In 2005, the global burden was projected to rise from roughly 0.9 billion in the year 2000 to 1.6 billion in 2025 . By 2010, the global burden of hypertension was estimated at approximately 1.4 billion, and is likely to substantially exceed 1.6 billion by 2025 . In 2016, noncommunicable diseases accounted for 40.5 million or 71% of deaths globally; 17.9 million or 44% of noncommunicable disease-related deaths were due to cardiovascular disease with hypertension as the leading risk factor . Prevention of hypertension is critically important; yet, effective, up-to-date management is vitally important for the large and rapidly growing number of individuals impacted worldwide.
In this regard, several well recognized hypertension guidelines recently recommended blood pressure (BP, mmHg) targets below the long-established level of 140/90 as a key step in preventing more cardiovascular events (CVEs) [3–8]. Given equal or greater prognostic importance of systolic BP (SBP) than diastolic BP (DBP) in predicting CVE for most patients, our comments focus on SBP .
In 2016, the Australian Hypertension Guideline recommended initiating antihypertensive therapy for SBP at least 160 in low-risk and at least 140 in moderate-risk adults (Tables 1 and 2) . For both groups, a SBP target below 140 was strongly recommended. For hypertensive adults aged above 75 years or at high risk, a SBP target below 120 was strongly recommended.
The 2017 and 2018 Canadian Hypertension Guidelines recommended initiating pharmacotherapy at SBP at least 160 in low-risk adults with target SBP below 140 (grade A) [6,7]. For adults with diabetes, the recommendation was to initiate pharmacotherapy for SBP at least 130 with target SBP below 130 (grade C). For adults at high risk and aged above 75 years, the guidance was to initiate pharmacotherapy for automated office SBP (AOSBP) at least 130 with target AOSBP below 120 (grade B).
In 2017, the US Hypertension Guideline redefined hypertension as SBP at least 130 with target SBP below 130 for all adults . The SBP target below 130 included adults with 10-year atherosclerotic CVE risk at least 10%, established cardiovascular disease, diabetes, chronic heart failure, or chronic kidney disease (class 1), and also adults with 10-year risk below 10% (class IIb).
In 2018, the European Hypertension Guideline recommended initiating pharmacotherapy for SBP at least 140 in most adults and at least 130 for those at very high risk for CVE . The European Guideline provided class I recommendations for SBP below 140 for all hypertensive adults, and a SBP range of 120–129 for adults aged below 65 years and 130–139 for adults aged at least 65 years. Caution was raised with regard to treating SBP to below 120, given greater risk of harm in high-risk and older adults.
RATIONALE FOR THE LOWER SYSTOLIC BLOOD PRESSURE TARGETS
The lower SBP targets across these four guidelines reflect both the findings of the Systolic blood PRessure INTervention study (SPRINT), and also meta-analyses of several randomized trials of antihypertensive treatment and clinical outcomes (Table 3) [10–12].
Study investigators reported that intensive treatment with an AOSBP target below 120 was associated with 25% fewer composite cardiovascular end-points including heart failure, and 27% lower all-cause mortality than standard treatment, with an AOSBP target below 140 .
The AOSBP values without additional rest before measurement are approximately 2 mmHg lower than daytime ambulatory BP, whereas usual attended office SBP is approximately 5 mmHg higher . With 5-min prior rest, AOSBP values were 7 mmHg lower than daytime ambulatory SBP among SPRINT participants receiving intensive treatment and another report [14,15]. AOSBP values preceded by 5-min rest are likely 10–15 mmHg lower than usual attended office SBP [16,17], whereas attended and unattended AOSBP are similar [18,19]. To help put this information in perspective, the AOSBP target of below 120 in SPRINT and the Canadian Guideline for patients aged above 75 years or at high risk for CVE appears roughly comparable to a SBP target below 130–135 based on usual office, and not research quality, BP measurement [16,20].
The lower SBP targets in recent guidelines were also based on meta-analyses of randomized clinical trials on antihypertensive treatment and clinical outcomes (Table 3). In the meta-analysis by Bundy et al., mean in-trial SBP of 120–124 was associated with significantly fewer CVE than mean in-trial SBP of 125–129 and higher. The CVE outcome benefit of in-trial SBP 120–124 was progressively greater as comparison in-trial SBP increased. The benefit of in-trial SBP 120–124 on total mortality was significant versus in-trial SBP of 130–134 and higher, with progressively greater benefit as in-trial SBP rose. In the meta-analysis by Thomopoulos et al., mean in-trial SBP below 130 was linked with significantly lower rates of myocardial infarction, stroke, heart failure, and cardiovascular death than in-trial SBP at least 130 .
There are several points, in addition to the methods for measuring clinic BP, which clinicians aiming to minimize CVEs in their patients through better hypertension control are encouraged to consider.
Extrapolating from SBP values in randomized trials to SBP treatment targets in usual clinical care
A mean SBP range of 120–124 mmHg in controlled clinical trials is not easily translated to a SBP target in clinical medicine for several reasons. First, as noted above, SBP values in high-quality clinical trials are likely substantially lower than those in usual clinical care. Second, mean in-trial SBP for a patient cohort over many visits during 3–5-year trials is not easily equated with actual BP values of individuals at various time points or across time .
In fact, a large proportion of participants in trials with a mean in-trial SBP of 120–124 probably had mean SBP values below 120 or at least 130. In the United States, mean SBP for all treated hypertensive adults in 2009–2012 was 130.1, and 72% had SBP below 140 (Table 4) . Moreover, approximately 18% had SBP 130–139, 24% had SBP 120–129, and 30% had SBP below 120. Among adults who were treated and controlled, the mean SBP was approximately 121, which is within the optimal range of 120–124 . Among this group, approximately 75% had SBP below 130, 33% had SBP 120–129, and 42% had SBP below 120. Individuals with a mean in-trial SBP of 120–124 likely have SBP values on a large proportion of visits outside this range. In other words, for individual patients, their mean SBP is best determined by averaging multiple BP values on different days .
When clinical trial evidence is translated to a clinical goal and metrics are created and used to ‘grade’ healthcare systems or clinicians on their performance, unanticipated problems can occur. For example, in the United States, hypertension control is determined only by BP obtained by a clinician in the provider’ office at the last visit for the calendar year . The last visit could be in primary care or in a specialty clinic where accurate BP measurement may be less important, although values obtained before a diagnostic test or surgical procedure are excluded. Given BP variability, mean SBP values required to achieve high control rates to below 140 and below 130 may be lower than expected (Table 5) .
SPRINT exclusion criteria
Roughly 75% or more of treated hypertensive adults in the United States would have been excluded from SPRINT, including many patients with more severe and treatment resistant hypertension [23–25]. This group is at very high risk for CVEs and would have required more than the mean of 2.8 antihypertensive medications received by SPRINT intensive treatment participants . Several reports suggest that cardiovascular benefits of SBP below 140 are attenuated among individuals with treatment-resistant hypertension [26–29]. For patients with treatment-resistant hypertension, benefits of a SBP target below 130 are not well established.
SPRINT: implicit assumptions
Systolic blood PRessure INTervention trial included two important implicit assumptions, which have profound implications for SBP targets . First, SPRINT implies that standard treatment to SBP below 140 achieved SBP values comparable to treated hypertensive adults receiving usual care. Yet, SPRINT standard treatment led to approximately 6 mmHg higher unattended automated office SBP values during the first year than attended SBP values among all hypertensive participants in the United States (Table 4). Suboptimal BP treatment in the standard treatment arm of SPRINT would overestimate benefits of intensive treatment on cardiovascular outcomes.
The SPRINT standard treatment protocol included reducing antihypertensive medication on any visit when SBP was below 130 or on any two consecutive visits when SBP was below 135 . The protocol facilitated wide separation of mean SBP between patients the two arms , but does not reflect usual care as evidenced by the lower mean SBP of patients in the United States than in SPRINT standard treatment . The hypertension guidelines do not recommend withdrawing antihypertensive medications when SBP values below 130–135 are well tolerated, although the European Guideline raises caution when SBP is below 120 [4–8].
Second, SPRINT implies that intensive treatment leads to a lower SBP than achieved in hypertensive adults achieving SBP below 140 in usual care. Otherwise, the main emphasis would be on improving the proportion of treated hypertensive adults with SBP below 140 rather than lowering the SBP target . Since 1999–2002, the mean SBP of adults in the United States with hypertension that is treated and controlled to below 140 mmHg has been in the ‘optimal’ range of 120–124 [10,17,30]. Estimates suggest that controlling 85–90% of patients to SBP below 140 will lead to mean values in the 120–124 range , which appears optimal for preventing CVEs and death (Table 5) .
SPRINT and previously untreated adults with SBP 130–139
More than 90% of SPRINT participants were previously on antihypertensive therapy [10,31]. Among the less than 10% previously untreated, their SBP was in the 130–179 range, that is, an even smaller percentage had SBP 130–139. Thus, SPRINT did not adequately address initiating antihypertensive therapy among untreated patients with SBP 130–139 mmHg . Also, SPRINT did not include individuals with a 10-year risk for atherosclerotic CVEs below 15% [10,23,24].
SPRINT intensive therapy benefits driven more by reducing heart failure than stroke
Stroke prevention is among the most consistent benefits of better BP control . In SPRINT, incident stroke was not significantly reduced [0.41 vs. 0.47%/year; hazard ratio 0.89 (0.63–1.25)], whereas heart failure was (0.41 vs. 0.67%/year; hazard ratio 0.62 (0.45–0.84)] . These outcomes suggest that BP-independent effects of pharmacotherapy may have contributed to the heart failure outcome, which accounted for a large proportion of benefit on the primary outcome [20,33]. Heart failure is often recognized clinically by symptomatic dyspnea and clinical evidence for increased pulmonary venous pressures, for example, a third heart sound or rales. Chlorthalidone, which is effective for reducing incident heart failiure , was the recommended thiazide-type diuretic in SPRINT [23,31]. Study participants assigned intensive treatment were more likely to be on thiazide diuretics than those on standard treatment (54.9 vs. 33.3%) . In addition, intensive therapy participants were more likely to receive other drugs linked with a significant reduction of heart failure including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (76.7 vs. 55.2%), β-blockers (41.1 vs. 30.8%), and aldosterone receptor antagonists (8.7 vs. 4.0%). Thus, BP-independent factors may have contributed to fewer heart failure events with SPRINT intensive than standard treatment [20,33].
Good blood pressure control is clinically important
The authors endorse a SBP goal below 140 for primary prevention in hypertensive adults including those 75 years and older. It is important to attain SBP below 140 early in the course of treatment and to sustain control over time . Because BP values vary within individuals over time and between individuals at the same time, controlling SBP in most patients at most of the visits should lead to mean SBP values in the 120–129 range for the group and a substantial proportion of patients (Tables 4 and 5) . The percentage of patients in the SBP range of 120–129 would likely increase with up-titration of antihypertensive medications for those with mean SBP at least 130 and down-titration in those with mean SBP below 120, although the feasibility, safety, and effectiveness of this approach are unknown.
Two lines of evidence support consistent control of BP as important in clinical outcomes. First, individuals who are controlled to less than 140 mmHg on a higher proportion of visits have better outcomes than individuals with BP controlled on a smaller proportion of visits . Second, greater variability in office BP values are also associated with poorer outcomes, especially for stroke . In this regard, SPRINT provided at least two important and related messages. First, when office SBP is controlled, especially in the 120–129 range and well tolerated, it is important to continue and not reduce antihypertensive treatment to raise SBP to 135–139 . Second, hypertensive patients, including those aged 65–75 years and older, derive significant clinical benefit from better SBP control (Table 2) [4–8,10].
The global burden of hypertension in 2010 was approximately 1.4 billion people and likely to exceed the projected 1.6 billion by 2025 [1,2]. In 2010, more than one billion hypertensive adults were living in low and middle-income countries where mean BP control rates were 7.7% . More optimal management is required to address the growing global burden of cardiovascular morbidity and mortality . To more effectively reduce hypertension-related cardiovascular disease, the Hypertension guidelines from Australia, Europe, and North America have all recently recommended SBP treatment targets below the long established goal of less than 140 for a large proportion of or for all adults with hypertension. The reduction in SBP targets was based on SPRINT, and meta-analyses of randomized clinical trials of antihypertensive therapy and clinical outcomes. We succinctly summarized key aspects of the four guidelines and limitations of SPRINT and the meta-analyses, especially the challenges of translating these reports into clinical guidelines. Given variability in clinic BP, its measurement and management, and the heterogeneity of patients, it is, at present, impossible to control all patients within a 5–10 mmHg SBP range. Moreover, achieving high control rates at the lower goals could result in a significant proportion of patients, reaching mean SBP values below 120, which can increase serious adverse events [8,20]. Based on current evidence, we recommend that SBP in newly diagnosed hypertensive patients with an indication for pharmacotherapy is controlled to below 140 within the first 3–6 months. We further recommend that SBP below 140 is maintained on subsequent visits in patients irrespective of the duration of hypertension . To attain and maintain SBP below 140, most patients will require more than one antihypertensive medication [4–8]. Liberal use of single-pill combinations with different classes of antihypertensive medications is useful in more rapidly achieving and maintaining control [4–8]. Given BP variability, high control rates to SBP below 140 will likely lead to mean SBP below 130 in the group and the majority of individual patients with a large proportion in the 120–129 range. As noted in the guidelines, these are general recommendations and not rules. Clinicians are encouraged to use their best judgment and a shared decision-making process with individual patients.
Funding: This study was supported in part by the Centers for Disease Control and Prevention (CDC 1305, CDC 1422) to the South Carolina Department of Health and Environmental Control with subcontracts to the Care Coordination Institute. The funding sources did not participate in the selection of the topic or the drafting, editing, or final approval of this paper.
Conflicts of interest
B.M.E. has received royalties from UpToDate, research support from Medtronic and Quintiles, income as a consultant from AstraZeneca, Medtronic, and Valencia, and honoraria for lectures from Merck-Serono and Emcure. S.E.K. has received in the past 3 years ad hoc speaking honoraria from ABDiiBRAHiM, Bayer, MSD, Sanofi, and Takeda, and study committee honorarium from Takeda.
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