Revisiting the prehypertension debate: Increasing evidence for treatment yet randomized clinical trials are lacking

Abstract

In 2009, Blood Pressure featured a debate about whether to treat patients with prehypertension (Kiely et al., Blood Press. 2009;18:300–303; McInnes GT, Blood Press. 2009;18:304–307). Our group supported pharmacotherapy for this condition at that time. Since then, additional evidence linking prehypertension with associated morbidities has emerged. These studies are detailed below and provide further evidence for the treatment of prehypertension.

Key Words::

• Cardiovascular risk
• prehypertension
• pharmacotherapy

Prehypertension and neurological disease

Prehypertension produces deleterious consequences for multiple organ systems. As with hypertension, researchers are now documenting prehypertension's association with neurological diseases, including stroke and dementia. In 2011, a paper published by Lee and colleagues documented prehypertension as a risk factor for incident stroke (3). This study presented a meta-analysis of 12 prior cohort studies searching for an association between baseline prehypertension and incident stroke. Seven studies included within their meta-analysis stratified their study populations into patients with low-range prehypertension (systolic blood pressure, SBP = 120–129 mmHg or diastolic blood pressure, DBP = 80–84 mmHg) and high-range prehypertension (SBP = 130–139 mmHg or DBP = 85–89 mmHg). For the entire range of pre-hypertensive individuals, they found that prehypertension increases the risk of incident stroke by approximately 50% (relative risk, RR = 1.55, 95% CI 1.35–1.79; p < 0.001). When looking at the risk of incident stroke for the low-range and high-range groups separately, prehypertension was not found to be significantly linked to stroke in the low-range prehypertension group (RR = 1.22, 95% CI 0.95–1.57). However, those within the high-range prehypertension group had a substantially increased risk of stroke (RR = 1.79, 95% CI 1.48–2.11).

The neurological morbidity contributed by prehypertension is not confined to cerebrovascular disease. A 2011 article indicated that prehypertension was also linked to dementia (4). A group of researchers at Kyushu University studied 668 community-dwelling Japanese adults without dementia at baseline. For 17 years, they were followed to assess the link between midlife and late-life hypertension and the development of Alzheimer's disease and vascular dementia. Though they were not able to demonstrate an association between prehypertension and Alzheimer's disease, they reported a link between both midlife and late-life prehypertension and vascular dementia. Late-life prehypertension had a stronger association and was reported to represent a 3.0-fold increased risk of vascular dementia (95% CI 0.68–13.31; p = 0.15). A link between dementia and prehypertension was also found by Launer et al. (5).

A recent association was also found between Parkinson's disease and prehypertension in women (6). This study reported on results from seven different surveys, including 59,540 participants, from 1972 to 2002. By the end of the study, 423 men and 371 women had developed Parkinson's. The correlation in men between prehypertension and Parkinson's disease did not prove to be significant. However, when compared with normotensive subjects, the multivariable-adjusted hazard ratio of Parkinson's associated with prehypertension for women was 1.63 (95% CI 1.07–2.47).

The association of prehypertension with kidney disease and diabetes

Hypertension has been implicated as a leading cause of chronic kidney disease. It now seems likely, however, that elevated blood pressure within the prehypertensive range represents an independent risk factor for kidney disease. A 2009 study by Hsu et al. examined in multivariate logistic regression models the association of albuminuria and prehypertension (7). After accounting for confounding variables like diabetes and atherosclerotic disease, their study showed that the high-normal range of prehypertension was independently associated with albuminuria. In fact, albuminuria was almost three times as likely within this prehypertensive group, a group that did not demonstrate additional risk factors for chronic kidney disease (OR = 2.76, 95% CI 1.61–4.73). Similar links between chronic kidney disease and prehypertension were recently found by Crews et al. (8) and Yano et al. (9).

It should also be noted that prehypertension has been proposed as a risk factor for the development of type II diabetes mellitus (10). The incidence of diabetes was examined in a large cohort (n = 2767) of non-diabetic, normotensive participants in the San Antonio Heart Study. In this patient population, 12.4% of participants with prehypertension were found to have diabetes, compared with 5.6% of subjects with normal blood pressure. After adjusting for age, sex and ethnicity, the odds of incident diabetes was 2.21 greater for prehypertensive than normotensive subjects (95% CI 1.63–2.98). However, with adjustment for BMI, impaired glucose tolerance, insulin resistance and secretion, and family history of diabetes, the association was not found to be statistically significant (OR = 1.42, 95% CI 0.99–2.02). Another recent study has further established the link between prehypertension and type II diabetes (11). In this study, 1125 participants were classified as normotensive, prehypertensive or hypertensive at baseline and were checked for new incidence of diabetes in a follow-up visit 8 years after study initiation. After adjusting for age, sex, BMI and physical activity, new-onset diabetes was more likely in prehypertensive (OR = 2.32, 95% CI 1.05–5.1, p = 0.03) and hypertensive (OR = 3.5, 95% CI 1.30–8.0, p = 0.002) patients than normotensive patients.

Pre-hypertension and risk of incident atrial fibrillation

Atrial fibrillation (AF) represents a major public health hazard through its association with thromboembolic disease, heart failure and decreased quality of life (12–14). It is the most common arrhythmia, and its incidence is increasing (15–17). As rhythm control has proven to be challenging and of questionable efficacy, a renewed focus has been placed on the prevention of AF (18–21). Hypertension is a common risk factor in incident AF.

Grundvold et al. (22) and Conen et al. (23) recently suggested that blood pressure within the pre-hypertension range is also a risk factor for AF. Grundvold et al. conducted a cohort study analyzing 2012 healthy Norwegian men between 1972 and 1975. After 35 years of follow-up, 270 men were diagnosed with AF. Within this group, they used a multivariate-adjusted Cox proportional hazards model to estimate the risk conferred by four quartiles of baseline blood pressure. Men within the upper-limit of normal blood pressure, which they defined as SBP of 128–138, had a 1.51-fold (95% CI 1.05–2.20) increased risk of AF. Similarly, Conen et al. prospectively followed 34,221 women who participated in the Women's Health Study for incident AF. In this report, 644 incident AF events occurred over a follow-up period of 12.4 years. Using multivariable-adjusted hazard ratios for SBP categories, the women with baseline SBP of 130–139 had a 1.56-fold (95% CI 1.22–2.01) increased risk of incident AF.

The role of pharmacotherapy in the treatment of prehypertension

Several investigations have addressed the feasibility of treating prehypertension with pharmacotherapy. In our 2009 paper published in Blood Pressure (1), we commented upon the most salient study to date, the TROPHY trial (24). The PHARAO study, an investigation undertaken in parallel to the TROPHY trial, further established the viability of using pharmacotherapy in prehypertension (25). The PHARAO study was a 3-year prospective, randomized, controlled, multicenter study. Patients were eligible for enrollment within this study if they were 50 years of age or older, not on pharmacotherapy for hypertension, found to have high-normal office blood pressure as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) or European Society of Hypertension (ESH). The subjects of this study were randomized to receive either placebo or ramipril. The subjects were followed for 3 years to determine the incidence of SBP and/or DBP > 140/90 mmHg or intake of an additional anti-hypertension medication. After the study period, 30.7% of the subjects in the ramipril group and 42.9% of the subjects in the control group met the endpoint for hypertension. This amounted to a relative risk reduction of 34.4% (HR 0.656; 95% CI 0.533–0.807; p = 0.0001), supporting the use of ramipril.

A major concern for the proposed medical treatment of prehypertension is the lack of controlled trials supporting the use of pharmacotherapy. This is beginning to change (26). It was recently found that the treatment of prehypertension decreased the risk of incident stroke (27). These researchers found that subjects within the treatment arm of their study had a 22% reduced risk of stroke compared with the placebo group. Additionally, another large controlled trial is being undertaken by Fuchs et al. to examine the effects of pharmacotherapy on prehypertensive patients (28). The future results of this study have the potential to provide enough evidence to silence the debate over using pharmacotherapy for prehypertension.

Given the abundance of evidence linking prehypertension to various sources of morbidity, disagreements over whether to employ pharmacotherapy seem to increasingly favor the treatment paradigm. Since safe and cost-effective antihypertensive drugs are available, in the future we expect to implement their use, especially for the high-normal prehypertensive range.

Potential limitations

The fact remains that the data incriminating pre-hypertension as a risk factor for cardiovascular, neurological and renal disease has been derived from cohort and case–control studies. There are no randomized clinical trials analyzing the efficacy of medical therapy in preventing the complications of pre-hypertension. The advocation of medicinal therapy for pre-hypertension remains speculative. Furthermore, many of the articles analyzing pre-hypertension focus on very specific target populations. It is unclear whether data from these studies apply to other populations.

There exist many effective, safe and affordable medications for blood pressure management. Given the prevalence and potential morbidity associated with pre-hypertension a randomized control trial must be undertaken to determine the true hazards associated with this variable. Yet, until the absolute risk reduction and the cost-effectiveness of medicinal therapy for pre-hypertension can be quantified, it is doubtful that there will be change in the treatment paradigm of hypertension.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.