Improving outcomes for older hypertensive patients: is more intensive treatment better?

KEYWORDS:

• Blood pressure
• cardiovascular outcome
• hypertension
• intensive treatment
• older patients

1. Introduction

Older patients with hypertension account for more than one half of total hypertensive adults worldwide. With population aging, hypertension management, specifically the determining of the optimal target for systolic blood pressure (SBP) reduction in older patients, is becoming an increasingly important question. Large clinical trials have repeatedly and consistently documented SBP lowering to <150 mmHg by generic antihypertensive agents evidently reduced the risk of morbidities and mortality in older patients [1,2]. However, studies regarding a more intensive SBP target for older patients have yielded contrasting results, and heated debates exist around the important issue of: will more intensive treatment be better for older hypertensive patients?

2. Evidence from observational trials

In several observational studies, a J-shaped association between blood pressure and cardiovascular outcomes was observed, with individuals with too high or too low blood pressure measurements demonstrating a higher risk of cardiovascular events [3,4]. Messerli et al. argued that low blood pressure may impair the perfusion of vital organs, and thus precipitate adverse vascular events, especially in older patients with arteriosclerosis [5]. Some studies have even observed inverse associations between blood pressure and cardiovascular events in very older patients (over 85 years old) [6]. Notably, the increased cardiovascular risk in patients with low blood pressure levels may be a result of clinical characteristics, such as age and comorbidities related to low blood pressure, rather than a response to lowering of blood pressure per se.

3. Evidence from clinical trials

Randomized controlled trials (RCTs) on the interrogation of the optimal blood pressure targets presented the highest hierarchical level for demonstration of causality between intensive treatment and cardiovascular outcomes.

On the premise of clear cardiovascular benefits with an SBP target <150 mmHg, several seminal trials further investigated the effect of a lower SBP target. The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients trial (JATOS) [7] showed similar incidences of cardiovascular disease in patients receiving strict treatment (SBP target <140 mmHg), compared with mild treatment (<160 mmHg). Consistent conclusion was drawn in the Valsartan in Elderly Isolated Systolic Hypertension Study (VALISH) [8]. In the subgroup of patients aged 65 years or older in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial [9], targeting SBP to <130 mmHg did not additionally reduce the incidence of stroke, compared with <150 mmHg. (Table 1)

Table 1. Summary of trials investigating the effect of intensive SBP targets on cardiovascular outcomes

Trial	Age (yr.)	Follow up (yr.)	Patients no.	SBP target (mmHg)		Mean achieved SBP (mmHg)		Definition of the primary outcome	Annual rate (%)*		HR	95% CI		Reference
				Strict	Usual	Strict	Usual		Strict	Usual		2.5%	97.5%
JATOS	65–85	2	4418	<140	140–160	135.9	145.6	Combined incidence of CV disease and renal failure	1.94	1.95	–	–	–	[7]
VALISH (ISH)	70–84	3.07	3260	<140	140–150	136.6	142	Composite of sudden death, stroke, MI, death of HF, other CV death, unplanned hospitalization for CV disease, and renal dysfunction	1.06	1.2	0.89	0.6	1.34	[8]
SPS3 (recent lacunar stroke)	$\ge$30	3.7	3023	<130	130–149	127	138	All stroke (including ischemic strokes and intracranial hemorrhages)	2.25	2.77	0.81	0.64	1.03	[9]
	$\ge$65^†		1263						2.53	2.86	0.89	0.62	1.26
SPRINT (high CV-risk)	$\ge$50	3.26	9361	<120	120–140	121.4	136.2	Composite of MI, other ACS, stroke, HF, or death from CV causes	1.65	2.19	0.75	0.64	0.89	[10]
SPRINT-age	$\ge$75	3.14	2636	<120	120–140	123.4	134.8	Composite of MI, other ACS, stroke, heart failure, or death from CV causes	2.59	3.85	0.66	0.51	0.85	[11]
STEP	60–80	3.34	8511	110–130	130–150	126.7	135.9	Composite of stroke, ACS, ADHF, coronary revascularization, AF, or death from CV causes	1	1.4	0.74	0.6	0.92	[13]

Abbreviations: SBP, systolic blood pressure; HR, hazard ratio; CI, confidence interval; JATOS, the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients trial; CV, cardiovascular; VALISH, the Valsartan in Elderly Isolated Systolic Hypertension Study; ISH, isolated systolic hypertension; MI, myocardial infarction; HF, heart failure; SPS3, the Secondary Prevention of Small Subcortical Strokes; SPRINT, the Systolic Blood Pressure Intervention Trial; ACS, acute coronary syndrome; STEP, the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial; ADHF; acute decompensated heart failure; AF, atrial fibrillation.

*The annual rate of the primary outcome.

^†Subgroup stratified by age.

The Systolic Blood Pressure Intervention Trial (SPRINT) trial [10]** signaled a historical tipping point of the perspective into intensive SBP treatment. Targeting SBP to <120 mmHg significantly reduced the risk of major adverse cardiac events, cardiovascular mortality, and all-cause mortality, compared to targeting SBP to <140 mmHg in patients with high cardiovascular risk. To astonish many, these benefits were consistent in the pre-designed subgroup of patients aged at least 75 years old [11]** in SPRINT. Subsequent to the SPRINT trial, the Heart Outcomes Prevention Evaluation (HOPE-3) [12] trial indicated that in patients with lower cardiovascular risk, those with the baseline SBP > 143.5 mmHg could be benefited from active-treatment (mean achieved SBP at 128.3 mmHg). Recently, the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial (STEP) [13]** which enrolled 8511 older hypertensive patients (60–80 years), reported an additional 26% reduction in the risk of cardiovascular events in patients with intensive treatment (SBP target, 110–130 mmHg), compared with standard treatment (130–150 mmHg). Among adverse events, hypotension was frequent with intensive SBP control.

4. Evidence from high-quality meta-analysis

High-quality meta-analyses have sufficient statistical power to investigate the problem in depth, and also yield compelling conclusions favoring a more intensive SBP target for the prevention of cardiovascular disease in older patients. In a meta-analysis that included 147 RCTs [14], Law et al. reported that blood pressure reduction of 10 mmHg systolic (or, approximately equivalently, 5 mmHg diastolic) was associated with a proportional reduction of stroke and coronary heart disease. These proportional reductions were regardless of baseline blood pressure (down to 110 mmHg systolic and 70 mmHg diastolic). In older age group (70–79 years), the percentage of reduction slightly diminished, but the absolute risk reductions appeared to be larger.

Similar results were described in a meta-analysis from the Blood Pressure Lowering Treatment Trialists’ Collaboration [15]*. In which, participant-level data from 51 RCTs (358,707 patients) were pooled, and the age-stratified, and baseline blood pressure-stratified effects of blood pressure lowering pharmacotherapy on the prevention of cardiovascular disease and death were detailed reported. No evidence suggested that the relative reduction in cardiovascular risk varied with age. Additionally, the benefits from intensive SBP treatment were consistent across a wide spectrum of baseline SBP, even including the ‘normal blood pressure levels’ (less than 120/70 mmHg).

5. What is missing?

When attempting to establish evidence based on treatment blood pressure therapy, it is obvious that one size does not fit all. For older patients, provision of the intensive SBP lowering strategies should be judicious due to highly heterogeneous conditions in this population, such as multiple comorbidities, dementia, severe frailty, or full dependence. It is not unexpected that the conclusions of the above studies can be extrapolated into ‘healthier’ older individuals. However, evidence remains for paucity in older patients with special conditions, who are routinely excluded from RCTs, despite representing the most compelling challenge in clinical practice.

6. Conclusions

In summary, mounting robust evidence indicates that a more intensive SBP target, lower than what is currently recommended, will improve the cardiovascular outcomes in older patients with hypertension. The intensive SBP target of <130 mmHg can be safely extrapolated to a majority of general older patients, regardless of baseline morbidities. However, for patients aged over 80 years, or with severe frailty, cautions should be exercised when administering an intensive SBP target. These findings collectively underscore that the common approach of withholding intensive SBP target for older adults in most current guidelines warrants imperative revisions. Age-stratified blood pressure thresholds may, therefore, be removed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Beijing Outstanding Young Scientist Program [BJJWZYJH01201910023029], the National Natural Science Foundation of China [81825002], and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [2021-I2M-1-007].