A controversial medical term, prehypertension first appeared in the 2003 JNC7 hypertension guidelines, where the committee defined the blood pressure range as 120C139/80C89 mm Hg. Compared with the previously considered optimal blood pressure range of <120/<80 mm Hg, prehypertension can increase the incidence of hypertension and cardiovascular events.
Although the term is controversial, the concept of prehypertension emerged in 1939, when researchers found that a blood pressure of 120C139/80C89 mmHg increased the risk of hypertension and death compared with a blood pressure of <120/<80 mmHg. As the global population ages, it is becoming increasingly important to focus on clinical practice in the treatment of hypertension, with the lifetime risk of hypertension in the United States being approximately 90% for those aged 55-65 years without hypertension.
Effective interventions for the lifetime risk of hypertension can delay or even reduce the risk of major cardiovascular events such as heart failure, myocardial infarction, and stroke. Making the public aware of the dangers of prehypertension is also an emerging challenge in primary care.
The JNC7 guidelines clearly state that prehypertension is not a disease and does not require drug therapy in the absence of mandatory indications (e.g., prior cardiovascular disease). Prehypertension is a common condition with potentially important implications for general health, but consensus is still lacking on certain aspects, such as whether lifestyle interventions alone are appropriate to prevent hypertension and cardiovascular disease? When is pharmacotherapy needed? In the JNC7 guidelines, the recommended treatment for prehypertension alone is lifestyle change.
The relative risks of the composite endpoints of stroke, myocardial infarction, heart failure, cardiovascular events, and all-cause death were reduced by 22%C23%, 20%, 23%, and 15%, respectively, with antihypertensive treatment in adults with prehypertension who had comorbid cardiovascular disease or diabetes. These findings are also why some clinicians believe that prehypertension can be given medication, even in the absence of clinical cardiovascular disease.
However, some believe that in the absence of comorbid cardiovascular disease, prehypertension does not require pharmacotherapy because the absolute risk is low, the number of people requiring treatment to prevent 1 event is very high, and the cost of pharmacotherapy is so high that the benefit of treatment is not clear.
Therefore, to guide clinicians and healthcare practitioners, Brent M. Egan and Sean Stevens-Fabry from the University of South Carolina School of Medicine present four key aspects of prehypertension, including the prevalence of prehypertension, its impact on the development of hypertension, its impact on cardiovascular events and death, and the impact of lifestyle and pharmacologic interventions on hypertension and cardiovascular events and death. A detailed description is published in Nature Reviews Cardiology.
Prevalence of prehypertension
Prehypertension is highly prevalent in populations of different ages, genders, ethnicities, and geographic regions worldwide. The prevalence is estimated to be 22%-38% in population-based samples. The estimated prevalence of prehypertension is based on in-office blood pressure measurements and does not include out-of-office blood pressure.
In a representative Chinese population aged 15 years and older, the prevalence of prehypertension was 34.5%. Data from the Korean survey showed that the prevalence of prehypertension was 31.6%, with a higher prevalence in women than in men. In the United States, prehypertension was more prevalent in men than in women, in young adults than in older adults, and in those with high BMI than in those with low BMI. Not surprisingly, the prevalence of prehypertension was higher in studies that excluded hypertensive patients than in studies that included hypertensive patients. After excluding differences in age, sex, inclusion of hypertension, and exclusion of hypertension, the prevalence of hypertension in population-specific studies was generally similar to that in population-based studies.
The prevalence of prehypertension reached ≥30% in all studies. In a US study, the prevalence of prehypertension was 59.4% and 48.2% in the diabetic and nondiabetic populations, respectively; a survey of 60,785 postmenopausal women in the US found that 38.8% were prehypertensive.
A Meta-analysis of 18 prospective studies showed that the estimated prevalence of prehypertension was 25.2%-46.0%, including 32.6%-41.1% in 5 US studies; 25.2%-46.0% in 5 Japanese studies; and 30.0%-35.3% in 3 Chinese studies. In the REGARDS study, after excluding hypertensive patients, the prevalence of prehypertension was higher in blacks than in whites among those aged 45 years and older. Overall, the prevalence of prehypertension in blacks was similar to that in whites after inclusion of hypertensive patients.
Risk of Progression to Hypertension
The risk of progression to hypertension in the prehypertensive population was 2 to 3 times higher than in normotensive individuals. The annual rate of transition to progression to hypertension in prehypertension is also affected by study design factors and by the different blood pressure ranges of the included population. The absolute percentage of progression to hypertension was usually higher with longer follow-up at similar baseline blood pressure values, but the annual rate of transition to hypertension onset was usually higher with shorter follow-up.
This observed phenomenon suggests that among the prehypertensive population, some susceptible individuals progress rapidly to hypertension, whereas others are relatively less likely to progress to hypertension. Distinguishing different populations based on their susceptibility to hypertension would help to accurately predict which segments of the population will progress to hypertension over time and thus guide interventions and resources for hypertension prevention.
Based on different studies, investigators have identified clinical factors that are used to predict progression to hypertension in prehypertension. For example, higher office blood pressure, blacks, older adults, elevated BMI, chronic kidney disease, and diabetes mellitus have all been independently and positively associated with the development of hypertension. In addition, frailty was independently associated with the risk of hypertension in men with prehypertension.
The TROPHY study showed that home blood pressure measurements were higher in people with stage 2 prehypertension (130C139/85C89 mmHg), most of whom met the criteria for occult hypertension, and that this group was at increased risk of progression to hypertension based on blood pressure measurements. Thus, it is practical to stratify the population at risk for progression to hypertension based on many simple and easily accessible clinical factors alone.
The Framingham study showed that the probability of progression to hypertension after 4 years in people with prehypertension was 30.3%. When limiting prehypertension to stage 2, 37% of those under 65 and 50% of those over 65 progressed to hypertension, compared with 5% and 16% of those with optimal blood pressure.
In a hypertension prevention trial, 44% of the pre-hypertension routine group at baseline progressed to hypertension at 4 years of follow-up. In contrast, the relative risk of progression to hypertension at 4 years was significantly lower in the 3 intervention groups (weight loss, sodium restriction, or a combination of both measures).
In the TROPHY study, 63% of placebo-treated patients (30-65 years of age) with stage 2 prehypertension progressed to hypertension within 4 years, and more than 40% progressed to hypertension within 2 years, defined as clinical hypertension as systolic BP >140 mmHg and/or diastolic BP >90 mmHg on any 3 occasions during the 4-year follow-up; whereas 52% progressed to hypertension after 4 years when using the commonly used criteria of ≥140/≥90 mmHg for hypertension; compared with placebo Moderate doses of renin angiotensin receptor blockers reduced the relative risk of hypertension by 66% at 2 years and by 15% at 4 years (2 years on medication).
The PHARAO study of pre-stage 2 hypertension showed that 43% of participants in the placebo group progressed to hypertension within 3 years; monotherapy with a low-dose renin angiotensin-converting enzyme inhibitor reduced the relative risk of hypertension beyond 3 years by 34% compared with placebo.
However, when only participants with stage 2 prehypertension at baseline were analyzed, the incidence of hypertension was similar in the PHARAO, TROPHY, and Framingham studies.
The annual prevalence of hypertension varied among the studies due to the duration of follow-up, ranging from 8% to 20% in the 2-4 year follow-up studies and 4% to 9% in the 7-8 year follow-up studies. In one of the studies, 57.3% of the non-hypertensive cohort progressed to hypertension within 3.5 years, while 60.3% progressed to hypertension within 7 years. Thus, the original cohort included at least two groups, one at high risk for hypertension at 3 years and another with a low risk of progression to hypertension, even at 7 years of follow-up.
Differences in progression to hypertension by race are important in reducing the prevalence of hypertension and its associated cardiovascular and renal complications. The prevalence of prehypertension in African Americans is slightly lower than in whites (30.4% vs 31.2%), but the prevalence of hypertension in African Americans is 40% higher than in whites.
Thus, this phenomenon also raised the speculation that blacks progress from prehypertension to hypertension faster than whites and that, if correct, interventions to reduce the progression from prehypertension to hypertension onset in African Americans might reduce the prevalence of hypertension and its complications, and subsequent related trials have confirmed these speculations.
Risk of Cardiovascular Events
There are a very large number of studies examining the relative risk of prehypertension and coronary heart disease, stroke, and total cardiovascular disease. blood pressure included in the studies in the Meta-analysis was based on office blood pressure, and most participants were free of cardiovascular disease at baseline. These studies confirm the findings of previous studies that prehypertension increases the relative risk for all 3 regressions, and that stage 2 prehypertension is associated with a higher risk than stage 1 prehypertension, in addition to the fact that the effect of prehypertension on total cardiovascular events is generally greater than the effect of fatal cardiovascular events.
Among those with prehypertension combined with clinical cardiovascular disease and/or diabetes, the annual prevalence of cardiovascular disease in the placebo group averaged 4.3%, with an estimated 10-year prevalence of 43%, whereas some studies have shown a higher risk in those with baseline congestive heart failure or hypertension and a lower than 4.3% annual risk of cardiovascular disease in those with baseline diabetes.
Although most of the studies provided relative risk for cardiovascular disease, they lacked absolute event rates to calculate the number of people requiring treatment. It is important to note that the prehypertensive population, particularly the stage 2 prehypertensive population, has multiple risk factors that increase cardiovascular risk, but most studies corrected for confounders such as age, sex, smoking, and total cholesterol and lipid composition when calculating risk for prehypertension. Given the high prevalence of prehypertension, it is estimated that approximately one-third of cardiovascular events worldwide occur in this population.
Based on data from previous studies of prehypertension and cardiovascular disease, we can estimate the prehypertension to normotension ratio. In general, the additional absolute risk of cardiovascular disease in the prehypertensive population increases by 0.39%C0.61% per year, with a mean of 0.5%.
There are an estimated 30 million people with stage 2 prehypertension in the United States, which, when combined with the above data, translates to approximately 117,000C183000 additional cardiovascular events per year in this population. In the middle-aged population, the annual prevalence of cardiovascular disease in the pre-stage 2 hypertensive population is 1% (310,000 total cardiovascular events); in the pre-stage 1 hypertensive population, it is 0.8%; and in the optimal blood pressure population, it is 0.5%. With an estimated 40 million people with stage 1 prehypertension in the United States, the absolute risk of cardiovascular disease in this population is estimated to be 0.8%, with an additional risk of 0.3%.
Thus, the population burden of cardiovascular disease associated with prehypertension is very high, but the absolute additional risk associated with prehypertension is very low for individuals without prior clinical cardiovascular disease. In conclusion, careful consideration is needed when developing and implementing prevention strategies to reduce absolute risk.
Strategies to prevent morbidity
The two main prevention strategies for high-risk populations include population-based approaches and medical strategies. Population-based approaches often revolve around promoting healthy nutrition and exercise patterns, maintaining a healthy weight, and avoiding tobacco products, drugs, and excess alcohol intake, while broad safety recommendations include the use of seat belts and the appropriate use of health screening services. Medical strategies focus on identifying those at excess residual risk and intervening with lifestyle interventions and appropriate evidence-based medications.
Risk factors are routinely and consistently monitored and followed up, and interventions are adjusted as needed to reduce risk factors and associated clinical events. In general, successful population strategies have very large benefits for large populations, but have limited effect on individuals. Conversely, medical strategies for high-risk populations (5-10% of the total population) are of great benefit to individuals, but of limited benefit to large populations.
In the United States, strategies targeting hypertension and cardiovascular risk have gradually shifted to high-risk strategies for a much larger proportion of the population, with relatively little emphasis on population-based strategies. For example, public health announcements and other educational programs in the United States from 1963-1975 were instrumental in significantly reducing per capita salt and saturated fat consumption and smoking. During this period, age-corrected coronary heart disease incidence was reduced by 38%, a figure that was higher than all other developed countries combined.
Analysis of the data over this period shows that more than 50% of the reduction in coronary heart disease can be attributed to lifestyle changes. In contrast, people with rapidly westernizing lifestyles are leading high-calorie diets and tend to lead sedentary lifestyles.
In a study of an affluent population in the northern Indian city of Lucknow, 32.3% of the population had prehypertension, 32.2% had hypertension, 56% of those with prehypertension had two other cardiovascular risk factors (central obesity, elevated LDL cholesterol, abnormal glucose tolerance, or smoking), and notably, 36% of those aged 30-39 had prehypertension.
In the United States, the incidence of coronary heart disease and stroke has continued to decline since 1980, despite substantial increases in overweight/obesity, cardiovascular metabolic syndrome/diabetes, sedentary lifestyle, and reduced diet quality.
According to data from the National Health and Nutrition Examination Survey (NHANES) from 1988-2010, the dramatic decline in cardiovascular disease is likely attributable to increased awareness, treatment, and control of hypertension and hypercholesterolemia and includes complementary primary and secondary prevention strategies such as smoking cessation and use of antiplatelet medications. During that time, the cost of high-risk strategies resulted in an annual increase in health care costs that exceeded 2-3% of overall U.S. economic growth.
Lifestyle interventions remain the cornerstone of treatment. Technological advances to get people out of the office have resulted in substantial lifestyle benefits, such as sustained weight loss. 2013 ACC/AHA cholesterol guidelines substantially increase the number of patients suitable for statin therapy, adding a majority of patients aged 40-75 years without diabetes at ≥7.5% 10-year risk of atherosclerotic cardiovascular disease, for whom moderate-to-high intensity statin therapy is recommended.
For individuals aged 40-75 years with a 10-year risk of atherosclerotic cardiovascular disease of 5.0% to 7.4%, moderate-intensity statin therapy may be considered. In addition, Meta-analyses of statin trials have shown that these drugs can lower blood pressure by 2C3/1C2 mmHg and can significantly reduce the likelihood of refractory hypertension.
An analysis of the NHANES study showed that 93% of individuals with prehypertension had at least one additional major cardiovascular risk factor. In prehypertensive patients with comorbid clinical cardiovascular disease or/and diabetes, there is substantial evidence that many antihypertensive agents can be used for secondary prevention of cardiovascular disease.
Out-of-office assessment of blood pressure can be effective in identifying individuals with prehypertension who are prone to progress to hypertension. One study found that mean blood pressure values calculated from 3-5 automated blood pressure measurements taken by patients alone in the office correlated more strongly with daytime out-of-office blood pressure values than blood pressure measurements taken by physicians or assistants in the office.
Evidence suggests that automated in-office blood pressure measurements may reduce the white coat effect and occult hypertension. In contrast, for individuals with out-of-office hypertension (≥135/≥85 mmHg) but whose office blood pressure did not meet the criteria for hypertension, this group of patients had an elevated risk of hypertension and cardiovascular events. Similarly, other risk factors for rapid progression to hypertension are also risk factors for cardiovascular events, including advanced age, obesity, diabetes mellitus, chronic kidney disease, and blackness.
In individuals with prehypertension without comorbid clinical cardiovascular disease, lifestyle interventions remain key to reducing the risk of hypertension and cardiovascular events. Renin-angiotensin system blockers reduce the risk of developing hypertension in people under 65 years of age. For patients with a 10-year risk of atherosclerotic cardiovascular disease ≥10% for stage 2 prehypertension, an estimated number of 20 people need to be treated over 10 years to prevent 1 major cardiovascular event, and a relative reduction in cardiovascular disease risk of 20% is required.
Importantly, the use of pharmacotherapy for primary prevention of cardiovascular disease in prehypertensive individuals remains unproven, but pharmacotherapy to reduce systolic blood pressure to 130 mmHg or 120 mmHg may reduce the risk of stroke in hypertensive patients, although the risk of coronary heart disease is not significantly reduced in this group.
The cardiovascular risk associated with prehypertension is particularly pronounced in African-Americans and diabetics compared with the overall prehypertensive population. In patients with diabetes, stage 1 prehypertension increased the risk of cardiovascular disease by a factor of 1 and stage 2 prehypertension increased the risk of cardiovascular disease by a factor of 3. Although prehypertension is associated with an increased risk of stroke, the risk of absolute event rates is low and the estimated number of people requiring treatment for primary prevention is very high.
Treatment of prehypertension
Clinical studies have shown that lifestyle interventions and pharmacotherapy can reduce the risk of developing hypertension, particularly with renin angiotensin system blockers, and other antihypertensive drugs are being investigated for prevention of hypertension. Despite the limited role of lifestyle interventions in the general population, existing guidelines for hypertension prevention do not recommend pharmacotherapy.
Meta-analyses of multiple clinical trials have shown that multiple antihypertensive agents may reduce the risk of cardiovascular events in prehypertensive patients with comorbid clinical cardiovascular disease and/or diabetes mellitus. However, there is a lack of clinical trial data on cardiovascular disease prevention in individuals with prehypertension for no apparent indication, and recent guidelines do not recommend pharmacotherapy.
Not surprisingly, the risk of hypertension onset and cardiovascular events is higher in individuals with stage 2 prehypertension than in those with stage 1 prehypertension. It should be noted, however, that blood pressure <120/<70 mmHg is likely to increase the risk of cardiac events, although blood pressure values in this range are associated with a reduced risk of stroke.
Therefore, it cannot be definitively concluded that a reduction in blood pressure to <120/<80 mmHg after pharmacologic treatment significantly reduces the risk of cardiovascular events in individuals with prehypertension. That said, virtually all guidelines only make recommendations, but clinicians are encouraged to exercise their best judgment in determining the appropriate treatment for each patient.
In individuals with stage 2 prehypertension (based on out-of-office blood pressure values) who progress to high risk for hypertension, most of whom are at very high risk for atherosclerotic cardiovascular events, low to moderate doses of renin angiotensin system blocking drugs may be given on a trial basis after attempting lifestyle changes.
In general, strategies to block the renin angiotensin system in the absence of sodium volume reduction can mildly reduce blood pressure in adults with prehypertension and are well tolerated. The risk of cardiovascular events and pharmacologic interventions are also increasing in patients with occult hypertension (out-of-office blood pressure ≥135/≥85 mmHg); however, data from clinical trials to reduce cardiovascular risk in patients with occult hypertension are still lacking.
Moderate-intensity statin therapy may be considered for individuals aged 40-75 years with a 10-year risk of 5.0%C7.4% for atherosclerotic cardiovascular disease, whereas for individuals with a 10-year risk ≥7.5%, moderate-intensity statin therapy may be given according to the 2013 ACC/AHA cholesterol guidelines. Interventional and observational studies have shown that improved nutrition, smoking cessation, and physical activity can reduce the risk of cardiovascular events, and these lifestyle change measures can be recommended when applicable to individuals with prehypertension.
A large number of studies have confirmed the 1939 observational report that prehypertension is very common and can increase the risk of hypertensive cardiovascular events and death. An effective public health strategy is important, but today we are still not there. Nevertheless, clinicians and patients can do more to reduce the risk of hypertension onset and cardiovascular events.