Among patients with diabetes mellitus, elevated blood. Hypertension

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1 Hypertension Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus The ADVANCE Trial Jun Hata, MD, PhD; Hisatomi Arima, MD, PhD; Peter M. Rothwell, MD, PhD; Mark Woodward, PhD; Sophia Zoungas, MD, PhD; Craig Anderson, MD, PhD; Anushka Patel, MD, PhD; Bruce Neal, MD, PhD; Paul Glasziou, MD, PhD; Pavel Hamet, MD, PhD; Giuseppe Mancia, MD, PhD; Neil Poulter, MD, PhD; Bryan Williams, MD, PhD; Stephen MacMahon, PhD; John Chalmers MD, PhD on behalf of the ADVANCE Collaborative Group Downloaded from by guest on December 22, 2016 Background Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. Methods and Results The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<5 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 ( ) for macrovascular events and 1.84 ( ) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 ( ) and 2.18 (4 4.58), respectively. Conclusion Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. Clinical Trial Registration URL: Unique Identifier: NCT (Circulation. 2013;128: ) Key Words: blood pressure diabetes mellitus, type 2 diabetic nephropathies myocardial infarction stroke Among patients with diabetes mellitus, elevated blood pressure (BP) is one of the major modifiable risk factors for macrovascular diseases such as coronary heart disease and stroke, and is also associated with progression of microvascular complications such as nephropathy and retinopathy. 1 As a result, the current guidelines for the management of BP in patients with diabetes mellitus recommend diagnostic and therapeutic approaches based on a usual BP value (defined as mean of BP over a period of time), and other cardiovascular risk factors and target organ damage, as well. 2 4 Clinical Perspective on p 1334 A recent study of several cohorts of patients with previous transient ischemic attack or stroke and of the Anglo- Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) reported that visit-to-visit Received March 19, 2013; accepted July 30, From The George Institute for Global Health, University of Sydney, Sydney, Australia (J.H., H.A., M.W., S.Z., C.A., A.P., B.N., S.M., J.C.); University of Oxford, Oxford, United Kingdom (P.M.R., S.M.); School of Public Health, Monash University, Clayton, Australia (S.Z.); Bond University, Gold Coast, Australia (P.G.); Université de Montréal, Montreal, Canada (P.H.); University of Milan-Bicocca, Milan, Italy (G.M.); Imperial College, London, United Kingdom (N.P.); and University College London (UCL) and the National Institute for Health Research UCL Hospitals Biomedical Research Centre, London, United Kingdom (B.W.). The online-only Data Supplement is available with this article at /-/DC1. Correspondence to John Chalmers, MD, PhD, The George Institute for Global Health, University of Sydney, Level 10, King George Building, Royal Prince Alfred Hospital, Missenden Rd, New South Wales, 2050 Australia. chalmers@georgeinstitute.org.au 2013 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 1326 Circulation September 17, 2013 Downloaded from by guest on December 22, 2016 variability in systolic blood pressure (SBP) and maximum SBP were significantly associated with future risks of stroke and other cardiovascular events independent of mean BP and other cardiovascular risk factors. 5 It was suggested that, although long-term mean BP is important in the long-term development of vascular disease, episodic peaks in BP (associated with increased variability and high maximum) might be important in the short-term triggering of vascular events. 6 Increased variability of BP may be partially explained by arterial stiffness 7 and abnormal autonomic function, 8 both of which are common complications of diabetes mellitus and have been associated with cardiovascular events. 9,10 However, there has been little evidence of the effects of visit-to-visit BP variability and maximum SBP on the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. The aim of the present study was to assess the effects of visit-to-visit SBP variability and maximum SBP on the risks of macrovascular and microvascular outcomes by using the data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial Methods Study Design ADVANCE was a factorial randomized controlled trial of BP lowering and intensive blood glucose control in patients with type 2 diabetes mellitus. The detailed design has been described previously In brief, a total of patients with type 2 diabetes mellitus aged 55 years who had a history of major macrovascular or microvascular disease, or at least 1 other risk factor for vascular disease, were recruited from 215 collaborating centers in 20 countries from Asia, Australasia, Europe, and North America. These patients entered a 6-week prerandomization run-in period during which they received a fixed combination of angiotensin-converting enzyme inhibitor, perindopril (2 mg), and thiazide diuretic, indapamide (0.625 mg). After the run-in period, participants were randomly assigned, in a factorial design, to a fixed combination of perindopril and indapamide (2 mg/0.625 mg for the first 3 months and 4 mg/1.25 mg thereafter) or matching placebo, and to either an intensive glucose control strategy (target hemoglobin A1c of 6.5%) or a standard glucose control strategy based on local guidelines. The use of concomitant treatments, including BP-lowering therapy, remained at the discretion of the responsible physician with 2 exceptions: the use of thiazide diuretics was not allowed, and open-label perindopril (maximum 4 mg/d) was the only angiotensin-converting enzyme inhibitor allowed. For the present analysis, 8811 patients who had not experienced major macrovascular or microvascular events or death during the first 24 months and had BP measurements at all of 6 occasions (3, 4, 6, 12, 18, and 24 months after randomization) were studied (Figure 1). Approval for the trial was obtained from each center s institutional review board, and all participants provided written informed consent. BP Measurements and Visit-to-Visit Variability BP was measured in duplicate, with an interval of at least 1 minute, after 5 minutes of rest in the seated position, by using a standardized automated sphygmomanometer (Omron HEM-705CP, Tokyo, Japan). BP recordings were made at registration, at randomization, at 3, 4, and 6 months after randomization, and at every 6 months thereafter; the mean of the 2 measurements was used as the BP value at each visit. To minimize any misclassification of BP variability due to randomized BP-lowering treatment, BP values from 3 to 24 months were used for the estimation of the mean SBP, visitto-visit variability of SBP, and maximum SBP (Figure 1). Mean SBP was defined as an average of SBP values measured on the 6 occasions. Visit-to-visit variability in SBP was defined by using standard deviation (SD) and coefficient of variation (CV, defined as SD/mean). Maximum SBP was defined as a highest SBP value among the 6 occasions. Follow-Up and Study Outcomes Participants were followed up from the 24-month visit to the end of the study (Figure 1). Primary outcomes were major macrovascular and microvascular events (both considered jointly and separately). Major macrovascular events were defined as myocardial infarction (both nonfatal and fatal), stroke (both nonfatal and fatal), or cardiovascular death. Major microvascular events were defined as new or worsening nephropathy (development of macroalbuminuria, doubling of the serum creatinine to a level of at least 200 μmol/l, need for renal replacement therapy, or death due to renal disease) or retinopathy (development of proliferative retinopathy, macular edema, diabetes mellitus related blindness, or retinal photocoagulation therapy). Secondary outcomes in the present study were all-cause mortality and components of primary outcomes (myocardial infarction, stroke, cardiovascular death, new or worsening nephropathy, and new or worsening retinopathy). For patients with multiple events, the first applicable event was used in each analysis. An independent end point advisory committee adjudicated all of these outcomes. BP measurement period Follow up period (median 2.4 years) patients randomized Exclusion: 994 patients with major macroor microvascular events or death in first 24 months 1335 patients with missing BP value at any of 6 occasions 8811 patients analyzed BP lowering intervention (perindopril + indapamide vs. placebo) BP measurement (6 occasions) Figure 1. Flow diagram for study participants. Blood pressure (BP) measured at 6 occasions (3, 4, 6, 12, 18, and 24 months after randomization) was used to determine the mean, visit-tovisit variability, and maximum of systolic BP. After excluding patients who had experienced major macrovascular or microvascular events or death within 24 months, and excluding patients with missing BP values at any of 6 occasions, 8811 patients were eligible for the present study Months after randomization

3 Hata et al Blood Pressure Variability in Type 2 Diabetes Mellitus 1327 Downloaded from by guest on December 22, 2016 Statistical Analyses Associations between baseline characteristics at registration and SD SBP or maximum SBP during the measurement period were evaluated by using univariate and multivariate linear regression analysis. The effects of SBP parameters (ie, mean, SD, CV, and maximum SBP) on study outcomes were estimated by using a Cox proportional hazards model with adjustment for age, sex, randomized BP-lowering intervention, and randomized glucose control intervention (model 1), or with additional adjustment for region of residence, duration of diabetes mellitus, current smoking, current alcohol drinking, heart rate, total cholesterol, triglycerides (log-transformed), body mass index, use of β-blockers, and use of calcium-channel blockers (model 2), or with additional adjustment for mean SBP during the measurement period (model 3). Each of SD and maximum SBP was categorized into 10 groups according to the tenths within each BP-lowering treatment group (the placebo and the active). Mean, SD, CV, and maximum SBP were also analyzed as continuous variables with hazard ratios (HRs) and 95% confidence intervals (CIs) shown per increase of 1 SD for each parameter. In addition, we performed 8 sets of sensitivity analyses: (1) Patients who discontinued the randomized BP-lowering treatment before the 24-month visit were excluded (n=8230). (2) Patients with a history of macrovascular or microvascular disease at registration were excluded (n=5519). (3) SBP parameters were determined at 4 occasions from 6 to 24 months after randomization (n=9128). (4) SBP parameters were determined at 5 occasions from 3 to 18 months (n=9276). (5) SBP parameters were determined at 7 occasions from 3 to 30 months (n=8364). (6) A study cohort included patients who had SBP measurements at 2 of 6 occasions from 3 to 24 months (n=9966). (7) A study cohort was the same as the original one (n=8811), but the groups of SD and maximum SBP were determined on the basis of the tenths within all patients, pooling those on active treatment and placebo. (8) A study cohort was the same (n=8811), but SD and maximum SBP were categorized into 5 groups according to the fifths. We also performed a subgroup analysis for patients with and without changes in BP-lowering medication regimen during the BP measurement period (n=4448 and 4363, respectively). All statistical analyses were performed with the use of SAS version 9.3 (SAS Institute). A 2-sided P<5 was considered to be statistically significant. Results The characteristics of the patients included and excluded for the present study are summarized in Table 1. Among the 8811 patients studied, the mean age was 66 years, 42% were female, and 37% were registered in Asia. Average BP at registration was 145/81 mm Hg and 69% had a history of hypertension. As shown in multivariate analysis in Tables I and II (in the onlineonly Data Supplement), age, currently treated hypertension, a history of microvascular disease, SBP at registration, and hemoglobin A1c at registration were positively associated with SD and maximum SBP during the measurement period. Female sex and a history of macrovascular disease were positively associated and baseline heart rate was inversely associated with SD SBP. Both BP-lowering and blood glucose control interventions reduced SD and maximum SBP. Among the SBP parameters, maximum SBP was strongly correlated with mean SBP (Pearson correlation coefficient, r=0.91), and CV SBP was strongly correlated with SD SBP (r=0.96) (Table III in the online-only Data Supplement). Figure I in the online-only Data Supplement shows the proportion of patients on 2 or more additional (open-label) BP-lowering drugs at the 24-month visit according to the tenths of SD and maximum SBP. The patients with higher levels of SD or maximum SBP were more likely to receive multiple drugs. During median follow-up of 2.4 years from the 24-month visit after randomization, 407 major macrovascular and 476 microvascular events were observed. The risks of primary outcomes (major macrovascular and microvascular events) and all-cause mortality according to participant groups defined by the tenths of SD and maximum SBP are shown in Figure 2. The risks of major macrovascular and microvascular events and all-cause mortality rose progressively with higher SD levels of SBP, even after adjustments for mean SBP and other cardiovascular risk factors (all P<5 for trend). Multivariable-adjusted HRs (95% CIs) in the highest SD group in comparison with the lowest group were 1.69 ( ) for combined macro- and microvascular events, 1.54 ( ) for major macrovascular events, 1.84 ( ) for major microvascular events, and 8 ( ) for all-cause mortality. Higher levels of maximum SBP were significantly associated with the risks of the combined primary outcomes, major macrovascular events and all-cause mortality (all P for trend <5). A similar but statistically nonsignificant association was observed between maximum SBP and major microvascular events (P=8 for trend). Multivariable-adjusted HRs (95% CIs) in the highest maximum SBP group were 2.68 ( ) for the combined primary outcomes, 3.64 ( ) for macrovascular events, 2.18 (4 4.58) for microvascular events, and 2.44 ( ) for all-cause mortality. In addition, we performed 8 sets of sensitivity analyses for Figure 2 (Figures II to IX in the online-only Data Supplement) and confirmed that the main results were essentially similar to the original analysis, although some probability values did not reach a level of significance. During the 24-month measurement period, the BP-lowering treatment regimen was changed for 4448 patients (50%). However, the effects of SD and maximum SBP on the risk of combined macro- and microvascular events were similar between the subgroups of patients with and without changes in BP-lowering medication (Figure X in the online-only Data Supplement). The risks for the components of the major macrovascular and microvascular outcomes are shown in Figures 3 and 4, respectively. Of note, each higher SD level of SBP was significantly associated with higher risks of myocardial infarction, cardiovascular death, and new or worsening nephropathy (all P<5 for trend). A similar pattern was observed for the outcome new or worsening retinopathy, although the association did not reach statistical significance (P=6 for trend). In contrast, SD levels of SBP did not show any clear associations with stroke. A higher maximum SBP was significantly associated with an elevated risk of myocardial infarction (P=4 for trend). Similar but nonsignificant trends were observed for cardiovascular death and new or worsening retinopathy (both P<0.1 for trend). The risk of stroke was clearly elevated in the highest tenth in comparison with the lowest tenth (HR, 3.27; 95% CI, 6 15; P=4), although the association did not show a clear dose response relationship (P=0.26 for trend). On the other hand, maximum SBP did not show any association with new or worsening nephropathy. The effects of SD and maximum SBP, and the mean SBP, as well, considered as continuous variables are shown in Table 2. In the analysis with adjustment for age, sex, and randomized treatments (model 1), all parameters were

4 1328 Circulation September 17, 2013 Table 1. Characteristics of ADVANCE Participants Analyzed and Excluded in the Present Study Downloaded from by guest on December 22, 2016 Variables Demographic factors at registration Total (n=11 140) Analyzed (n=8811) Excluded (n=2329) Age, y 66 (6) 66 (6) 67 (7)* Female 4735 (43) 3735 (42) 1000 (43) Residence in Asian countries (China, India, 4136 (37) 3263 (37) 873 (37) Malaysia, and Philippines) Medical and lifestyle history at registration Currently treated hypertension 7655 (69) 6046 (69) 1609 (69) Duration of diabetes mellitus, y 7.9 (6.4) 7.7 (6.3) 8.7 (6.7)* History of major macrovascular disease 3590 (32) 2772 (31) 818 (35)* History of major microvascular disease 1152 (10) 775 (9) 377 (16)* Current smoking 1682 (15) 1325 (15) 357 (15) Current alcohol drinking 3396 (30) 2730 (31) 666 (29)* BP at registration SBP, mm Hg 145 (22) 145 (21) 146 (22)* DBP, mm Hg 81 (11) 81 (11) 80 (11)* SBP parameters during the measurement period Mean SBP, mm Hg 138 (16) 137 (15) 140 (17)* SD SBP, mm Hg 11 (5) 11 (5) 12 (6)* CV SBP, % 8.0 (3.6) 7.9 (3.4) 8.3 (4.2)* Maximum SBP, mm Hg 153 (19) 152 (19) 154 (21)* Risk factors at the 24-mo visit Heart rate, bpm 74 (12) 73 (12) 74 (12)* Hemoglobin A1c, % 7.0 (1.3) 7.0 (1.2) 7.3 (1.4)* Total cholesterol, mmol/l 4.9 (1.1) 4.9 (1.1) 5.0 (1.2)* Triglycerides, mmol/l 1.6 ( ) 1.6 ( ) 1.6 ( ) Body mass index, kg/m (5.2) 28.3 (5.2) 27.9 (5.3)* Randomized treatments Active BP-lowering treatment with 5569 (50) 4418 (50) 1151 (49) perindopril-indapamide Intensive blood glucose control 5571 (50) 4479 (51) 1092 (47)* Additional BP-lowering treatments at the 24-mo visit β-blockers 3336 (30) 2619 (30) 717 (31) Calcium-channel blockers 3797 (34) 2993 (34) 804 (35) Diuretics 1793 (16) 1263 (14) 530 (23)* Angiotensin-converting enzyme inhibitors 5640 (51) 4553 (52) 1087 (47)* Angiotensin II receptor blockers 804 (7) 610 (7) 194 (8)* Other antihypertensive agents 1161 (10) 910 (10) 251 (11) Any BP-lowering agents 8543 (77) 6752 (77) 1791 (77) Blood glucose treatments at the 24-mo visit Oral hypoglycemic agents (gliclazide and others) (94) 8348 (95) 2105 (90)* Insulin 1944 (17) 1520 (17) 424 (18) Values are mean (SD) for continuous variables (except for triglycerides), median (interquartile range) for triglycerides, and number (%) for categorical variables. BP indicates blood pressure; CV, coefficient of variation; DBP, diastolic blood pressure; SBP, systolic blood pressure; and SD, standard deviation. *P<5 vs analyzed patients. History of myocardial infarction or stroke. Macroalbuminuria at baseline or a history of microvascular eye disease (proliferative retinopathy, macular edema, diabetes mellitus related blindness, or retinal photocoagulation therapy). Defined using SBP values at 3, 4, 6, 12, 18, and 24 months after randomization. When data at the 24-month visit were missing, the latest data before the 24-month visit were applied. Randomized BP-lowering treatment with perindopril-indapamide was not included.

5 Hata et al Blood Pressure Variability in Type 2 Diabetes Mellitus 1329 SD SBP Hazard ratio (95% CI) Combined macro- and microvascular events P for trend < Tenths of SD SBP Major macrovascular events (407 events) P for trend = Tenths of SD SBP Major microvascular events (476 events) P for trend = Tenths of SD SBP All-cause mortality (846 events) (374 events) P for trend < Tenths of SD SBP Downloaded from by guest on December 22, 2016 Max SBP Hazard ratio (95% CI) P for trend = P for trend = P for trend = Tenths of maximum SBP Tenths of maximum SBP Tenths of maximum SBP positively associated with the risks of major macrovascular and microvascular events (P<01 for all). These associations remained significant even after adjustments for other confounding factors and mean SBP (models 2 and 3), with the exception of maximum SBP, which failed to reach statistical significance for the outcome microvascular events in model 3. SD and maximum SBP were positively associated with all-cause mortality (both P<01 in all models), whereas mean SBP did not show a clear association with all-cause mortality. When major macrovascular events were divided into their components, greater SD and maximum SBP were significantly associated with elevated risks of myocardial infarction and cardiovascular death in all models. However, no significant associations were observed for stroke in model 3. With regard to the components of major microvascular events, the associations of SD and maximum SBP with nephropathy and retinopathy did not reach a level of significance in model 3. These associations were essentially unchanged when we determined visit-to-visit SBP variability using CV instead of SD. Discussion The present large-scale observational analysis of 8811 patients with type 2 diabetes mellitus from the ADVANCE trial has demonstrated that the levels of visit-to-visit SBP variability P for trend = Tenths of maximum SBP Figure 2. Hazard ratios and 95% confidence intervals (CIs) for major macrovascular and microvascular events and death according to tenths of standard deviation (SD) or maximum (Max) of systolic blood pressure (SBP). SBP values measured at 6 occasions (from 3 24 months after randomization) were used to determine SD and maximum SBP. Each parameter was categorized into 10 groups according to the tenths within each BP-lowering treatment group. The ranges of SD SBP were 0.6 to 5.2, 5.3 to 6.8, 6.9 to 8.1, 8.2 to 9.3, 9.4 to 10.5, 10.6 to 11.7, 11.8 to 13.2, 13.3 to 15.2, 15.3 to 18.0, and 18.1 to 47.3 mm Hg in the placebo group; 0.4 to 5.0, 5.1 to 6.6, 6.7 to 7.7, 7.8 to 8.8, 8.9 to 9.9, 1 to 1, 11.1 to 12.5, 12.6 to 14.2, 14.3 to 16.7, and 16.8 to 33.5 mm Hg in the active group. The ranges of maximum SBP were 97.5 to 133.5, to 14, to 144.5, to 149.5, 15 to 153.5, to 158.5, to 164.0, to 17, to 18, and to 26 mm Hg in the placebo group; 9 to 127.0, to 133.5, to 138.0, to 14, to 146.5, to 150.5, 15 to 156.0, to 162.5, 16 to 172.5, and 17 to mm Hg in the active group. Hazard ratios were adjusted for age, sex, randomized blood pressure lowering intervention, randomized glucose control intervention, region of residence, duration of diabetes mellitus, current smoking, current alcohol drinking, heart rate, total cholesterol, log of triglycerides, body mass index, use of β-blockers, use of calcium-channel blockers, and mean SBP during the measurement period. defined by using SD and CV are positively associated with the risks of major macrovascular events, microvascular events, and death. These associations persisted after the adjustment for mean SBP, other cardiovascular risk factors, and randomized treatments. Similar associations were also observed for maximum SBP. Previous studies using the data from ambulatory BP monitoring reported that short-term or circadian variability of BP was an important prognostic factor of cardiovascular outcomes Similarly, a number of observational studies have investigated the impact of long-term or visit-to-visit BP variability on the risks of cardiovascular outcomes. 5,18 21 Rothwell and colleagues 5 recently reported that visit-to-visit SBP variability was a strong predictor of cardiovascular disease among patients with transient ischemic attack or stroke and among hypertensive patients in the ASCOT-BPLA trial. The Ohasama Study also reported that day-by-day SBP variability was associated with cardiovascular and all-cause death in a general population from Japan. 18 However, there has been little investigation of the effects of BP variability on cardiovascular events among patients with type 2 diabetes mellitus. 19 The analyses reported here expand the findings of previous studies and suggest that the association of visit-to-visit SBP variability with cardiovascular events is also observed in patients with type 2 diabetes mellitus.

6 1330 Circulation September 17, 2013 Myocardial infarction Stroke Cardiovascular death Downloaded from by guest on December 22, 2016 SD SBP Hazard ratio (95% CI) Max SBP 14 Hazard ratio (95% CI) (125 events) P for trend = Tenths of SD SBP Tenths of maximum SBP (176 events) P for trend = Tenths of SD SBP Tenths of maximum SBP In the present analysis of the ADVANCE trial, visitto-visit SBP variability was clearly associated with myocardial infarction and cardiovascular death, but not with stroke. In contrast, Rothwell and colleagues 5 reported that visit-to-visit SBP variability was predictive of both stroke SD SBP Hazard ratio (95% CI) Max SBP Hazard ratio (95% CI) (170 events) P for trend = Tenths of SD SBP P for trend = 4 P for trend = 0.26 P for trend = New or worsening nephropathy (230 events) P for trend = Tenths of SD SBP P for trend = Tenths of maximum SBP New or worsening retinopathy (266 events) P for trend = Tenths of SD SBP P for trend = Tenths of maximum SBP Figure 4. Hazard ratios and 95% confidence intervals (CIs) for components of microvascular outcomes according to tenths of standard deviation (SD) or maximum (Max) of systolic blood pressure (SBP). The definition and categorization of each SBP parameter and the covariates in the multivariable model were the same as in Figure Tenths of maximum SBP Figure 3. Hazard ratios and 95% confidence intervals (CIs) for components of macrovascular outcomes according to tenths of standard deviation (SD) or maximum (Max) of systolic blood pressure (SBP). The definition and categorization of each SBP parameter and the covariates in the multivariable model were the same as in Figure 2. and coronary heart disease in patients with previous transient ischemic attack or stroke and in ASCOT-BPLA. The Ohasama Study showed that day-by-day SBP variability was associated with stroke mortality but not with cardiac mortality in a general Japanese population. 18 In a hospitalbased case-control study of Japanese patients, the variability of office SBP was higher in patients with stroke than in controls, 20 but not in patients with myocardial infarction. 21 The reasons for the differences among ADVANCE and previous studies are not clear but may be associated with underlying differences in the study populations, in the definitions of BP variability, in the length of follow-up, and in the covariates included in the multivariable analyses, or the differences may be due to chance associations. The impact of BP variability on stroke may be stronger in Asian populations or nondiabetic populations than in non-asian or diabetic populations. In addition, the Ohasama Study 18 was based on home BP in which white coat effect was absent, but other studies, including ADVANCE, used BP measured mainly at the clinic or hospital. Another new and important finding of the present analysis was that visit-to-visit variability of SBP clearly predicted the future development of major microvascular complications among patients with type 2 diabetes mellitus. Although there has been limited evidence of the association of BP variability with the microvascular complications of diabetes mellitus, a cross-sectional study of 422 Japanese patients with type 2 diabetes mellitus has shown a close association between SBP variability and the prevalence of albuminuria. 22 The Diabetes Control and Complications Trial also reported that SD in SBP and diastolic blood pressure were predictive of future development of nephropathy among patients with type 1 diabetes mellitus. 23 These findings support the hypothesis that BP variability is an important predictor of microvascular complications among patients with type 2 diabetes mellitus.

7 Hata et al Blood Pressure Variability in Type 2 Diabetes Mellitus 1331 Table 2. Effects of 1-SD Increments in Mean, SD, CV, and Maximum SBP on Primary and Secondary Outcomes Downloaded from by guest on December 22, 2016 No. of events Model 1* Model 2 Model 3 HR (95% CI) P HR (95% CI) P HR (95% CI) P Combined 846 macro- and microvascular events Mean SBP 1.28 ( ) < ( ) < ( ) <01 SD SBP 1.22 ( ) < ( ) < (6 1.22) <01 CV SBP 1.16 (9 1.24) < (7 1.22) < (6 1.21) <01 Maximum SBP 1.30 ( ) < ( ) < (9 1.48) 02 Major 407 macrovascular events Mean SBP 1.24 ( ) < (9 1.33) < (9 1.33) <01 SD SBP 1.25 ( ) < ( ) < (7 1.30) <01 CV SBP 1.20 ( ) < (8 1.30) < (7 1.29) <01 Maximum SBP 1.28 ( ) < ( ) < ( ) 05 Major 476 microvascular events Mean SBP 1.33 ( ) < ( ) < ( ) <01 SD SBP 1.20 ( ) < (8 1.28) < (1 1.21) 3 CV SBP 1.13 (4 1.23) (2 1.21) (1 1.20) 3 Maximum SBP 1.33 ( ) < ( ) < ( ) 6 All-cause 374 mortality Mean SBP 9 ( ) 9 6 ( ) ( ) 0.26 SD SBP 1.31 ( ) < ( ) < ( ) <01 CV SBP 1.30 ( ) < ( ) < ( ) <01 Maximum SBP 1.18 (7 1.30) (4 1.28) ( ) <01 Myocardial 125 infarction Mean SBP 1.30 ( ) (5 1.50) (5 1.50) 1 SD SBP 1.39 ( ) < ( ) < ( ) 01 CV SBP 1.32 ( ) < ( ) ( ) 02 Maximum SBP 1.38 ( ) < ( ) < (7 2.26) 2 Stroke 176 Mean SBP 1.35 ( ) < ( ) < ( ) <01 SD SBP 1.18 (3 1.36) (1 1.35) 3 8 ( ) 0.30 CV SBP 1.10 ( ) ( ) ( ) 0.30 Maximum SBP 1.36 ( ) < ( ) < ( ) 0.15 Cardiovascular 170 death Mean SBP 1.15 ( ) ( ) ( ) 0.25 SD SBP 1.35 ( ) < ( ) < ( ) <01 CV SBP 1.33 ( ) < ( ) < ( ) <01 Maximum SBP 1.24 (7 1.43) (2 1.38) ( ) 09 (Continued)

8 1332 Circulation September 17, 2013 Table 2. Continued. No. of events Model 1* Model 2 Model 3 HR (95% CI) P HR (95% CI) P HR (95% CI) P Downloaded from by guest on December 22, 2016 New or 230 worsening nephropathy Mean SBP 1.49 ( ) < ( ) < ( ) <01 SD SBP 1.27 ( ) < (6 1.35) ( ) 0.12 CV SBP 1.16 (2 1.31) ( ) ( ) 0.15 Maximum SBP 1.48 ( ) < ( ) < ( ) 0.31 New or 266 worsening retinopathy Mean SBP 1.24 ( ) < ( ) < ( ) <01 SD SBP 1.18 (6 1.32) (5 1.33) ( ) 6 CV SBP 1.14 (1 1.28) (0 1.27) (0 1.26) 6 Maximum SBP 1.26 ( ) < ( ) < ( ) 7 HR (95% CI) per increase of 1 SD for each parameter was shown. SD values in the placebo group were 14.6 mm Hg for mean SBP, 5.3 mm Hg for SD SBP, 3.5% for CV SBP, and 18.9 mm Hg for maximum SBP. SD values in the active group were 14.8 mm Hg for mean SBP, 4.8 mm Hg for SD SBP, 3.4% for CV SBP, and 18.1 mm Hg for maximum SBP. CI indicates confidence interval; CV, coefficient of variation; HR, hazard ratio; SBP, systolic blood pressure; and SD, standard deviation. *Model 1 was adjusted for age, sex, randomized blood pressure lowering intervention, and randomized glucose control intervention. Model 2 was adjusted for age, sex, randomized blood pressure lowering intervention, randomized glucose control intervention, region of residence, duration of diabetes mellitus, current smoking, current alcohol drinking, heart rate, total cholesterol, log of triglycerides, body mass index, use of β-blockers, and use of calciumchannel blockers. Model 3 was adjusted for all variables in model 2 and mean SBP. The impact of SBP variability on combined major macrovascular and microvascular events seemed to be weaker than that of mean SBP (Table 2). However, it does not mean that SBP variability is less important. Because the effects of SBP variability were independent of mean SBP, higher variability may be an important factor for the prediction of future vascular events and a potential therapeutic target, even in patients without hypertension. In addition, Rothwell and colleagues 5 observed positive associations of maximum SBP with risks of cardiovascular events. In the present study, we confirmed similar findings in patients with type 2 diabetes mellitus. The impacts of maximum SBP were strong and independent of a wide set of potential confounding variables. They also appeared to be independent of mean SBP, although the strong correlation between mean and maximum SBP (r=0.91, Table III in the online-only Data Supplement), and the relatively wide CIs for the HRs comparing the extreme tenths of maximum SBP in Figures 2 to 4, suggests that caution should be applied to our estimates and 95% CIs of effects of maximum SBP adjusted for mean SBP. There are several possible mechanisms to explain the link between visit-to-visit BP variability or maximum SBP and macrovascular and microvascular events. First, BP variability may be a marker of arterial stiffness and thus associated with vascular outcomes. The elevation in variability of BP has been associated with reduced compliance of large elastic arteries, 7 which is an intermediate stage of vascular disease and a strong predictor of the future vascular events. 9 Second, instability of BP may reflect abnormal autonomic function. 8 Increased sympathetic activity may directly promote the development of arterial and organ damage 8 and increase the risk of vascular events. 10 However, in the present study, the effects of variability and maximum of SBP remained significant even after the adjustment for heart rate, a marker of autonomic function. Third, animal studies have suggested that elevated BP variability causes direct endothelial damage, renin-angiotensin system activation, inflammation and cardiomyocyte apoptosis augmentation, and thus cardiovascular remodeling and end-organ damage. 24 It is reasonably considered that maximum SBP is also a marker of arterial stiffness or abnormal autonomic function, or a direct cause of vascular dysfunction. Fourth, poor adherence with BP-lowering medications and inadequate BP control might have played a role in the link between increased BP variability or maximum SBP and poor clinical outcomes, although risk estimates were essentially unchanged even in the sensitivity analysis that excluded patients who discontinued BP-lowering intervention during the measurement period (Figure II in the online-only Data Supplement). In the previous analysis of the ASCOT-BPLA trial, risk associations were actually strengthened after the exclusion of poorly compliant patients. 5 Fifth, changes in BP-lowering treatment regimen during the measurement period might affect the association between variability and outcomes. In the ADVANCE protocol, the dose of active perindopril/indapamide was doubled at the 3-month visit, and the use of other BP-lowering drugs was at the discretion of the physician. However, the sensitivity analysis that excluded BP measurements at 3- and 4-month visits (Figure IV in the online-only Data Supplement) was similar to the original analyses, and the impacts of variability were comparable between the subgroups of patients with and

9 Hata et al Blood Pressure Variability in Type 2 Diabetes Mellitus 1333 Downloaded from by guest on December 22, 2016 without changes in BP-lowering treatment (Figure X in the online-only Data Supplement). The patients with higher SBP variability were more likely to end up on multiple drugs than patients with less variability (Figure I in the online-only Data Supplement). Therefore, we consider that SBP variability predicted an increased risk of vascular events independent of the changes in treatment, even though the patients with higher variability were treated more intensively than average. The method to calculate visit-to-visit variability may be debatable. SBP was measured twice at each occasion, and the mean value was used in the present study. In the ASCOT- BPLA trial, 5 analyses based on the mean of 3 measurements and the mean of 2 (the second and the third) measurements revealed no material difference. Accordingly, we believe that our data based on 2 measurements is satisfactory. Next, the calculation of SBP variability was based on 6 visits and their intervals were not equal (ie, 3, 4, 6, 12, 18, and 24 months).the sensitivity analyses using BP values from equally spaced visits (ie, 6, 12, 18, and 24 months; Figure IV in the online-only Data Supplement) or different number of visits (Figures V and VI in the online-only Data Supplement) made no difference. There are substantial gaps in our understanding of the best ways to apply this knowledge to the practical management of BP in patients with type 2 diabetes mellitus, and more work is needed to determine the best and simplest way to evaluate visit-to-visit BP variability in routine clinical practice. In addition, it remains uncertain how best to treat patients with type 2 diabetes mellitus who have high BP variability or maximum SBP. Recent analyses of individual patient data from 2 trials 25 and a systematic review 26 suggested that calcium-channel blockers and nonloop diuretic drugs were particularly effective for reducing BP variability, but no studies have reported on optimal therapeutic ranges of BP variability. Although this is the first and the largest prospective study to have demonstrated the clear effects of visit-to-visit SBP variability and maximum SBP on macrovascular and microvascular complications in type 2 diabetes mellitus, the study still had relatively limited power to show corresponding definitive evidence about the effects of SBP variability on each component of the microvascular outcome (nephropathy and retinopathy). However, the HRs of SD and CV of SBP for nephropathy and for retinopathy were similar to those for composite microvascular events (Table 2). The adjustment for covariates in multivariable analysis might be substantively incomplete, and the degree of independence of SBP variability or maximum SBP might be overestimated as a consequence. Moreover, the present evaluation was performed in the context of a clinical trial and may not be generalizable to an unselected population with type 2 diabetes mellitus. Nevertheless, the exclusion of subjects with macrovascular or microvascular disease before the registration or within the first 24 months from the present analyses makes the findings more representative of a general population with type 2 diabetes mellitus (Table III in the online-only Data Supplement). In conclusion, visit-to-visit variability in SBP and maximum SBP were predictive of macrovascular complications and of mortality in a population with type 2 diabetes mellitus from 20 countries worldwide. In addition we report that this variability is predictive of microvascular events. The prognostic values of BP variability and maximum SBP were independent of mean BP and of the other major cardiovascular risk factors. Sources of Funding The ADVANCE trial was funded by grants from the National Health and Medical Research Council of Australia and Institut de Recherches Internationales Servier. Disclosures Dr Hata holds an International Society of Hypertension Visiting Postdoctoral Award from the Foundation for High Blood Pressure Research of Australia and the Banyu Fellowship Program from the Banyu Life Science Foundation International. Dr Arima holds an Australian Research Council Future Fellowship. Dr Rothwell is funded by a National Institutes of Health Research (NIHR, the United Kingdom) Senior Investigator Award, a Wellcome Trust Senior Investigator Award, and the NIHR Biomedical Research Center, Oxford. Dr Woodward holds a Senior Research Fellowship from the National Health and Medical Research Council of Australia and has recently received consulting fees from Roche and lecturing fees from Servier. Dr Zoungas holds a National Health and Medical Research Council of Australia Health Professional Research Fellowship and reports being a member of an advisory board for Merck and receiving lecture fees from Servier, GlaxoSmithKline, and Sanofi-Aventis and grant support from Novo Nordisk and Pfizer. Dr Anderson holds a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia and has received consulting and lecture fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Sanofi-Aventis and Servier. Dr Patel holds a National Heart Foundation of Australia Career Development award and reports receiving lecture fees from Servier, Pfizer, and Abbott and grant support from Servier, Pfizer, and Sanofi-Aventis. Dr Neal holds an Australian Research Council Future Fellowship. Dr Williams is an NIHR Senior Investigator and his research is supported by the NIHR University College London Hospitals Biomedical Research Centre and has received lecture fees from Novartis, Boehringer Ingelheim, and Servier. Dr MacMahon reports being a member of advisory boards for Servier, Pfizer, and Novartis and receiving lecture fees from Servier and Pfizer and grant support from Servier, Pfizer, and Novartis. Dr Chalmers reports receiving research grants and lecture fees from Servier. References 1. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42: Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:

10 1334 Circulation September 17, 2013 Downloaded from by guest on December 22, Diabetes Australia Guideline Development Consortium. National Evidence Based Guidelines for the Management of Type 2 Diabetes Mellitus: Blood Pressure Control in Type 2 Diabetes. National Health and Medical Research Council (Australia). Accessed on August 3, Rothwell PM, Howard SC, Dolan E, O Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375: Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet. 2010;375: Imai Y, Aihara A, Ohkubo T, Nagai K, Tsuji I, Minami N, Satoh H, Hisamichi S. Factors that affect blood pressure variability. A communitybased study in Ohasama, Japan. Am J Hypertens. 1997;10: Palatini P, Julius S. The role of cardiac autonomic function in hypertension and cardiovascular disease. Curr Hypertens Rep. 2009;11: Stehouwer CD, Henry RM, Ferreira I. Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia. 2008;51: Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26: ADVANCE Management Committee. Study rationale and design of ADVANCE: Action in Diabetes and Vascular Disease-Preterax and Diamicron MR Controlled Evaluation. Diabetologia. 2001;44: ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370: ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358: Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension. 1994;24: Pringle E, Phillips C, Thijs L, Davidson C, Staessen JA, de Leeuw PW, Jaaskivi M, Nachev C, Parati G, O Brien ET, Tuomilehto J, Webster J, Bulpitt CJ, Fagard RH; Syst-Eur investigators. Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population. J Hypertens. 2003;21: Tamura K, Tsurumi Y, Sakai M, Tanaka Y, Okano Y, Yamauchi J, Ishigami T, Kihara M, Hirawa N, Toya Y, Yabana M, Tokita Y, Ohnishi T, Umemura S. A possible relationship of nocturnal blood pressure variability with coronary artery disease in diabetic nephropathy. Clin Exp Hypertens. 2007;29: Pierdomenico SD, Di Nicola M, Esposito AL, Di Mascio R, Ballone E, Lapenna D, Cuccurullo F. Prognostic value of different indices of blood pressure variability in hypertensive patients. Am J Hypertens. 2009;22: Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, Inoue R, Hoshi H, Hashimoto J, Totsune K, Satoh H, Imai Y. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama Study. Hypertension. 2008;52: Hsieh YT, Tu ST, Cho TJ, Chang SJ, Chen JF, Hsieh MC. Visit-to-visit variability in blood pressure strongly predicts all-cause mortality in patients with type 2 diabetes: a 5 5-year prospective analysis. Eur J Clin Invest. 2012;42: Hata Y, Kimura Y, Muratani H, Fukiyama K, Kawano Y, Ashida T, Yokouchi M, Imai Y, Ozawa T, Fujii J, Omae T. Office blood pressure variability as a predictor of brain infarction in elderly hypertensive patients. Hypertens Res. 2000;23: Hata Y, Muratani H, Kimura Y, Fukiyama K, Kawano Y, Ashida T, Yokouchi M, Imai Y, Ozawa T, Fujii J, Omae T. Office blood pressure variability as a predictor of acute myocardial infarction in elderly patients receiving antihypertensive therapy. J Hum Hypertens. 2002;16: Okada H, Fukui M, Tanaka M, Inada S, Mineoka Y, Nakanishi N, Senmaru T, Sakabe K, Ushigome E, Asano M, Yamazaki M, Hasegawa G, Nakamura N. Visit-to-visit variability in systolic blood pressure is correlated with diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. Atherosclerosis. 2012;220: Kilpatrick ES, Rigby AS, Atkin SL. The role of blood pressure variability in the development of nephropathy in type 1 diabetes. Diabetes Care. 2010;33: Su DF. Treatment of hypertension based on measurement of blood pressure variability: lessons from animal studies. Curr Opin Cardiol. 2006;21: Rothwell PM, Howard SC, Dolan E, O Brien E, Dobson JE, Dahlöf B, Poulter NR, Sever PS; ASCOT-BPLA and MRC Trial Investigators. Effects of beta blockers and calcium-channel blockers on withinindividual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9: Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensivedrug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375: Clinical Perspective Elevated blood pressure (BP) is a modifiable risk factor for macrovascular diseases such as coronary heart disease and stroke, and microvascular complications of diabetes mellitus such as nephropathy and retinopathy. In the present analyses, we proved that visit-to-visit variability of systolic blood pressure (SBP), defined as the standard deviation or coefficient of variation during 24 months, was a significant risk factor for major macrovascular and microvascular complications of diabetes mellitus, and for all-cause mortality, as well, by using data from a large-scale randomized controlled trial of patients with type 2 diabetes mellitus, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE). These associations were independent of usual BP, defined as the mean SBP during the same period, and other cardiovascular risk factors and BP-lowering treatment. Similar associations were found for maximum SBP during the same period. Our findings suggest that the higher variability or maximum of SBP may be an important factor for the prediction of future vascular events and a potential therapeutic target, even in patients without hypertension. However, there are substantial gaps in our understanding of the best ways to apply this knowledge to the practical management of BP in patients with type 2 diabetes mellitus, and it remains uncertain how best to treat patients with type 2 diabetes mellitus who have high BP variability or maximum SBP. More work is needed to determine how to evaluate and treat the instability of BP in routine clinical practice.

11 Downloaded from by guest on December 22, 2016 Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus: The ADVANCE Trial Jun Hata, Hisatomi Arima, Peter M. Rothwell, Mark Woodward, Sophia Zoungas, Craig Anderson, Anushka Patel, Bruce Neal, Paul Glasziou, Pavel Hamet, Giuseppe Mancia, Neil Poulter, Bryan Williams, Stephen MacMahon and John Chalmers on behalf of the ADVANCE Collaborative Group Circulation. 2013;128: ; originally published online August 7, 2013; doi: /CIRCULATIONAHA Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation is online at:

12 SUPPLEMENTAL MATERIALS Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus The ADVANCE Trial Authors: Jun Hata, MD, PhD; Hisatomi Arima, MD, PhD; Peter M Rothwell, MD, PhD; Mark Woodward, PhD; Sophia Zoungas, MD, PhD; Craig Anderson, MD, PhD; Anushka Patel, MD, PhD; Bruce Neal, MD, PhD; Paul Glasziou, MD, PhD; Pavel Hamet, MD, PhD; Giuseppe Mancia, MD, PhD; Neil Poulter, MD, PhD; Bryan Williams, MD, PhD; Stephen MacMahon, PhD; John Chalmers MD, PhD on behalf of the ADVANCE Collaborative Group

13 Table I. Associations between patient characteristics and standard deviation (SD) of systolic blood pressure (SBP) (mmhg) Univariate analysis Multivariable analysis Characteristics at registration Beta SE P Beta SE P estimate estimate Age (per 10 years) < <01 Female < <01 Residence in Asian countries Currently treated hypertension < <01 Duration of diabetes (per 1 years) History of major macrovascular disease* History of major microvascular disease Current smoking < Current alcohol drinking SBP (per 1 mmhg) 5 02 < <01 Heart rate (per 10 bpm) Hemoglobin A1c (per 1%) Total cholesterol (per 1 mmol/l) Triglycerides (per 1 log mmol/l) Body mass index (per 1 kg/m 2 ) Active BP lowering treatment < <01 Intensive blood glucose control SE indicates standard error; BP, blood pressure. SD SBP was defined using SBP values at 3, 4, 6, 12, 18 and 24 months after randomization. * History of myocardial infarction or stroke. Macroalbuminuria at baseline or a history of microvascular eye disease (proliferative retinopathy, macular edema, diabetes-related blindness, or retinal photocoagulation therapy).

14 Table II. Associations between patient characteristics and maximum of systolic blood pressure (SBP) (mmhg) Univariate analysis Multivariable analysis Characteristics at registration Beta SE P Beta SE P estimate estimate Age (per 10 years) < <01 Female Residence in Asian countries < Currently treated hypertension < <01 Duration of diabetes (per 1 years) < History of major macrovascular disease* History of major microvascular disease < Current smoking < Current alcohol drinking SBP (per 1 mmhg) < <01 Heart rate (per 10 bpm) Hemoglobin A1c (per 1%) <01 Total cholesterol (per 1 mmol/l) < Triglycerides (per 1 log mmol/l) < Body mass index (per 1 kg/m 2 ) < Active BP lowering treatment < <01 Intensive blood glucose control < <01 SE indicates standard error; BP, blood pressure. Maximum SBP was defined using SBP values at 3, 4, 6, 12, 18 and 24 months after randomization. * History of myocardial infarction or stroke. Macroalbuminuria at baseline or a history of microvascular eye disease (proliferative retinopathy, macular edema, diabetes-related blindness, or retinal photocoagulation therapy).

15 Table III. Pearson s correlation coefficients for mean, SD, CV, and maximum SBP Mean SBP SD SBP CV SBP SD SBP 0.32 CV SBP Maximum SBP SBP indicates systolic blood pressure; SD, standard deviation; CV, coefficient of variation.

16 Figure I. Proportion of patients on 2 or more blood pressure (BP) lowering drugs at 24-month visit by tenths of standard deviation (SD) and maximum systolic blood pressure (SBP) Randomized BP lowering treatment (perindopril/indapamide or placebo) was not included in the number of drugs. P for trend <01 for both the placebo and active groups, for both SD and maximum SBP.

17 Figure II. Sensitivity analysis (1) The measurement period for SD and maximum SBP (6 occasions from 3 to 24 months after randomization), and the follow-up period (median 2.4 years) were the same as in the original analysis in Figure 2, but 581 patients who discontinued perindopril-indapamide/placebo before the 24-month visit were excluded and the remaining 8230 patients were analyzed in this sensitivity analysis. Definitions of tenths were the same as those in in Figure 2. Hazard ratios were adjusted for the same covariates as in Figure 2.

18 Figure III. Sensitivity analysis (2) The measurement period for SD and maximum SBP (6 occasions from 3 to 24 months after randomization), and the follow-up period (median 2.4 years) were the same as in the original analysis in Figure 2, but 3292 patients with a history of macrovascular or microvascular disease at registration were excluded and the remaining 5519 patients were analyzed in this sensitivity analysis. Definitions of tenths were the same as those in in Figure 2. Hazard ratios were adjusted for the same covariates as in Figure 2.

19 Figure IV. Sensitivity analysis (3) Systolic blood pressure (SBP) values measured at 4 occasions (6, 12, 18 and 24 months after randomization) were used to determine standard deviation (SD) and maximum SBP. For this sensitivity analysis, 9128 patients who had not experienced major macrovascular or microvascular events or death within 24 months and had BP measurements at all of the 4 occasions were included. Median follow-up was 2.4 years from the 24-month visit after randomization. Each parameter was categorized into 10 groups according to the tenths within each BP lowering treatment group. The ranges of SD SBP were 0-4.0, , , , , , , , and mmhg in the placebo group; 0-3.9, , , , , , , , and mmhg in the active group. The ranges of maximum SBP were , , , , , , , , and mmhg in the placebo group; , , , , , , , , and mmhg in the active group. Hazard ratios were adjusted for the same covariates as in Figure 2.

20 Figure V. Sensitivity analysis (4) Systolic blood pressure (SBP) values measured at 5 occasions (3, 4, 6, 12 and 18 months after randomization) was used to determine standard deviation (SD) and maximum SBP. For this sensitivity analysis, 9276 patients who had not experienced major macrovascular or microvascular events or death within 18 months and had BP measurements at all of the 5 occasions were included. Median follow-up was years from the 18-month visit after randomization. Each parameter was categorized into 10 groups according to the tenths within each BP lowering treatment group. The ranges of SD SBP were , , , , , , , , and mmhg in the placebo group; , , , , , , , , and mmhg in the active group. The ranges of maximum SBP were , , , , , , , , and mmhg in the placebo group; , , , , , , , , and mmhg in the active group. Hazard ratios were adjusted for the same covariates as in Figure 2.

21 Figure VI. Sensitivity analysis (5) Systolic blood pressure (SBP) values measured at 7 occasions (3, 4, 6, 12, 18, 24 and 30 months after randomization) were used to determine standard deviation (SD) and maximum SBP. For this sensitivity analysis, 8364 patients who had not experienced major macrovascular or microvascular events or death within 30 months and had BP measurements at all of the 7 occasions were included. Median follow-up was years from the 30-month visit after randomization. Each parameter was categorized into 10 groups according to the tenths within each BP lowering treatment group. The ranges of SD SBP were , , , , , , , , , mmhg in the placebo group; , , , , , , , , and mmhg in the active group. The ranges of maximum SBP were , , , , , , , , and mmhg in the placebo group; , , , , , , , , and mmhg in the active group. Hazard ratios were adjusted for the same covariates as in Figure 2.

22 Figure VII. Sensitivity analysis (6) Systolic blood pressure (SBP) values measured at 6 occasions (3, 4, 6, 12, 18 and 24 months after randomization) were used to determine standard deviation (SD) and maximum SBP. For this sensitivity analysis, 9966 patients who had not experienced major macrovascular or microvascular events or death within 24 months and had BP measurements at 2 of 6 occasions were included. Median follow-up was 2.4 years from the 24-month visit after randomization. Each parameter was categorized into 10 groups according to the tenths within each BP lowering treatment group. The ranges of SD SBP were 0-5.1, , , , , , , , and mmhg in the placebo group; 0-4.8, , , , , , , , and mmhg in the active group. The ranges of maximum SBP were , , , , , , , , and mmhg in the placebo group; , , , , , , , , and mmhg in the active group. Hazard ratios were adjusted for the same covariates as in Figure 2.

23 Figure VIII. Sensitivity analysis (7) The measurement period for SD and maximum SBP (6 occasions from 3 to 24 months after randomization), and the follow-up period (median 2.4 years) were the same as in the original analysis in Figure 2 (n=8811). Each parameter was categorized into 10 groups according to the tenths within all patients, pooling those on active treatment and placebo. The ranges of SD SBP were , , , , , , , , and mmhg. The ranges of maximum SBP were , , , , , , , , and mmhg. Hazard ratios were adjusted for the same covariates as in Figure 2.

24 Figure IX. Sensitivity analysis (8) The measurement period for SD and maximum SBP (6 occasions from 3 to 24 months after randomization), and the follow-up period (median 2.4 years) were the same as in the original analysis in Figure 2 (n=8811). Each parameter was categorized into 5 groups according to the fifths within each BP lowering treatment group. The ranges of SD SBP were , , , and mmhg in the placebo group; , , 8.9-1, and mmhg in the active group. The ranges of maximum SBP were , , , and mmhg in the placebo group; , , , and mmhg in the active group. Hazard ratios were adjusted for the same covariates as in Figure 2.

25 Figure X. Hazard ratios and 95% confidence intervals (CIs) for combined macrovascular and microvascular events according to tenths of standard deviation (SD) and maximum of systolic blood pressure (SBP) in the subgroups of patients with or without changes in blood pressure (BP) lowering medication The measurement period for SD and maximum SBP (6 occasions from 3 to 24 months after randomization), definitions of tenths, and the follow-up period (median 2.4 years) were the same as in the original analysis in Figure 2. Among the eligible 8811 patients, BP lowering treatment regimen were changed for 4448 patients (i.e. discontinuation of randomized BP lowering treatment, or any changes in additional open-label BP lowering drugs) and not changed for 4363 patients, during the first 24-month period. Hazard ratios were adjusted for the same covariates as in Figure 2.