14 and stroke.15 How the BP gap and cumulative BP affect the cardiovascular system differently among ages and sexes remains unknown.

Hypertension and CVD

Complicated Relationship Between BP and CVD

Hypertension, a significant etiologic factor, accelerates development of CVD and chronic kidney diseases.16 However, BP level is influenced by various factors that are either primarily or secondarily modified. Functional and structural cardiovascular abnormalities are both a cause and effect of BP elevation. Aware that early markers of CVD frequently occur before BP elevation, Giles and colleagues17 separated increased BP (a disease manifestation) from hypertension (the disease). The Hypertension Writing Group in 2005 incorporated in its definition cardiovascular risk factors, early disease markers, and target organ damage, instead of a specific BP threshold.18 Nevertheless, because it lacked an explicit BP value, Pickering19 criticized their definition as vague, leaving both physicians and patients confused.

Hypertension and Vasculature Alterations With Aging

Aging is associated with increasing hypertension prevalence in both sexes and various racial groups. Data from the Third National Health and Nutrition Education Survey (NHANES III) demonstrated that, among untreated patients with hypertension, approximately 26% were aged 18 to 49 years, with 74% older than 50.20 Arterial aging is related to isolated systolic hypertension (IsoSH), diastolic heart failure, and cerebral small vessel disease and other organ damage.21 IsoSH, defined by SBP ≥140 mm Hg and DBP <90 mm Hg, is the most prevalent hypertension phenotype, accounting for 87% among those older than 60 years.22

The Framingham Heart Study23 revealed persistent SBP elevation throughout the geriatric years with DBP declining after age 60 in normotensive and untreated hypertensive patients, leading to a widened pulse pressure (PP) and an asymptotic MAP. A widened PP reflects increased arterial stiffness.20 With aortic stiffening, pulse wave velocity accelerates and wave reflection speeds up; hence, SBP rises.24, 25 Decreased aorta elasticity is also associated with a greater peripheral runoff during systole,24 resulting in a fall in DBP.26 Antihypertension therapy has reduced morbidity and mortality in individuals older than 60 years,27, 28, 29 but doubt exists about whether treating geriatric IsoSH is beneficial or actually increases risk.26 Because the increase in BP with aging may be, at least partially, a normal physiological process, attempts to reduce BP in the elderly may be unreasonable, as is using the same criterion for hypertension for both younger and older populations.

Effects of BP Variability on Vascular Complications

Hypertension is the main determinant risk factor for progression of macrovascular and microvascular complications.30, 31 The underlying BP, conceived as the average value over long periods, is important in causing adverse effects and should form the basis of hypertension diagnosis.32 However, the significance of BP variability and maximum BP, particularly SBP, in predicting future cardiovascular events has been gradually recognized.33 Visit‐to‐visit SBP variability and maximum SBP are suggested to be closely correlated to stroke morbidity, independent of mean SBP among patients with previous TIA or treated hypertension.33 Hsieh and colleagues34 reported in patients with type 2 diabetes that neither baseline nor follow‐up SBP, DBP, PP, or MAP, but BP variability, determines CVD mortality and proposed BP variability as a potential therapeutic target in type 2 diabetes. The Ohasama study35 revealed that increased day‐by‐day SBP or DBP variability in a general Japanese population was a strong predictor for cardiovascular and stroke mortality, although not for cardiac mortality.

White‐coat hypertension (WCHT) refers to the condition in which BP is elevated in the office but normal out of the office. Conversely, masked hypertension (MHT) is when BP is normal in the office but abnormally high outside of the medical environment. Studies indicated that, for WCHT, the incidence of cardiovascular events was intermediate between sustained hypertension and true normotension, and for MHT, the incidence was approximately two times higher than normotension and was similar to sustained hypertension.4

Defining hypertension only on the basis of an office BP measurement may lead to excessive and insufficient therapy for WCHT and MHT, respectively, which illustrates why a threshold‐based hypertension criterion is not reasonable.

BP Management in Ischemic Stroke

In a statement for healthcare professionals from the AHA/ASA, patients with stroke, and atherosclerotic stroke particularly, were considered to be at high risk (≥20% over 10 years) of further coronary and cardiovascular events.36 The association between hypertension and risk of ischemic stroke is well‐established.37 The link between BP and the risk of a first stroke is observed at a low threshold of 115/75 mm Hg; among individuals aged 40 to 69 years, each increase of 20/10 mm Hg doubles the death rate from stroke.38 The benefit of BP‐lowering therapy for stroke prevention depends positively on the magnitude of the reduction.39, 40

Antihypertension Treatment in Acute Ischemic Stroke

Despite the known benefits of BP‐lowering therapy, limited data are available elaborating on immediate BP management in acute ischemic stroke. A US nationwide study revealed that approximately 70% have elevated SBP ≥140 mm Hg in the acute period.41 SBP rises in the acute period, helping to maintain cerebral perfusion,42 and decreases spontaneously over the next few days.43

Most guidelines favor cautious recommendations over progressive measures, although conflicts exist. Therapeutic intervention indicated for established SBP/DBP ≥140/90 mm Hg or preexisting hypertension, is suggested to start beyond the first several days from stroke onset,1, 37 or at least after the first 24 hours.44 Treatment within the first 24 hours is warranted only for patients eligible for fibrinolytic therapy (to maintain BP <185/110 mm Hg) or with SBP >220 mm Hg or DBP >120 mm Hg.37, 44 However, the benefits of treating hypertension in the acute setting of ischemic stroke remain controversial,44 especially for those with SBP/DBP <140/90 mm Hg.1 Furthermore, an optimal target is not specified in most guidelines, but instead, individualization is recommended.1, 44

Antihypertension Treatment in Secondary Stroke Prevention

Controversy also remains regarding the timing of optimal BP reduction as well as the target or ideal antihypertensive agent for recurrent stroke prevention,45 although evidence strongly supports that antihypertension treatment contributes to secondary stroke prevention and risk reduction for cardiac events in patients with previous stroke or TIA.46

The best time to restart long‐term antihypertension therapy is not well‐established,44 but after the initial 24 hours is considered reasonable.44, 47 An individualized therapeutic goal is suggested, with a recommendation of <140/90 mm Hg in the newest 2014 AHA/ASA stroke guidelines.1 Antihypertension treatment should be more aggressive for patients with diabetes37 or a recent lacunar stroke.1 Lifestyle modifications associated with lowering BP are highly recommended, including salt restriction, weight loss, healthy diet, regular aerobic physical activity, and limited alcohol consumption.47 Particularly, both the 2011 and 2014 AHA/ASA guidelines highly recommend considering specific patient characteristics for specific drugs and goals determination.1, 47

Antihypertension Treatment in Cerebral Arterial Stenosis

Regarding secondary stroke prevention, problems associated with lowering BP in patients with cerebral arterial stenosis are particularly debatable.

Rothwell and colleagues48 compared the correlation between BP and stroke risk in TIA and stroke patients with documented carotid disease and with low carotid disease prevalence. In patients with bilateral ≥70% carotid stenosis, a decreased stroke risk was associated with SBP ≥150 mm Hg and increased with <130 mm Hg, although for those with unilateral carotid stenosis, incidence was not influenced by BP. This finding suggests that progressive antihypertension treatment is not appropriate for patients with severe carotid stenosis. In the United States, a consensus among experts was reached that BP ≥140/90 mm Hg be allowed for intracranial stenosis.49

However, data from the Warfarin‐Aspirin Symptomatic Intracranial Disease (WASID) trial found that elevated mean SBP and DBP increased ischemic stroke risk, even after adjustment for risk factors.50 Accordingly, both the 2011 and 2014 AHA/ASA stroke guidelines1, 47 recommended maintaining SBP <140 mm Hg for patients with stroke or TIA induced by 50% to 99% stenosis of a major intracranial artery. The 2011 guidelines for extracranial carotid and vertebral artery disease specified that a target BP <140/90 mm Hg is reasonable for patients with hypertension and asymptomatic extracranial carotid atherosclerosis,51 but also noted that the relationship between specifically targeted therapy and cerebral ischemia risk exacerbation has not been established.51

Arterial stenosis is a special etiology of ischemic stroke. The target of <140/90 mm Hg is not universally applicable in this special situation, and hypertension treatment should differ according to locations of unilateral or bilateral arterial stenosis.

Perspectives

Stroke prevalence is associated with hypertension, and antihypertension therapy plays a significant role in stroke prevention. The concept of individualization for hypertension management has been more and more emphasized. However, its application in clinical practice is not clearly elaborated, leaving physicians confused in attaining optimal BP goals.

The main harmful effect of hypertension is target organ damage. There is an independently continuous correlation between BP and the incidence of several cardiovascular events (stroke, myocardial infarction, sudden death, heart failure, and peripheral artery disease) as well as end‐stage renal disease.38, 52 This holds true among individuals of different ages and in all ethnic groups.53, 54 The 1993 WHO/ISH guideline7 for mild hypertension classified hypertension into stage I, II, and III according to the extent of organ damage. Likewise, the 1999 WHO/ISH guideline55 emphasizes that hypertension management should not be based on BP alone, but also on the presence of other risk factors, concomitant diseases, and specific situations, and thus proposed three aspects of critical factors, including target organ damage, to stratify hypertension risk as low, medium, high, and very high. Organs affected by hypertension‐induced damage include heart, brain, kidney, optic fundi, and blood vessels. Table 2 summarizes the subclinical signs or clinical manifestations of and methods for detecting target organ damage.4, 7, 55, 56, 57

Table 2.

Subclinical Signs or Clinical Manifestations of and Methods for Detecting Target Organ Damage

Target Organs	Subclinical or Clinical Manifestations	Detection Methods
Heart	Left ventricular hypertrophy, coronary artery stenosis, angina, myocardial infarction, and heart failure	Radiography, electrocardiography, echocardiography, angiography, and plasma myocardial enzymes test
Brain	Cerebral small vessel disease (lacunar infarction or lacune, white matter lesion, perivascular space enlargement, cerebral microbleeds), intracranial and extracranial artery stenosis, transient ischemic attack, and stroke (ischemic or hemorrhagic)	MRI, CT, and angiography
Kidney	Microalbuminuria (20–300 mg/24 h), proteinurin (>0.5 g/24 h), and chronic kidney disease/chronic renal failure	24‐h urinary protein quantity, urine routine, and renal function examination (eGFR calculation)
Optic fundi	Focal or general narrowing of retinal artery, arteriovenous nicking (arterial wall refective enhancement, arteriovenous ratio <2/3), retinal hemorrhages/microaneurysms/hard exudates/cotton wool spots, papilloedema, and/or macular edema	Fundoscopy and fundus fluorescein angiography
Arteries	Intima‐media thickness of the carotid artery, atherosclerosis plaque (aorta, subclavian, carotid, iliac, and femoral arteries) large artery stenosis/stiffening (aorta, subclavian, carotid, iliac, femoral arteries), aneurysm, and peripheral arterial disease	Vascular ultrasound, angiography, pulse wave velocity, and ankle‐brachial index

Abbreviations: CT, computed tomography; DSA, digital subtraction angiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging.

Considering that some individuals develop target organ damage before their BP levels reach the current hypertension threshold and the adverse effects of organ damage are fatal, we propose taking target organ damage, combined with increased BP, into account in hypertension management. Hypertension should be established when an individual's SBP and/or DBP exceeds some difference, determined on an individual basis, from their own baseline in young adulthood, accompanied by manifestations of hypertension‐induced target organ damage confirmed by multiple detection methods. Differences between baseline and hypertension diagnosis would vary among individuals, with no specific threshold. The initial time and therapeutic target should also be determined to ultimately avoid or reduce target organ damage.

To implement this nonthreshold‐based hypertension criterion, individuals would need to have BP measurements performed in early adulthood to establish a baseline BP. In late adulthood, once early subclinical signs (results of laboratory examinations rather than clinical manifestations) of target organ damage appear, combined with one's BP surpassing baseline, despite <140/90 mm Hg, the diagnosis of hypertension can be established and treatment should begin immediately in case of serious complications. For those without any subclinical signs of relevant organ damage but with BP ≥140/90 mm Hg, it would be necessary to closely monitor the development of target organs and initiate treatment as soon as the appearance of early damage. For young individuals in early adulthood, hypertension should be diagnosed if subclinical signs of target organ damage emerge, irrespective of BP level. Moreover, it is crucial to seek out the real causes of early hypertension in addition to initiating immediate antihypertension therapy. For young patients who have baseline BP already ≥140/90 mm Hg in early adulthood, but have not yet developed any early lesions of target organs, we highly suggest measuring BP and observing target organ development strictly, as well as start treatment once subclinical damage arises.

For setting therapeutic goals, the aim of preventing target organ damage is of great concern. To apply this proposal to stroke prevention in patients with hypertension, the therapeutic target for primary prevention should be as close as possible to an individual's own baseline in young adulthood. For secondary stroke prevention, hypertension management should be individualized according to sex, age, stroke subtypes, underlying angiopathy, and patient‐specific conditions with the purpose of reducing target organ damage.

Our proposal is likely to be criticized for going against the principle of early prevention and treatment. It must be emphasized, however, that we suggest careful monitoring of target organ development for those with BP ≥140/90 mm Hg but with no subclinical signs of organ damage and initiating treatment immediately following the appearance of subclinical signs, rather than clinical manifestations of relevant organ damage. Furthermore, a high BP level is only a measured value that predicts hypertension, but organ protection is the ultimate goal of hypertension management; hence, a hypertension definition should take into account not only BP level but also target organ damage.

Conclusions

It is essential to improve the current threshold‐based hypertension definition, because it is far from perfect in many aspects. Although our proposal is not yet comprehensive, it does add detail to the principle of individualization for hypertension management. Moreover, the science, as well as its practicability in a clinical setting, awaits further investigation.

J Clin Hypertens (Greenwich). 2015;17:232–238. DOI: 10.1111/jch.12471. © 2015 Wiley Periodicals, Inc.