44.5 Blood pressure thresholds for treatment and blood pressure treatment targets in hypertension

The benefits of blood pressure (BP)-lowering treatment in patients with hypertension have been well established by clinical trials, over many decades. A recent meta-analysis has shown that a 20 mmHg reduction in systolic BP can almost halve the risk of cardiovascular events. Treatment involves lifestyle interventions, drug therapy, and more recently device-based therapies have emerged. Key questions are ‘At what level of BP should treatment be considered?’ and ‘How low should BP be lowered by treatment?’ Guidelines recommend lifestyle interventions for all patients with borderline or established hypertension to reduce BP and cardiovascular disease risk, therefore, the debate about ‘when to treat’ is principally about when to consider starting drug therapy. The level of BP at which drug treatment should be considered is the ‘treatment threshold’ and the level to which BP should be lowered is ‘the treatment target’. Throughout this chapter, the BP values referred to are seated office BP values as these have traditionally formed the basis for the classification of hypertension and for monitoring the BP response to treatment.

The benefits of blood pressure (BP)-lowering treatment in patients with hypertension have been well established by clinical trials, over many decades. A recent meta-analysis has shown that a 20 mmHg reduction in systolic BP (SBP) can almost halve the risk of cardiovascular (CV) events (Figure 44.5.1).¹ Treatment involves lifestyle interventions, drug therapy, and more recently device-based therapies have emerged. Key questions are ‘At what level of BP should treatment be considered?’ and ‘How low should BP be lowered by treatment?’ Guidelines recommend lifestyle interventions for all patients with borderline or established hypertension to reduce BP and cardiovascular disease (CVD) risk, therefore, the debate about ‘when to treat’ is principally about when to consider starting drug therapy. The level of BP at which drug treatment should be considered is the ‘treatment threshold’ and the level to which BP should be lowered is ‘the treatment target’. Throughout this chapter, the BP values referred to are seated office BP values as these have traditionally formed the basis for the classification of hypertension (see Chapter 44.2) and for monitoring the BP response to treatment. However, there is increasing use of home BP monitoring (HBPM) or 24 h ambulatory BP monitoring (ABPM) to diagnose hypertension and monitor BP control and corresponding BP thresholds and targets are provided later in this chapter.

The definition of hypertension according to the classification referred to above is arbitrary because BP is normally distributed within populations and there is no single value above which risk associated with BP suddenly increases. The risk associated with BP is continuous and the gradient this relationship will vary according to the presence of other CV factors, age, co-morbidities, and individual patient susceptibility to hypertension-mediated organ damage. Hypertension is perhaps best defined as the level of BP at which treatment to lower BP results in significant clinical benefit. This definition acknowledges that the treatment thresholds are subject to change according to evidence from randomized clinical trials (RCTs) and may vary according to the characteristics of individual patients. It is also important to note that the thresholds discussed below are based on the assumption that the BP has been confirmed to be persistently elevated, either by repeated office BP measurements or by use of HBPM or ABPM.

There is no controversy about the benefits of BP-lowering treatment in patients with grade 2 hypertension (office BP ≥160/100 mmHg) or higher. The evidence supporting the benefits of treatment for patients with grade 2 or grade 3 hypertension, independent of the baseline CV risk, is unequivocal and substantial (see later discussion).² This is true for all adults, even those over the age of 80 years—the latter with some additional considerations discussed later in this chapter. In patients with grade 2 or 3 hypertension, BP-lowering treatment should be initiated immediately alongside lifestyle interventions to reduce CV risk.²

There has been much more debate about whether grade 1 hypertension (BP 140–159/90–99 mmHg) should be routinely treated in all patients. This uncertainty in large part relates to the fact that patients with grade 1 hypertension have much less commonly been included in RCTs, especially those with lower risk profiles. To some extent, decisions by guideline developers are influenced not only by the level of BP per se, but also the presence or absence of CVD and the CV risk of the patient. There are also other considerations, notably, the impact of age, frailty, and co-morbidities such as diabetes or chronic kidney disease (CKD), which can all influence the treatment threshold. In this regard, guidelines are consistent in recommending that patients with grade 1 hypertension and high CV risk or evidence of hypertension-mediated organ damage (e.g. retinopathy, left ventricular hypertrophy, or CKD) should be treated with BP-lowering drugs.^{2,  3}

Recent meta-analyses show significant treatment-induced reductions in CV events and mortality in patients with grade 1 hypertension.^4,5,6 However, one of these analyses included a substantial number of patients who had grade 1 hypertension while on treatment and were therefore, likely to have had initial BPs above the grade 1 range. Furthermore, many of the patients had diabetes and were therefore at high CV risk.⁶ Another meta-analysis, limited to RCTs in patients with grade 1 hypertension and low–moderate risk (five RCTs, 8974 patients), demonstrated a significant reduction in all major CV events by BP-lowering drug treatment (combined stroke and coronary artery disease (CAD) reduced by 34% and all-cause mortality by 19% for a SBP reduction of approximately 7 mmHg).¹ A third analysis demonstrated THE benefit of BP lowering in reducing death and CVD in patients with a baseline BP of 140/90 mmHg or higher but not when baseline BP was lower.⁵ These findings have been supported by the results of a subgroup analysis of the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, showing a significant 27% reduction in major CV outcomes in patients at intermediate CV risk and baseline SBP values in the grade 1 hypertensive range (i.e. >143.5 mmHg (mean 154 mmHg)), when SBP was lowered by drug treatment by a mean of 6 mmHg.⁷

Based on these new data, the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) hypertension guidelines recommend that for patients with grade 1 hypertension and established CVD and very high or high CVD risk, or hypertension-mediated organ damage, lifestyle advice and BP-lowering treatment should be initiated simultaneously.² For patients with grade 1 hypertension and low-to-moderate CV risk, BP-lowering drug treatment is recommended if BP remains uncontrolled after a period of lifestyle intervention.² These recommendations are broadly consistent with the US hypertension guidelines, with two caveats; (1) the US guidelines recommend immediate treatment in all patients with grade 1 hypertension (which they classify as stage 2 hypertension); (2) the US guideline also recommends drug treatment for patients with high-normal BP (130–139/80–89 mmHg), which they somewhat controversially call stage 1 hypertension, if these patients have established CVD or an estimated 10-year CVD risk of 10% or more.³

Discussions of the treatment of hypertension in the ‘elderly’ or ‘older’ people have been complicated by the various definitions of older age used in RCTs.² The definition of older has been inconsistent and in the earliest trials was defined as older than 60 years, whereas this has progressively increased to 65, 70, and finally 75 years or 80 years in the most recent trials.^8,9 It is now well accepted that chronological age is often a poor surrogate for the fitness, independence, or frailty, that is, the biological or functional age of an individual patient. What is clear is that frailty and lack of independence can influence the perceived benefit and likely tolerability of BP-lowering medications. The recent 2018 ESC/ESH hypertension guidelines defined ‘old’ as at least 65 years and ‘very old’ as at least 80 years and even then, noted that frailty, dependence, and overall functional capacity were often more important than age per se.² With regard to treatment thresholds, previous guidelines¹⁰ had noted that all prior evidence on the benefits of BP lowering in older patients had been obtained in patients whose office baseline SBP was 160 mmHg or greater. There is strong evidence that older patients with grade 2 hypertension should be offered BP-lowering drug treatment.^2,3,9

Undoubtedly, there are RCTs showing outcome benefits with BP-lowering treatment in older patients with a baseline SBP lower than 160 mmHg, but these patients were often on background antihypertensive treatment and most likely had higher baseline BP prior to treatment and thus, they cannot be defined as true grade 1 hypertension. This is exemplified by recently published data from the Systolic Blood Pressure Intervention Trial (SPRINT) trial, which deliberately included a significant cohort of patients older than 75 years. In these patients, more intensive versus less intensive BP lowering substantially reduced the risk of major CV events and mortality but many of these patients were already treated with background antihypertensive medication and therefore their true baseline BP is unknown.^8,11 That said, in most RCTs showing a protective effect of BP-lowering treatment in patients with an untreated baseline BP in the grade 1 hypertension range, older patients have been well represented, the mean age of patients in BP-lowering trials is typically approximately 65 years, suggesting that typically half of the patients were over that age and would be classified as older. This was recently illustrated by the HOPE-3 trial, which showed beneficial effects of BP lowering on CV outcomes in patients, many with grade 1 hypertension (SBP >143 mmHg and mean BP 154 mmHg), whose mean age was approximately 66 years, and in whom only 22% had prior treatment of hypertension.⁷

Taken together, the evidence supports the 2018 ESC/ESH hypertension guidelines recommendation that older patients (>65 years, including patients >80 years) should be offered BP-lowering treatment if their SBP is 160 mmHg or higher and that there is now justification to recommend BP-lowering treatment for old patients (>65–80 years) at a lower BP (i.e. grade 1 hypertension; SBP between 140 and 159 mmHg).² This recommendation is consistent with the US hypertension guideline which recommends that BP-lowering drugs should be offered to all patients, irrespective of age, when BP is in the grade 1 hypertensive range.³ An important statement in the 2018 European hypertension guidelines is that BP-lowering treatment should not be withdrawn on the basis of age alone. This is because it is now well established that BP-lowering treatment withdrawal leads to a marked increase in risk of subsequent CV events.²

These new recommendations on BP-lowering thresholds for treatment in older patients contrast sharply and are more aggressive than prior recommendations from Europe and the United States.^10,12 The former recommended treatment for the ‘elderly’ at grade 2 hypertension and that treatment may only be considered when BP at grade 1 hypertension in people aged older than 65 years.¹⁰ The prior US Eighth Joint National Committee (JNC 8) guidelines were even more conservative in only recommending treatment at grade 2 hypertension in people aged 60 years or older.¹² Clearly, recent trials have markedly shifted the attitude towards more aggressive treatment of older patients with grade 1 hypertension. However, all of the above-mentioned new recommendations relate to relatively fit and independent older patients, because physically and mentally frail or institutionalized patients are unlikely to volunteer to participate in RCTs or have been excluded from most RCTs of patients with hypertension. Another important consideration is that older patients often have multiple co-morbidities that may influence their tolerability of BP-lowering medication, thus treatment has to be individualized, taking account of more than just age.

The recent US hypertension guidelines reclassified hypertension and stated that a BP of 130–139/80–89 mmHg was stage 1 hypertension.³ This has caused considerable debate because it increased the overall prevalence of ‘hypertension’ in the United States by approximately 50% and doubled the prevalence in younger patients, overnight. It also recommended treating many of these patients (approximately 30%) with BP-lowering drug therapy if they were at moderate to high CV risk.³ The 2018 ESC/ESH hypertension guidelines have not followed this trend and have not changed the classification of hypertension, referring to patients with a BP of 130–139/85–89 mmHg as having a ‘high-normal BP’.² The question remains as to whether any of these patients with a high-normal BP should be treated with BP-lowering drug therapy. The 2103 ESH/ESC hypertension guidelines recommended not to initiate antihypertensive treatment in people with high-normal BP and low-to-moderate CV risk.¹⁰ The 2018 ESC/ESH hypertension guidelines state that this prior recommendation is further supported by new evidence, notably: (1) in all RCTs (including SPRINT) and meta-analyses that have reported reduced major outcomes by lowering BP in the high-normal range, the ‘baseline’ BP was commonly measured on a background of antihypertensive treatment.¹ Therefore, these studies do not provide evidence to support treatment initiation in patients without hypertension. (2) The HOPE-3 trial, in which only 22% of the patients at intermediate CV risk had background antihypertensive treatment, showed that BP-lowering treatment did not reduce the risk of major CV events in patients with baseline SBP values in the high-normal range.⁷ (3) A meta-analysis of 13 RCTs or RCT subgroups (involving 21,128 individuals) in patients at low-to-moderate CV risk and untreated baseline BP in the high-normal and normal range, showed no effect of BP-lowering treatment on any CV outcomes.¹³ (4) Another recent analysis, including patients with high-normal BP, concluded that BP lowering was associated with reduced risk for death and incident CVD if baseline SBP was 140 mmHg or higher, but at lower BP levels (i.e. high-normal BP), treatment was not associated with any benefit in primary prevention.⁵ (5) The 2018 ESC/ESH hypertension guidelines noted that the situation may be different in very high-risk patients with a high-normal BP and established CVD.² In a meta-analysis of ten RCTs, or RCT subgroups, that also included individuals at high or very high CVD risk, mostly with previous CVD and untreated high-normal and normal BP (n = 26,863), BP-lowering drug treatment, achieving a SBP reduction of 4 mmHg, reduced the risk of stroke but not any other CVD events.¹³ Another analysis of trials including people with previous coronary and mean baseline SBP of 138 mmHg, treatment was associated with a reduced risk for major CVD events (relative risk 0.90; 95% confidence interval 0.84–0.97), but was not associated with survival (relative risk 0.98; 95% confidence interval 0.89–1.07).⁵ Thus, the benefit for treating people with high-normal BP appears marginal, and if present, appears to be restricted to those at very high CV risk and established CVD, especially CAD.

Based on these analyses, the 2018 ESC/ESH hypertension guidelines recommended that patients with high-normal BP and low-to-moderate CV risk should be offered lifestyle advice to reduce their risk of progressing to established hypertension and potentially further reduce their CV risk. However, the guidelines concluded that these patients should not be offered BP-lowering drug treatment.² Nevertheless, based on the data from the HOPE-3 trial, the guideline noted that drug treatment may be considered in these patients if their BP is close to the hypertension diagnostic threshold of 140/90 mmHg, after a prolonged attempt to control BP with lifestyle changes. Furthermore, BP-lowering drugs may be considered for patients with high-normal BP and established CVD, especially CAD.²

An elevated BP is extremely common in patients with diabetes, especially type 2 diabetes. High BP is a common feature of type 1 and, particularly, type 2 diabetes. Elevated BP has been implicated in the development of almost all macrovascular and microvascular complications of diabetes. Substantial evidence supports the benefits of BP reduction in people with diabetes to reduce major macrovascular and microvascular complications of diabetes, as well as reducing mortality. Proven benefits of BP-lowering treatment in diabetes also include a significant reduction in the rate of end-stage renal disease,^14,15 retinopathy,¹⁶ and albuminuria.¹⁶ In contrast, diabetic neuropathy has never been included as an outcome in RCTs of BP-lowering treatment. When considering treatment for hypertension, it is important to exclude significant postural hypotension by measurement of lying and standing BP. Postural hypertension can be marked in people with diabetes due to autonomic neuropathy.¹⁵ In the 2018 ESC/ESH hypertension guidelines, initiation of antihypertensive drug therapy was recommended when the office BP is greater than 140/90 mmHg.² ABPM over 24 h may be especially helpful in characterizing BP in patients with diabetes because office BP may underestimate the true 24 h BP load due to the common occurrence of an elevated night-time BP, especially in those with autonomic dysfunction, albuminuria, or CKD.

Hypertension is a major risk factor for the development and progression of CKD, irrespective of the cause of CKD.¹ In patients with CKD, resistant hypertension, masked hypertension, and elevated night-time BP are common, and are associated with a lower glomerular filtration rate, higher levels of albuminuria, and hypertension-mediated organ damage. All guidelines recommend that patients with CKD should receive lifestyle advice, especially sodium restriction, and drug treatment when their office BP is 140/90 mmHg or greater.^{2,  3}

Hypertension is a major risk factor for ischaemic and haemorrhagic stroke. RCTs of antihypertensive treatment (placebo controlled) in patients with a previous stroke or transient ischaemic attack, in a stable clinical condition and with BP of 140/90 mmHg or greater, have shown that BP lowering reduces the risk of recurrent stroke.^1,2,3,17 Consequently, all guidelines recommend treatment of hypertension with lifestyle advice and medication when office BP is 140/90 mmHg or greater. There is no evidence to suggest that recurrent stroke is prevented by initiating therapy when BP is in the high-normal range.

There are strong epidemiological relationships between CAD and hypertension. CAD is the commonest complication attributable to an elevated BP.^18,19 Epidemiological studies suggest that of the approximately 10 million deaths attributable to an elevated BP per annum, half are due to CAD.¹⁹ There is compelling evidence of a reduced risk of myocardial infarction by BP treatment. A recent meta-analysis of RCTs of antihypertensive therapy showed that for every 10 mmHg reduction in SBP, CAD was reduced by 17%.¹ A similar risk reduction has been reported by others with more intensive BP control.²⁰ The benefits of reducing cardiac events are also evident in high-risk groups, such as those with diabetes. Current guidelines all recommend that BP should be treated when office BP is 140/90 mmHg or greater. The US hypertension guideline has also suggested treating all high-risk patients when BP is 130/80 mmHg or greater.³ This was not endorsed by the most recent European guidelines which noted that the benefits are likely to be marginal but suggested that BP treatment may be considered in very high-risk patients when BP is in the high-normal range, especially at the upper end of that range and especially in those with CAD, where the evidence, although still not compelling, appears stronger than that for other manifestations of vascular disease.²

Two recent meta-analyses of RCT have shown that when BP-lowering data are stratified according to CV risk, the relative risk reductions do not differ across the various risk strata; not surprisingly, the absolute risk reduction is greater with increasing baseline CV risk.^4,21 These data have been taken as support for the hypothesis that BP-lowering treatment should be based on CV risk and target those at greatest CV risk, irrespective of their BP.²¹ It has recently been made clear, however, that whereas patients at high or very high CV risk exhibit the greatest absolute reduction in CV outcomes with BP-lowering treatment, they also have the highest residual risk, which means failure of treatment to exert full protection.⁴ It is the opinion of the ESC/EHS Task Force that these data support earlier treatment of patients with BP values greater than 140/90 mmHg when their CV risk is still low to moderate, to prevent the accumulation of hypertension-mediated organ damage and a high incidence of late treatment failure (residual risk), which would otherwise occur if treatment was delayed by a purely CV risk-based approach. The most effective strategy to reduce risk is to prevent the development of high CV risk situations with earlier intervention. In general, the decision to use BP-lowering treatment should not be based solely on the level of CV risk because even in patients at the highest risk (with established CVD), when baseline BP is below 140/90 mmHg, the benefits of BP-lowering treatment are at best marginal and most evident in patients with CAD at the upper end of the high-normal BP range.⁵

While there is less evidence based on the use of ‘out-of-office’ BP measurement for the initiation of treatment of hypertension, epidemiological evidence shows much stronger associations between home, and especially ABPM, with the risk of hypertension-mediated organ damage and CV and total mortality.²³ Furthermore, there is increasing use of HBPM and 24 h ABPM to define the presence of hypertension. Using these measurement techniques, an office BP of 140/90 mmHg or higher is equivalent to a home BP average of 135/85 mmHg or higher, a 24 h average BP of 130/80 mmHg or higher, and a daytime average ABPM value of 135/85 mmHg or higher.^{2,  3}

The 2018 ESC/ESH hypertension guidelines² have recommended that for patients with grade 2 or 3 hypertension, BP-lowering drug treatment should be initiated alongside lifestyle interventions. In patients with grade 1 hypertension and high-risk or hypertension-mediated organ damage, drug treatment should also be initiated simultaneously with lifestyle interventions. In lower-risk patients with grade 1 hypertension, BP-lowering drug treatment should be initiated after 3–6 months, if BP is not controlled by lifestyle interventions alone (Table 44.5.1 and Figure 44.5.2). The US 2017 hypertension guideline has recommended lower BP thresholds for the initiation of BP-lowering treatment (Table 44.5.2).

The BP targets for treated hypertension have been a moving target in recent years. In 2013, the ESH/ESC hypertension guidelines recommended an office BP treatment target of less than 140/90 mmHg for most patients, regardless of the number of co-morbidities and level of CV risk.¹⁰ For patients aged 80 years and over, the guideline recommended a more conservative target of less than 150/90 mmHg.¹⁰ The US JNC 8 guideline was even more conservative in recommending a target of less than 150/90 mmHg in people aged over 60 years.¹² These recommendations were based on results from RCTs, meta-analysis, and post hoc analysis of large-scale RCTs all of which showed no obvious incremental benefit of lowering BP to below 130/80 mmHg. Since then, new information has emerged from post hoc analyses of large outcome trials in patients at high CV risk, registries in patients with coronary disease, and, more importantly, new RCTs and meta-analyses of all available RCT evidence.^23,24 In the post hoc RCT analyses and registry data, compared with a target SBP of between 130 and 139 mmHg, lowering SBP to less than 130 mmHg was, in general, associated with no further benefit on major CV events, except perhaps for further reductions in the risk of stroke. A consistent finding was that reducing SBP to less than 120 mmHg increased the incidence of CV events and death.

An RCT particularly relevant to the issue of target BP was SPRINT, which compared two different SBP targets (<140 or <120 mmHg) in more than 9000 patients at high CV risk, but excluded patients with diabetes or previous stroke.⁸ In SPRINT, more intensive BP-lowering treatment, which achieved a SBP of 121 versus 136 mmHg in the less intensively treated group, was associated with a 25% reduction in major CV events and a 27% reduction in all-cause death (but no significant reduction in stroke or myocardial infarction). This outcome unquestionably provides strong support for the beneficial effects of more intensive versus less intensive BP-lowering treatment strategies in higher-risk patients. However, there has been controversy about the methods for measuring BP in SPRINT (unattended automatic office BP measurement) which had not been used in any previous RCTs that provide the evidence base for the treatment of hypertension. This controversy has arisen because unattended automated office BP measurement results in lower BP values, relative to conventional office BP measurement, due in particular to the absence of a ‘white coat’ effect. Thus, it has been suggested that the BP values reported in SPRINT (described earlier) may correspond to conventional office SBPs in the 130–140 and 140–150 mmHg ranges, in the more versus less intensive BP-lowering groups, respectively.

Some new information on SBP and diastolic BP targets for drug treatment has been provided by recent large meta-analyses of RCTs of BP lowering. In these meta-analyses, achieved SBP was stratified according to three SBP target ranges (149–140 mmHg, 139–130 mmHg, and <130 mmHg).²⁴ Lowering SBP to less than 140 mmHg reduced the relative risk of all major CV outcomes (including mortality). Similar benefits were seen when SBP was lowered to less than 130 mmHg (average 126 mmHg). Importantly, the latter was also true when the achieved SBP in the comparator group was in the range 130–139 mmHg. Stratification of RCTs for achieved diastolic BP, to either 89–80 mmHg or less than 80 mmHg, also showed a reduction in all types of CV outcomes compared with higher diastolic BP values.²⁴

A second meta-analysis, which also included the SPRINT trial,² noted that every 10 mmHg reduction in SBP reduced the rate of major CV events and death for baseline SBP values greater than 160 mmHg to baseline values between 130 and 139 mmHg, implying benefit at achieved SBP values of less than 130 mmHg.¹ Furthermore, a benefit of a 10 mmHg reduction in SBP was also reported for patients with a baseline SBP of less than 130 mmHg, thereby achieving values less than 120 mmHg. However, there were far fewer patients in these subgroups. Moreover, this last set of data will have been heavily influenced by the unusually low BP values in the SPRINT trial, due to the method of BP measurement (see earlier). Importantly, this analysis showed consistent benefit from intensive BP lowering in patients at all levels of risk, including those with and without existing CVD, stroke, diabetes, and CKD.

An important point, illustrated in these meta-analyses is that the incremental benefit of BP lowering on events decreases as the target BP was lowered. Furthermore, an additional meta-analysis by the same group found that permanent treatment discontinuation because of treatment-related adverse effects was significantly higher in those targeted to lower BP values.²⁵ Therefore, the 2018 ESC/ESH hypertension guidelines noted that advocating more intensive BP-lowering targets for all has to be viewed in the context of an increased risk of treatment discontinuations due to adverse events, which might offset, in part or completely, the limited incremental reduction in CV risk. As interesting as the debate is about how far BP should be lowered, this should be viewed while mindful of the fact that less than 50% of patients treated for hypertension currently achieve a target office SBP of less than 140 mmHg.²⁶

Largely influenced by the data from SPRINT, the US 2017 hypertension guideline adopted much more aggressive BP targets than the previous US JNC 8 guideline in 2013, in recommending an office BP target of less than 130/80 mmHg in all treated patients (including older patients) (Table 44.5.2).³ There has been concern expressed that a routine target BP of less than 130/80 mmHg is unlikely to be achievable or tolerated in many older patients, especially those commencing treatment with a high baseline BP (e.g. grade 3 hypertension).

The 2018 ESC/ESH hypertension guidelines recommended that when BP-lowering drugs are used, the first objective should be to lower BP to less than 140/90 mmHg in all patients, including older patients. The guideline went on to state that provided that the treatment is well tolerated, treated BP values should be targeted to 130/80 mmHg or lower, in most patients, while recognizing that the evidence for a SBP treatment target was less compelling for older patients (>65 years) in whom the SBP should be targeted to between 130 and 140 mmHg² The guideline also recommended that diastolic BP should be lowered to an optimal target range of less than 80–70 mmHg.² An important caveat was that SBP should not be targeted to less than 120 mmHg in any patient and not usually less than 130 mmHg in older patients (Table 44.5.3).

An important aspect of the 2018 European guidelines was the introduction of a target range for treated BP. This was because the lower safety boundary of BP assumes even greater importance when BP is targeted to lower levels than previously advocated. In all treated patients achieving these new, lower target BP levels, close monitoring for adverse effects (including renal function) is recommended and in some cases back-titration of treatment, rather than treatment withdrawal, may be needed.

There have not been adequate studies in patients with type 1 diabetes to provide recommendations on the optimal BP target to prevent CV events or death. This is because these patients have tended to be younger and the focus has been on demonstrating the benefit of BP-lowering treatment on renoprotection in patients with albuminuria. In these studies, BP lowering (especially with renin–angiotensin system blockade as part of the treatment) has been shown to have renoprotective effects. In contrast, in type 2 diabetes, there have been many BP-lowering treatment RCTs, either exclusively dedicated to patients with type 2 diabetes, or hypertension trials that have included a large cohort of patients with type 2 diabetes.^1,14,16 Most of these RCTs have shown that BP lowering to less than 140/90 mmHg is beneficial in patients with type 2 diabetes and hypertension. However, the results have been less clear about whether a lower BP target is associated with further benefits. The evidence was recently summarized in the 2018 ESC/ESH guidelines as follows:

Thus, there seems to be no doubt that BP should be lowered to less than 140/90 mmHg in patients with diabetes. There has been controversy about whether BP should be lowered further but the evidence seems consistent in showing further reductions in stroke in particular at lower achieved BP levels. The 2018 European guidelines concluded that in patients with diabetes receiving BP-lowering drugs, that office BP should be targeted to a SBP of 130 mmHg, and lower if tolerated.² In older patients (aged ≥65 years), the SBP target range should be 130–140 mmHg if tolerated.² Diastolic BP should be lowered to less than 80 mmHg and SBP should not be lowered to less than 120 mmHg. These recommendations are consistent with the 2017 US hypertension guidelines which recommended that in people with diabetes, treated office BP should be lowered to less than 130/80 mmHg.³

The definition of ‘older’ is complex. As populations age, there is increasingly wide variation between a patient’s chronological age and their functional status, ranging from fit, active, and independent, through to frail and dependent. The anticipated benefits versus potential harm of BP treatment in older patients will be influenced by the patient’s ability to tolerate treatment and their health and functional status. The 2018 ESC/ESH guidelines defined ‘older’ patients as those aged 65 years and older.²

In the 2013 ESH/ESC hypertension guidelines, the target SBP for older hypertensive patients was set at 140 to less than 150 mmHg because this was the range of systolic values achieved by major outcome trials demonstrating a beneficial effect of antihypertensive treatment in these patients.¹⁰ A similar SBP target was suggested by the Hypertension in the Very Elderly Trial (HYVET) trial, in which treating to a SBP target of less than 150 mmHg (achieving a mean SBP of 144 mmHg) in the very old (>80 years), demonstrated significant reductions in mortality, fatal stroke, and heart failure, with the caveat that the ‘very old’ patients in this study were active and independent.⁹ More recent evidence supports a lower SBP target for older patients (≥65 years):

Based on the new data, the targets suggested by the previous guidelines now appear too conservative for many old and very old patients, especially those who are active and independent. Consequently, the most recent European guidelines recommend that in older patients treated for hypertension, BP should be lowered to less than 140/80 mmHg, but not below an SBP of 130 mmHg.² The guidelines emphasize that the impact of BP lowering on the well-being of the patient should be closely monitored because the increased risk of adverse events (e.g. injurious falls) with lower BP values, could be more pronounced in older patients in the real-life setting, rather than in the closely monitored conditions of RCTs.

Current evidence suggests that in patients with CKD, BP should be lowered to less than 140/90 mmHg and towards 130/80 mmHg. Lifestyle advice, especially sodium restriction, may be especially effective at aiding BP lowering in patients with CKD. Because BP lowering reduces renal perfusion pressure, it is expected and not unusual for the estimated glomerular filtration rate to be reduced by 10–20% in patients treated for hypertension.^2,3 Thus, careful monitoring of blood electrolytes and estimated glomerular filtration rate is essential, but clinicians should not be alarmed by the anticipated decline in glomerular filtration rate when treatment is initiated. This decline usually occurs within the first few weeks of treatment and stabilizes thereafter. If the decline in glomerular filtration rate continues or is more severe, the treatment should be stopped, and the patient investigated to determine the presence of renovascular disease.

The appropriate BP targets to prevent recurrent stroke are uncertain but should be considered in the context of a consistent finding in many meta-analyses that stroke is the one major CV event that is reduced at lower achieved BP levels.^1,4 This is supported by the results from the recent Secondary Prevention of Small Subcortical Strokes (SPS) 3 study in patients with a recent lacunar stroke, which suggested a SBP target of less than 130 mmHg,³⁰ and other studies.³¹

There remains some inconsistency over the optimal BP target in hypertensive patients with overt CAD, and whether there is a J-curve relation between achieved BP and CV outcomes in CAD. A recent analysis of 22,672 patients with stable CAD and treated for hypertension found that after a median follow-up of 5.0 years, a SBP of at least 140 mmHg and diastolic BP of at least 80 mmHg were each associated with increased risk of CV events³² (Figure 44.5.3). A SBP of less than 120 mmHg was also associated with increased risk, as was a diastolic BP of less than 70 mmHg. Similar findings were also reported from another analysis of RCT data evaluating the relationships between achieved BP and risks of CV outcomes²³ (Figure 44.5.4). Whether a J-curve phenomenon exists in patients with CAD who have been revascularized remains uncertain. A target BP of approximately less than 130/80 mmHg in patients with CAD appears safe and can be recommended, but aiming for a BP less than 120/80 mmHg is not recommended.

There has been much less focus on optimal diastolic BP targets and there is much less certainty about the optimal BP target for diastolic BP. This reflects the fact that SBP is a more important risk factor for CV events, especially in older patients. Indeed, as people age, diastolic BP usually falls as a consequence of conduit artery stiffening. Thus, many older patients with hypertension and especially those with CKD or diabetes will have isolated systolic hypertension where the SBP is elevated and the diastolic BP is normal or low. There has been concern that an excessive reduction in diastolic BP may reduce coronary perfusion in particular and there is no doubt that a reduced diastolic BP prior to treatment is associated with an enhanced CV risk. Whether this is due to the low diastolic BP per se, or simply reflects the coexisting arterial disease is unclear but the latter seems more likely—accounting for reverse causality in analyses of achieved diastolic BP on treatment has been a challenge in interpreting the data from RCTs. Importantly, some of the most impressive benefits of BP reduction in terms of absolute risk reduction have occurred in RCTs involving patients with isolated systolic hypertension in whom an already low diastolic BP was further reduced by treatment. Thus, a low diastolic BP is not a barrier for treatment to lower SBP but patients with a low diastolic BP at baseline must be monitored carefully for adverse effects mindful of the fact that diastolic BP is the major component of mean BP which drives perfusion in the circulation. As discussed earlier in this chapter, all guidelines now recommend reducing diastolic BP to less than 80 mmHg but not to less than 70 mmHg, with the caveat that it may be necessary to go lower in order to achieve optimal SBP control in some patients.^2,3 These recommendations are supported by a more recently published analysis of the relationship between achieved diastolic BP and CV outcomes in the ONTARGET and Telmisartan Randomised Assessment Study in Angiotensin-Converting Enzyme Inhibitor-Intolerant Subjects with Cardiovascular Disease. (TRANSCEND) trials.³³ The study showed that in patients with SBP controlled to 120 or greater but less than 140 mmHg, an achieved diastolic BP greater than, or less than a diastolic BP range of less than 80 but not less than 70 mmHg, was associated with an increased risk of CV events, demonstrating a ‘J’ curve relationship (Figure 44.5.5). Importantly, the risk was greater in those with a treated diastolic BP remaining above 80 mmHg rather than those with a diastolic BP less than 70 mmHg³³

To date, there have been no outcome-based RCTs that have used home or ambulatory BP to guide the treatment of hypertension. Nevertheless, treated out-of-office BP levels, particularly ABPM, are stronger predictors of outcome than office BP in treated and untreated patients.²² Moreover, ABPM can reveal significant rates of uncontrolled BP in patients considered to be controlled according to office BP measurement—this has been termed masked uncontrolled hypertension and appears to be more common in patients at high CV risk.³⁴ Nevertheless, in the absence of RCT data, the ambulatory BP and home BP targets that correspond to the recommended office BP targets are necessarily based on extrapolation from observational data rather than on outcome trials. The 2018 European hypertension guidelines do not provide formal ambulatory or home BP targets for treated patients but noted that²:

These conclusions of the European 2018 hypertension guidelines about corresponding office and out-of-office BP levels at various BP thresholds or targets are consistent with those recommended by the US 2017 hypertension guidelines (Table 44.5.4).^{2,  3}