Effect of Intensive Blood Pressure Control on Subtypes of Mild Cognitive Impairment and Risk of Progression From SPRINT Study

Sarah A. Gaussoin MS; Nicholas M. Pajewski PhD; Gordon Chelune PhD; Maryjo L. Cleveland MD; Michael G. Crowe PhD; Lenore J. Launer PhD; Alan J. Lerner MD; Jennifer Martindale-Adams EdD; Linda O. Nichols PhD; Paula K. Ogrocki PhD; Bonnie C. Sachs PhD; Kaycee M. Sink MD; Mark A. Supiano MD; Virginia G. Wadley PhD; Valerie M. Wilson MD; Clinton B. Wright MD; Jeff D. Williamson MD; David M. Reboussin PhD; Stephen R. Rapp PhD

Disclosures

J Am Geriatr Soc. 2022;70(5):1384-1393. 

In This Article

Methods

Trial Design

The trial design and methodology have been published.[10,11] Participants were 50 years of age or older and had a screening systolic blood pressure (SBP) between 130 and 180 mm Hg. Participants qualified for the study if they had clinical or subclinical cardiovascular disease, chronic kidney disease (estimated glomerular filtration rate below 60 ml/min/1.73m2), or a Framingham cardiovascular disease (CVD) risk score of 15% or greater, or if they were 75 years of age or older. Individuals residing in a nursing home, persons with a diagnosis of dementia (based on medical record review) or treated with medications primarily used for dementia therapy were excluded, as were persons with prevalent diabetes mellitus or a history of stroke. Individuals were randomized by the Data Coordinating Center (1:1) to an SBP goal of less than 120 mm Hg (intensive treatment group, n = 4678) or a goal of less than 140 mm Hg (standard treatment group, n = 4683), with the randomization stratified by clinic site. The algorithms and formulary for the trial are listed in the published study protocol.[10,11] Race and ethnicity were collected via self-report using fixed categories to satisfy the National Institutes of Health Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research.

Standard Protocol Approvals, Registrations, and Patient Consents

The study was approved by the institutional review board at each participating site and each participant provided informed consent. The ClinicalTrials.gov identifier is NCT01206062.

Ascertainment for Mild Cognitive Impairment and Probable Dementia

In SPRINT MIND ascertainment of cognitive status, which occurred at years 2 and 4 of follow-up, as well as at study closeout if that was >1 year removed from the 4-year follow-up visit, followed a three-step process.[10] In-person cognitive screening assessments were administered to all participants at baseline and during follow-up by centrally trained and certified examiners at each clinic site, and included a test of global cognitive function (Montreal Cognitive Assessment, MoCA),[12] verbal learning and memory (Logical Memory I and II),[13] and processing speed (Digit Symbol Coding).[14] For participants scoring below pre-set race/ethnicity and education specific thresholds on the MoCA,[10] a pre-identified proxy was administered the functional activities questionnaire (FAQ).[15] In addition, participants underwent further testing with an extended cognitive battery that measured attention/concentration, verbal and nonverbal memory, language, and executive function.[10,16] A validated telephone battery was administered to participants who could not be assessed in person during follow-up.[17] For participants receiving the telephone battery, the FAQ was obtained if the participant scored below 31 on the modified telephone interview for cognitive status (TICSm).[18] If a participant had died or was otherwise unable to communicate by telephone, the dementia questionnaire (DQ)[19] was administered to their pre-identified proxy.

All participants were administered standardized measures of depressive symptoms, perceived health status, and quality of life,[20] and reported current medications, medical problems, and current health behaviors. Hospitalizations were also recorded as part of a standardized protocol for the ascertainment of serious adverse events.[11] These data were independently reviewed by two clinicians experienced in the diagnosis of MCI and dementia and who were part of an expert adjudication panel that included neurologists, neuropsychologists, geriatricians, and geropsychologists. The adjudicators, masked to treatment assignment, classified each case as: no cognitive impairment, MCI, probable dementia using standardized diagnostic criteria,[21,22] or cannot classify. MCI classifications were further subtyped as amnestic-single domain, amnestic-multi-domain, non-amnestic-single domain, or non-amnestic multi-domain.[5] Classification agreements were considered final. Disagreements on primary classification (no impairment, MCI, probable dementia) were discussed by the full adjudication panel on regularly scheduled conference calls with the classification decision achieved by a majority vote. Disagreements on MCI subtype were discussed between the two primary adjudicators until consensus was reached or referred to committee for review with final classification decided by majority vote. No subclassification of probable dementia was made.

Duration of Follow-up

Trial enrollment began in November 2010 and ended in March 2013. The trial planned cognitive assessments at baseline, 2 and 4 years of follow-up, as well as at study closeout if that was >1 year removed from the 4-year follow-up visit (Figure S1). The trial intervention was stopped early on August 20, 2015 after the Director of the National Heart, Lung, and Blood Institute accepted the Data and Safety Monitoring Board recommendation to inform the investigators and participants of the cardiovascular results. Many of the planned year 4 cognitive assessments had not been completed as of this date, and so were completed at study closeout while the trial was still providing medication at no cost to the participant. After the trial was stopped and during the closeout visits, BP management decisions were returned to the participant's primary care physician. After the closeout visit, medications were no longer provided by the trial. A final extended follow-up visit, which included an additional cognitive assessment, was conducted between October 2017 and July 2018. For this analysis, the final date of follow-up was July 22, 2018.

Study Outcomes

Study outcomes included the occurrence of adjudicated probable dementia and MCI. Protocol-defined MCI included two consecutive occurrences of an adjudicated classification of MCI, or a classification of MCI followed by an adjudication of probable dementia (Figure S2). Although all MCI cases were classified into four subtypes, due to data sparseness, we instead examined subtypes of MCI by collapsing across dimensions, contrasting amnestic versus non-amnestic subtypes of MCI, and single versus multi-domain MCI subtypes. Because the protocol definition of MCI required two consecutive classifications of cognitive impairment (with the first classification being MCI), the subtype from the initial MCI classification was used.

Statistical Methods

The occurrence of MCI overall and for subtypes of MCI was compared between treatment groups using Cox proportional hazards regression with the baseline hazard function stratified by clinical site.[23] Participants without MCI and probable dementia were censored on the date of their last cognitive assessment with the exception of those who were administered the DQ. If they were deceased, they were censored on their date of death. If they were alive, they were censored on the date of the DQ administration.

To examine transitions in cognitive status, we used a 5-state (normal cognitive function, MCI, intermittent MCI, probable dementia, or death) survival model based on first-order Markov assumptions to compare the risk for transition between these states between intensive and standard treatment (Figure 1). Intermittent MCI refers to cases where an adjudication of MCI is followed by the participant either not meeting screening criteria for adjudication or being formally adjudicated as having normal cognitive function. Since such individuals are at higher risk of dementia than individuals who are consistently cognitively normal,[24] we include it as a transition state rather than treat it as reversion. The multistate model allowed bidirectional movement between intermittent MCI and MCI, treated probable dementia and death as absorbing states, and also included an adjustment for whether the time period was before or after the decision to stop the trial intervention on August 20, 2015. Probable dementia was treated as an absorbing state because participants adjudicated with probable dementia were not subsequently assessed for cognitive function. Note that the Markov assumption implies that MCI is modeled from the perspective of current status, and so does not entail the confirmation of MCI at a second assessment time point as in the trial's protocol definition of MCI. Due to insurmountable model complexity, we were not able to consider multistate models with additional states reflecting MCI subtypes. Because only the first transition in a multistate framework represents a purely randomized comparison, these models evaluate the association between intensive treatment and transition risk. The multistate models were fit using the msm package for the R Statistical Computing Environment.[25]

Figure 1.

Five-state model for cognitive status

Data Availability Statement

Data are available for investigators providing an IRB/Ethics approval or certification of exemption from IRB/Ethics review, and also agreeing to the terms and conditions of a data use agreement. Data are available in BioLINCC (https://biolincc.nhlbi.nih.gov/studies/sprint).

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