DOI: https://doi.org/10.21203/rs.3.rs-1943479/v1
Background: Time in target range (TTR) of systolic blood pressure was a novel measure to assess the effect of blood pressure control, but its prognostic value in diabetes mellitus remains uncertain.
Methods: A total of 2882 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial were included into the present study, with average age of 63.0±6.8 years old. The target range was defined as 120 to 140 mm Hg and 110 to 130 mm Hg for standard and intensive therapy, respectively. Cox proportional hazard regressions were conducted to investigate the effect of systolic blood pressure TTR on the first occurrence of outcomes.
Results: After adjusting for covariates, 1-SD increase of TTR was significantly associated with decreased risk of primary outcome (HR 0.83, 95% CI: 0.74-0.94, P=0.0026), as well as all-cause mortality (HR 0.83, 95% CI: 0.72-0.97, P=0.018), cardiovascular death (HR 0.70, 95% CI: 0.54-0.89, P=0.0045) and nonfatal myocardial infarction (HR 0.85, 95% CI: 0.73-0.99, P=0.034). TTR sustained significance of primary outcome (P≤0.012), and all-cause (P≤0.017) and cardiovascular mortality (P≤0.022) even after additional adjustment for mean systolic blood pressure or systolic blood pressure variability. Similar results were got when TTR was treated as categorical variable.
Conclusions: In patients with T2DM, TTR of systolic blood pressure was significantly associated with decreased risk of major outcomes, while controlling for blood pressure mean and variability during the same exposure time. Long-term monitoring and control of blood pressure in the target range was important for improving outcomes.
Trial Registration: ClinicalTrials.gov number: NCT00000620.
Hypertension is one of the most common cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM), which leads to excessive cardiovascular morbidity and mortality1. Blood pressure control has been demonstrated as an effective and practical strategy in reducing cardiovascular risk by several clinical trials2-4. The 2017 update of the American College of Cardiology (ACC)/American Heart Association (AHA) BP treatment guidelines5 and the 2019 version of guidelines on diabetes, pre-diabetes, and cardiovascular diseases by European Society of Cardiology (ESC) in collaboration with European Association for the Study of Diabetes (EASD)6 recommended the optimal blood pressure lowering target of less than 130 mm Hg for T2DM patients.
However, as blood pressure fluctuates continuously, current clinical assessment of blood pressure control usually takes blood pressure data acquired at single visit into consideration, neglecting the dynamics of blood pressure. Further, researchers have found that there is a J-shaped association between systolic blood pressure and adverse cardiovascular events7-9, indicating proper blood pressure therapeutic range was rather crucial.
Recently, a post hoc analysis of a large veteran study in the United Sates firstly proposed time in target range (TTR) of systolic blood pressure as a novel measure of hypertension management and verified the significant prognostic value of all-cause mortality10. Since then, TTR of systolic blood pressure, which reflects both the average of blood pressure and the degree of blood pressure variability10, gradually receives attention. Evidence of studies highlights the protective effect of TTR of systolic blood pressure on cardiovascular outcomes in patients with heart failure11, 12 and with high cardiovascular risk13. However, few studies have focused on the predictive effect of systolic blood pressure TTR in T2DM patients.
Therefore, we employed the database of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial in the present study to explore the associations between TTR of systolic blood pressure and cardiovascular outcomes among T2DM patients.
Study Population
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial was a nonblinded trial, conducted in a subgroup of ACCORD study and randomized as 2×2 factorial design. Participants were randomly assigned to standard or intensive therapy (systolic target of less than 140 mm Hg vs less than 120 mm Hg). The ACCORD BP entry criteria and main findings have been described previously (online study protocols: https://biolincc. nhlbi.nih.gov/studies/accord/)4, 14, 15. Briefly, participants enrolled in the ACCORD BP trial should met the following criteria: systolic blood pressure between 130 to 180 mm Hg on 3 or fewer anti-hypertensive medication, and 24-hour urine protein excretion <1.0 g.
For the purpose of the current analysis, we included participants in ACCORD BP trial with at least 2 BP recordings during the exposure time (month 0-4), and excluded those whose baseline systolic blood pressure reached the BP lowering target range (120-140 mm Hg for standard group and 110-130 mm Hg for intensive group). Additionally, participants who experienced events during the exposure time or lost follow-up were also excluded in the time-to-event analysis of the certain outcome.
Blood Pressure Management
During the follow-up, participants in standard group were scheduled for visits in the first and fourth month and every 4 months thereafter, and participants in intensive group were once a month for the first 4 months and every 2 months since then4, 14. At each visit, blood pressure was recorded as the average of 3 continuous measurements on seated position after 5 minutes rest by automated blood pressure device (Omron 907, Omron Healthcare, Inc., Japan) 4, 14.
Antihypertensive drugs demonstrated effective for diabetic patients were encouraged to use in BP lowering regimens, including diuretic, beta-blocker, calcium channel blocker, angiotensin converting-enzyme inhibitor, and angiotensin receptor blocker.
Medication dose titration or addition of another drug was indicated whenever systolic blood pressure reached ≥160 mm Hg once or ≥140 mm Hg twice successively in standard arm. For participants in intensive group, whenever systolic blood pressure was ≥120 mm Hg, addition of another drug from different class was required.
Systolic Blood Pressure Time in Target Range
We selected systolic blood pressure recordings during exposure period (month 0-4). Linear interpolation model16 was used to calculate systolic blood pressure time in target range (TTR) for each individual. The target range was defined as 120 to 140 mm Hg and 110 to 130 mm Hg for standard and intensive group, respectively. The upper threshold of the intensive arm was set as 130 mm Hg in order to match the current guideline recommendation5, 6. Systolic blood pressure average and variability were calculated as mean and standard deviation (SD) of systolic blood pressure recordings during 0-4 month.
For the sensitivity analysis, systolic blood pressure measurements during 0-8 month were used.
Outcomes
The primary outcome was a composite of the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death4. Secondary outcomes analyzed in the study were all-cause mortality, cardiovascular death, chronic heart failure, nonfatal myocardial infarction and total stroke.
Statistical Analysis
Characteristics of study population in the current study were presented by 4 TTR groups (0≤TTR<25%, 25%≤TTR<50%, 50%≤TTR<75% and TTR≥75%). Continuous variables were summarized as mean±SD or median (interquartile range), and categorical variables were shown as count (percentage). Analysis of variance test and chi-square test were used to estimate difference across TTR groups.
Cox proportional hazard regressions were used to explore the associations of systolic blood pressure TTR to the first occurrence of outcomes as continuous and categorical variable. In addition to crude model, there were 2 multivariable adjusted models, first adjusted for demographic variables (sex, age, black race and education) and sequentially adjusted for glycemia group, blood pressure group, smoking status, baseline cardiovascular history, body mass index (BMI), glycated hemoglobin, total cholesterol, estimated glomerular filtration rate and baseline systolic blood pressure. Restricted cubic spline was also conducted in the full adjusted model to analyze the association between continuous systolic blood pressure TTR exposure and the risk of outcomes. All models in the study fulfilled the testing of the Schoenfeld residuals. Because there was no significant interaction between TTR and BP groups, the main analyses were conducted in the overall study population to maximize statistical power.
For the sensitivity analyses, we assessed the associations between systolic blood pressure TTR and outcomes on the presence of systolic blood pressure average and systolic blood pressure variability. Second, for the reason of few participants with mean systolic blood pressure below the target range, similar analyses were conducted in participants whose mean systolic blood pressure were beyond or within the target range during 0-4 month. Lastly, we expanded the exposure time from 4th to 8th month in order to add at least 1 extra BP recording to estimate the stability of the prognostic value of systolic blood pressure TTR.
SAS software (Version 9.4, SAS Institute Inc., Cary, NC) and R software (Version 4.2, R Foundation for Statistical Computing, Vienna, Austria) were used for database management and statistical analysis. Two-tailed P value<0.05 was defined as statistically significant.
Characteristics of Study Population
We excluded 34 participants with missing baseline data, 1782 having baseline systolic blood pressure within BP lowering target and 35 having less than 2 blood pressure measurements during 0-4 month. Finally, 2882 participants were included into the present study (Supplemental Figure S1). The average baseline age of overall study population was 63.0±6.8 years old, 1400 (48.6%) participants were female, 691 (24.0%) were black race and 974 (33.8%) participants had cardiovascular disease at baseline.
During the exposure time (0-4 month), the mean systolic blood pressure achieved was 139.6±13.3 mm Hg in standard group and 131.2±11.9 mm Hg in the intensive group (P<0.001), and the systolic blood pressure variability was 12.3±6.9 mm Hg for the standard arm and 13.6±5.5 mm Hg for the intensive arm (P<0.001). Meanwhile, the systolic blood pressure TTR was 45.9%±34.4% in the standard group and 45.6%±29.7% in the intensive group (P=0.76).
Compared with the lowest TTR group, the participants in the highest TTR group were younger, received higher education (P=0.021), and had lower level of baseline glycated hemoglobin, low-density lipoprotein cholesterol and blood pressure and higher level of estimated glomerular filtration rate (P≤0.040). The proportion of black race were higher in participants with TTR between 75% to 100% than those of 0 to 25% (P<0.001, Table 1). The frequency of baseline cardiovascular disease, smokers and intensive glycemic therapy did not show difference across TTR groups (Table 1). The relationship between TTR groups and mean systolic blood pressure was shown in Figure 1, which presented greater TTR was correlated with higher proportion of blood pressure within target range (P<0.001).
Associations of Systolic Blood Pressure Time in Target Range and Outcomes
The primary outcome occurred in 280 participants with median follow-up of 4.96 years (incidence rate: 20.65 per 1000 person-years, 95% CI: 18.30-23.21). Systolic blood pressure TTR was significantly associated with 20.0% decreased risk of first primary events per 1-SD increase in unadjusted model (HR 0.80, 95% CI: 0.71-0.90, P<0.001). In both two adjusted models, systolic blood pressure TTR was also significantly associated with primary outcomes (HR 0.81, 95% CI: 0.72-0.91, P<0.001; HR 0.83, 95% CI: 0.74-0.94, P=0.0026, Table 2).
The associations of systolic blood pressure TTR and secondary outcomes were also assessed in the study. In fully adjusted models, systolic blood pressure TTR was significantly associated with all-cause mortality (HR 0.83, 95% CI: 0.72-0.97, P=0.018), cardiovascular death (HR 0.70, 95% CI: 0.54-0.89, P=0.0045) and nonfatal myocardial infarction (HR 0.85, 95% CI: 0.73-0.99, P=0.034) (Table 2).
The relationships among systolic blood pressure TTR and outcomes did not significantly differ between the standard and intensive therapy (P for interaction ≥0.086, Supplemental Table S1-4). In fully adjusted models, systolic blood pressure TTR was significantly associated with primary outcome, and all-cause and cardiovascular mortality (P≤0.042) in the standard arm, no matter whether systolic blood pressure average and variability were included in the regression models (Supplemental Table S1-4).
To estimate the independency of the associations between systolic blood pressure TTR and outcomes, we further adjusted systolic blood pressure average and variability during exposure time based on full models. Results showed that systolic blood pressure TTR was independently associated with primary outcome (P≤0.012), all-cause mortality (P≤0.018) and cardiovascular death (P≤0.022) when systolic blood pressure average and variability were included in the regression models (Table 3).
Fully adjusted models were also conducted for systolic blood pressure TTR groups stratified by the threshold of 25%, 50% and 75%. The participants of systolic blood pressure TTR of 75% to 100% had significantly decreased risk of primary outcome (HR 0.57, 95% CI: 0.41-0.80, P=0.0012), all-cause mortality (HR 0.62, 95% CI: 0.41-0.95, P=0.027), cardiovascular death (HR 0.36, 95% CI: 0.17-0.76, P=0.0071) and nonfatal myocardial infarction (HR 0.54, 95% CI: 0.35-0.82, P=0.0042). A linear trend was found for primary outcome, all-cause mortality, cardiovascular death and nonfatal myocardial infarction across TTR groups (All P for trend ≤0.025). When further adjusted with systolic blood pressure average and variability, the highest systolic blood pressure TTR group was also significantly associated with decreased risk of various outcomes (P≤0.027 for all), as similar as the results in full models (Table 4).
In order to better understand the relationship of systolic blood pressure TTR and outcomes, restricted cubic spline was further conducted (Figure 2). The associations between TTR and outcomes showed linear relationships and no nonlinearity was detected in the analysis (P≥0.23 for all).
Subgroup Analysis of Systolic Blood Pressure Time in Target Range and Outcomes
For the further assessment of the prognostic value of systolic blood pressure TTR, similar analyses were conducted in participants with different characteristics (Supplemental Table S5). The interactions between subgroups and systolic blood pressure TTR were also detected. Though the correlation of systolic blood pressure TTR and outcomes did not significantly differ across age and gender groups (P for interaction ≥0.086), there was a significant interaction of systolic blood pressure TTR on primary outcome and total stroke between different BMI groups (BMI ≤30 kg/m2 vs BMI >30 kg/m2; primary outcome: HR, 0.69 vs 0.94, P for interaction=0.022; total stroke: HR, 0.55 vs 1.01; P for interaction=0.022), indicating better protective effect of systolic blood pressure TTR in thinner participants.
The distribution of systolic blood pressure TTR in different blood pressure control groups was shown in Supplemental Figure S2. Among participants whose mean systolic blood pressure levels beyond target range, 1-SD increase of systolic blood pressure TTR was correlated with 20% and 41% decreased risk of primary outcome and cardiovascular death (HR, 0.80, 95% CI: 0.66-0.99, P=0.035; HR, 0.59, 95% CI: 0.37-0.93, P=0.024, respectively) in full model, and sustained significance when systolic blood pressure average and variability (P ≤0.018) were included into the models (Supplemental Table S6).
In sensitivity analysis, systolic blood pressure TTR was significantly associated with primary outcome (HR, 0.83, 95% CI: 0.74-0.94, P=0.0031), all-cause mortality (HR, 0.83, 95% CI: 0.71-0.96, P=0.015), chronic heart failure (HR, 0.79, 95% CI: 0.65-0.96, P=0.015), nonfatal myocardial infarction (HR, 0.85, 95% CI: 0.73-0.99, P=0.034) and total stroke (HR, 0.74, 95% CI: 0.57-0.95, P=0.020) in full models when exposure time expanded to 8th month (Supplemental Table S7), and it sustained the significant prognostic values of primary outcome (P≤0.017) and all-cause mortality (P≤0.022) after adjusting for systolic blood pressure average and variability (Supplemental Table S8).
In the present secondary analysis of ACCORD BP trial, we focused on the prognostic value of TTR of systolic blood pressure. To our knowledge, this study was the first analysis assessing the associations of systolic blood pressure TTR and cardiovascular outcomes among T2DM patients. We demonstrated that higher TTR of systolic blood pressure was significantly associated with decreased risks of primary outcome, and all-cause and cardiovascular mortality in T2DM patients before and after adjusting for mean systolic blood pressure and systolic blood pressure variability.
The benefit of blood pressure lowering for patients with hypertension has been wildly accepted, but the optimal blood pressure target for blood pressure management still remains debated 3, 4, especially in diabetic patients17, 18. Recent guidelines recommend the lower blood pressure target of less than 130 mm Hg for T2DM patients5, 6, without providing the lower bound. As the growing evidence indicates the J-shaped association between blood pressure and cardiovascular outcomes7–9, it is urgent to figure out the proper therapeutic range to guide the management of blood pressure. Li et al. investigated the optimal blood pressure range in hypertension patients and found that cardioprotective effect persisted at as low as systolic blood pressure of 110–120 mm Hg irrespective of diabetes status19. Hence, we defined systolic target range of 120–140 mm Hg for standard group and 110–130 mm Hg for intensive group in the current research.
In clinical practice, blood pressure measure at single visit or blood pressure average during follow-up was usually used to evaluate the consistency of blood pressure control, however, blood pressure is a dynamic and unstable indicator in essence. For this reason, recent studies have focused on the variability of blood pressure to measure the stability of blood pressure levels, and verified that higher blood pressure variability was significantly corelated with higher risk of cardiovascular diseases and mortality20–23. Indeed, neither blood pressure average nor blood pressure variability could provide a comprehensive overview of the status of blood pressure management. Doumas et.al firstly propose TTR of systolic blood pressure as a novel measure which to assess the consistency of blood pressure control10. After defining the systolic therapeutic range, TTR of systolic blood pressure calculated by linear interpolation model16 estimated the time of systolic blood pressure within target range and indicated both the blood pressure level and stability across treatment10–13.
A post hoc analysis of a large veteran cohort followed over10 years found an inverse association between TTR of systolic blood pressure and all-cause mortality, and there was a significant increased risk of death in lowest TTR quartile compared with the highest quartile (HR 2.18, 95% CI 2.06–2.32, P < 0.001)10. After adjusting for mean systolic blood pressure and systolic blood pressure variability, TTR of systolic blood pressure was significantly associated with a decreased risk of cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT)13. Recently, Chen et al.11 and Huang et al.12 coincidentally focused on the prognostic value of systolic blood pressure TTR in patients with heart failure, and verified systolic blood pressure TTR as an independent predictor of cardiovascular outcomes regardless of the target range definition11, 12. Consistent with previous findings, our study demonstrated the predictive value of systolic blood pressure TTR on cardiovascular outcomes among T2DM patients.
In addition, our subgroup analysis found a significant interaction between BMI and TTR, indicating a stronger cardiovascular-protective effect of TTR in participants with BMI less than 30 kg/m2. The potential explanation of the phenomenon might because obese participants (BMI > 30 kg/m2) with T2DM in ACCORD BP trial had higher prevalence of smoker and dyslipidemia, which could cause vascular injuries and bring difficulty in systolic blood pressure control. Therefore, lower systolic blood pressure TTR showed insignificant associations with outcomes in participants whose BMI > 30 kg/m2. Sensitivity analysis showed significant associations of TTR and some outcomes among patients whose mean systolic blood pressure was beyond target range. As shown in Supplemental Figure S2, few TTR values were below 10% in participants within target range, which might conceal the prognostic value of TTR.
The clinical implication of TTR would be prominent. Due to the reflection of the average blood pressure value and the blood pressure variation degree, TTR of systolic blood pressure could be a better indicator to assess the effect of blood pressure control and to adjust the antihypertensive medication. In this study, we detected the linear relationship between TTR and cardiovascular outcomes, and it underlined the importance of blood pressure consistency when treating T2DM patients with high blood pressure. As TTR gradually attracts attention, clinicians may face a greater challenge in achieving and sustaining blood pressure control.
There are some limitations of our study. Firstly, the current study was a secondary analysis of database from ACCORD BP trial, which was not originally designed for systolic blood pressure TTR. Secondly, consensus has not been reached on blood pressure target range for T2DM patients, the therapeutic range used in the study might cause potential biases. Moreover, we only estimated systolic blood pressure TTR of 0–4 month in main analyses and in 0–8 month in sensitivity analyses. Further analysis should be conducted to evaluate the prognostic value of long-term TTR in large and well-designed clinical trials.
TTR of systolic blood pressure was significantly associated with decreased risk of major outcomes independent for blood pressure mean and variability in T2DM patients. Long-term monitoring in these patients and control of blood pressure in the target range in clinical practice was important for a benign prognosis.
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Availability of data and materials
All data generated or analyzed during this study are available in this published article.
Competing interests
The authors declare no conflict of interest.
Funding
This work was supported by the Shanghai Talent Development Fund (2021087), the Chinese National Natural Science Foundation (81770418, 81400346 and 81270935), Ministry of Health (2016YFC1300103 and 2016YFC0905001), and Shanghai Pujiang Talents Plan (18PJ1407200).
Authors' contributions
Chang-Sheng Sheng and Jingyan Tian had full access to all the data in the study and take responsibility for the accuracy of the data analysis, and participated in the study design and paper revision. Yi Cheng and Dan Wang performed the studies and drafted the manuscript. Yulin Yang and Ya Miao checked the accuracy of the analysis and involved in review the English language and grammar. All the authors reviewed the final manuscript.
Acknowledgements
The investigators acknowledge and thank the ACCORD investigators and the National Heart, Lung, and Blood Institute for conducting the trials and making datasets publicly available.
Table 1
Baseline Characteristics of Participant Population.
TTR<25% |
25≤TTR<50% |
50≤TTR<75% (n=676) |
TTR≥75% (n=727) |
P |
|
(n=885) |
(n=594) |
||||
Baseline |
|
|
|||
Female, n (%) |
442(49.9) |
304(51.2) |
323(47.8) |
331(45.5) |
0.16 |
Age, years |
63.5±6.7 |
63.3±6.2 |
62.7±6.9 |
62.4±7.0 |
0.0055 |
Black race, n (%) |
267(30.2) |
158(26.6) |
141(20.9) |
125(17.1) |
<0.001 |
Education, n (%) |
|
|
0.16 |
||
Less than high school |
175(19.8) |
108(18.2) |
102(15.1) |
106(14.6) |
|
High-school graduate or GED |
246(27.8) |
158(26.6) |
192(28.4) |
191(26.3) |
|
Some college |
265(29.9) |
194(32.7) |
216(32.0) |
244(33.6) |
|
College degree or higher |
199(22.5) |
134(22.6) |
166(24.6) |
186(25.6) |
|
Glycemia intensive therapy, n (%) |
445(50.3) |
295(49.7) |
356(52.7) |
354(48.7) |
0.50 |
Blood pressure therapy, n (%) |
478(54.0) |
398(67.0) |
45.4(67.2) |
351(48.3) |
<0.001 |
Smoking status, n (%) |
|
|
0.55 |
||
Never |
433(48.9) |
264(44.4) |
306(45.3) |
346(47.6) |
|
Former |
343(38.8) |
242(40.7) |
282(41.7) |
282(38.8) |
|
Current |
109(12.3) |
88(14.8) |
88(13.0) |
99(13.6) |
|
Cardiovascular disease history, n (%) |
310(35.0) |
188(31.6) |
221(32.7) |
255(35.1) |
0.44 |
Body mass index, kg/m2 |
32.1±5.5 |
32.5±5.5 |
32.0±5.4 |
31.8±5.7 |
0.14 |
Systolic blood pressure, mm Hg |
150.5±18.0 |
145.8±15.9 |
142.9±14.1 |
142.8±13.4 |
<0.001 |
Diastolic blood pressure, mm Hg |
78.8±11.1 |
77.9±10.8 |
77.3±10.2 |
77.6±10.6 |
0.027 |
Heart rate, bpm |
72.5±11.7 |
72.4±12.3 |
73.3±11.3 |
72.9±11.2 |
0.48 |
Fasting glucose, mg/dl |
175.9±60.0 |
176.5±61.5 |
177.8±57.7 |
171.4±58.9 |
0.20 |
Glycated hemoglobin, % |
8.5±1.1 |
8.4±1.1 |
8.3±1.0 |
8.3±1.1 |
0.0050 |
Total cholesterol, mg/dl |
197.1±45.9 |
194.7±45.0 |
195.0±46.1 |
192.9±45.2 |
0.32 |
Low-density lipoprotein cholesterol, mg/dl |
113.1±37.7 |
112.9±36.5 |
111.2±36.6 |
109.2±37.4 |
0.16 |
High-density lipoprotein cholesterol, mg/dl |
47.0±14.5 |
46.7±13.1 |
46.1±12.8 |
46.3±13.7 |
0.60 |
Triglycerides, mg/dl |
147.0(95.0-231.0) |
143.0(94.3-209.0) |
150.0(100.0-224.2) |
145.0(99.0-227.0) |
0.52 |
Estimated glomerular filtration rate, ml/min/1.73 m2 |
89.8±25.4 |
90.7±26.7 |
94.7±41.9 |
92.6±27.4 |
0.011 |
During 0-4 month exposure time |
|
|
|||
Mean of systolic blood pressure, mm Hg |
144.2±15.9 |
132.8±10.5 |
129.0±8.1 |
130.0±8.1 |
<0.001 |
Standard deviation of systolic blood pressure, mm Hg |
12.2±6.9 |
15.6±6.6 |
14.0±5.0 |
11.2±4.7 |
<0.001 |
Time in target range, % |
6.1±8.3 |
37.7±6.8 |
61.9±6.9 |
85.3±6.4 |
<0.001 |
GED, general equivalency diploma.
Table 2
Associations of Systolic Blood Pressure Time in Target Range and Outcomes.
Outcomes |
N |
IR (95% CI) |
Unadjusted |
Model 1 |
Model 2 |
|||
HR (95% CI) |
P |
HR (95% CI) |
P |
HR (95% CI) |
P |
|||
Primary outcome |
280 |
20.65(18.30-23.21) |
0.80(0.71-0.90) |
<0.001 |
0.81(0.72-0.91) |
<0.001 |
0.83(0.74-0.94) |
0.0026 |
All-cause mortality |
182 |
12.67(10.90-14.65) |
0.80(0.69-0.93) |
0.0028 |
0.84(0.72-0.97) |
0.017 |
0.83(0.72-0.97) |
0.018 |
Cardiovascular death |
70 |
4.94(3.86-6.25) |
0.68(0.53-0.86) |
0.0015 |
0.70(0.55-0.89) |
0.0038 |
0.70(0.54-0.89) |
0.0045 |
Chronic heart failure |
113 |
8.17(6.73-9.83) |
0.81(0.67-0.97) |
0.024 |
0.83(0.69-0.99) |
0.044 |
0.85(0.70-1.02) |
0.082 |
Myocardial infarction |
177 |
12.95(11.11-15.01) |
0.84(0.73-0.97) |
0.022 |
0.84(0.73-0.98) |
0.023 |
0.85(0.73-0.99) |
0.034 |
Stroke |
61 |
4.37(3.35-5.62) |
0.70(0.54-0.91) |
0.0069 |
0.72(0.56-0.94) |
0.014 |
0.78(0.60-1.01) |
0.060 |
IR, incidence rate; CI, confidence interval.
IR per 1000 person-years; hazard ratio per 1-SD increase in time in target range.
Model 1 was adjusted with sex, age, black race and education.
Model 2 was further adjusted with glycemia group, blood pressure group, smoking status, baseline CVD history, body mass index, glycated hemoglobin, total cholesterol, estimated glomerular filtration rate and baseline systolic blood pressure.
Table 3
Associations of Systolic Blood Pressure Time in Target Range and Outcomes With or Without Adjustment for Mean and Standard Deviation of Systolic Blood Pressure.
Outcomes |
Fully adjusted |
Fully adjusted with Mean SBP |
Fully adjusted with SBP SD |
|||
HR (95% CI) |
P |
HR (95% CI) |
P |
HR (95% CI) |
P |
|
Primary outcome |
0.83(0.74-0.94) |
0.0026 |
0.84(0.73-0.96) |
0.012 |
0.83(0.73-0.93) |
0.0021 |
All-cause mortality |
0.83(0.72-0.97) |
0.018 |
0.81(0.68-0.96) |
0.017 |
0.83(0.71-0.96) |
0.014 |
Cardiovascular death |
0.70(0.54-0.89) |
0.0045 |
0.72(0.54-0.95) |
0.022 |
0.70(0.54-0.90) |
0.0050 |
Chronic heart failure |
0.85(0.70-1.02) |
0.082 |
0.88(0.71-1.10) |
0.26 |
0.83(0.68-1.01) |
0.061 |
Myocardial infarction |
0.85(0.73-0.99) |
0.034 |
0.85(0.72-1.00) |
0.056 |
0.85(0.73-0.98) |
0.030 |
Stroke |
0.78(0.60-1.01) |
0.060 |
0.76(0.56-1.02) |
0.070 |
0.76(0.58-0.99) |
0.045 |
CI, confidence interval.
Hazard ratio per 1-SD increase in time in target range.
Table 4
Association of Time in Target Range Groups and Outcomes With or Without Adjustment for Mean and Standard Deviation of Systolic Blood Pressure.
Fully adjusted |
Fully adjusted with Mean SBP |
Fully adjusted with SBP SD |
|||||
HR (95% CI) |
P |
HR (95% CI) |
P |
HR (95% CI) |
P |
||
Primary outcome |
25≤TTR<50% |
0.91(0.67-1.25) |
0.57 |
0.93(0.67-1.31) |
0.69 |
0.88(0.64-1.22) |
0.46 |
50≤TTR<75% |
0.74(0.54-1.02) |
0.070 |
0.76(0.53-1.09) |
0.13 |
0.73(0.52-1.01) |
0.055 |
|
TTR≥75% |
0.57(0.41-0.80) |
0.0012 |
0.59(0.41-0.85) |
0.0046 |
0.57(0.41-0.80) |
0.0013 |
|
All-cause mortality |
25≤TTR<50% |
0.87(0.58-1.28) |
0.47 |
0.84(0.55-1.28) |
0.41 |
0.81(0.55-1.22) |
0.32 |
50≤TTR<75% |
0.78(0.52-1.17) |
0.23 |
0.75(0.49-1.17) |
0.20 |
0.75(0.50-1.13) |
0.17 |
|
TTR≥75% |
0.62(0.41-0.95) |
0.027 |
0.60(0.38-0.94) |
0.027 |
0.62(0.41-0.95) |
0.028 |
|
Cardiovascular death |
25≤TTR<50% |
0.75(0.41-1.36) |
0.34 |
0.79(0.42-1.50) |
0.47 |
0.76(0.41-1.41) |
0.39 |
50≤TTR<75% |
0.51(0.26-0.99) |
0.047 |
0.55(0.26-1.13) |
0.10 |
0.510.26-1.01) |
0.055 |
|
TTR≥75% |
0.36(0.17-0.76) |
0.0071 |
0.39(0.17-0.85) |
0.019 |
0.36(0.17-0.76) |
0.0071 |
|
Chronic heart failure |
25≤TTR<50% |
0.63(0.37-1.07) |
0.084 |
0.65(0.37-1.15) |
0.14 |
0.53(0.31-0.91) |
0.021 |
50≤TTR<75% |
0.64(0.38-1.07) |
0.086 |
0.67(0.38-1.18) |
0.16 |
0.57(0.34-0.95) |
0.033 |
|
TTR≥75% |
0.60(0.37-1.00) |
0.052 |
0.63(0.36-1.10) |
0.11 |
0.62(0.37-1.03) |
0.064 |
|
Myocardial infarction |
25≤TTR<50% |
0.70(0.45-1.07) |
0.097 |
0.69(0.44-1.07) |
0.10 |
0.67(0.43-1.04) |
0.071 |
50≤TTR<75% |
0.83(0.57-1.23) |
0.36 |
0.82(0.54-1.25) |
0.36 |
0.81(0.55-1.20) |
0.29 |
|
TTR≥75% |
0.54(0.35-0.82) |
0.0042 |
0.53(0.34-0.83) |
0.0061 |
0.54(0.35-0.82) |
0.0044 |
|
Stroke |
25≤TTR<50% |
1.28(0.69-2.38) |
0.43 |
1.29(0.66-2.52) |
0.46 |
1.15(0.61-2.18) |
0.66 |
50≤TTR<75% |
0.41(0.16-1.00) |
0.051 |
0.41(0.16-1.07) |
0.067 |
0.38(0.15-0.94) |
0.037 |
|
TTR≥75% |
0.67(0.33-1.36) |
0.27 |
0.67(0.31-1.46) |
0.32 |
0.67(0.33-1.36) |
0.27 |
TTR, time in target range.
TTR<25% was defined as reference.