THE EVIDENCE FOR A GENERAL BLOOD PRESSURE GOAL OF < 130/80 MMHG IS STRONG CONTROVERSIES IN HYPERTENSION: PRO

Introduction

Hypertension is a leading risk factor for cardiovascular disease (CVD) and death and ranks first in disability-adjusted life years in the United States and globally^1–3. Over half a century of evidence emanating from both cohort studies and randomized clinical trials^4–6 has informed the development of clinical practice guidelines for prevention, detection, evaluation and management of high blood pressure (BP), starting in 1977 with the National Heart, Lung, and Blood Institute (NHLBI) sponsored report of the first Joint National Committee (JNC)⁷.

Subsequently, the JNC high BP guidelines were updated and revised on a regular basis. The report of the Seventh Joint National Committee (JNC-7) in 2003 defined hypertension in the general population as an average BP ≥140/90 mmHg with a treatment goal of <140/90 mmHg in most patients with hypertension⁸. In 2013, the NHLBI transferred responsibility for CVD prevention guidelines to the American College of Cardiology (ACC) and American Heart Association (AHA)⁹. In 2014 the ACC/AHA, in partnership with 9 other professional organizations, assembled and charged a 21-member multidisciplinary writing committee whose members had no relevant relationships with industry to develop a guideline for prevention, detection, evaluation, and management of high BP in adults¹⁰. Based on new evidence since 2003, the 2017 ACC/AHA BP guideline redefined hypertension as BP ≥130/80 mmHg and recommended a general BP treatment goal of <130/80 mmHg¹¹. In the past, hypertension guidelines that recommended lower than previous treatment goals have been associated with a downward shift in overall population BP and reduction in CVD and stroke risks¹². The higher BP targets specified in guidelines published prior to 2017 were based on the evidence available at the time. The aim of this report is to identify the evidence in support of a general BP treatment goal <130/80 mmHg.

Evidence from SPRINT

The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized controlled trial that examined the effects of a more intensive high BP treatment goal than had been recommended in the JNC-7¹³. The trial randomized 9,361 patients with hypertension who were at high risk for CVD to intensive treatment, with a systolic BP (SBP) goal <120 mmHg, or to standard treatment, with an SBP goal <140 mmHg. Principal inclusion criteria were age ≥50 years, SBP 130–180 mmHg and CVD or high CVD risk; principal exclusions were history of stroke, diabetes mellitus and extremes of health. The primary outcome was a CVD composite that included myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure (HF) and CVD death. Following randomization, there was a rapid separation of SBP between the two treatment groups, with an average SBP that was 13.1 mmHg lower in the intensive compared to standard treatment group and an average SBP of 121.5 mmHg in the intensive treatment group. The average number of antihypertensive medications used in the intensive and standard treatment groups was 3.0 and 1.9, respectively. Incidence of the CVD composite primary outcome was reduced by 25% in the intensive treatment group (HR 0.75; 95% CI, 0.64–0.89) and all-cause mortality by 27% (HR 0.73; 95% CI, 0.60–0.90). Intensive treatment was significantly better than standard treatment irrespective of age, sex, race, starting level of BP, and presence/absence of CVD or chronic kidney disease (CKD)¹³.

The SPRINT main results were published in 2015¹³. No external reanalysis of the SRINT data has contradicted or weakened the primary results of SPRINT. A strongly positive, large, well-powered, randomized controlled trial such as SPRINT that was conducted in a diverse population should be considered substantial evidence, especially when it confirms a pattern of positive results from previous smaller trials testing a similar hypothesis. Indeed, not considering SPRINT in the 2017 ACC/AHA Guideline would have been both scientifically inappropriate and unethical. While limitations in generalizability are inherent for all efficacy trials, the SPRINT results provide a strong measure of confidence supporting the SBP goal <130 mmHg.

Systematic Reviews and Meta-analyses

Systematic reviews and clinical trials meta-analyses allow for use of formal approaches that facilitate summarizing and pooling of results from multiple trials. Traditionally, pooling has been based on use of trials in which the treatments of interest are directly compared. However, network meta-analyses in which both direct comparisons and indirect comparisons of treatments that have employed the same control enhance precision and are becoming increasingly common. The ACC/AHA BP Guideline Writing Committee systematically reviewed the available evidence and also charged the ACC/AHA BP Guideline independent Evidence Review Committee (ERC) to conduct a formal systematic review and meta-analysis of trials that would inform recommendations related to intensity of treatment. The key question regarding BP control was determined to be “What is the optimal target for BP lowering during antihypertensive therapy in adults?” The Writing Committee considered this question to be important and relevant for a substantial number of patients and also felt there was a high likelihood that the ERC findings could be translated into actionable guideline recommendations.

The Writing Committee developed a detailed request with many specific requirements for the ERC. The ERC reviewed trials (1966–2016) that had randomly assigned participants to different BP targets. In performing this task, the ERC adapted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and recommendations of the ACC Foundation/AHA Methodology Manual and Policies^14,15. The ERC literature search protocol defined the outcomes to be assessed (including benefits, harms and adverse events), electronic search parameters and methods, data abstraction, risk of bias, and statistical analysis, including sub-group and sensitivity analyses.

As described in the original ERC systematic review manuscript and sequential publications^16,17, 15 clinical trials in which participants were randomly assigned to different BP targets were selected based on a review of approximately 6,000 manuscripts. The risk of bias for these trials was assessed as low, with the most common concern being difficulty in masking intervention assignment. Clinical and statistical heterogeneity was determined to be acceptable for a summary analysis. The trials were consistent in reporting primary outcomes, but the reporting of adverse events and harms was limited and not uniform. Therefore, pooling of a sufficient number of trials with common methods for reporting adverse events and/or harms was not possible. A direct meta-analysis was performed using estimates of BP-lowering effects, because individual-level data were unavailable for most of the trials.

Greater BP lowering significantly reduced the risk of major adverse cardiovascular events (MACE) (RR 0.81, 95% CI, 0.70–0.94) as well as MI, stroke, and HF (Table 1)^16,17. The ERC also examined the reduction in risk of these outcomes for randomized controlled trials with a SBP target <130 mmHg in the lower BP target group and again found a significantly reduced risk of MACE (0.84, 95% CI 0.73–0.99), stroke (RR 0.82; 95% CI, 0.70–0.96) and MI (RR 0.85; 95% CI, 0.73–1.00)¹⁶. Limiting the analyses to studies that included only participants with diabetes mellitus or CKD or with a mean participant age ≥60 years had no significant impact on the findings.

Table 1.

Systematic reviews and meta-analyses comparing intensive with standard blood pressure lowering in randomized clinical trials in patients with hypertension.

First author (year)	Meta-analysis Type	No. of Trials	Total Patients	SPRINT	Comparison (random)	Outcome	RR (95% CI)
Law18 (2009)	Direct (group data; random-effects model)	71 45	Not available but 871 CHD and 763 stroke events	Not included	10 mmHg SBP or 5 mmHg DBP lower in more intensively treated group	CHD Stroke	0.78 (0.73–0.83) 0.59 (0.52–0.67)
Xie19 (2016)	Direct (group data; random-effects model)	14 14 13 10 13 19	44,989 (overall, in 19 trials)	Not Included	More vs. less intensive treatment	MACE Stroke MI HF CVM ACM	0.86 (0.78–0.96) 0.78 (0.68–0.90) 0.87 (0.76–1.00) 0.85 (0.66–1.11) 0.91 (0.74–1.11) 0.91 (0.81–1.03)
Ettehad6 (2016)	Direct (group data; fixed-effects model)	55 54 56 43 57	265,578 265,323 265,534 222,851 267,998	Included	SBP 10 mmHg lower in more intensively treated group	MACE Stroke CHD HF ACM	0.80 (0.77–0.83) 0.73 (0.68–0.77) 0.83 (0.78–0.88) 0.72 (0.67–0.78) 0.87 (0.84–0.91)
Thomopoulos20 (2016)	Direct (group data; random-effects model)	9 13 14 10 15 16 7 8 5 9 9	52,844 (overall, in 18 trials)	Included	SBP/DBP 10/5 mmHg lower in more intensively treated group SBP <130 mmHg vs. SBP >130 mmHg	MACE Stroke CHD HF CVM ACM Stroke CHD HF CVM ACM	0.75 (0.66–0.83) 0.71 (0.60–0.84) 0.80 (0.68–0.95) 0.80 (0.49–1.31) 0.79 (0.63–0.97) 0.83 (0.69–1.03) 0.71 (0.61–0.84) 0.86 (0.76–0.97) 0.81 (0.51–1.30) 0.80 (0.67–0.97) 0.84 (0.73–0.95)
Verdecchia21 (2016)	Cumulative Sequential Direct (group data; random-effects model) Restricted to trials that allocated to lower or higher BP	13 13 9 15 18	53,405 (overall)	Included	More vs. less intensive treatment	Stroke MI HF CVM ACM	0.80 (0.68–0.95) 0.85 (0.76–0.96) 0.75 (0.57–0.99) 0.82 (0.67–0.99) 0.89 (0.77–1.02)
Bangalore22 (2017)	Network (group data; random-effects model) Restricted to trials that allocated to lower or higher BP	17	55,163 (overall)	Included	SBP <120 vs. <160 mmHg SBP <130 vs. <160 mmHg SBP <130 vs. <140 mmHg	Stroke MI Stroke Stroke	0.54 (0.29–1.00) 0.68 (0.47–1.00) 0.62 (0.36–1.07) 0.83 (0.58–1.18)
Bundy23 (2017)	Network (& Direct) (group data; random-effects model)	42	144,220 (overall)	Included & Excluded	SBP 120–124 vs. >160 mmHg SBP 130–134 vs. >160 mmHg SBP 130–134 vs. 140–144 mmHg	MACE Stroke CHD CVM ACM MACE Stroke CHD CVM ACM MACE Stroke CHD CVM ACM	0.36 (0.26–0.51) 0.27 (0.12–0.51) 0.47 (0.29–0.78) 0.34 (0.17–0.76) 0.47 (0.32–0.67) 0.51 (0.39–0.69) 0.39 (0.23–0.63) 0.59 (0.39–0.91) 0.51 (0.31–0.84) 0.65 (0.47–0.85) 0.83 (0.74–0.94) 0.74 (0.54–1.00) 0.88 (0.72–1.08) 0.81 (0.62–1.08) 0.82 (0.68–0.93)
Reboussin16 (2018)	Direct (group data; random-effects model)	7 12 11 8 10 15 5 7 6 4 5 9	23,617 33,018 31,926 23,066 40,266 49,934	Included & Excluded	More vs. less intensive treatment SBP <130 mmHg vs. higher	MACE Stroke MI HF CVM ACM MACE Stroke MI HF CVM ACM	0.81 (0.70–0.94) 0.77 (0.65–0.91) 0.86 (0.76–0.99) 0.75 (0.56–0.99) 0.86 (0.67–1.12) 0.89 (0.77–1.02) 0.84 (0.73–0.99) 0.82 (0.70–0.96) 0.85 (0.73–1.00) 0.81 (0.58–1.14) 0.81 (o.58–1.14) 0.92 (0.79–1.06)
Sakima24 (2019)	Direct (group data; random-effects model) Restricted to trials that allocated to lower or higher BP	14 13 12 7 6 5	55,529 53,603 52,509 22,286 22,206 21,112	Included	More vs. less intensive treatment SBP <130 and DBP <80 mmHg	MACE Stroke MI MACE Stroke MI	0.86 (0.78–0.94) 0.78 (0.68–0.90) 0.87 (0.77–0.98) 0.89 (0.80–0.99) 0.81 (0.66–1.01) 0.89 (0.76–1.03)

ACM, all-cause mortality; BP, blood pressure; CHD, coronary heart disease; CVM, cardiovascular mortality; DBP, diastolic blood pressure; HF, heart failure; MACE, major adverse cardiovascular events; MI, myocardial infarction; SBP, systolic blood pressure.

Several independent systematic reviews (Table 1) have reached conclusions that are consistent with the ERC findings^6,18–24. In a 2009 direct meta-analysis, Law et al.¹⁸ reported a 22% reduction in coronary heart disease (CHD) and 41% reduction in stroke for adults with hypertension with a 10 mm Hg lower treatment SBP or 5 mm Hg lower DBP. Four direct meta-analyses were published in 2016^6,19–21. In a study conducted by Xie et al.¹⁹, which did not include SPRINT, more intensive BP lowering to an average SBP/DBP of 133/76 mmHg reduced MACE significantly (RR 0.86, 95% CI 0.78–0.96) compared to less intensive treatment to an average SBP/DBP of 140/81 mm Hg. Later that year, Ettehad et al.⁶ also reported a significant reduction in MACE (RR 0.80, 95% CI 0.77–0.83) for a 10 mm Hg lower treatment SBP. A systematic review and meta-analysis by Thomopoulos et al.²⁰ not only provided strong evidence that a lower target was desirable but in a stratified analysis comparing an achieved SBP <130 with ≥130 mmHg reported a RR for stroke, CHD, CVD mortality and all-cause mortality of 0.71 (95% CI, 0.61–0.84), 0.86 (95% CI, 0.76–0.97), 0.80 (95% CI, 0.67–0.97) and 0.84 (95% CI, 0.73–0.95), respectively. In a sequential meta-analysis by Verdecchia et al.²¹, restricted to 18 trials that randomly allocated participants to a lower or higher BP, more (average SBP/DBP of 129/76 mmHg) compared to less (average SBP/DBP of 138/81 mmHg) BP lowering resulted in a RR for stroke of 0.80 (95% CI, 0.67–0.95) and for MI of 0.85 (95% CI, 0.76–0.96). Two network meta-analyses were published in 2017^22,23. Bangalore et al.²², who restricted their analysis to 17 trials in which participants were randomly assigned to different BP targets, demonstrated progressive benefit with lower BP targets down to an SBP <120 mmHg for several individual CVD outcomes. A larger network meta-analysis by Bundy et al.²³ included 42 randomized controlled two-arm trials in which the more and less intensively treated groups had an SBP that differed by ≥ 5 mmHg. In randomized comparisons, a progressive reduction in MACE, stroke, CHD, CVD mortality and all-cause mortality was observed at lower compared to higher levels of achieved SBP. For example, randomized groups achieving a mean SBP 120–124 mmHg had a hazard ratio for all-cause mortality of 0.73 (95% CI, 0.58–0.93), 0.59 (95% CI, 0.45–0.77), 0.51 (95% CI, 0.36–0.71), and 0.47 (95% CI, 0.32–00.67) compared to those achieving SBP of 130–134, 140–144, 150–154 and ≥160 mmHg, respectively. Similar findings were observed in sensitivity analyses when the SPRINT results were excluded and when 4 trials, deemed to be at risk for bias, were excluded. Similar results were also noted when a direct meta-analysis was employed²³.

A 2019 systematic review and direct meta-analysis by Sakima et al.²⁴, restricted to 19 trials in which adults with hypertension were randomly assigned to a different BP target, reported a significant reduction in major CVD events, MI and stroke in those assigned to more versus less intensive treatment and in subgroup analysis identified a BP target of < 130/80 mmHg as optimal for CVD protection.

Thus, in addition to the systematic review and meta-analysis conducted by the ACC/AHA BP Guideline ERC¹⁶, at least eight other independent meta-analyses have documented the effectiveness of intensive BP lowering for prevention of CVD events and death compared to standard treatment^6,18–24 and confirmed the benefit of an SBP treatment target <130 mm Hg^16,20,23.24. This was true even when the results of SPRINT were excluded^16,19,23.

Evidence in Older Adults

SPRINT included 2,636 community-dwelling adults age ≥ 75 years (28% of the study sample)^13,25. In this subgroup, there was a 34% lower risk of developing the primary composite CVD outcome and a 33% lower risk of all-cause mortality with intensive versus standard treatment [numbers needed to treat (NNT) 27 and 41, respectively)]. The results did not differ for those who were most frail or had impaired gait speed. Importantly, there was no difference in serious adverse events, including falls, or in self-assessed quality of life, irrespective of frailty status²⁵.

During trial follow-up, the incidence of mild cognitive impairment (MCI) was significantly reduced in the SPRINT intensive compared to standard treatment group (HR 0.83; 95% CI, 0.70–0.99)²⁶. During extended trial and post-trial follow-up (median of 5.1 years), the composite of MCI and dementia was significantly less common in older adults randomized to the intensive compared to standard treatment [HR 0.85 (95% CI, 0.74–0.97)] and there was a nonsignificant trend for a benefit in dementia, per se [HR 0.83 (95% CI, 0.67–1.04)]. The Kaplan-Meier curve separation by treatment arm occurred much later for probable dementia than for CVD events, suggesting that a longer follow up period, with more events, would be required to document a significant reduction in dementia, per se²⁶.

During a median follow-up of 4 years, an MRI sub-study conducted in 670 SPRINT participants reported significantly less progression of cerebral small vessel ischemic disease as indicated by white matter lesions, characteristically associated with Alzheimer’s disease, in the intensive compared to standard group²⁷. A similar benefit has been noted during intensive BP treatment in the INFINITY trial²⁸ and during extended follow-up in the ACCORD trial²⁹. Recently, the beneficial effect on major CVD events, mild cognitive impairment and death was reaffirmed in SPRINT participants age ≥ 80 years³⁰. Taken together, these findings should provide confidence that intensive therapy is, at a minimum, safe with respect to brain function during antihypertensive treatment in ambulatory noninstitutionalized adults.

While there was an increased risk for changes in kidney function in the intensive treatment group, the clinical and biological importance of these findings is unclear^31,32 and there was no difference in the incidence of injurious falls³⁰. As recognized by the SPRINT and SPRINT MIND investigators, the SPRINT results are not directly relevant to institutionalized older adults or those with clinical dementia, limited life expectancy, or a high burden of comorbidities

Limitation of Evidence in Younger Adults

No randomized event-based trials have addressed the optimal BP target in adults < 40 years of age. An adequately powered randomized clinical trial with clinical endpoints is unlikely to be conducted in this group due to sample size requirements and cost.

However, epidemiological data strongly suggest that elevated BP in young adults leads to target organ damage (eg. left ventricular hypertrophy) and predicts lifetime risk of CVD³³. Young adults with elevated BP and stage 1 or stage 2 hypertension before age 40 years of age, as defined in the 2017 ACC/AHA BP guidelines, have a significantly higher risk for subsequent CVD events compared to those with normal BP³⁴. Thus, the new ACC/AHA BP classification system may help identify young adults with a high lifetime risk of CVD as candidates for antihypertensive pharmacologic treatment³⁴. Nonpharmacological and low-dose antihypertensive drug treatment trials have demonstrated effectiveness to lower BP, prevent and treat hypertension and regress left ventricular mass/hypertrophy in such settings^35,36.

Population Impact of Achieving and Maintaining the BP Target <130/80 mmHg

At least two studies have modeled the impact of achieving and maintaining a BP < 130/80 mmHg in US adults. In a study by Bundy et al.³⁷, the incidence of CVD events and death with adherence to antihypertensive drug recommendations in the 2014 evidence-based panel³⁸ was compared with adherence to the 2017 ACC/AHA BP guideline¹¹. For the 2014 panel, the BP threshold for initiation of antihypertensive drug therapy was ≥ 140/90 mmHg for adults < 60 years and ≥ 150/90 mmHg for those ≥ 60 years and the BP treatment goal was <140/90 mmHg for those < 60 years and < 150/90 for those ≥ 60 years. For the 2017 ACC/AHA guideline, the BP thresholds for initiating antihypertensive drugs was ≥ 130/80 mmHg for adults with CVD or high CVD risk (≥ 140/90 mmHg for all others) and the BP treatment goal was < 130/80 mmHg.

With adherence to the 2014 evidence-based panel recommendations for adults ≥ age 40, the predicted annual CVD event reduction was 270,000 and the annual reduction in death was 177,000. In contrast, the annual CVD event reduction for the 2017 ACC/AHA guideline was 610,000 and the annual reduction in deaths was 334,000. Sensitivity analysis determined that, even if 100% implementation of the 2017 guideline recommendations was not achieved, the CVD event rate and death reductions would remain substantially higher than using the 2014 panel recommendations³⁸.

In a second study, Bress et al.³⁹ simulated the population impact of achieving and maintaining 2017 ACC/AHA guideline drug treatment BP goals in US adults ≥ age 45 years with hypertension as compared to (1) maintaining current BP drug treatment and control levels, (2) achieving drug treatment BP goals recommended in the 2003 JNC-7 Panel Members Report⁸, and (3) achieving the 2014 evidence-based panel drug treatment BP goals³⁸. Over a 10-year period, the total number of CVD events expected to be prevented was 3.0 million with the 2017 ACC/AHA treatment goal compared to 2.6 million and 1.6 million with the JNC-7 and the 2014 recommendations, respectively.

Thus, two well-performed simulation studies have demonstrated a highly positive potential population impact of following the 2017 ACC/AHA hypertension guideline recommendations for lowering BP in adults with hypertension compared to following previous recommendations. Bundy et al.³⁷ showed that about twice as many CVD events and deaths would be prevented annually by adhering to the 2017 ACC/AHA guideline instead of the 2014 evidence-based panel recommendations. Bress et al.³⁹ also predicted substantially greater health benefits would result from adherence to the 2017 ACC/AHA antihypertensive drug treatment recommendations compared to following the JNC-7 or 2014 panel report.

Summary and Conclusion

The SPRINT results provide convincing evidence that treatment to a lower BP goal than previously recommended prevents CVD events. Likewise, the 2017 ACC/AHA BP guideline ERC systematic review and meta-analysis, performed using best practices, identified a 19% reduction in major adverse CVD events for an SBP goal < 130 mmHg compared to higher SBP targets. At least eight additional independent systematic reviews have reached conclusions entirely consistent with the ERC report, three showing CVD benefit for a SBP treatment target of <130 mmHg compared with higher targets, and two in the absence of the SPRINT results. Adverse events resulting from treatment to a BP goal <130/80 mm Hg are infrequent and generally reversible. They should not be equated with the benefits of preventing major CVD events and all-cause mortality. Two careful population simulation studies suggest use of treatment recommendations in the 2017 ACC/AHA BP Guideline would yield important CVD benefits compared to use of prior recommendations. Taken together, the evidence strongly supports a more intense BP goal (<130/80 mmHg) in the management of hypertension.