Intensive Blood Pressure Management in the STEP Trial: A Geriatric Cardiology Perspective
Geriatric Cardiology Take Home Points
- The three largest and most important anti-hypertension trials that addressed the benefits of a more intensive systolic blood pressure (SBP) goal of ≤120 mm Hg were: ACCORD1 (2010), SPRINT2 (2015), and STEP3 (2021) trials. The mean age in each trial were as follows: ACCORD: 62.2 years, unknown proportion of participants ≥75-years; SPRINT: 67.9 years, 28.5% were ≥75-years; STEP: 66.2 years, 70-80 years (approximately 25%). STEP excluded adults beyond the age range of 60-80 years.
- Balancing the benefits (major adverse cardiovascular event reduction [MACE]) of hypertension treatment with treatment-related harm (increase in serious adverse events [SAE]) are substantial challenges in the care of older adults.
- In regard to treatment-related benefit: STEP, like SPRINT but unlike ACCORD, demonstrated a lower incidence with more intensive SBP lowering for the primary composite MACE outcome with variations in the treatment-related decreased incidences of the individual MACE outcomes.
- In regard to treatment-related harm: ACCORD, SPRINT and STEP demonstrated treatment-related harm but varied substantially in the measurement of harm. The community perceptions of harm are based on these measurement variations and the lack of consistent composite treatment-related harm outcomes.
- Exclusion and inclusion criteria variations between trials: SPRINT excluded participants with diabetes, while STEP included participants with diabetes but excluded them if Hba1c >8.0%. STEP, SPRINT, and ACCORD trials all excluded patients with a history of stroke. STEP excluded patients with cognitive impairment and did not include their baseline functional status. STEP trial only included East Asians and was not ethnically diverse, which limits the generalizability of their findings to this group.
- STEP incorporated an important and practical focus of managing hypertension which includes accurate and consistent home blood pressure measurements as an adjunct to office blood pressure values.
- Pertinent considerations towards the care of older adults revolve around the 5M's (Mind, Mobility, Multimorbidity, Medications [polypharmacy] and Matters Most):
- Mind: No report is currently available on baseline and follow up changes in cognitive function.
- Mobility: No report is currently available on baseline and follow up changes in physical function.
- Medications: No report is currently available on the extent and associations of polypharmacy with MACE and SAE outcomes.
- Multimorbidity: Multimorbidity or multiple chronic conditions is the most common comorbidity. Further knowledge on multimorbidity would be pertinent in the care of older adults. Some scores that have been developed to address multimorbidity include the Elixhauser comorbidity score, Charlson score, and others.
- Matters Most: Older adults often need to balance treatment-related benefit (reduction of MACE) with treatment-related harm (increase in SAE). Furthermore, a discussion of the outcome desired should be considered as a function of the treatment burden willing to be endured.
- Time to Benefit: The time to benefit based on the cumulative incidence function is approximately 3-6 months in STEP and approximately 1 year in SPRINT.4
- Time to Harm: No data has been shown on time to harm in STEP. The time to harm in SPRINT for a composite SAE outcome was at around 3 months.4
- Restricted Mean Survival Time: RMST, a translational statistic that provides information on the number of days gained because of reductions in the primary cardiovascular composite outcome and the number of days lost to treatment-related harm, could be beneficial for shared-decision making treatment considerations. At 4.2 years in SPRINT, participants treated with intensive BP therapy had a statistically significant 13.8 (95% confidence interval [CI]: 3.9-23.6, P = 0.006) more MACE-free days compared to those treated with standard BP therapy. At 4.2 years, participants treated with intensive therapy had 37.7 fewer SAE-free days (95% CI: -54.2 to -21.1, P = 0.0001) compared to those treated with standard therapy.5
- Competing Risks: It is to be noted that the investigators did not present a Kaplan Meier curve but rather presented a cumulative incidence function (which considers the competing risk of death). Addressing the competing risk of mortality in older adults will result in more accurate assessment of the incidence of outcome and usually without a change in the study conclusions.
- Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL): An assessment of ADL and IADLs was not performed and knowledge in these areas would aid greatly in the care of the older adult with hypertension.
Commentary based on Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med 2021;385:1268-79.
Rationale for STEP trial: Determination of appropriate SBP target in a Chinese cohort of older adults with hypertension.
Funding: Chinese Academy of Medical Sciences, Fuwai Hospital
Study Methods: Chinese patients 60-80 years of age with hypertension randomized to a SBP target of 110 to <130 mm Hg (intensive treatment) and a target of 130 to <150 mm Hg (standard treatment) with a planned follow-up of 4 years.
Study Design: 2-arm, multi-center, prospective, randomized, open-labeled, blinded-endpoint trial.
- Older adults of Han ethnicity
- Age 60-80 years
- SBP between 140-190 mm Hg in three screening visits or currently receiving anti-hypertension treatment
- Provided written consent
- Systolic BP ≥190 mm Hg, or diastolic BP <60 mm Hg
- Secondary cause of hypertension
- Large atherosclerotic or hemorrhagic stroke
- History of atrial fibrillation or ventricular arrhythmia
- Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) in the last 6 months or planned in the future 12 months
- Myocardial infarction (MI) or unstable angina in previous 6 months
- NYHA III-IV heart failure or hospitalization for heart failure exacerbation in previous 6 months
- Severe valvular disease or valvular disease likely to require surgery or percutaneous valve replacement during the trial
- Dilated or hypertrophic cardiomyopathy
- Rheumatic heart disease
- Congenital heart disease
- Uncontrolled diabetes (serum fasting glucose ≥200 mg/dl [11.1 mmol/L], HbA1>8%)
- Abnormal liver or kidney function (alanine transaminase [ALT] more than 3 times the upper limit of normal value, or end stage renal disease [ESRD] on dialysis, or estimated glomerular filtration rate (eGFR) <30 mL/min, or serum creatine >2.5 mg/dl [>221 umol/L]
- Severe cognitive impairment or mental disorders
Exposure: Treatment intensity
Primary composite outcome(s):
- Stroke (ischemic or hemorrhagic)
- Acute coronary syndrome (acute MI and hospitalization for unstable angina)
- Acute decompensated heart failure
- Coronary revascularization
- Atrial fibrillation
- Cardiovascular death
- Individual components of the primary outcome
- All-cause mortality
- Composite of individual components of the primary outcome except stroke
- Renal outcomes
Statistical Analysis: In the analyses of the primary outcome and secondary outcomes except for death from any cause, the Fine–Gray subdistribution hazard model was used to account for the competing risk of death. For death from any cause, the Cox regression model was used. All analysis were done with intention to treat approach.
Results: Primary-outcome events occurred in 147 of 4,243 patients (3.5% [1.0% per year]) in the intensive-treatment group, as compared with 196 of 4,268 patients (4.6% [1.4% per year]) in the standard-treatment group (HR, 0.74; 95% CI, 0.60 to 0.92; P=0.007).
- Acute coronary syndrome 55 (1.3%) versus 82 (1.9%); HR 0.67 (0.47-0.94)
- Stroke 48 (1.1%) versus 71(1.7%); HR 0.67 (0.47- 0.97)
- Acute decompensated heart failure 3 (0.1%) versus 11(0.3%); HR 0.27 (0.08 - 0.98)
- Coronary revascularization 22 (0.5%) versus 30 (0.7%); HR 0.69 (0.40 - 1.18)
- Atrial fibrillation 24 (0.6%) versus 25 (0.6%); HR 0.96 (0.55 -1.68)
- Death from cardiovascular causes 18 (0.4%) versus 25(0.6%); HR 0.72 (0.39 - 1.32)
- Death from any cause 67 (1.6%) versus 64(1.5%); HR 1.11 (0.78 - 1.56)
- MACE 100 (2.4%) versus 138 (3.2%); HR 0.72 (0.56- 0.93)
Benefit: In older adults between the age of 60-80 years, intensive control of SBP between 110 to <130 mm of Hg lead to reduction in incidence of the primary composite outcome.
Harm: The incidence of hypotension was significantly higher in the intensive-treatment group than in the standard-treatment group (3.4% vs. 2.6%, P=0.03).
- Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
- Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
- Zhang W, Zhang S, Deng Y, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med 2021;385:1268-79.
- Krishnaswami A, Peterson ED, Goyal P, Kim DH, Rich MW, Lee SJ. Time to benefit and harm of intensive blood pressure treatment: insights from SPRINT. Eur Heart J Qual Care Clin Outcomes 2021;7:e1-e2.
- Krishnaswami A, Peterson ED, Kim DH, Goyal P, Rich MW. Efficacy and safety of intensive blood pressure therapy using restricted mean survival time-insights from the SPRINT trial. Am J Med 2020;133:e369-e370.
Keywords: ESC Congress, ESC21, Geriatrics, Activities of Daily Living, Glycated Hemoglobin A, Antihypertensive Agents, Blood Pressure, Multimorbidity, Multiple Chronic Conditions, Polypharmacy, Survival Rate, Confidence Intervals, Decision Making, Shared, Follow-Up Studies, Functional Status, Functional Status, Hypertension, Diabetes Mellitus, Stroke, Cognition, Asian Continental Ancestry Group, Perception, Perception, Reference Standards
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