Amanda Giffin, MD, FRCPC1, Kenneth M. Madden, MD, FRCPC2, David B. Hogan, MD, FRCPC1
1Division of Geriatric Medicine, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
2Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, UBC, Vancouver, BC, CanadaDOI: https://doi.org/10.5770/cgj.23.429
ABSTRACT
In 2017, Hypertension Canada removed advanced age and frailty as considerations for caution when deciding on intensive therapy in their guidelines for the diagnosis, risk assessment, prevention, and treatment of hypertension in adults. Dementia is not mentioned. In this commentary, we review why advanced age and frailty were removed, and examine what is currently known about the relationship between hypertension and both incident and prevalent dementia. We make the case that the presence of frailty (especially when severe) and dementia should be considered when deciding on intensive therapy in future iterations of Hypertension Canada guidelines.
Key words: hypertension, clinical practice guidelines, frailty, dementia, old age
In this commentary, we focus on Hypertension Canada guideline recommendations that specifically deal with treatment indications and blood pressure (BP) targets in older patients. From 2016 onwards, the influence of the Systolic Blood Pressure Intervention Trial (SPRINT)(1) can be seen with a call to consider intensive therapy (target systolic BP <120 mmHg) in high-risk patients. The 2017 guidelines removed both advanced age (i.e., ≥80) and frailty as treatment considerations. We will describe what led to these changes and how solid the underlying evidence for them might be. Then we’ll address the presence of dementia, which is currently not mentioned. We believe frailty should be a treatment consideration, and dementing illnesses need to be addressed in future iterations of the guidelines. We advocate for a more explicitly individualized approach in the management of hypertension in older patients who range in health status from the very fit to the severely frail.
Both the 2016(2) and 2017(3) Hypertension Canada guidelines advised treatment for average diastolic BPs of 100+ and/or systolic BPs of 160+ in those without macrovascular target organ damage or other cardiovascular risk factors (see Table 1). If either were present, treatment was strongly considered for those with diastolic BPs of 90+ and/or systolic BPs of 140+. Suggested treatment goals were <140 systolic and <90 diastolic except for high-risk patients where a target of <120 systolic would be a consideration. Among the high-risk criteria listed was age ≥75. In selecting patients for intensive therapy, the 2016 guidelines(2) suggested that: SPRINT inclusion and exclusion criteria be considered (they form the basis of the clinical indications, cautions, and contraindications for intensive therapy recommended by Hypertension Canada); risks and benefits be carefully weighed with caution used for clinical conditions where this is limited evidence supporting a lower systolic BP target; automated office BP (AOBP) readings be used to guide therapy (in a systematic review and meta-analysis routine office systolic BP readings were found to be on average 14.5 mmHg higher than AOBP determinations);(4) and, patients should be prepared for more clinical encounters, more monitoring, and greater medication use if offered intensive therapy (SPRINT patients were followed monthly until target BP was achieved and were on an average of 2.7 medications). Indications, cautions, and contraindications for intensive therapy in the 2017 guidelines remained the same, other than that the mention of frailty was removed(3) (Table 1).
The 2016 Hypertension Canada guidelines included both advanced age (i.e., ≥80) and frailty as considerations when deciding on either the initiation of hypertension therapy or the target BP(2) (see Table 1). Advanced age and frailty as treatment considerations were then removed from the 2017 guidelines.(3) Frailty was deleted because of post hoc analyses of HYpertension in the Very Elderly Trial (HYVET)(5,6), which had a target BP of <150/80, and SPRINT.(7) Both had used frailty indices (FIs) to assess the status of participants. The analyses mentioned didn’t find evidence that frailty influenced treatment outcomes. Based on their review of these two papers, the authors of the 2017 guidelines concluded that older persons with hypertension benefitted from BP reduction regardless of baseline frailty. The only concern raised with intensive therapy was a significant risk of renal dysfunction. It was noted that both HYVET and SPRINT excluded individuals with limited life expectancy, dementia, or requiring institutional care. As for advanced age (i.e., ≥80), the rationale for its removal as a treatment consideration was less clearly stated. Mention was made of a systematic review and metaanalysis published in 2016 that showed intensive BP reduction was as beneficial in reducing major cardiovascular events in older adults as compared to younger ones, but this paper defined “older” as ≥62 years of age.(8)
TABLE 1 Comparison of 2016 and 2017 Hypertension Canada recommendations(2,3)
Dementia was not mentioned in the 2016, 2017 or 2018 guidelines.(2,3,9) The 2018 ones didn’t alter the 2017 recommendations mentioned in the preceding paragraph.(9) No update of Hypertension Canada guidelines was released in 2019.(10)
As noted, the reason for removing advanced age as a factor requiring consideration in the 2017 guidelines is unclear. The only paper directly referenced used 62 as the age with which to divide older from younger patients.(7) The relevant section of the 2017 guidelines (pages 566–67)(3) does suggest advanced age was being equated with frailty. Observational studies suggest a U-shaped relationship between all-cause mortality and attained BP in patients ≥80 treated for hypertension in routine care. For example, in a large English study, greater mortality risk was seen with both systolic BPs > 154 and <135. The latter finding is possibly explained by residual confounding.(11)
The 2017 Hypertension Canada recommendations about frailty went beyond what the authors of the referenced work suggested. While the HYVET paper concluded frailty should not be used as a criteria for deciding on BP treatment in patients ≥80 years of age, there was also a call for further work on characterizing the benefit-to-risk ratio of therapy among those with dementia and the very old with more severe degrees of frailty as indicated by the presence of disability.(6) The SPRINT investigators urged caution in interpreting their finding of no apparent effect modification by frailty as this analysis was not pre-specified in the trial protocol and the study was possibly underpowered.(7) The strength of the underlying evidence for the contention that baseline frailty should not influence treatment decisions is dependent on whether the full range of frailty was present in sufficient numbers among HYVET and SPRINT participants. In Hypertension Canada guidelines, frailty is dealt with as a categorical variable (i.e., present or not) rather than one with gradations from milder to more severe forms. The exclusion criteria of HYVET and SPRINT barred many potential participants. Among US adults ≥75 with treated hypertension, it was estimated that less than a third (31.3%) would have none of the SPRINT exclusion criteria.(12) Certain of the exclusion criteria found in the Supplementary Appendix to the 2015 SPRINT paper(13) would disproportionately affect those with severe degrees of frailty. Examples where this would be likely are as follows: one-minute standing systolic BP of less than 110; diabetes mellitus; history of stroke; estimated GFR < 20 ml/min /1.73m2 or end-stage renal disease; symptomatic heart failure within the past six months or left ventricular ejection fraction (by any method) < 35%; life expectancy < than three years or cancer diagnosed and treated within the last two years (except for non-melanoma skin cancer, early-stage prostate cancer, localized breast cancer); unintentional weight loss of >10% in the last six months; dementia; and, nursing home residency.(13)
Data from the studies indicate those with more severe degrees of frailty were under-represented. Median FI scores were 0.17 (interquartile range [IQR] 0.11, 0.24) in HYVET(6) and 0.16 (IQR 0.11, 0.22) in SPRINT.(14) To put these values in perspective, mean electronic FI (eFI) values among primary care patients in the UK between the ages of 65 and 95 are ~0.14.(15,16) Frailty can be categorized as mild (>0.12–0.24), moderate (>0.24–0.36), and severe (>0.36). This is a more nuanced approach than the one used by the SPRINT investigators where frailty was defined as present (if FI >0.21) or not (if ≤0.21) without any range in severity.(14) In HYVET there were more withdrawals among those with higher FI values, and few participants had a FI >0.36.6 Likewise few SPRINT participants had FI values in the severe range.(7) Many, if not most, individuals in HYVET and SPRINT would be categorized as well with treated comorbid disease or vulnerable (categories 3 and 4) on the Clinical Frailty Scale.(17) Because HYVET and SPRINT had a limited number of moderately and few severely frail participants, they were underpowered to comment on the relative benefits and risks of treatment for these segments of the frailty spectrum.(18,19) Even within the truncated frailty range of SPRINT, a FI >0.21 was associated with a higher risk of syncope, hypotension, and falls (though it should be noted that falls were not more common in those receiving intensive compared to standard therapy).(20)
Mid-life hypertension is a recognized risk factor for the development of late-life cognitive impairment, and there is promising evidence that its management might lower this risk.(21) While the HYVET-COG did not yield positive results,(22) in the SPRINT MIND trial those assigned to intensive therapy had significantly reduced risks of incident mild cognitive impairment (MCI) and a combined outcome of incident MCI and dementia, though not incident dementia when considered on its own.(23)
An area of practice uncertainty not mentioned in the Hypertension Canada guidelines is the management of hypertension in people with a co-existing dementia. The two conditions frequently occur together, but there is little trial information to guide care as older persons with prevalent dementia have been excluded from most hypertension trials.(24,25) Examples of studies excluding those with a dementia are HYVET and SPRINT. Their exclusion from the latter study means we have no data on the relative effects of intensive therapy compared to standard in the setting of a dementia. While reasonable to assume that patients with dementia would experience equivalent cardiovascular morbidity and mortality benefits, it is unclear whether they would be more prone to adverse effects arising from the treatment of hypertension or what would be the impact of this treatment on cognition. Some, though not all, observational studies indicate lower systolic BPs in cognitively normal and impaired older patients being treated for hypertension are associated with accelerated cognitive decline.(26–28) This might be related to the development of orthostatic hypotension (OH) with treatment, as OH has been shown to increase the risk of subsequent cognitive impairment.(29) The association may also reflect reverse causation. Epidemiological studies show that BP begins dropping two to five years before the diagnosis of a dementia(30) and continues to drop as the dementia progresses,(31) with declines in cognition possibly more pronounced among those being treated for hypertension.(32) The decline in BP immediately prior to and during the course of a dementing illness would suggest caution in the choice of BP target and the need for close monitoring of BP in treated hypertensive patients with a dementia.
William Osler is quoted as saying, “It is much more important to know what sort of a patient has a disease than what sort of disease a patient has.” An individualized approach taking into account the values and goals of the older patient, as well as their overall health status (e.g., comorbidities, life expectancy), should be utilized in deciding on the intensity of hypertension therapy.(33) In the absence of frailty, disability, and significant multi-morbidity, BP targets should be considered independent of the person’s age.(19) There is also evidence that intensive therapy in carefully selected individuals with mild degrees of frailty is beneficial.(6,7) We don’t believe, though, the benefits of intensive therapy have been proven for those with more severe degrees of frailty, and would encourage Hypertension Canada to re-evaluate their conclusions that baseline frailty does not matter when deciding on the intensity of therapy. In their annual updates, we would also suggest that the emerging evidence of the role of BP control in preventing age-related cognitive decline be noted, and the lack of data on the management of hypertension among those with a dementia be included. In addition to the points already raised, there are particular challenges in, for example, obtaining informed consent and ensuring adherence to therapy in this particular patient population. As a minimum, dementia should be included in the list of conditions where we have limited or no evidence when contemplating intensive BP lowering therapy.
The authors declare that no conflicts of interest exist.
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Canadian Geriatrics Journal, Vol. 23, No. 2, June 2020