Intensive Systolic Blood Pressure Lowering Strategy in Adults With Hypertension: Is Lower Still Better?

Hypertension is highly prevalent, affecting 46.7% of US adults and is the single most important modifiable risk factor for morbidity due to cardiovascular (CV), cerebrovascular, and renal diseases, as well as for mortality and disability-adjusted life years in the United States and worldwide.1 Lowering blood pressure (BP) reduces fatal and non-fatal CV events, and all-cause mortality.2,3 Despite extensive research and a wealth of information, there is still a lack of clarity in defining the threshold that distinguishes normotension and hypertension. This ambiguity arises from the presence of a linear relationship between the reduction of CV events and a decrease in systolic BP (SBP).4 Epidemiological and clinical studies have determined that among the hypertensive population, an elevated SBP rather than diastolic BP is the primary predictor of adverse outcomes.5 A large patient-level meta-analysis of randomized clinical trials has shown a reduction of ≈10% in CV events with a 5 mm Hg decrease in SBP, regardless of baseline BP.2 However, the optimal treatment target for SBP at which the benefits outweigh the harms of antihypertensive treatments remains an area of ongoing debate. This debate has intensified with the publication of several influential guidelines over the past decade, which have presented conflicting recommendations for the management of high BP/hypertension. As summarized in Table 1, the Eighth Joint National committee,6 Joint American College of Physicians and American Academy of Family physicians (AAFP),7 and AAFP8 writing committees presented substantial congruity and recommended a conservative approach to BP management (target SBP <140–150 mm Hg). In contrast, the American College of Cardiology (ACC)/American Heart Association (AHA),9 Joint European Society of Cardiology (ESC)/European Society of Hypertension (ESH),10 and International Society of Hypertension11 advocated intensive lowering of SBP (<130–140 mm Hg). Of all guidelines, the ACC/AHA9 practice recommendations are the most stringent and reclassified approximately 14% of the US population into the hypertensive range. According to these guidelines, patients with SBP ≥140 mm Hg should immediately be initiated on pharmacological therapy to achieve a target BP <130 mm Hg irrespective of age or the presence of CVD. Comparisons of recommended lower systolic blood pressure targets for the management of hypertension by professional societies Comparisons of recommended lower systolic blood pressure targets for the management of hypertension by professional societies Before the release of these guidelines, one of the most important clinical trials, the Systolic Pressure Intervention Trial (SPRINT) was published in the hypertension field.12 The SPRINT study challenged the conservative approach to lowering SBP and demonstrated a 25% reduction in composite endpoint (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from CV causes) through intensive SBP lowering to <120 mm Hg, compared to <140 mm Hg at a median follow-up of 3.26 years in a hypertensive population without diabetes or stroke but with pre-existing CVD, chronic kidney disease (CKD) stage 2–3, age >75 years, or a Framingham 10-year CVD risk score of ≥15%. The results of the SPRINT study support tailoring SBP-lowering goals based on individual CV risk profiles. Based on the estimates derived from the SPRINT findings, ≈16.8 million US adults, 8.2 million of those receiving treatment for hypertension, meet the SPRINT eligibility criteria, therefore, these individuals have the potential to benefit from an intensive lowering SBP. In this issue of the American Journal of Hypertension, Derington et al.13 investigated SPRINT participants (n = 9,361, mean age 68 years) and SPRINT-eligible participants in two large studies, the REasons for Geographic And Racial Differences in Stroke (REGARDS) (n = 2,785, mean age 72 years) and the National Health and Nutritional Examination Survey (NHANES) (n = 1,297, mean age 64 years), to determine CVD event rates with intensive SBP lowering to <120 mm Hg compared with standard treatment (<140 mm Hg). The study demonstrated 6–8 fewer CVD events per 1,000 person-years in SPRINT participants and SPRINT-eligible participants in REGARDS and NHANES studies. Using a previously published algorithm, the investigators identified low, intermediate, and high-benefit subgroups in accordance with outcomes of intensive versus standard SBP-lowering treatment. The absolute risk differences observed were 2.59% and 1.7% in CV events with corresponding numbers needed to treat were <38 and ≥58 for the highest and the lowest benefit subgroups, respectively. The study investigators should be commended for their thorough analysis, which also involved extrapolating the study results to estimate the potential impact on SPRINT-eligible patients across the United States. According to their estimations, a total of 14.1 million adults in the United States could benefit from intensive SBP reductions, targeting levels <120 mm Hg, with an annual reduction of 84,340 CV disease (CVD) events and 70,262 deaths from all causes if implemented.13 Although the data are compelling and indicate that a considerable proportion of US adults are eligible based on the SPRINT study criteria, it remains uncertain to what extent the findings can be applied to a broader population of individuals with hypertension in the US, who are predominantly managed in community healthcare settings. The clinical practice guidelines have placed a strong emphasis on accurate BP measurements and consistently recommended confirming elevated BP through out-of-office readings using ambulatory BP or home BP monitoring methods; this approach aims to recognize normotension, white coat, masked, or sustained hypertension and aligns with the US Preventive Services Task Force recommendation.14 However, the standardization procedures for BP measurement have not been fully implemented in many clinical practices for various reasons, including underappreciation of the significance of standardized measurements and challenges in practical application.15,16 The SPRINT, REGARDS, and NHANES relied on standardized BP measurement, none of the measurements were validate with out-of-office recordings.17 The findings of the study by Derington et al.10 and those of initial SPRINT argue against the current clinical practice guidelines for the management of hypertension, which recommend treating SBP to a goal of <130–150 mm Hg with ESC/EHS even endorsing a “lower safety boundary” of 120 mm Hg SBP. Furthermore, the joint ACP/AAFP7 report on the treatment of hypertension in adults aged ≥60 years concluded that lower SBP targets (<140 mm Hg) provided no statistically significant reduction in all-cause mortality and incidence of cardiac or stroke events compared with higher SBP targets (SBP ≥140 mm Hg). However, the results of the SPRINT were largely driven by a reduction in heart failure event rate with no significant decrease in myocardial infarctions or strokes. Furthermore, the initial SPRINT and the study by Derington et al. excluded several important groups of patients with a high prevalence of comorbid hypertension, including those with pre-existing diabetes, stroke, heart failure, end-stage kidney disease, and many other key clinical conditions; the beneficial effect of intensive lowering of SBP in these exclusion groups is yet to be determined. In patients with diabetes, intensive SBP lowering, like that achieved in the SPRINT or the current study by Derington et al.,18 did not protect against CV events or mortality compared to those in the standard SBP treatment group. These findings are in line with the 2023 American Diabetes Association recommendations, which support an on-treatment SBP goal of <130 mm Hg for individuals with diabetes mellitus and hypertension. It is worth noting that patients who achieved an SBP <120 mm Hg experienced a three-fold increase in serious adverse effects, including hypotension, syncope, electrolyte abnormalities, and kidney injury compared to those in the standard SBP group (<140 mm Hg). Consequently, careful, and resource-intensive monitoring becomes necessary, which may impact the routine management of adults towards a lower SBP goal, particularly for many primary care physicians working in community-based settings. A review of literature suggests that there is growing evidence to support the approach of intensive SBP lowering in specific hypertensive populations. A meta-analysis of 42 clinical trials including 144,220 participants found a linear association between the achieved mean SBP and risk of CVD and mortality with the lowest risk observed at 120–124 mm Hg,19 a value similar to that achieved in the SPRINT and the study by Derington et al.13. A similar systematic review and meta-analysis of 61 prospective studies demonstrated the benefits of lowering SBP to as low as 115 mm Hg, irrespective of age.4 The Kidney Disease Improving Global Outcomes clinical practice guidelines19 align with the results of the SPRINT and recommend a target SBP <120 mm Hg for individuals with chronic kidney disease (CKD) and an estimated glomerular filtration <60 mL/min/1.73 m2. This recommendation is based on the understanding that most patients with CKD are more susceptible to CV events than progression to end-stage kidney disease.20 If tolerated without significant adverse effects, intensive lowering of SBP to <120 mm Hg in selected hypertensive populations may provide additional benefits in reducing CV events and all-cause mortality, compared to lowering SBP to the current target of <130–150 mm Hg, which is recommended by the United States, European, and international clinical practice guidelines. We emphasize the importance of individualizing the SBP target based on a range of factors, including the presence of underlying comorbid conditions, cardiovascular risk, potential adverse effects associated with antihypertensive medications, cost considerations, and patient preferences. By considering these factors, healthcare professionals can tailor the treatment approach to each patient’s unique circumstances, ensuring the best possible outcome in the management of hypertension. No funds are received for this manuscript. Dr. Barkoudah reports research support payments from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bristol Myers Squibb and Janssen, payments made to Brigham and Women’s Hospital for performing clinical endpoints sponsored by various entities, payments from WebMD and Advisory Board fees from Medscape, Janssen, Novartis, and Pfizer. The other authors declared no conflict of interest.