Background: The association between blood pressure control and clinical outcomes is unclear among patients with heart failure with preserved ejection fraction. Both too high and too low of systolic blood pressure (SBP) have been reported to be related to poor clinical prognosis. This study aimed to assess the association between time in SBP target range and adverse clinical events among patients with heart failure with preserved ejection fraction. Methods and Results: This study was a secondary analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, a randomized clinical trial that compared the efficacy and safety of spironolactone in patients with heart failure with preserved ejection fraction. Time in target range (TTR) was calculated using linear interpolation, with the target range of SBP defined as 110 to 130 mm Hg. The association between TTR with adverse outcomes was estimated using multivariable Cox regression to adjust for multiple confounders. Participants with greater TTR were younger, more likely to be White, had less comorbidities, and lower body mass index. After adjusting for multiple covariates including mean SBP, 1‐SD increment (38.3%) of TTR was significantly associated with a decreased risk of primary composite end point (hazard ratio [HR], 0.81 [0.73–0.90]), as well as a lower risk of all‐cause mortality (HR, 0.81 [0.73–0.90]), cardiovascular death (HR, 0.78 [0.68–0.90]), and heart failure hospitalization (HR, 0.85 [0.74–0.97]). Results were similar when participants were categorized by TTR groups. Subgroup analyses showed that the associations were more significant in young people than in the old ( P _interaction =0.028). Conclusions: In patients with heart failure with preserved ejection fraction, greater time in SBP target range was statistically associated with a decreased risk of cardiovascular outcomes and mortality events beyond blood pressure level, especially among younger patients.

Background: There is a paucity of evidence regarding the association between visit‐to‐visit blood pressure variability and residual cardiovascular risk. We aimed to provide relevant evidence by determining whether high systolic blood pressure (SBP) variability in the optimal SBP levels still influences the risk of cardiovascular disease. Methods and Results: We studied 7065 participants (aged 59.3±5.6 years; 44.3% men; and 82.9% White) in the ARIC (Atherosclerosis Risk in Communities) study with optimal SBP levels from visit 1 to visit 3. Visit‐to‐visit SBP variability was measured by variability independent of the mean in the primary analysis. The primary outcome was the major adverse cardiovascular event (MACE), defined as the first occurrence of all‐cause mortality, coronary heart disease, stroke, and heart failure. During a median follow‐up of 19.6 years, 2691 participants developed MACEs. After multivariable adjustment, the MACE risk was higher by 21% in participants with the highest SBP variability (variability independent of the mean quartile 4) compared with the lowest SBP variability participants (variability independent of the mean quartile 1) (hazard ratio, 1.21; 95% CI, 1.09–1.35). The restricted cubic spline showed that the hazard ratio for MACE was relatively linear, with a higher variability independent of the mean being associated with higher risk. These association were also found in the stratified analyses of participants with or without hypertension. Conclusions: In adults with optimal SBP levels, higher visit‐to‐visit SBP variability was significantly associated with a higher risk of MACE regardless of whether they had hypertension. Therefore, it may be necessary to further focus on the visit‐to‐visit SBP variability even at the guideline‐recommended optimal blood pressure levels.

The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes. This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications. A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62–0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59–0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54–0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27–0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant. In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.

Background: The associations of time‐averaged cumulative blood pressure (BP) from midlife to late life with microvasculature expressed as retinal vessel diameters is not well studied. The aim of this study was to evaluate the association of cumulative systolic BP and diastolic BP (DBP) with retinal vessel calibers, focusing on race differences. Methods and Results: The analysis included 1818 adults from the ARIC (Atherosclerosis Risk in Communities) study attending the fifth visit (2011–2013; age 77±5 years, 17.1% Black participants). Time‐averaged cumulative BPs were calculated as the sum of averaged BPs from adjacent consecutive visits (visits 1–5) indexed to total observation time (24±1 years). Summarized estimates for central retinal arteriolar equivalent and central retinal venular equivalent at the fifth visit represent average retinal vessel diameters. The arteriole:venule ratio was calculated. We tested for effect modification by race. Results from multiple linear regression models suggested that higher time‐averaged cumulative DBP (β [95% CI] per 1‐SD increase: −1.78 [−2.53, −1.02], P <0.001 and −0.005 [−0.009, −0.002], P =0.004, respectively) but not systolic BP (−0.52 [−1.30, 0.26], P =0.189 and 0.001 [−0.002, 0.005], P =0.485, respectively) was associated with smaller central retinal arteriolar equivalent and arteriole:venule ratio. The association between time‐averaged cumulative DBP and arteriole:venule ratio was strongest in White participants (interaction P =0.007). The association of cumulative systolic BP and DBP with central retinal venular equivalent was strongest in Black participants (interaction P =0.015 and 0.011, respectively). Conclusions: Exposure to higher BP levels, particularly DBP, from midlife to late life is associated with narrower retinal vessel diameters in late life. Furthermore, race moderated the association of cumulative BP exposure with retinal microvasculature.

Aims: We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. Methods and results: We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI ≤ 31.71 kg/m2 and baseline ALP ≤ 80 U/L, n = 759); Group 2 (BMI ≤ 31.71 kg/m2 and ALP > 80 U/L, n = 1088); Group 3 (BMI > 31.71 kg/m2, and WBC ≤ 6.6 cells/μL, n = 633); Group 4 (BMI > 31.71 kg/m2 and WBC > 6.6 cells/μL, n = 832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high-risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P = 0.045) but increased the risk in low-risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P = 0.041; P for interaction = 0.020) but showed similar risk of drug discontinuation (P for interaction = 0.498). Conclusion: Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.