Pharmacological treatment of high‐normal blood pressure (prehypertension) in high‐risk patients for primary prevention of cardiovascular events

Abstract

Currently, the best treatment strategy for patients with a high‐normal blood pressure (prehypertension) is not known. The authors aimed to determine whether pharmacological reduction of systolic blood pressure (SBP) to a normal level (<120 mm Hg) would prevent cardiac morbidity and mortality in prehypertensive patients. In this secondary analysis, the authors obtained the data from SPRINT from the National Heart, Lung, and Blood Institute data repository center. Among 9361 patients enrolled in SPRINT, 289 high‐risk (ASCVD risk = 24.8% ± 13.0 [10‐65]) prehypertensive patients without previous cardiovascular disease and not receiving any antihypertensive medications were enrolled. One hundred and forty‐eight of them were assigned to standard treatment which consisted of clinical follow‐up till SBP goes above 140 mm Hg and then staring medications to keep SBP <140 mm Hg. One hundred and forty‐one were assigned to the intensive treatment receiving pharmacological SBP reduction to <120 mm Hg upon enrollment. The primary composite outcome was myocardial infarction, and other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Throughout the 3.06 years of follow‐up, a primary outcome event was confirmed in three participants (0.74% per year) in the intensive‐treatment group and 8 (1.61% per year) in the standard‐treatment group (hazard ratio [HR], 0.19; P = .045). Rates of serious adverse events were not increased by intensive‐treatment (HR, 0.83; P = .506). Based on this secondary post hoc analysis, intensive SBP reduction may probably be beneficial for primary prevention of cardiovascular morbidity and mortality in high‐risk prehypertensive patients. This finding needs to be evaluated in a larger trial designed specifically to answer this question.

1. BACKGROUND

High blood pressure is the leading risk factor for cardiovascular diseases (CVDs) ¹ and affects more than 1 billion adults worldwide. ² Observational studies on individuals without CVD show a graded increase in risk at systolic blood pressure (SBP) levels above 115 mm Hg. ³ It has been suggested that lowering blood pressure at any level above this value will reduce the risk of cardiovascular events. ⁴ Currently, there is an inconsistency about the definition of hypertension. The European society of cardiology (ESC) defines hypertension as an office SBP above 140 mm Hg and/or diastolic blood pressure (DBP) above 90 mm Hg, ⁵ while ACC/AHA provides a definition of SBP higher than 130 mm Hg and DBP higher than 80 mm Hg. ⁶ A normal blood pressure is defined as a SBP below 120 mm Hg and DBP below 80 mm Hg. Patients with blood pressure between the mentioned ranges have gotten several names from “transient hypertension” in the 1940s ⁷ to “borderline hypertension” in the 1970s, ⁸ “high‐normal blood pressure” in the 1990s, ⁹ and “prehypertension” in 2003. ¹⁰ Currently, ACC/AHA defines patients with a SBP of higher than 119 mm Hg and lower than 130 mm Hg as “Elevated blood pressure.” ⁶ ESC defines a SBP above 129 mm Hg and lower than 140 mm Hg as “High‐normal blood pressure.” ⁵ Regardless of this condition being named or defined, several investigations have defined the clinical characteristics, elevated cardiovascular risk, and treatment options for people with this degree of BP elevation. ¹¹ In a study by Vasan et al, ¹² it was revealed that high‐normal blood pressure is associated with excess morbidity and death from cardiovascular causes and Leitschuh et al ¹³ have shown that it is a precursor of hypertension. In addition, other cardiovascular risk factors have shown to have associations with high‐normal blood pressure. ¹⁴ , ¹⁵

Currently, the best treatment approach for these patients is not clear. While the ESC guideline does not recommend treating high‐normal blood pressure, ⁵ the ACC/AHA recommends pharmacological treatments in these patients if the ASCVD risk is about 10%. ⁶ Here, we aim to find an answer for this question. To do so, we have used the data from Systolic Blood Pressure Intervention Trial (SPRINT).

SPRINT demonstrated that among non‐diabetic patients with increased cardiovascular risk, intensive management of SBP to a target of 120 mm Hg resulted in lower rates of cardiovascular events and all‐cause mortality. ¹⁶ In particular, many of the participants who were enrolled in SPRINT had a SBP below 140 mm Hg and DBP below 90 mm Hg and a group of these patients were not on antihypertensive medication; this means they were prehypertensive at enrollment. SPRINT did not thoroughly investigate the outcomes of intensive blood pressure management in participants with high‐normal blood pressure at baseline. We aimed to perform a secondary analysis for patients with baseline high‐normal blood pressure from SPRINT who were not on antihypertensive medication on enrollment to find out whether intensive blood pressure control to a SBP target of less than 120 mm Hg (intensive treatment) compared to maintaining the SBP lower than 140 mm Hg (standard treatment) is beneficial for prevention of cardiovascular morbidity or mortality.

2. METHODS

2.1. Ethical considerations

The study protocol conforms to Declaration of Helsinki and is approved by ethical committee of Shiraz University of Medical Sciences and is registered in Iran National Committee for Ethics in Biomedical Research by number IR.SUMS.MED.REC.1398.420.

2.2. Data acquisition

We used data from the SPRINT, obtained from the National Heart, Lung, and Blood institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center with a request ID of 4612.

2.3. Study design and population

The rationale and study design for the SPRINT have been reported in detail elsewhere. ¹⁶ Briefly, SPRINT was a randomized, controlled, open‐label trial including 9361 non‐diabetic participants with elevated CVD risk and SBP of ≥130 mm Hg. The participants were randomly assigned to an intensive‐treatment arm with target SBP <120 mm Hg or a control arm targeting an SBP <140 mm Hg. The inclusion criteria were SBP of 130‐180 mm Hg, age of ≥50 years, and high risk of cardiovascular events. The high risk of cardiovascular events was described according to one or more of the following criteria: (a) chronic kidney disease (except polycystic renal disease) with eGFR ranging from 20 to <60, calculated by the Modification of Diet in Renal Disease (MDRD) formula; (b) presence of clinical or subclinical CVD except stroke; (c) a 10‐year risk of ≥15% for CVD, according to the Framingham Risk Score; and (d) age ≥75 years.

Recalculation of ASCVD risk was done for all, and only those with an ASCVD risk above 10% were included. Among them, only patients with baseline SBP below 140 mm Hg and DBP below 90 mm Hg who were not on antihypertensive medications on enrollment and had no clinically presented previous CVDs (Prehypertensive patients) were enrolled in final analysis. We have analyzed the outcomes and adverse effects of this selected population of patients from SPRINT, to see whether normalizing blood pressure in this population can help to prevent cardiovascular morbidity and mortality.

2.4. Intervention and measurements

All the participants were educated to follow healthy life styles and follow guideline recommendation to reduce BP with life style modifications. Medications for the intensive‐treatment group were prescribed every month to reach an SBP of <120 mm Hg. On the other hand, the drugs were prescribed to reach a target SBP of 135‐139 mm Hg in the standard‐treatment group; if SBP was below 130 mm Hg in a single visit or below 135 mm Hg in two successive visits, the dosage was decreased.

The patients' baseline demographic information was recorded. The clinical and laboratory information of the participants was collected at the beginning of the study and then every 3 months. In order to identify the CVD outcomes, structured interviews were performed in the two groups within 3‐month intervals. Serious adverse events were described as fatal or critical events, which caused a major or persistent clinical disorder, requiring a longer hospital stay or the researcher's decision to determine whether the condition poses a major clinical risk to the patient (necessitating treatment to inhibit the adverse outcomes).

2.5. Outcomes

The primary analysis compared the time to the first occurrence of a primary outcome event (a composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes).

2.6. Statistical analyses

In this analysis, we used Cox proportional hazards regression with two‐sided tests with a significance level of 5%, and stratification according to the clinic. t Test was used to compare the SBP or number of medication between the study groups. We checked BP levels every 3 months and when the SBPs became more than 140 mm Hg for two consecutive measurements, we considered it as transition to hypertension stage. Annual incidence rates were calculated based on Cox proportional hazard analysis considering new onset hypertension as an outcome. All the analyses were performed using the statistical Package for Social Sciences, version 17.0 (SPSS Inc).

3. RESULTS

3.1. Study participants

Four thousand seven hundred and eight patients with a baseline SBP below 140 mm Hg and DBP below 90 mm Hg were enrolled in SPRINT (Figure 1). A total of 289 participants had no previous cardiovascular events and were not on antihypertensive medication on enrollment, so they were considered as baseline population with high‐normal blood pressure levels without clinical CVDs (148 in standard‐treatment group and 141 in intensive‐treatment group). Descriptive baseline statistics are presented in Table 1.

FIGURE 1.

CONSORT flow diagram of the study

TABLE 1.

Baseline characteristics of the study participants ^a , ^b

Characteristic	Intensive treatment (N = 141)	Standard treatment (N = 148)
Age, y	65.86 ± 9.06	67.09 ± 9.88
Race or ethnic group—no. (%) c
Non‐Hispanic black	37 (26.2)	33 (22.3)
Hispanic	15 (10.6)	11 (7.4)
Non‐Hispanic white	87 (61.7)	100 (67.6)
Other	2 (1.4)	4 (2.7)
Black race c , d	40 (28.4)	34 (23)
Baseline blood pressure, mm Hg
Systolic	130.31 ± 6.75	130.97 ± 6.70
Diastolic	77.41 ± 7.4	76.75 ± 8.05
Serum creatinine, mg/dL	1.00 ± 0.22	0.99 ± 0.26
Estimated GFR, mL/min/1.73 m2	77.67 ± 18.63	78.76 ± 18.62
Ratio of urinary albumin (mg) to creatinine (g)	17.55 ± 35.22	16.79 ± 36.36
Fasting total cholesterol, mg/dL	195.24 ± 39.56	202.12 ± 42.35
Fasting HDL cholesterol, mg/dL	50.26 ± 13.11	52.04 ± 12.72
Fasting total triglycerides, mg/dL	122.84 ± 62.80	124.65 ± 79.69
Fasting plasma glucose, mg/dL	96.97 ± 12.81	97.19 ± 10.77
Dyslipidemia—no./total no. (%)	33 (23.4)	42 (28.4)
Statin use—no./total no. (%)	28 (19.9)	37 (25.2)
Aspirin use—no./total no. (%)	61 (43.3)	52 (35.4)
Smoking status—no. (%)
Never smoked	52 (36.9)	70 (47.3)
Former smoker	56 (39.7)	57 (38.5)
Current smoker	31 (22.0)	20 (13.5)
Missing data	2 (1.4)	1 (0.7)
Female sex—no. (%)	35 (24.8)	29 (19.6)
ASCVD 10‐y cardiovascular disease risk score, %	26.6 ± 11.5	23.2 ± 14.2
Framingham 10‐y cardiovascular disease risk score, %	24.29 ± 10.66	25.3 ± 11.76
Body mass index e	28.68 ± 5.01	28.30 ± 4.77

To convert the values for creatinine to micromoles per liter, multiply by 88.4.

To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

Abbreviations: GFR, glomerular filtration rate; HDL, high‐density lipoprotein.

^aPlus‐minus values are means ± SD. There were no significant differences (P < .05) between the two groups except for statin use (P = .04).

^bIncreased cardiovascular risk was one of the inclusion criteria.

^cRace and ethnic group were self‐reported.

^dBlack race includes Hispanic black and black as part of a multiracial identification.

^eThe body mass index is the weight in kilograms divided by the square of the height in meters.

3.2. Blood pressure

Both treatments caused a rapid and constant difference between the groups in terms of SBP (Figure 2). Throughout the 3.06 years of follow‐up, the mean SBP was 120.6 ± 6.1 mm Hg in the intensive‐treatment group and 132.4 ± 6.4 mm Hg in the standard‐treatment group, for an average difference of 11.7 mm Hg (P < .001). The mean number of blood pressure medications was 1.6 ± 0.7 and 0.5 ± 0.5, respectively. In the standard‐treatment group, 38 patients did not need any medication to maintain SBP below 140 mm Hg, and 38 patients needed only occasional visits and did not need a long‐term maintenance therapy. Seventy‐two patients (48.6%) were transited from high‐normal blood pressure into stage 1 hypertension during follow‐up and needed continuous antihypertensive medications (with an annual incidence rate of 11.49%).

FIGURE 2.

Systolic and diastolic blood pressure in the two treatment groups over the course of the trial. The systolic blood pressure target in the intensive‐treatment group was less than 120 mm Hg, and the target in the standard‐treatment group was less than 140 mm Hg. I bars represent 95% confidence intervals

3.3. Clinical outcomes

A primary outcome event was confirmed in 11 participants—3 (0.74% per year) in the intensive‐treatment group and 8 (1.61% per year) in the standard‐treatment group (hazard ratio [HR] with intensive treatment, 0.19; 95% confidence interval [CI], 0.04‐0.96; P = .045) (Figure 3A). A complete report of secondary outcomes is provided in Table 2.

FIGURE 3.

Primary outcome and serious adverse events. Shown are the cumulative hazards for the primary outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes) (panel A) (hazard ratio with intensive treatment, 0.19; 95% confidence interval, 0.04‐0.96; P = .045) and for serious adverse events (panel B) (hazard ratio with intensive treatment, 0.83; P = .506)

TABLE 2.

Primary and secondary outcomes among the participants

Outcome	Intensive treatment (N = 141)		Standard treatment (N = 148)		Hazard ratio (95% CI)	P value
	No. of patients (%)	% per year	No. of patients (%)	% per year
Primary outcome a	3 (2.1)	0.67	8 (5.4)	1.74	0.192 (0.38‐0.963)	.045
Secondary outcomes
Myocardial infarction	0 (0)	0	3 (2.0)	0.64	0.018 (0.00‐176)	.062
Acute coronary syndrome	1 (0.7)	0.20	0 (0)	0	—	.725
Stroke	2 (1.4)	0.40	3 (2.0)	0.64	0.69 (0.11‐4.17)	.693
Heart failure	0 (0)	0	4 (2.7)	0.85	0.01 (0.00‐37.97)	.012
Death from cardiovascular causes	0 (0)	0	1 (0.7)	0.2	—	.610
Death from any cause	1 (0.7)	0.2	4 (2.7)	0.85	—	.187
Primary outcome or death	4 (2.8)	0.8	10 (6.8)	2.17	0.23 (0.062‐0.915)	.023

Abbreviations: CI, confidence interval; CKD, chronic kidney disease.

^aThe primary outcome was the first occurrence of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death from cardiovascular causes.

3.4. Serious adverse events

Serious adverse events occurred in 31 participants in the intensive‐treatment group (21.9%) and in 39 participants in the standard‐treatment group (26.3%) (HR with intensive treatment, 0.83; P = .506) (Figure 3B). A complete report of adverse events is provided in Table 3.

TABLE 3.

Serious adverse events, conditions of interest, and monitored clinical events

Variable	Intensive treatment (N = 141)	Standard treatment (N = 148)	Hazard ratio	P value
	No. of patients (%)
Serious adverse event a	31 (22.0)	39 (26.4)	0.82	.422
Emergency department visit or serious adverse event
Hypotension	2 (1.4)	1 (0.7)	4.82	.152
Syncope	4 (2.8)	0	5.27	.129
Bradycardia	2 (1.4)	2 (1.4)	1.09	.931
Electrolyte abnormality	2 (1.4)	1 (0.7)	3.82	.270
Injurious fall b	7 (5.0)	12 (8.1)	0.91	.704
Acute kidney injury or acute renal failure c	1 (0.7)	1 (1.7)	0.75	.526
Monitored clinical events
Adverse laboratory measure d
Serum sodium <130 mmol/L	4 (2.6)	2 (1.2)	0.01	.471
Serum sodium >150 mmol/L	—	—	—	—
Serum potassium <3.0 mmol/L	6 (3.8)	0 (0)	25.44	.795
Serum potassium >5.5 mmol/L	4 (2.6)	8 (4.8)	0.34	.228
Orthostatic hypotension e
Alone	20 (12.8)	28 (17)	0.81	.573
With dizziness	0 (0)	1 (0.6)	0.00	.582

^aA serious adverse event was defined as an event that was fatal or life‐threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that was judged by the investigator to represent a clinically significant hazard or harm to the participant that might require medical or surgical intervention to prevent one of the other events listed above.

^bAn injurious fall was defined as a fall that resulted in evaluation in an emergency department or that resulted in hospitalization.

^cAcute kidney injury or acute renal failure was coded if the diagnosis was listed in the hospital discharge summary and was believed by the safety officer to be one of the top three reasons for admission or continued hospitalization. A few cases of acute kidney injury were noted in an emergency department if the participant presented for one of the other conditions of interest.

^dAdverse laboratory measures were detected on routine or unscheduled tests; routine laboratory tests were performed at 1 mo, then quarterly during the first year, and then every 6 mo.

^eOrthostatic hypotension was defined as a drop in systolic blood pressure of at least 20 mm Hg or in diastolic blood pressure of at least 10 mm Hg at 1 min after the participant stood up, as compared with the value obtained when the participant was seated. Standing blood pressures were measured at screening, baseline, 1 mo, 6 mo, 12 mo, and yearly thereafter. Participants were asked if they felt dizzy at the time the orthostatic measure was taken. ¹⁶

4. DISCUSSION

Here, we showed that pharmacological reduction of SBP in non‐diabetic patients without clinically apparent CVD and at high cardiovascular risk (ASCVD risk above 10%) and with a SBP above 130 and below 140 mm Hg, to a level below 120 mm Hg, would reduce the chance of major cardiovascular events and may be useful for primary prevention of CVDs.

In our study, during the 3 years of follow‐up, 48.6% of patients were transited from high‐normal blood pressure into stage 1 hypertension and needed continuous antihypertensive medications (annual incidence rate of 11.49%). This is similar to the findings of TROPHY trial. In that study, Julius et al ¹⁷ have shown that over a period of 4 years, stage 1 hypertension developed in nearly two‐thirds of patients with untreated prehypertension, and treatment with candesartan had a relative risk reduction of 66.3% for prevention of developing stage 1 hypertension. In a PHARAO's study, Luders et al showed that there was an annual incidence rate of 18.8% from high‐normal blood pressure to stage 1 hypertension. This would be reduced to 13% if the patients were treated with ramipril (relative risk reduction = 34.4%). ¹⁸ In PREVER‐Prevention trial, Fuchs et al ¹⁹ showed that treatment with diuretic thiazides reduced the annual incidence of hypertension development from 19.5% to 11.7% (HR = 0.56).

Although some clinical trials ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ have shown a significant delay of the onset of hypertension during, but not after, antihypertensive drug treatment in patients with high‐normal blood pressure, whether this is cost‐effective and would prevent cardiovascular events was not shown clearly in previous investigations leading to controversies about the best treatment approach for this population. While the ESC guidelines do not recommend treating them, ⁵ the ACC/AHA recommends pharmacological treatments in these patients if the ASCVD risk is above 10%. ⁶ The recommendations in ACC/AHA guidelines are based on a secondary analysis of SPRINT. ²¹ In that the study by Attar et al, 4298 patients from SPRINT were enrolled and categorized based on the baseline 10‐year Framingham Risk Score: <10% (low risk); ≥10% and <15% (intermediate risk); and ≥15% (high risk). They show that with intensive treatment, there was a significant reduction in the primary outcome events in patients at high risk (HR = 0.51), and at intermediate risk (HR = 0.37), but not for those at low risk (HR = 1.14). They concluded that intensive SBP reduction may be beneficial for primary prevention of cardiovascular morbidity and mortality in non‐diabetic patients with more than low cardiac risk (above 10%). ²¹ However, many of the patients involved in that study had a baseline SBP above 140 mm Hg and many were on antihypertensive medications on enrollment. The participants of our study were truly newly diagnosed patients with high‐normal blood pressures and our results may address the treatment issue of this challenging condition more appropriately. To the best our knowledge, our study is the first to evaluate major cardiovascular events in this population and no clinical trial has yet been conducted to evaluate the effect of pharmacological antihypertensive treatment on cardiovascular outcome specifically. Among the trials conducted with a primary end point of hypertension prevention, only the PHARAO study had some MACE outcomes as the secondary outcome. The secondary end points were a reduction in cerebrovascular and cardiovascular events, defined as stroke, transient ischemic attack (TIA), intracerebral bleeding, myocardial infarction, new onset of heart failure requiring hospitalization (first occurrence in each category), and deaths, none of which showed a statistical difference with treatment. ¹⁸ The absence of clinical benefit in that study probably relates to its structure. In PHARAO, a fixed dose of ramipril was given to all patients without dose adjustment to keep SBP in a specific range. In contrast, in SPRINT, dynamic changes on medications were done to keep SBP below 120 mm Hg persistently.

This study had some limitations. Our findings are based on a post hoc subgroup analysis of a large trial and the finding cannot be considered as definitive since the randomization and sample volume determination was not done specifically for this purpose. In addition, the observed level of significance is borderline (P = .045) which relates to the small sample of patients' population. Consequently, conduction of a large clinical trial designed for this specific purpose is mandatory to draw a more definitive conclusion.

5. CONCLUSIONS

Overall, it seems that in non‐diabetic prehypertensive patients without previous apparent clinical CVDs, pharmacological reduction of blood pressure to normal levels (a SBP of less than 120 mm Hg) as compared with postponing treatment till hypertension is developed and starting medications to keep SBP below 140 mm Hg may be beneficial for primary prevention of fatal and nonfatal major cardiovascular events. These results are based on a small subgroup of patients at SPRINT, and future research with higher sample volumes is recommended to reach more definitive conclusions.

CONFLICT OF INTEREST

The authors have declared that no competing interests exist.

AUTHOR CONTRIBUTIONS

RB contributed in the data acquisition, data analysis, and statistical analysis, drafting and revising manuscript, and final approval and agreed for all aspects of the work. MS contributed in the concept and design, drafting and revising manuscript, and final approval and agreed for all aspects of the work. PD, JK, and PI contributed in the concept and design, drafting and revising manuscript, and final approval and agreed for all aspects of the work. AA contributed in the data analysis and statistical analysis, drafting and revising manuscript, and final approval and agreed for all aspects of the work.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study protocol conforms to Declaration of Helsinki and is approved by ethical committee of Shiraz University of Medical Sciences and is registered in Iran National Committee for Ethics in Biomedical Research by number IR.SUMS.MED.REC.1398.420. All participants signed the informed consent form.

Borazjani R, Kojuri J, Abdi-Ardekani A, et al. Pharmacological treatment of high‐normal blood pressure (prehypertension) in high‐risk patients for primary prevention of cardiovascular events. J Clin Hypertens. 2020;22:1627–1634. 10.1111/jch.13994

DATA AVAILABILITY STATEMENT

The data that support the findings of this study will be available from the corresponding author on reasonable request.