Authors: Mark A. Supiano
Categories: Article, age-friendly care, cognitive impairment, dementia, patient-centered, clinical guidelines, randomized clinical trials, therapeutic nihilism
Source: Clinics in geriatric medicine
Authors: Mark A. Supiano
There have been several important updates to the body of evidence available to inform clinicians and patients regarding the optimal blood pressure target across all ages, inclusive of older adults since the last issue of Clinics devoted to Geriatric Hypertension was published in 2009. Given this review’s focus on older adults, it is important to state at the outset that it is possible to solely utilize the systolic blood pressure (SBP) to define stages of hypertension, as well as for the target or goal BP. Also, since isolated diastolic hypertension is so uncommon among older patients, one may correctly classify an older patient’s hypertension in almost all cases based entirely on the level of their SBP.
The operational definition for an “optimal” SBP target utilized herein is the “benefit-based SBP treatment goal based on patient age, comorbidities, and cardiovascular and cognitive impairment risk factors.” Appropriately incorporating patient preferences into this risk/benefit framework requires that additional nuances be considered to assess time to benefit and/or time to harm. Within this framework, this review will outline the clinical trial evidence (highlighting randomized clinical trials published since 1990), clinical practice guideline recommendations that have incorporated trial evidence over this time period, and recommend an age-friendly, patient-centric approach to develop a benefit-based SBP optimal target for older adults. One last point regarding any SBP promulgated to be optimal, is that the cardiovascular disease risks doubles for every 20 mm Hg in SBP above 115 mm Hg.^1^
The “Systolic Hypertension in the Elderly Program (SHEP)” trial began in 1984 with a primary objective to test the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal (total) stroke in adults 60 years and older with isolated systolic hypertension, i.e. a SBP above 160 mm Hg.^2^ The trial enrolled 4,736 participants with a mean age of 72 years, 57% were women, and who had a mean entry SBP of 170 mm Hg (range,160 to 219 mm Hg). Participants were randomized to placebo or stepped care active treatment with low dose thiazide (step 1) or beta-blocker (step 2) to achieve a target SBP of a 20 mm Hg reduction from baseline (if below 180 mm Hg) or less than 160 mm Hg if baseline exceeded 180 mm Hg. Its results provided the first evidence that antihypertensive drug treatment in older patients with isolated systolic hypertension could be safely accomplished in older adults, and that treatment resulted in a significant (36%) reduction in the incidence of fatal and nonfatal stroke.
The “Hypertension in the Very Elderly Trial (HYVET)” extended the SHEP age boundary by enrolling only adults age 80 years and older to address a very similar primary objective. ^3^ HYVET recruited 3,845 participants (mean age 83.6 years, 60% were female, with an average SBP 173 mm Hg) who were randomized to placebo or active treatment consisting of a non-thiazide diuretic and, if required, an ACE inhibitor. The treatment target was a SBP below 150 mm Hg. Due to an unexpected 21% reduction in all-cause mortality in the active treatment group, the trial’s data safety committee recommended the trial be ended with median follow-up of only 1.8 years. The active treatment group also had a 30% reduction in fatal and nonfatal stroke, and a 64% decrease in the rate of congestive heart failure. The distribution of frailty among HYVET subjects determined from a deficit accumulation approach was found to be very similar to that of comparably aged community-based populations. Moreover, both frail and nonfrail HYVET participants benefited from active treatment.^4^ Finally, results from an open-label extension study in which placebo subjects switched to active treatment demonstrated that the prior-placebo group achieved the same reduction in stroke by 12 months, suggesting that the time to treatment benefit in this age group is relatively short.^5^
The “Systolic Blood Pressure Intervention Trial” (SPRINT) and its companion SPRINT “Memory and Cognition in Decreased Hypertension” (MIND) study results – cognitive impairment and brain MRI – were published in 2015 and 2019 respectively.^6,7^ After the results from both SHEP and HYVET were published, it was no longer ethically permissible to design a placebo-controlled trial to address the optimal SBP target question. Instead, the SPRINT study design randomized 9,361 hypertensive individuals aged 50 years and older without prevalent diabetes but with high cardio-vascular disease risk to one of two SBP targets – usual (< 140 mm Hg) or intensive (< 120 mm Hg). A subset of 2,636 participants aged 75 years and older were recruited into its SPRINT-Senior cohort.^8^ Among the older subjects randomized to the intensive arm there was a significant 34% reduction in the primary composite CVD outcome and a significant 33% reduction in all-cause mortality at 3.14 years of follow-up when, similar to HYVET, the trial ended early due to its highly positive outcomes (numbers needed to treat 27 and 41, respectively). These results did not differ for the most frail subgroup nor for those with impaired gait speed.
SPRINT MIND was designed to address the hypothesis that the incidence of dementia would be lower with intensive SBP treatment. Although the 17% reduction in adjudicated all-cause probable dementia in the intensive relative to the standard group did not achieve statistical significance, there were significant reductions of the same magnitude in the occurrence of mild cognitive impairment (MCI; 19%; P=0.01) and in the composite outcome of MCI or dementia (15%; P=0.02). Longer term cognitive outcome data are currently being obtained in the SPRINT MIND 2020 study to further evaluate the dementia outcome as more cases accrue with extended follow-up. Results are expected by the end of 2024. The companion SPRINT-MRI study provided complementary results demonstrating that intensive therapy was associated with slower progression in the accumulation of white matter hyperintensity volume without significant differences in total brain volume.
The “Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients” (STEP), began in China shortly after SPRINT.^9^ 8,511 Chinese patients with hypertension (age range 60 to 80 years) were randomized to an intensive treatment goal (SBP 100 to < 130 mm Hg) or a standard goal (130 to < 150 mm Hg). In addition to the different racial composition relative to SPRINT, participants in the (STEP) trial were younger (mean age 66.2 years) and in general had lower CVD risk. There were also differences in the measurement protocols, achieved SBP in the two arms, and the anti-hypertensive drug regimens used to achieve the treatment target goals. Nonetheless, similar to SPRINT, the trial ended early, at a follow-up of 3.3 years, when it was evident that its primary CVD outcome was met in favor of the intensive treatment goal. The STEP trial’s major conclusion that “a reduction in the systolic blood pressure to less than 130 mm Hg resulted in cardiovascular benefits in older patients with hypertension in China” is largely confirmatory of the SPRINT results. No cognitive outcomes were adjudicated in STEP.
Finally, another RCT conducted in China and quite similar in design to STEP has recently been completed – the “Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs (ESPRIT)” trial.^10^ Its preliminary findings were reported in late 2023 are well-aligned with the intensive treatment benefits reported in both SPRINT and STEP, but the results have not yet been published.
Informed by the historical context of these key clinical trials, the parallel evolution of the major clinical practice guidelines will next be discussed with a focus on their recommendations most pertinent to older adults.
Six years after the SHEP trial results were published, the AHA Joint National Committee’s Sixth Report (JNC 6) was the first guideline to specifically recommend a SBP target for older adults.^11^ The “isolated systolic hypertension” classification was effectively sunset in the 1997 JNC 6 guideline when the conjunction linking systolic and diastolic pressures was changed from “and” to “or.” Further, hypertension was defined as any SBP in excess of 140 mm Hg. These definitions also emphasize that SBP is a more important CVD risk factor than diastolic blood pressure (DBP) – especially for individuals older than 50 years. Its section devoted to special populations stated, “Treatment of hypertension in older persons has demonstrated major benefits.” With regard to a treatment goal, it recommended, “The goal of treatment in older patients should be the same as in younger patients (to <140/90 mmHg if at all possible), although an interim goal of SBP below 160 mm Hg may be necessary in those patients with marked systolic hypertension.”
Very little changed with respect to recommendations for older adults in the Joint National Committee’s Seventh Report (JNC 7) published in 2003. ^1^ It stated, “Treatment recommendations for older individuals with hypertension … should follow the same principles outlined for the general care of hypertension.”
The “Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee” (also known as JNC-8) recommended a goal BP of less than 150/90 mmHg for patients between the ages of 60 and 80 – a deviation from the SBP target level of less than 140 mm Hg that was previously recommended.^12^ Significant controversy surrounded this recommendation when it was published in 2014. A dissenting minority opinion from this panel argued for maintaining this goal below 140 mm Hg.^13^ Applying benefit-based therapy to adults age 60 and older with systolic hypertension who are at high CVD risk is one of the points emphasized by this group in support of their view that the appropriate SBP goal for this group should remain below 140 mm Hg. In addition, the JNC-8 recommendation was at odds with the target goals published in clinical guidelines from many other organizations.
The 2017 Report of the American College of Cardiology/American Heart Association Task Force “Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults” marked a departure from the National Heart, Lung, and Blood Institute (NHLBI) Joint National Committee structure with its decision to partner with other entities to develop these recommendations.^14^ With respect to older adults, this guideline “a SBP treatment goal of less than 130 mm Hg is recommended for noninstitutionalized ambulatory community-dwelling adults (≥ 65 years of age) with an average SBP of 130 mm Hg or higher.” The reduction from 140 to 130 mm Hg in the definition of hypertension and, in turn, the optimal SBP recommendation was primarily due to evidence from the SPRINT study. The guideline’s second recommendation – “For older adults (≥65 years of age) with hypertension and a high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit is reasonable for decisions regarding intensity of BP lowering and choice of antihypertensive drugs” encapsulates the nuances inherent in the complexity of providing care to older persons. Perhaps especially among the heterogeneous population of older adults with hypertension, a personalized, patient-centric approach that carefully integrates the individual’s risks and benefits of more intensive BP control is necessary. This evaluation should incorporate the patient’s additional comorbidities, frailty status, prognosis with regard to projected time to benefit from the intervention, and goals of care.
Also published in 2017, the “Clinical Practice Guideline from the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP)” focused on treatment recommendations for adults age 60 years and older.^15^ Notably, these groups recommended a higher SBP target of 150 mm Hg aligning with the 2014 JNC8 guideline. That said, this recommendation was qualified for those with a history of cerebrovascular disease or at high cardiovascular risk suggesting a target SBP of less than 140 mm Hg for those individuals. These qualifications suggest that there are more similarities than differences between the ACP/AAFP guideline and the ACC/AHA task force guideline. In particular, the ACP/AAFP conclusion, “… recommend that clinicians select the treatment goals for adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient*”* aligns quite closely with second recommendation of the ACC/AHA guideline. The challenges inherent in attributing an individual’s risks and benefits will be discussed in the final section with a goal to utilize an age-friendly, patient-centric approach to develop a benefit-based SBP optimal target for older adults.
The inherent complexity and heterogeneity of older adults with multiple comorbidities that may include cognitive impairment and frailty who also have elevated SBP likely explains why it is challenging to apply a “one size fits all” treat-to-target therapy approach to this population. This leads into the necessity to embrace a patient-centric, age-friendly approach to address an individual patient’s optimal SBP target.
The age-friendly health system initiative was developed to meet a need to more broadly disseminate evidence-based geriatric models of care.^16^ A first step in this process was to consolidate this evidence into four domains – mobility, medications, mentation and what matters most – now referred to as the 4 Ms of geriatrics. This framework may be utilized to develop an individualized, patient-centric approach to hypertensive management in older adults.
The morbidity and mortality associated with falls in older adults are undeniable. An underlying geriatric medicine principle is that functional status supersedes chronological age. To that end, a first step in maximizing mobility in older adults is to assess their frailty status and fall risk. A number of frailty assessment tools are available and easily incorporated into clinical care. The NIA Toolkit’s Short Performance Physical Battery is one comprehensive example.^17^ Its components – usual gait speed and chair stands – may be used independently. Another example is the clinical frailty scale.^18^ It bears emphasis that while injurious falls and other adverse events increased with both older age and greater frailty in both HYVET and SPRINT study cohorts, these outcomes were not greater among those randomized to more intensive SBP control.^4,19^ In SPRINT, age greater than 75 years was associated with greater risk of syncope, hypotension, and falls, but there was no age-by-treatment interaction for any of the these adverse outcomes.^19^ Finally, it should be kept in mind that fall risk is highest in the period of time immediately following initiation or intensification of antihypertensive therapy. Given this, it is important to inform patients of this period of increased risk and to include frequent BP monitoring.
Underlying orthostatic or postural hypotension is a well-recognized fall risk. An important lesson learned from SPRINT was that the prevalence of orthostasis, defined as a SBP less than 110 mm Hg following one minute of upright posture, was 10 percent among patients 75 years and older at the screening, baseline visit. This was an exclusion criterion for the trial, and, since patients with this risk factor for falls were not enrolled, the overall tolerance of the intensive 120 mm Hg target was high, even among the oldest and most frail participants.
A final point of relevance to mobility that overlaps with what matters, is that two common chronic conditions in hypertensive older adults – heart failure and stoke – have a profoundly deleterious impact on mobility functional status. Given that intensive SBP management significantly attenuates the incidence of these two outcomes, maintaining mobility will follow.
Although counterintuitive and contradictory to another tenet of geriatric medicine – avoiding polypharmacy – there is little evidence from any of the clinical trials that the higher number of anti-hypertensive medications needed to achieve the intensive SBP target was associated with more serious adverse events. Almost all SPRINT participants achieved the120 mm Hg intensive target on a combination of three antihypertensive medication drug classes (an ACE or ARB, calcium channel blocker, and a thiazide diuretic, most commonly chlorthalidone). The exception is that higher rates of electrolyte abnormalities were identified in SPRINT, undoubtedly related to thiazide diuretic usage. Additional, counterintuitive, information suggests that there are fewer adverse events with lower doses of multiple antihypertensives than with the formerly espoused stepped care approach wherein maximal dosage of a single antihypertensive was utilized.^20^
Beyond polypharmacy, it is important to ensure that age-appropriate medications and dosages (most often adjusting for renal function) are being prescribed and to minimize exposure to potentially inappropriate medications for older adults.^21^ In addition, comprehensive medication reconciliation should also target any medications, including non-steroidal anti-inflammatory medications and others, that are known to elevate blood pressure.
Maintaining cognitive health in older adults with hypertension is another important factor to consider. For this reason, the primary outcome in SHEP, and one that is reported in the other trials, was the reduction in stroke rates in the actively treated participants. Today, there is no question that more intensive SBP control is associated with a significant reduction in the incident stroke rate. Moreover, a meta-analysis of stroke outcomes, that included the four RCTs cited earlier, identified that the time to benefit for stroke prevention is rather brief. The study’s findings suggested that “200 adults aged ≥65 years would need to be treated for 1.7 years to avoid 1 stroke.”^22^ Since this is the average remaining life expectancy for a 106 year old woman, these results suggest that almost all older adults with hypertension would benefit with respect to stroke prevention from more intensive treatment.
The potential beneficial effect of intensive SBP control in older adults to maintain cognitive function was not known prior to the SPRINT study results being published. The SPRINT MIND study was the first evidence that the outcomes for adjudicated mild cognitive impairment and the composite of mild cognitive impairment and all-cause dementia were significantly reduced among participants randomized to the intensive SBP target arm. Several subsequent secondary analyses from SPRINT MIND have provided additional important 1) greater cognitive benefit was identified in participants who had the highest baseline risk for cognitive decline,^23^ and 2) greater time spent in therapeutic BP target range of 110 to 130 mm Hg in the first three months post-randomization was associated with lower rates for subsequent dementia.^24,25^ More details of the intersection between BP control and brain health are provided in de Havenon A et al. ^26^.
Balancing the overall risk-benefit equation across these three domains in a patient-centric matter aligns with both “what matters” and the art of medicine. It also aligns with nuances included in the AHA 2017 guideline’s second recommendation, “For older adults with a high burden of comorbidity and limited life expectancy, clinical judgment, patient preference, and a team-based approach to assess risk/benefit is reasonable for decisions regarding intensity of BP lowering and choice of antihypertensive drugs.”^2^ Eliciting what matters most to older adults with hypertension needs to be factored into their ultimate, individualized optimal SBP target. It is important that clinicians fully inform patients of the inherent risks and benefits of managing their hypertension to ensure that a given target SBP level aligns with the patient’s preferences. One component of this conversation is an attempt to frame the cardiovascular and cognitive function benefits that are evident with more intensive SBP control in the context of the patient’s other competing risks from other chronic conditions. For example, a patient who is at high risk to develop cognitive impairment and for whom preventing dementia matter most, may opt to attempt a more intensive, less than 120 mm Hg, SBP target goal. In other patients with risks that conspire to limit their remaining life expectancy, their time to benefit to achieve the benefits from more intensive SBP control may not be realized and a less aggressive target may be appropriate. Moreover, especially in the setting of severe baseline cognitive impairment and dementia or functional loss and frailty, the BP-lowering benefits may not be achievable nor indicated.
First, of note, neither of the 2017 guidelines incorporated the subsequently published SPRINT MIND evidence that more intensive (a SBP target of 120 mm Hg) target led to a significant reduction in the incidence of mild cognitive impairment. The 2024 AHA/ACC guideline update is currently being developed. Second, there is compelling evidence that ageism contributes to therapeutic nihilism and the reticence of some clinicians to escalate anti-hypertensive therapy in older adults to achieve their optimal SBP.^27,28^
Third, blood pressure control rates are low across all age groups, and lowest in older adults. Advances in implementation science are needed to help improve these control rates. Fourth, greater public awareness of new information that is altering (lowering) the SBP range considered to be optimal is needed, including the cognitive benefits inherent with a lower SBP.