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Year : 2012  |  Volume : 23  |  Issue : 2  |  Page : 223-233
Prehypertension - Time to Act

1 Central Government Health Scheme, New Delhi, India
2 Division of Nephrology, The Ottawa Hospital, Ottawa, Canada
3 Nephrology Division, University of Tennessee, Memphis, USA

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Date of Web Publication28-Feb-2012


The term "prehypertension" defined as systolic blood pressure between 120 and 139 mmHg and/or diastolic pressures between 80 and 89 mmHg has now gained general acceptance. Prehypertension is associated with ~3-fold greater likelihood of developing hypertension, and roughly twice the number of cardiovascular events, than BP < 120/80 mmHg. When compared with normotensive individuals, prehypertensive individuals are more likely to be overweight and obese, to have other cardiovascular risk factors, to progress to established hypertension, and to experience premature clinical cardiovascular disease. The major unresolved issue is the appropriate manage­ment of such patients. Lifestyle modification is recommended for all patients with prehypertension as it effectively reduces rate of cardiovascular events. Presently pharmacological therapy is indicated for some patients with prehypertension who have specific comorbidities, including diabetes mellitus, chronic kidney disease, and coronary artery disease.

How to cite this article:
Gupta P, Nagaraju SP, Gupta A, Mandya Chikkalingaiah KB. Prehypertension - Time to Act. Saudi J Kidney Dis Transpl 2012;23:223-33

How to cite this URL:
Gupta P, Nagaraju SP, Gupta A, Mandya Chikkalingaiah KB. Prehypertension - Time to Act. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2022 Sep 27];23:223-33. Available from: https://www.sjkdt.org/text.asp?2012/23/2/223/93143

   Introduction Top

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) defined prehypertension (PHT) as a blood pres­sure (BP) of 120-139 mmHg systolic and/or 80-89 mmHg diastolic, which in the past was called transient hypertension, borderline hyper­tension, or high-normal BP. [1]

JNC-7 was not the original source for the term PHT or the BP range that defines it. In 1939, Robinson and Brucer observed that systolic BP in the range 120-140 mmHg, especially in younger individuals, was associated with high risk of progression to definitive hypertension (HT) and cardiovascular disease (CVD) later in life. They referred those individuals as having "prehypertension" at that time. [2] In 2003, this concept of PHT again came into limelight by incorporating it into the guidelines for the management of BP through the JNC-7. [2] The evidence for creating this terminology came from the results of two landmark trials. A meta-analysis, that included approximately one million individuals from 61 long-term epidemiological studies, demonstrated that mortality from ischemic heart disease and stroke in individuals aged 40-89 years increases in a log-linear proportionately with both systolic and diastolic BP. [3] There was a two-fold increase in mortality associated with coronary artery disease and stroke for every 20 mmHg increase in systolic BP or 10 mmHg increase in diastolic BP over 115/75 mmHg. [3]

Secondly, the longitudinal data from the Framingham Heart Study (FHS) have clearly shown that the individuals with 120-139/80-89 mmHg BP are at increased risk of developing full-blown HT and CVD later in life than the individuals with less than 120/80 mm Hg. [4],[5]

The objectives of creating such a category in the classification was to increase awareness of the importance of identifying individuals in whom early intervention by adoption of healthy lifestyles could lower BP and thus decrease the rate of progression to hypertensive levels and also reduce the risk of CVD. An additional rationale for use of this terminology was the greater likelihood of the affected individual to follow healthcare recommendations. [6]

However, arguments against using this term include the fact that there is heterogeneity with­in this category because the risk of progressing to HT and developing cardiovascular events is higher in patients with BP 130-139/85-89 mmHg range than in those with BP 120-129/80-84 mmHg; there were also concerns that the term PHT would create anxiety among the general population. [6],[7]

   Epidemiology Top

PHT is very commonly prevalent in the ge­neral population. Based on the third National Health and Nutrition Examination Survey (NHANES III; 1999-2000) the prevalence of PHT among adults in the United States was 31%. [8] In the Women's Health Initiative Report, preva­lence by race-ethnic groups was provided and ranged from 32-40%. [9]

From 2005 to 2006, approximately three of eight adults in the United States had BP in the prehypertensive range of 120-139/80-89 mmHg and roughly one in eight adults had BP in the range of 130-139/85-89 mmHg. [10]

In terms of race/ethnic variables, NHANES III found no diference in the prevalence between non-Hispanic whites, non-Hispanic blacks, Me­xican Americans or others, [8] whereas the re­cently concluded REGARDS study in 2011 found a prevalence of PHT higher in the Africo Americans than in whites (62.9% in blacks compared to 54.1% in whites). [11] In the NHANES III report, men were more likely to have PHT than women (40% versus 23%) and PHT was higher in individuals with overweight/obesity. [8] The REGARDS study also observed a higher prevalence of PHT in obese individuals and self-reported heart disease in addition to those with elevated hs-CRP or dia­betes or microalbuminuria, and those with heavy alcohol consumption. [11]

   PHT and CVD Top

CVD is the leading cause of death in the United States and globally, representing 30% of all deaths worldwide. [12] Many prospective co­hort studies have established a strong, graded, and independent positive association between BP levels and risk of CVD, stroke, and pre­mature death. [1],[13] Increased CVD risk begins at systolic BP levels as low as 115 mmHg. [14]

There is enough evidence to show that indi­viduals may experience cardiovascular morbi­dity and mortality with BP in the PHT range. In the study by Vasan et al, by controlling for other comorbidities, the investigators found that men in the upper-half of the "prehypertensive" range, those with BPs of 130-139 mmHg sys­tolic or 85-89 mmHg diastolic, experienced 1.6 times, and women 2.5 times as many as many cardiovascular events as their normotensive counterparts. [15] Hansen et al calculated that the overall 10-year risk of a major cardiovascular event for the population with baseline BP at or above 130/85 is 18.7%, up from 5.1% in those below this threshold. [16] Similarly Liszka et al showed that in subjects with BP ≥120/80, the risk of a major cardiovascular event 1.37 times higher than others. [17]

Data from the Women's Health Initiative fur­ther supported these findings, demonstrating a 1.66-fold increase in the risk of myocardial in­farction, stroke, heart failure, and cardiovascular death for both white and nonwhite postmenopausal women with PHT over 7.7 years of follow-up. [9]

   PHT and Associated Risk Factors for CVD Top

Most individuals with PHT have one or more concomitant conditions associated with in­creased cardiovascular risk [Figure 1]. The NHANES II and the NHANES II Mortality Study showed that 90% of individuals with PHT had at least one other cardiovascular risk factor. [18] These include dyslipidemias, an early family history of CVD, cigarette use and abdo­minal obesity, hyperinsulinemia and insulin resistance, impaired fasting glucose, a prothrombotic state, endothelial dysfunction, and im­paired vascular distensibility.
Figure 1. Association of prehypertension with other risk factors and inflammatory mediators leading to cardiovascular morbidity and mortality.
CVD: cardiovascular disease, CRP: C-reactive protein

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A study of 36,424 individuals demonstrated that, compared with normotensive individuals, those with PHT had higher levels of blood glucose, total cholesterol, LDL cholesterol and triglycerides, higher BMI, and lower levels of HDL cholesterol. [19] BMI was the strongest predictor of PHT and PHT was more prevalent in diabetics than in nondiabetics. [19]

Nontraditional cardiovascular risk factors such as markers of inflammation may be found elevated with PHT. In the NHANES III and the REGARDS studies, individuals with PHT were found to have a higher level of C-reactive protein. [8],[11] In the ATTICA study, a range of inflammatory markers such as tumor necrosis factor-α, amyloid A, endothelin 1, homocysteine, advanced glycation products, and ele­vated white blood cell counts have been found significantly higher in prehypertensives com­pared with normotensives.[20] Microalbuminuria, a marker of endothelial dysfunction, and an independent risk factor for CV events, is also highly associated with PHT. [21],[11] These studies evidently demonstrate that PHT is often asso­ciated with multiple cardiovascular risk factors and predisposes for increased risk of CVD.

   PHT and Vascular/Structural Changes Top

PHT is associated with both microvascular and macrovascular pathology. Generalized re­tinal arteriolar narrowing is an important sign of HT, and a lower arteriolar:venular diameter ratio can predict risk of HT. [22],[23] Accordingly, in the Rotterdam study, individuals with PHT had significantly smaller arteriolar and venular dia­meters and arterio-venular ratios compared to normotensives. [24]

Prehypertensive individuals also often have increased evidence of subclinical atheroscle­rosis, manifested by increased common carotid artery intima-media thickness and increased calcium deposition in the coronary arteries and also accelerated development of left ventricular hypertrophy and diastolic dysfunction. [25] Markus et al in the MONICA/KORA Augsberg study of individuals with PHT for a follow-up of ten years found a significantly greater age-related increase in LV wall thickness (11.9 versus 4.7%, P<0.001) and LV mass (15.7 versus 8.6%, P=0.006) and an increased incidence of LV concentric remodeling [hazard ratio (HR) 10.7; 95% CI 2.82-40.4] and LV hypertrophy (HR 5.3; 95% CI 1.58-17.9), compared with individuals with normal BP. [26]

This evidence clearly shows that an indivi­duals with PHT can develop end-organ da­mages both microvascular and macrovascular similar to HT.

   PHT and New Onset Diabetes and HT Top

Patients with PHT are at greater risk for deve­loping HT as well as diabetes than patients with normotension. [27],[28],[29] Meisinger et al in their study of 11,001 German population for a follow-up period of 12.5 years, found a 1.8-fold higher incidence of diabetes in men with PHT. [29] In the Framingham Heart Study, approximately 37% of patients younger than 65 years and 50% of patients older than 65 years with stage 2 PHT (130-139/85-89 mmHg) progressed to HT in four years compared with 5% and 16% of patients with a normal BP less than 120/80 mmHg, respectively. [30] In the Trial of Preventing Hypertension (TROPHY), around 52% of placebo-treated patients with stage 2 PHT progresssed to clinical HT within four years. [31] The German Hypertension League Study on HT prevention reported a 43% incidence over three years of de novo HT among patients with stage 2 PHT randomized to placebo, which is similar to the rates observed in the TROPHY and the Framingham Studies. [32]

   PHT and Progression of Chronic Kidney Disease Top

The majority of information regarding chronic kidney disease (CKD) progression and PHT are from epidemiological analyses of large data­bases or small limited-outcome studies and are summarized in [Table 1]. [33],[34],[35],[36],[37] Taken together, these studies have a follow-up range between seven and 21 years and show that prehypertensive individuals with BP >130/80 mmHg have a varied high risk from 11 to 91% of worsening renal function over follow-up. How­ever, it should be noted that many individuals in these studies did have concomitant risk fac­tors, including hyperlipidemia and other meta­bolic disturbances.
Table 1. Epidemiological studies of chronic kidney diasease/end-stage renal disease risk and

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Studies in preexisting conditions, such as dia­betes, provide stronger data about the relation­ship of PHT and CKD risk. In a population-based sample of adults with type 1 diabetes, lower BPs were protective against incident proteinuria and estimated glomerular filtration rate reductions to < 60 mL/min per 1.73 m 2 . The maximum protective effect was observed at BP levels of < 120/80 mmHg. [38] Furthermore, the data from 137 patients with type I diabetes in Denmark showed that increases in systolic BP above 125 mmHg predicted development of nephropathy. [39] It is established that patients with type I diabetes and BP increases into the high prehypertensive range, and who have in­creases in albuminuria from baseline, are more likely to have CKD progression. In the Diabetes Control and Complication trial, 19 of 21 (90%) progresssors reached clinical diabetic nephropathy before the diagnosis of HT was made. [40] Accordingly, it is evident that increases in albuminuria/microalbuminria parallel BP in­creases in PHT range and antedate development of HT.

In addition to the clinical evidence, now there are also data for association of PHT and histological evidence of CKD progression, espe­cially in diabetes and IgA nephropathy, sho­wing changes in mesangial proliferation and degree of arteriolar hyalinosis. [41]

Prehypertensie subjects had a greater degree of renal arteriosclerosis and mesangial prolife­ration, whereas no changes were noted among those with BP <120/80 mmHg. [42] Taken together, these data support the fact that increases in BP over time within the prehypertensive range are associated with morphological changes within the kidney as well as the behavior of the endothelium. Thus, in high-risk CKD patients, both the change in albuminuria within the microalbuminuria range and BP within the prehypertensive range need to be monitored. [40]

   Management of PHT Top

The current data support mainly lifestyle inter­vention, i.e., nonpharmacological as the cor­nerstone of therapy for the general population and use of pharmacological therapy only in special circumstances such as diabetes, CKD, or cardiac disease.

Nonpharmacological strategi es

Lifestyle modifications, such as weight loss, dietary alterations, reduced sodium intake, exer­cise, and moderation of alcohol, have been shown consistently in randomized controlled trials to effectively lower BP and are recom­mended for patients with PHT [Table 2].
Table 2. Nonpharmacological management of prehypertension.
*Additional information for health care providers can be found at www.nhlbi.nih.gov

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The DASH trial and the PREMIER trial showed that BP was significantly reduced in prehypertensive and stage I hypertensive individuals by simply using a diet rich in vegetables and fruits (high potassium), and reduced saturated and total fat independent of dietary sodium res­triction and weight loss. [43],[44],[45]

A substudy of the DASH trial also showed that by reducing sodium intake (<100 mmol daily) in addition to the previous dietary changes provided greater benefit than either approach alone. [44] Extensive clinical trial data document a substantial and significant BP-lowering effect of weight loss. Reductions in BP occur even without attainment of normal body mass index (BMI). In a meta-analysis of 25 randomized, controlled trials, weight loss of 1 kg was associated with ~1 mmHg reduction in SBP and DBP in individuals with PHT. [46] The largest of the trials included in this analysis was Trials of Hypertension Prevention (TOHP). [47]

A number of clinical trials demonstrate that increased physical activity can lower BP inde­pendent of any effect on body weight, although this finding is not universal. [48],[49],[50] However, two meta-analyses concluded clearly that physical activity independently lowers BP. [51],[52] In one of these meta-analyses, 27 of 50 studies reported results in nonhypertensive subgroups, which presumably include a large proportion of par­ticipants with PHT. [52]

The results from clinical trials on moderation of alcohol intake and reduction in BP have been inconsistent. [53],[54] Nonetheless, a well-conducted study [53] and a meta-analysis [55] suggest that mo­deration of alcohol intake can independently lower systolic BP. Almost half of the studies in that meta-analysis included a population with BP in the PHT range. [55]

Studies have also observed that multicomponent behavioral interventions incorporation and increasing physical activities have further reduced long-term chances of developing HT and arterial disease. Hence, early adoption of these approaches would not only lower BP but also prevent progression to HT with reduction in target organs damages and cardiovascular events.

The largest population-based experience of lifestyle modification as a strategy to reduce cardiovascular risk factors, CVD, and mortality was reported from Finland.

In this study, by using a comprehensive community-level approach that encompassed the health and other services like voluntary organizations, local media, businesses (inclu­ding the food Industry) and changes to public policy, it could demonstrate a reduction in mortality from coronary artery disease by 55% in men and by 68% in women over a 20 year period (1972-1992). [56]

On the basis of the evidence reviewed above, each of these nonpharmacologic strategies for lowering BP is currently recommended for adults with PHT (JNC 7). [1]

Pharmacological therapies

Patients with PHT and comorbidities

The current recommendations for pharmaco-therapy in PHT are considered for only those patients with associated co-morbidities such as diabetes mellitus, CKD, and CVD. [57],[58] Up till now, conflicting results have been reported for the treatment of PHT patients with CVD. Several randomized controlled trials of BP lowering for the prevention of CVD demonstrated benefit among persons with PHT or normal BPs, [59],[60] while others did not. [61],[62] As an explanation for these conflicting results, the recent meta-analysis of randomized controlled trials by Angela et al clearly showed that among patients with clinical history of CVD but without HT, antihypertensive treatment re­sulted in a decreased risk of stroke, congestive heart failure, composite CVD events, and all-cause mortality. [63]

BP control is an important target in patients with established atherosclerotic disease, and treating BP to a prehypertensive level has a less favorable effect on disease progression than treatment to normotensive levels. In a substudy of the CAMELOT trial, the patients underwent coronary intravascular ultrasound examination at baseline and after two years of amlodipine, enalapril, or placebo therapy. [64] Patients who re­ceived active treatment and achieved BP values within the "normal" BP had a decrease in atheroma volume, whereas those who achieved a prehypertensive range revealed no major change in atheroma volume, and patients who remained hypertensive showed a significant increase in atheroma volume. This result was the first demonstration that lowering of systolic BP to ≤120 mmHg - a level below the pre-hypertensive range - effectively reduces inter­mediate end-points of cardiovascular disease. [64]

This finding enabled the American Heart Association-American College of Cardiology to recommend a BP goal of <120/80 mmHg for patients with coronary artery disease. However, in the recent ACCORD BP trial, which eva­luated the effect of targeting a systolic BP of 120 mmHg, compared with a goal of 140 mmHg, among patients with type 2 diabetes at high risk for cardiovascular events, the results showed that the strategy of intensive BP control did not show any benefit in reducing the rate of a composite of major cardiovascular events in the study patients. Moreover, compared with the standard-therapy group, the intensive-therapy group demonstrated significantly higher rates of serious adverse events attributed to antihypertensive treatment, as well as higher rates of hypokalemia and elevations in serum creatinine levels. [65]

Therefore, the present JNC-7 recommen­dations define a target of BP <130/80 mmHg in the prehypertensive population with comorbidities. [1]

However, it is unclear whether reaching BP <120/80 mmHg will result in more benefit or cause more adverse effects in this population; further studies are required to determine the optimal BP.

Pharmacotherapy for isolated PHT

When it comes to treating isolated PHT, the current recommendation is lifestyle modifi­cation. Certainly physical activity, weight loss, moderate alcohol intake, and a healthy diet with limited sodium have been shown to effectively lower BP and should be encouraged. [66] How­ever, adopting lifestyle change is notoriously difficult. It requires motivation and willingness to change spending habits in many cases; many patients lack one or the other. Given the un­deniable fact that uncomplicated PHT carries morbidity, question of treating PHT using pharmacotherapy has been posed in two prospec­tive, randomized clinical trials. The TROPHY study tested whether treatment with candesartan can prevent or delay the transition from PHT to stage 1 HT. [31] Results showed that candesartan for patients with PHT is safe and at least partially effective in reducing the risk of HT. However, no difference in the occurrence of cardiovascular events was observed between the two treatment groups and also the trial was not sufficiently powered to detect such a dif­ference, had it occurred. [31]

In the PHARAO trial, the effect of ramipril on preventing or delaying HT in individuals with PHT was studied. [32] HT developed in 31% of participants in the ramipril group and 43% of those in the placebo group, with a statistically significant 34% reduction in risk for the ramipril group, although the incidence of cerebrovascular and cardiovascular events was low and not significantly different between groups. In both TROPHY and PHARAO studies, adverse effects with drug use (candesartan and ramipril) were generally comparable to placebo.

Both studies documented that BP can be lo­wered safely in patients with PHT. Therefore, pharmacological treatment of prehypertensive individuals remains a matter of debate.

Arguments against the use of antihypertensive drugs for PHT include the lack of evidence that they reduce target organ damage and cardio­vascular morbidity and mortality in these patients. [31],[32] The ongoing PREVER trial in Brazil using diuretics in PHT to investigate the effi­cacy, safety, and feasibility of a population-based intervention to prevent the incidence of HT as well as target organ damage. [67] Further randomized controlled trials with long-term follow-up to detect the benefits of treatment in PHT population are still required.

We still have additional questions concerning appropriate choices, doses, and safety of agents, and duration of treatment.

Arguments in favor of pharmacotherapy in­clude the convenience of drugs and more likely adherence to therapy than complex lifestyle-modifying regimens. In the absence of further information about these issues and in light of the fact that lifestyle approaches favorably influence global cardiovascular risk as well as BP, they currently remain the first choice for the treatment of individuals with PHT without comorbid conditions. Patients with diabetes mellitus, CKD or coronary artery disease, clearly benefit from aggressive intervention, and phar­macological treatment should be administered to them if BP exceeds 130/80 mmHg with a caution of not reducing systolic BP levels < 120 mmHg. We conclude that individuals with PHT have an increased risk of full-blown HT, target organs damages, and cardiovascular-related mor­bidity and mortality. Lifestyle modifications can lower BP, reduce morbidity and mortality associated with cardiovascular events, and are recommended for all patients with PHT. Phar­macological treatment reduces progression from PHT to HT; however, more studies are needed to determine their efficacy on target organs damages and cardiovascular mortality in addi­tion to their safety and cost-effectiveness and to determine whether particular drug classes are more effective than others in this patients' group.

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Shankar Prasad Nagaraju
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PMID: 22382212

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