Risk on dementia not reduced with intensive BP-lowering arm in SPRINT
In SPRINT MIND, no reduction was seen in probable dementia, after a median of 5 years of follow-up and 3.3 years of intervention, but mild cognitive impairment was reduced in the intensively treated arm.
Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia. A Randomized Clinical TrialLiterature - SPRINT MIND Investigators - JAMA. Published online January 28, 2019. doi:10.1001/jama.2018.21442
Introduction and methods
Observational studies have suggested that hypertension is a potentially modifiable risk factor for mild cognitive impairment (MCI) and dementia [1,2]. MCI is a clinical state between normal cognitive aging and dementia [3]. Evidence on the effect of blood pressure (BP) reductions on cognitive assessment is scarce and inconclusive, and follow-up was never longer than 4 years, nor were MCI and dementia adjudicated by experts.
The Systolic Blood Pressure Intervention Trial (SPRINT) evaluated the effect of more intensive BP control on CV, renal, and cognitive outcomes in persons without diabetes or pre-existing stroke [4,5]. 9361 Patients were randomized to a systolic BP (SBP) target of<120 mmHg (intensive BP control) or of <140 mmHg (standard BP control). This analysis compares the effect of the two BP control strategies on the rate of adjudicated probable dementia (primary cognitive outcome) and MCI (secondary).
Enrolment took place between November 2010 and March 2013. While the SPRINT trial was stopped early due to benefit on its primary CV endpoint and all-cause mortality on August 20, 2015, follow-up of cognitive outcomes continued until July 22, 2018. Median duration of intervention was 3.34 years, and median follow-up for the primary cognitive outcome was 5.11 years. Mean age of participants was 67.9 years (SD: 9.4 years), and 28.2% were 75 years or older.
Cognitive screening assessments were done at baseline and at years 2 and 4 during follow-up and at the end of the study if the year-4 visit was more than one year ago. Cognitive assessment consisted tests of global cognitive function, learning and memory and processing speed.
Main results
- 149 (7.2 per 1000 person-years [PY]) persons in the intensively controlled group had adjudicated probable dementia, as compared with 176 participants (8.6 per 1000 PY) in the control group (HR: 0.83, 95%CI: 0.56-1.04).
- A similar effect of intensity of BP control on probable dementia was seen when death was considered a competing risk (HR: 0.84, 95%CI: 0.68-1.05).
- No significant interactions were seen between pre-specified subgroup-characteristics (age, sex, black/non-black race, history of CV disease, CKD, SBP tertile or orthostatic hypotension) and the effect of treatment intensity on the primary cognitive outcome of probable dementia.
- MCI occurred in fewer participants in the intensively controlled group (14.6 vs. 18.3 per 1000 PY, HR: 0.81, 95%CI: 0.69-0.95).
- The composite outcome of MCI or probable dementia showed a significantly lower rate in the intensively treated group (20.2 vs. 24.1 per 1000 PY, HR: 0.85, 95%CI: 0.74-0.97). No significant interactions were observed between pre-specified subgroup criteria and treatment assignment with respect to the composite outcome.
Conclusion
Intensive BP control to SBP<120 mmHg as performed in the SPRINT, did not significantly reduce the incidence of probable dementia, as compared to standard BP control. The previously suggested risk of hypotension and cerebral hypoperfusion and possible negative consequences for the brain, that have been associated with lowering SBP to below 150 mmHg are not confirmed in this study. Importantly, these results show that BP lowering to <120 mmHg does not result in harm to cognition after a median intervention period of 3.34 years and a median follow-up of 5.11 years. In fact, it may be beneficial, as the occurrence of MCI was reduced in the intensively controlled group. The consequences of this secondary outcome on longer-term incidence of dementia remain to be established. The early study termination and a number of dementia cases that was lower than expected, may have affected the power to detect this endpoint.
Editorial comment
Yaffe [6] notes the disappointments of the past decades in drug development for Alzheimer disease (AD), and no drugs with disease-modifying benefit are available. Identification of preclinical or early clinical phases, such as MCI, is crucial for primary and secondary prevention approaches. It is thought that risk factors may be modified during the preclinical course, or even earlier in life. CVD risk factors such as diabetes and hypertension have been identified as risk factors for AD and vascular cognitive impairment.
Yaffe calls SPRINT MIND ‘the first trial that has demonstrated an effective strategy for prevention of age-related cognitive impairment’. The interpretation of the data is challenged by the early termination of the trial, as the extended follow-up may have attenuated the effect size as compared with when the intervention had continued as planned. This is likely because the SBP differences between treatment groups declined from 13 mmHg to 6 mmHg during the extended follow-up. Moreover, adverse events were no longer monitored after the intervention phase ended. In the initial SPRINT report, the intensively treated group showed more orthostatic hypotension, syncope, electrolyte abnormalities and acute renal failure. This information is critical to weigh benefits of treatment with adverse outcomes, which in itself may also affect cognition. No information is given to be able to compare effects of different classes of antihypertensive agents on cognitive outcomes.
‘The SPRINT trial has already changed clinical care. It will be of great interest to watch how the results of SPRINT MIND influence approaches to maintaining brain health and preventing cognitive impairment.’ An important question to answer will be when to treat elevated SBP and whether the same goal of care should be applied in the very elderly, as well as in young adults. ‘Nonetheless, the connection between heart and vascular health and brain health is not appreciated by many patients and physicians, and it is essential to highlight this relationship in a public health campaign for people of all ages.’
SPRINT MIND demonstrated that intensive SBP control can reduce the development of cognitive impairment in those with hypertension. This approach may be combined with other preventive vascular health interventions such as physical activity: multidomain risk reducing strategies personalized based on individual risk profiles should be studied. Such strategies should eventually be combined with disease-modifying drugs to offer an effective strategy for prevention of cognitive impairment in those identified to be at risk of AD and related dementia.
References
1. Kivipelto M, Helkala EL,Hänninen T,et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology. 2001;56(12):1683-1689.
2. Qiu C, Winblad B, Fratiglioni L.The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4(8):487-499.
3. Morris JC, Storandt M, Miller JP, etal. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58(3):397-405.
4. Wright JT Jr, Williamson JD, Whelton PK, etal; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
5. Williamson JD, Supiano MA, Applegate WB, et al; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years: a randomized clinical trial. JAMA. 2016;315(24):2673-2682.
6. Yaffe K. Prevention of Cognitive Impairment With Intensive Systolic Blood Pressure Control. JAMA. January 28, 2019.