How far to lower systolic blood pressure? Should the ESH/ESC Hypertension Guidelines be revisited after SPRINT?

Introduction

The European Society of Hypertension (ESH)/European Society of Cardiology (ESC) Guidelines for the management of arterial hypertension [1] were updated in 2013. One of the important features of the guidelines was the recommendation to lower conventional office systolic blood pressure to <140 mmHg in nearly all hypertensive patients with few exceptions (Table 1). In the meantime, the results of the Systolic Blood Pressure Intervention Trial (SPRINT) [2] became available, with the following conclusions: “Among patients at high risk for cardiovascular events but without diabetes or stroke, targeting a systolic blood pressure of less than 120 mmHg, as compared with less than 140 mmHg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive treatment group”. Therefore, the question of whether the recommended target systolic blood pressure of <140 mmHg of the 2013 ESH/ESC Hypertension Guidelines [1] should be revisited arises.

Table 1. Blood pressure goals in hypertensive patients. The European Society of Hypertension (ESH)/European Society of Cardiology (ESC) Guidelines for the management of arterial hypertension [1].

Abbreviations: Class: class of recommendation; DBP: diastolic blood pressure; LoE: level of evidence; SBP: systolic blood pressure.

The Systolic Blood Pressure Intervention Trial

In the randomised controlled open-label SPRINT trial [2] 9,361 hypertensive patients, aged ≥50 years (mean age: 67.9 years), were randomised to a standard treatment group with target systolic blood pressure of <140 mmHg (135-139 mmHg) and an intensive treatment group with target systolic blood pressure of <120 mmHg. Eligible patients had an increased risk of cardiovascular events, defined by one or more of the following: clinical or subclinical cardiovascular disease other than stroke; chronic kidney disease; a 10-year risk of cardiovascular disease of ≥15% based on the Framingham risk score; or age ≥75 years. Systolic blood pressure had to be between 130 and 180 mmHg and averaged 139.7 mmHg at baseline; it is of note that 90.6% of the patients were on antihypertensive treatment so that the true untreated blood pressure remains unknown. Exclusion criteria included: diabetes; prior stroke; heart failure within the past six months or left ventricular ejection fraction <35%; dementia; expected survival of less than three years; unintended weight loss of >10% within the past six months; systolic blood pressure <110 mmHg after one minute standing; or residing in a nursing home. After randomisation, baseline antihypertensive regimens were adjusted according to the study protocol and lifestyle modification was encouraged as part of the management strategy. Systolic blood pressure throughout the 3.26 years of follow-up averaged 134.6 mmHg in the standard treatment group and 121.5 mmHg in the intensive treatment group. In the intensive treatment group, the primary outcome, a composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure and cardiovascular death, was reduced by 25% (p<0.001), death from any cause by 27% (p=0.003), cardiovascular death by 43% (p=0.005) and heart failure by 38% (p=0.002). The incidence of myocardial infarction, acute coronary syndrome or stroke was not different between the two treatment groups. On the other hand, serious adverse events of hypotension, syncope, electrolyte abnormalities and acute kidney injury or acute renal failure occurred more frequently in the intensive treatment group (p<0.05 for each of them), but not injurious falls. Serious adverse events which were classified as possibly or definitely related to the intervention occurred in 4.7% in the intensive treatment group and in 2.5% in the standard treatment group (p<0.001). These adverse events need to weighed against the benefits with respect to cardiovascular events and death associated with intensive control of systolic blood pressure.

In a separate manuscript on the participants aged ≥75 years [3] the authors concluded that “among ambulatory adults aged 75 years or older, treating to a systolic blood pressure target of less than 120 mmHg compared with a systolic blood pressure target of less than 140 mmHg resulted in significantly lower rates of fatal and nonfatal cardiovascular events and death from any cause”. During follow-up, systolic blood pressure averaged 134.8 mmHg in the standard treatment group and 123.4 mmHg in the intensive treatment group. The primary outcome was 34% (p=0.001) lower in the intensive treatment group than in the standard treatment group and death from any cause was reduced by 33% (p=0.009). 

Should target systolic blood pressure be lowered to <120 mmHg?

To answer this question it is important to consider the method of blood pressure measurement in the SPRINT trial. In the main publication of the trial [2] blood pressure was defined as the average of three blood pressure measurements at each office visit, measured in the seated position, after five minutes of quiet rest, with the use of a validated automatic measurement system. Later on, it became clear that blood pressure measurement was carried out unattended, that is to say that the study personnel left the room after setting the device to start the measurement five minutes after leaving. Studies have shown that unattended automated office blood pressure is up to 20 mmHg lower than conventionally measured office blood pressure. Therefore, blood pressures taken in SPRINT cannot be directly compared with blood pressures in other trials. The treatment arm of <120 mmHg in SPRINT compares with a higher systolic blood pressure value in the other trials, but the magnitude of the difference remains unclear [4]. It is also of note that the achieved systolic blood pressure in the intensive treatment group averaged 121.5 mmHg overall [2] and 123.4 mmHg in the ≥75-year-old participants [3], and was not consistently lower than 120 mmHg in the majority of participants.

In the blood pressure arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (ACCORD BP) [5] 4,733 high-risk persons with type 2 diabetes were randomised to a target conventional systolic blood pressure of <120 mmHg or a target systolic blood pressure of <140 mmHg. Patients aged ≥40 years with cardiovascular disease, or ≥55 years with atherosclerosis, albuminuria, left ventricular hypertrophy or ≥ two risk factors, and systolic blood pressure of 130-180 mmHg on £three antihypertensive drugs, were randomly assigned to either intensive therapy or standard BP control. The main exclusion criteria were: body mass index >45 kg/m2, renal dysfunction or other serious illness. The mean age was 62.2 years and cardiovascular disease was present in 33.7%. During a mean follow-up of 4.7 years, systolic blood pressure averaged 119.3 mmHg in the intensive treatment group and 133.5 mmHg in the standard treatment group. The primary outcome, a composite of myocardial infarction, stroke and cardiovascular death, was not significantly different between the two groups (hazard ratio (HR): 0.88; p=0.20) and this was also the case for major coronary events (HR: 0.94; p=0.50), heart failure (HR: 0.94; P=0.67), all-cause mortality (HR: 1.07; P=0.55) and cardiovascular death (HR: 1.06; p=0.74). Stroke occurred less frequently in the intensive treatment group (HR: 0.59; p=0.01), but the overall incidence of stroke was small. Serious adverse events attributed to antihypertensive treatment occurred in 3.3% of the participants in the intensive treatment group and in 1.3% in the standard treatment group (p<0.001). The authors concluded that “in patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mmHg, as compared with less than 140 mmHg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events”.

Based on the implications of the unattended blood pressure measurement in SPRINT, an achieved systolic blood pressure of 121.5 mmHg overall and 123.4 mmHg in the elderly, not consistently below 120 mmHg in the majority of participants, in the intensive treatment group and the conclusions from the ACCORD BP trial, there appears to be no reason for guidelines to lower target systolic blood pressure to <120 mmHg in conventional clinical practice, at least not in patients at high cardiovascular risk or with diabetes.

Should target systolic blood pressure be lowered to <130 mmHg?

In a recently updated meta-analysis (with inclusion of SPRINT), Thomopoulos et al [6] aimed to clarify further the practical question of blood pressure targets of antihypertensive therapy. The authors selected randomised controlled trials comparing more with less intensive blood pressure lowering and randomised controlled trials comparing active antihypertensive treatment versus placebo, enrolling hypertensive patients or cohorts with ≥40% hypertensive patients aged ≥ 18 years, with follow-up of ≥ six months and reporting at least one type of cardiovascular event or all-cause mortality, with minimum of five events during follow-up. Trials investigating patients with acute myocardial infarction, heart failure, acute stroke, renal dialysis or secondary hypertension were excluded. The effects of blood pressure lowering were assessed in three strata with mean systolic blood pressure achieved by active or more intensive treatment versus mean systolic blood pressure achieved in the placebo or less intensive treatment groups: 140-149 vs. ≥150 mmHg (actually achieved systolic blood pressure: 143.3 vs. 157.1 mmHg); 130-139 vs. ≥140 mmHg (137.2 vs. 144.3 mmHg); and <130 mmHg vs. ≥130 mmHg (125.8 vs. 134.9 mmHg), the most relevant comparison for the current discussion. The meta-analysis showed that stroke, coronary heart disease, cardiovascular death and all-cause mortality – but not heart failure – can be significantly reduced by lowering systolic blood pressure to a few mmHg below 130 mmHg versus above 130 mmHg. However, the absolute risk reduction is smaller at lower blood pressure targets than at higher blood pressure targets. This smaller benefit should be taken into account when deciding the blood pressure target to achieve in the individual patient, especially in view of a possible increase of adverse effects and a consequent decrease in the patient’s adherence to the treatment [6]. One should also consider that meta-analyses are not a real substitute for large and good randomised controlled trials and that meta-analyses comprise trials with heterogeneous cohorts; thus identifying those individuals who would benefit most from intensive treatment to lower blood pressure targets is difficult [6]. In addition, the only three large randomised controlled trials - SPRINT [2], ACCORD BP [5], and the Secondary Prevention of Small Subcortical Strokes trial (SPS3) [7] - which specifically aimed to investigate the possible benefits of lowering systolic blood pressure well below 130 mmHg have given some contrasting results and had important limitations [6].

The SPRINT [2] and ACCORD BP [5] trials have been discussed above. The SPS3 trial [7] investigated the effects of different systolic blood pressure targets on recurrent stroke in patients with recent MRI-defined symptomatic lacunar infarctions: these are small subcortical brain infarcts, which represent about 25% of ischaemic strokes. Normotensive and hypertensive patients aged ≥30 years were randomly assigned to a systolic blood pressure target of 130-149 mmHg or <130 mmHg, at least two weeks after the index stroke, with stratification for baseline hypertensive status. The main exclusion criteria comprised disabling stroke, previous intracranial haemorrhage from non-traumatic causes or cortical ischaemic stroke; 3,020 patients with a mean age 63 years were enrolled. Blood pressure was the average of three automated blood pressure measurements overseen by a physician. During follow-up, systolic blood pressure averaged 127 mmHg in the lower target group and 138 mmHg in the higher target group; blood pressure was within the assigned target range in 65% of the lower and in 75% of the higher target group. During a mean total follow-up of 3.7 years the incidence of the primary endpoint of all strokes was not significantly different between the two treatment groups (HR: 0.81; p=0.08). Among other endpoints (disabling or fatal stroke; ischaemic stroke or stroke of unknown origin; intracranial haemorrhage; myocardial infarction or vascular death; all-cause mortality), only the incidence of intracerebral haemorrhage was significantly lower in the higher target group (HR: 0.37; p=0.03); it is of note that the number of intracerebral haemorrhages was small. The intervention was safe and well-tolerated. The conclusion of the authors that the results suggest that management of systolic blood pressure to levels lower than 130 mmHg is likely to reduce the risk of recurrent stroke in patients with lacunar infarction should be taken with a grain of salt, and the results can certainly not be extrapolated to hypertensive patients in general.

In addition to the comments with regard to the meta-analysis by Thomopoulos et al [6], one should consider the results of the HOPE-3 study (Heart Outcomes Prevention Evaluation) [8]. The aim of this double-blind randomised placebo-controlled trial was to evaluate the role of blood pressure lowering therapy in persons at intermediate risk, defined as an annual risk of major cardiovascular events of about 1%, who do not have cardiovascular disease or renal dysfunction, and with systolic blood pressure <160 mmHg without symptomatic hypotension. Inclusion criteria comprised men aged ≥55 years and women aged ≥65 years with at least one cardiovascular risk factor, and women aged ≥60 years with two or more cardiovascular risk factors. Participants were not selected on the basis of history of hypertension, which was reported in 38% of the 12,705 participants. Systolic blood pressure at baseline averaged 137.9 mmHg in the placebo group and 138.2 mmHg in the active treatment group, in which therapy consisted of a fixed-dose combination of candesartan (16 mg) and hydrochlorothiazide (12.5 mg). During 5.6 years of follow-up systolic blood pressure decreased by 4.0 mmHg to 133.9 mmHg in the placebo group and by 10.0 mmHg to 128.2 mmHg in the active treatment group. However, the first primary outcome, a composite of cardiovascular death, myocardial infarction and stroke, was not significantly different between the two groups (HR: 0.93; p=0.40), which was also the case for the second primary outcome (the first primary outcome plus resuscitated cardiac arrest, heart failure and revascularisation) (HR: 0.95; p=0.51). In addition, the incidence of stroke, heart failure, mortality from cardiovascular causes or from any cause, was not significantly different between the two groups. Discontinuation of the trial occurred for reasons of symptomatic hypotension, dizziness or light-headedness was more frequent in the active therapy group than in the placebo group (p<0.001), but not discontinuation owing to syncope or renal dysfunction or abnormalities in serum potassium level. In conclusion the more intense therapy was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who do not have cardiovascular disease. The results of HOPE-3 are compatible with the hypothesis that treating persons without cardiovascular disease who have a systolic blood pressure above approximately 140 mmHg appears beneficial, but treatment would not be of benefit and may even be harmful in persons with lower blood pressure levels.

Conclusions

There appears to be no compelling indication for a change in the current recommendation of the 2013 ESH/ESC Hypertension Guidelines to reduce the target conventional office systolic blood pressure of <140 mmHg to a lower level in the vast majority of hypertensive patients in normal clinical practice. This is based on:

• The implication of the unattended automated blood pressure measurement in SPRINT.
• The heterogeneity of trials included in meta-analyses.
• Meta-analyses not being substitutes for large randomised controlled trials.
• The contrasting results and limitations of randomised controlled trials with regard to the possible benefits of lowering conventional blood systolic blood pressure to <130 mmHg.
• The smaller absolute risk reduction and the possible increase of adverse events at lower target blood pressure.                                               

It is up to Guideline Committees to carefully consider current levels of evidence and classes of recommendation based on current and future evidence.