There has been recent debate on how to place current research assessing different targets of blood pressure therapy into a real-world context. This article summarises the main clinical studies in this area and illustrates how the current evidence base can be used to guide treatment decisions. It also highlights those patient groups where the evidence does not extend.
Hypertension is estimated to account for up to 6% of deaths worldwide,1 and is the most commonly treated modifiable risk factor for cardiovascular (CV) disease. There is a clear relationship between reducing blood pressure (BP) for hypertensive patients and reduction in cardiovascular death and mortality, although this benefit may be attenuated with multimorbidity and age.2
Historically, BP targets have varied considerably as the understanding of the pathophysiology and risk of cardiovascular morbidity and mortality developed. Indeed, there were moves not to treat hypertension in the 1930s as many physicians deemed high blood pressure an ‘essential’ response to maintain circulatory blood flow,3 hence the term ‘essential hypertension’.
The first two landmark studies assessing hypertension were published in 1967 and 1970,3 with diastolic blood pressure targets suggested <=90mmHg. Since then there has been increasing evidence that systolic hypertension is a more accurate predictor of cardiovascular risk,2 and numerous studies have been published with BP targets reduced from 160mmHg to current targets.
In 2016, Australian guidelines were updated to reflect the new clinical data with other countries following suit. Current targets for the general population with diagnosed hypertension are ≤140/90mmHg, with a lower target of <120mmHg systolic for patients with at high CV risk [>=20% 10 year risk] if tolerated and after patient-centered discussion.4
In contrast, patients at low CV risk [<10% 5-year risk] should have lifestyle advice provided in the clinic, with anti-hypertensive therapy only commenced if BP is persistently >160/100mmHg or risk score changes.4 This balance of overall risk and the BP number is an important change in clinical decision-making. The guidelines, in line with other international guidelines, have strongly recommended the use of ambulatory BP monitoring for patients with BP readings >140/90mmHg in the clinic as out of clinic BP monitoring are a stronger predictor of outcome.4
There continues to be interest in evaluating the risk:benefit ratio of lower BP targets, with this being the focus of recent research5,6,7,8,9,10 and whether specific subgroups of patients may benefit from intensive BP treatment such as patients with diabetes7,9 and older adults.11,12
Three studies that have been important in guiding BP targets for the general population, and patients with diabetes, are summarised in Table 1.
The Systolic Blood Pressure Intervention Trial (SPRINT) (n=9361) reported at the end of last year has been the catalyst for possible change of hypertension guidelines (Table 1). The study reported that for patients at high CV risk (>=20% 10 year CV risk) intensive treatment (<120mmHg) was associated with reduced cardiovascular disease and mortality compared to standard treatment (<140mmHg) with the trial being terminated early.8
The trial protocol rapidly up-titrated medications to achieve BP targets and stressed the importance of gold standard BP measurements. Patients in the intensive group required a mean of 2.8 medications compared to 1.8 medications in the standard therapy group. Although there are limitations to the SPRINT trial, including its early termination and the fact that much of the primary outcome was driven by the 38% relative risk reduction in heart failure, the trial has changed clinical practice recommendations for patients at high CV risk.4
SPRINT provided more weight to the recommendations for intensive treatment for high-risk patients of CVD. Systematic reviews have reported that there are benefits in intensive treatment for patients at high CV risk.5,6
|TABLE 1: KEY CLINICAL TRIALS RELATING TO HYPERTENSION TARGETS|
|SPRINT trial8 2015||ACCORD trial9 2011||HOT trial10 1998|
|Study Type||9,361 (CVR >=20% over 10 years)
Excluded T2DM patients
|4,733 (T2DM at high risk CVD)||18,790 with hypertension and DBP between 100-115mmHg|
|Participant Numbers||Intensive BP treatment (<120mmHg) v Standard BP treatment (<140mmHg)||Intensive BP treatment (<120mmHg) v Standard BP treatment (<140mmHg)||Three DBP targets: <=90 mmHg (n=6264); <=85 mmHg (n=6264), and <=80 mmHg (n=6262)|
|Intervention||3.3 years||4.7 years||3.8 years|
|Recommendations||Functionally well non-diabetic patients at high CV risk, should be considered for intensive BP treatment based upon patient choice and comorbid disease.||In patients with T2DM targeting lower BP target was not associated with improvements in cardiovascular death or mortality.||Intensive lowering of diastolic blood pressure in patients with hypertension was associated with a low rate of cardiovascular events.|
|RCT – Randomised controlled trial; T2DM – Type-2 diabetes mellitus; CVD – cardiovascular disease; CV – cardiovascular disease; MI – myocardial infarction; BP- blood pressure; DBP – diastolic blood pressure; ACS – acute coronary syndromes|
In 2016, Xie et al systematically reviewed 19 randomised controlled trials (n=44,989) with a mean follow-up of 3.8 years.5 When the group with an attained BP of 133/76mmHg was compared to the group with attained BP of 140/81mmHg the intensive treatment group had a 14% relative risk reduction in cardiovascular mortality (number needed to treat = 36) with net benefits of treatment outweighing sideeffects in the authors opinion.5
Another systematic review reported that intensive BP treatment reduced not only stroke (relative risk reduction—29%) and coronary events (relative risk reduction—20%), but also cardiovascular mortality (relative risk reduction—21%).6
Importantly, absolute risk reduction becomes smaller as BP is reduced from 130mmHg with intensive treatment suggesting patients at lower initial SBP were at a lower level of cardiovascular risk.6
The picture is different for patients with diabetes. There is considerable variation between different guidelines7 some guidelines recommending <130/80mmHg and others recommending <140/90mmHg. More recently, the ACCORD trial9 (Table 1) found no overall benefit with intensive BP treatment for diabetic patients compared to standard treatment.
A BMJ systematic review of 49 trials (n=73,738), which included both published and unpublished data, assessed the effect of BP therapy on patients with diabetes at different levels.7 The authors reported that the evidence for BP treatment for patients with a BP >140/90mmHg is clear.7 However, for patients receiving additional treatment with systolic BP <140mmHg, there was increased CV mortality and adverse events.7
The benefit of intensive BP treatment appears to be related to the baseline CV risk of patients. This was reflected in one of the HOPE-3 analyses13 that assessed BP treatment of patients at intermediate CV risk without CV disease. The trial reported no overall benefit of treating normotensive patients and higher rates of side-effects; the only sub-group of patients benefiting were those with a BP above the currently recommended target of 140/90mmHg.13
Most international guidelines recommend treating older patients (>65 years old) with a SBP greater than 150mmHg to a target of <150mmHg, and to consider treating functionally well and independent octogenerians with SBP greater than 160mmHg to a target of <150mmHg.12 The guidelines are based on the evidence base to date, with several aspects of the recommendations being expert consensus as a result of limited gold standard trial data.
It has been well documented that clinical trials have historically excluded older patients,14 and patients with significant comorbidity14 to try to maintain internal validity of the trial often at the expense of external validity and subsequent limited generalisability of the trial conclusions.15 Therefore, the active involvement of older patients in hypertension research is most welcome.
A pre-specified analyses of the SPRINT data for patients >= 75 years old (n=2636) reported that intensive BP therapy was associated with lower rates of fatal and nonfatal CV events and death from any cause.11 It should be stressed that although frailty scores were similar compared to community dwelling older adults, patients residing in nursing homes and those with diagnosis of dementia were excluded from the trial and there was a low relative three-year mortality for this patient group.11 Thus, these data cannot be extrapolated from functionally well independent older adults to more complex frail patients residing in nursing homes.12
The SPRINT sub-group analysis findings were similar to those reported in the Hypertension in the Very Elderly Trial (HYVET) study.16
The HYVET study (n=3845) assessed treatment of persistent hypertension (SBP >160mmHg) with indapamide +/- perindopril versus matched placebo for older adults >= 80 years old. HYVET reported a difference of 15mmHg in SBP between treatment and placebo group with significant reduced 21% risk of death of all cause and 23% risk of death from cardiovascular cause.16 In a pre-specified analysis between patients where a frailty index score could be calculated (n=2,656), frailty scores had no significant interaction between treatment effect of any end-points.17 A one-year open label extension of the study reported sustained differences between total and cardiovascular mortality.18
However, it should be noted that the HYVET trial had robust exclusion criteria and many patients had a high frailty score. Patients with loss of independence, major cardiovascular comorbidities, significant orthostatic hypotension and dementia were excluded from the study. Furthermore, as HYVET only treated patients with grade 2 hypertension, the results are not necessarily generalisable to patients >=80 years old with grade 1 hypertension.
Clearly, the treatment of older patients, where multi-morbidity is often the norm, is not without risk. Indeed, older adults are more prone to the adverse risks associated with hypotension and electrolyte disturbance.
A UK-based retrospective observational cohort study (n= 11,167) recently reported that a low systolic blood pressure was independently associated with mortality, acute renal failure and hospital admission.19 The authors reported systolic blood pressure (SBP) was below 120mmHg in 1,297 people (844 on antihypertensives), below 110mmHg in 474 (313 on antihypertensives) and below 100mmHg in 128 (89 on antihypertensives).19 The authors suggest that single disease orientated guidelines may lead to pursuit of BP control at the risk of over-treatment for higher risk groups of patients.19
The longituditional PARTAGE (Predictive Value of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population) study reported that the benefits of treating hypertension observed in middle-aged patients are not necessarily seen in frailer older (>=80) adults in nursing homes.20 The PARTAGE study reported that in this patient group the number with the highest mortality were patients with a SBP of less than 130mmHg, which persisted even after adjustment for age, sex, history of previous cardiovascular disease, cognition, activities of daily living and comorbidity (Charlson) index.20 Other studies have reported similar relationships between reducing benefits between SBP reduction and subsequent cardiovascular health in older patients.21,22
There has been interest in trying to best select older patients at risk of side-effects of antihypertensive treatment, with a recent study looking at the association between walking speed (as a marker of frailty) and mortality. The authors reported that participants with high walk speeds had increased mortality with increased SBP and would benefit from anti-hypertensive treatment.22 However, for patients who were unable to complete the walk test an elevated SBP was associated with a lower risk of death suggesting that active treatment could cause harm.22
Hypertension as a modifiable risk factor for vascular disease with its associated morbidity and mortality is important to treat. This article has outlined some of the recent development in hypertension guidelines secondary to new data clinical data regarding the management of hypertension in patients at high CVD risk and diabetic patients.
The management of hypertension for older adults remains more of a challenge. Trial data strongly suggests benefits of treating functionally well and independent older adults at high cardiovascular risk to targets in line with younger adults. Current targets of <140mmHg may be appropriate, but risks and benefits of treatment should be monitored and reviewed regularly with patients. For patients >=80 years old, active treatment should be considered for robust patients when SBP >160mmHg to a target of between 130-150mmHg.
For less independent and more frail, multimorbid and poly-medicated adults a more cautious approach to blood pressure management is advisable and the evidence for this group is sparse. In this patient group the relationship between high blood pressure treatment and benefit is less clear, and an individualised approach is recommended.
Current recommendations for this complex patient group includes a rapid assessment of frailty, and to consider a target SBP of 150mmHg after performing an evaluation of functional capacities, cognitive status, polypharmacy and prioritisation of therapeutic goals. However, the risk of adverse events is much greater.
In line with much of medicine at the present time, one of the important aspects of clinical decisionmaking relates to a patient’s overall risk rather than a specific BP reading, with treatment decisions guided based upon these assessments and shared decision making as patients often have differing wishes and expectations.
Lloyd D Hughes, GP Registrar Kelty Medical Practice, NHS Fife
Conflict of interest: none declared
5. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials. J Hypertens 2016; 34(4): 613–22
10. The HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–62
11. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults >=75 years. A Randomised Controlled Trial. JAMA; 315(24): 2673–82
15. Van Spall HGC, Toren A, Kiss A, et al. Eligibility criteria of randomized controlled trials published on high-impact general medical journals: a systematic sampling review. JAMA 2007; 297: 1233–40
17. Warwick J, Falaschetti E, Rockwood, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the Hypertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Medicine 2015;13: 78
19. Morrissey Y, Bedford M, Irving J, Farmer CKT. Older people remain on blood pressure agents despite being hypotensive resulting in increased mortality and hospital admission. Age and Ageing 2016; 45(6): 783–88