Pre-hypertension in high-cardiovascular risk population

Background

In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) published its last guidelines for hypertension prevention and management (1).
One of the main issues was the establishment of definition for a new category of blood pressure (BP) levels, i.e. prehypertension, that included individuals with a systolic BP of 120 to 139 mmHg, or a diastolic of 80 to 89 mmHg. Those patients were proved to show an increased risk for progression to hypertension, especially those included between 130/80 to 139/89 mmHg range, who were at twice the risk of developing hypertension than those with lower values (2).

At the same time, the European Society of Hypertension and the European Society of Cardiology (ESH-ESC) published their guidelines for the management of arterial ypertension and, for the same range of BP, two different categories of BP were defined: normal BP (systolic BP of 120 to 129 mmHg, or diastolic BP of 80 to 84 mmHg) and high-normal BP (systolic BP of 130 to 139 mmHg, or diastolic BP of 85 to 89 mmHg) (3).

In 2007, the ESH/ESC Committee decided against using the term “prehypertension” for several reasons (4). First, the risk of developing hypertension was unquestionably higher in subjects with high-normal than in those with normal BP (2,5). Second, although lifestyle changes recommended by the 2003 JNC-7 Guidelines as the sole treatment for all prehypertensive patients (1), in fact this group is a highly-differentiated one, as there were subjects with no need of any intervention (e.g. an elderly individual with a BP of 120/80 mmHg), as well as those with a high or a very high-risk profile (e.g. after stroke (6), coronary artery disease (7), or with diabetes (8) or metabolic syndrome), in whom pharmacological treatment is necessary.

In the latest reappraisal of European guidelines on hypertension management (9) published recently this year, trial evidence concerning drug treatment in patients with high-normal BP with or without previous cardiovascular events is thus far controversial, and further trials must be completed before firm recommendations can be given.
The present review will focus on the benefits of antihypertensive therapy in patients with high or very-high cardiovascular (CV) risk and high-normal BP. 

Table 1: Recent reports on Hypertension (concerning pre-hypertension or normal-high groups).

1) High-normal blood pressure and cardiovascular risk

Numerous epidemiologic studies have shown that systolic and diastolic BP values have a strong, permanent and graded association with cardiovascular disease (CVD) outcomes (10). Although subjects with high-normal BP are expected to have an elevated CV risk, there was a lack of information concerning the real risks of CVD in these patients.

Vasan et al. published a prospective assessment of the risk of CVD in men and women with high-normal BP, and proposed to explore the association between BP category and the incidence of CVD during a mean follow-up of 11.1 years among participants in the Framingham Heart Study. Cardiovascular-event rates increased in a stepwise way across the three BP categories (optimal, normal and high-normal BP) (5).

In addition, Lewington et al. demonstrated that, among subjects without previous CVD, the standard BP values are definitely associated with the risks of death due to vascular disease, not only among hypertensive or high-normal BP patients, but also among those typically considered normotensive (even down to BP levels of 115/75 mmHg). Given the continuous association observed between BP and risk of death from CVD, the absolute benefits of a lower BP level are expected to be greater for those at highest absolute risk of CVD. Each difference of 20 mmHg usual systolic BP or 10mm Hg usual diastolic BP the study goes on to show, is related with approximately two-fold differences in stroke death rate and in the death rates from ischemic heart disease and other vascular causes, concerning the period of age 40-69 years, with annual absolute differences in risk even greater in old age (80-89 years) (11).

Although the association between BP categories and CV risk is powerfully recognized, there is limited evidence concerning the risk of CV events in subjects with normal and high-normal BP, although it is well known that these groups have a substantial risk of developing hypertension over a short-term period.

In the Framingham cohort, after a 4-year follow-up, the hypertension incidence rates progressed according to baseline BP category and age, specially in older people (age 65-94 years)(2). Data from the Women’s Health Study have shown that 30.1% of women without baseline hypertension progressed to hypertension (12); this increase was proportional across the recognized groups (normal BP, high-normal BP and baseline hypertension). Compared to women with high-normal BP, those with normal BP had a lower risk of a major cardiovascular event and of incident hypertension. Women who progressed to hypertension during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive. Women with high-normal BP at baseline who progressed to hypertension had similar outcome rates to those with baseline hypertension (12).

Recent data confirm that a substantial proportion of CVD is attributable to high BP, even those who are not classified as hypertensive (13). Worldwide, 7.6 million premature deaths (about 13.5% of the global total) and 92 million disability-adjusted life years (6.0% of the global total) were attributed to high BP. About 50% of this burden occurred in subjects previously diagnosed with hypertension, but the rest was in those with lesser degrees of high BP (13).

Table 2: High-normal blood pressure and cardiovascular risk study findings.

2) Blood pressure associated with CV risk factors

A small percentage of the hypertensive population has an elevation of BP alone, with the large mainstream exhibiting added CV risk factors, with an association between the severity of the BP increase and the alterations in glucose and lipid metabolism. Additionally, when they are concurrently present, BP and metabolic risk factors potentiate each other, reaching a total CV risk which is greater than the sum of its individual components (4). Actually, following the algorithm of ESH-ESC to stratify cardiovascular risk, subjects with high-normal BP presenting three additional CV risk factors, target organ damage, metabolic syndrome or diabetes are considered as high-risk patients (4).

The Strong Heart Study showed that normal and high-normal BP was more prevalent in diabetic than nondiabetic individuals (59.4% versus 48.2%),  with hazard ratios greater for those in the higher group, but there was a significant risk even in those in the lower group. Both groups of BP levels, when added to diabetes, had the highest cumulative incidence of CVD during follow-up (14). The coexistence of impaired glucose tolerance, or impaired fasting glucose and lower degrees of high BP also increased CVD risk significantly compared with normotensive participants with normal glucose tolerance (14).

3) High-normal blood pressure and antihypertensive therapy

The recommendation to initiate antihypertensive pharmacological therapy in high CV risk patients o with previous CV events when BP is still in high-normal range is currently supported by European Guidelines (4), although there is no prospective trial evidences (9). Currently, monitoring subclinical organ damage, and particularly microalbuminuria and left ventricular hypertrophy (LVH), seems to be the best direction to settle on the BP values for treatment beginning as well as treatment goals in this group of patients.
Related careful recommendations may be given to diabetic population, for whom present trial data is also contentious relating to both initiation of drug treatment when BP is in the high normal range, and the advantage of aiming at a BP target of less than 130/80mmHg.

The recent Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes trial (ADVANCE) results support these findings. BP-lowering treatment with perindopril-indapamide was administered regularly to individuals with type 2 diabetes, regardless of their BP at entry. In whom systolic BP was brought down to less than 135mmHg, macrovascular and microvascular benefits were obtained (specially in renoprotection, dropping the risk of renal events by 21%, with a reduced risk of developing micro and macroalbuminuria)(15, 16).

Attitude directed to treat a high CV risk patient with high-normal BP levels was influenced by clinical evidence obtained from trials designed to identify relevant differences on the final consequences of CV and renal diseases (non fatal events, chronic or terminal renal insufficiency, and cardiovascular mortality). Consequently, premature detection of an elevated CV risk through the clustering of cardiovascular risk factors and/or the presence of target organ damage should be followed by early intervention. In fact, the Losartan Intervention for Endpoint Reduction (LIFE) study clearly demonstrated that regression of electrocardiographic (ECG) LVH, with antihypertensive treatment improved prognosis, independent of BP (17).

The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to evaluate whether ACE inhibitors and nondihydropyridine calcium-channel blockers prevent microalbuminuria in subjects with hypertension, type 2 DM and normal urinary albumin excretion (18). The results showed that, in subjects with type 2 diabetes and hypertension, normoalbuminuria and normal renal function, these antihypertensive therapies, alone or in combination, prevented the onset of microalbuminuria (18). In this way, Ruggenenti proved recently that ACE inhibition has a protective effect against the establishment of ECG-LVH that is additional to its blood pressure–lowering effect (19).
The implementation of guidelines for management of hypertension and CV risk factors facilitates the attainment of similar BP and LDL-cholesterol goals, in patients with and without high CV risk and high-normal BP. In diabetic patients with high-normal BP, the American Diabetes Association recommends lifestyle therapy alone for a maximum of 3 months, and then, if targets are not achieved, patients should be treated with the addition of pharmacological agents (20).

Latest reappraisal of ESH-ESC guidelines recommend lifestyle changes plus drug treatment at the outset (9). Pharmacological treatment should be always initiated when BP is 140/90mmHg or more. In high-normal BP population, initiation of treatment is at the moment not suitably supported by outcome evidence from trials. It can, however, be recommended, particularly when microalbuminuria is onset, based on the evidence of its positive effect on regression and progression of this subclinical organ damage (9).
Subjects with a high CV risk, due to factors other than diabetes, and BP in high-normal range, should be also advised to implement intense lifestyle measures, and BP might be strictly monitored because of the high probability these patients have of developing hypertension, which would then require pharmacological treatment (9).
However, antihypertensive drugs may sometimes be considered, particularly those more effective in protecting against organ damage, new onset hypertension and new onset diabetes (4). In effect, pharmacologic treatment of prehypertension may prevent or postpone the development of hypertension.

The TROPHY (Trial of Preventing Hypertension) showed a significant reduction in incident hypertension in participants with prehypertension who had received candesartan, up to a 26.5%. (21).
Chronic blockade of the renin-angiotensin system appears to be particularly effective in preventing renal and CV events in hypertensive patients, who are at increased CV risk, which is amplified by the co-existence of type 2 diabetes. It appears, consequently, extremely attractive to block the renin-angiotensin system in all patients with hypertension and/or type 2 diabetes, not only because of the BP lowering obtained, but also due to the underlying contribution of angiotensin II to the pathogenesis of these conditions and, possibly, of their renal and cardiovascular complications. Ideally, this should be done promptly during the course of the disease, as blockers of the renin-angiotensin system are effective in reducing abnormalities that may be encountered before the existence of structural vascular damage (22).
In addition, blockers of the renin-angiotensin system have clear advantages compared with other classes of antihypertensive agents, specially beta-blockers and diuretics, as they improve insulin sensitivity and may protect against the progressive impairment of beta-cell secretory function observed in patients with type 2 diabetes (23), decreasing, also, the risk of new onset diabetes in prediabetic patients (24).

Table 3: Latest trials referred to the antihypertensive drug treatment in high-normal BP

Conclusion:

Epidemiologic studies have demonstrated that systolic and diastolic BP values have a strong, continuous, graded and etiologically significant positive association with CVD outcomes. This is especially relevant among subjects with high-normal BP, considering that most will or will not receive a more aggressive pharmacologic therapy to control BP values, depending on the presence or absence of concomitant comorbidities (diabetes, clustering of cardiovascular risk factors, target organ damage, metabolic syndrome). It is well established that the use of pharmacologic therapy from the early stages of BP in these patients will greatly facilitate the achievement of adequate BP control, which will contribute to the prevention of cardiovascular complications.