Global Sodium Consumption and Death from Cardiovascular Causes

INTRODUCTION

- A high dietary intake of Sodium is associated with elevated blood pressure, a major risk factor for cardiovascular disease.

- The United Nations (UN), World Health Organization (WHO), Centers for Disease Control and Prevention (CDC) and other organizations have emphasized the relationship between dietary sodium and cardiovascular outcomes.

- As part of the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group

(NUTRICODE), we

i) Systematically identified and analyzed data on sodium consumption worldwide and calculated the dose-response effects of sodium on blood pressure in a new meta-analysis of trials.

ii) Compiled data to calculate the effects of blood pressure on cause-specific cardiovascular mortality and to characterize current blood-pressure levels and numbers of cause-specific deaths according to country, age, and sex

iii) Used data relating levels of sodium intake to blood pressure and cardiovascular events, as well as data on the lowest current levels of sodium intake according to country, to define a reference range for sodium consumption

iv) Used data (Table S1 in the Supplementary Appendix) to estimate the impact of current levels of sodium intake on cardiovascular mortality throughout the world

METHODS

Assessment of Global Sodium Consumption

- Search Period: March 2008 to December 2011

- Systematic searches were conducted for previously conducted national or subnational surveys on individual-level sodium consumption based on urinary excretion, estimated dietary intake, or both

- Data Included: 142 surveys with data from 24-hour urine collections and 91 with estimates of dietary intake, including 28 with both types of data (Table S2 in the Supplementary Appendix).

- These surveys included data from 66 countries, accounting for 74.1% of adults in the world.

- Using a hierarchical Bayesian model, we estimated the mean level of sodium consumption and statistical uncertainty according to age, sex, and calendar year in 187 nations.

- An article with detailed results of these analyses has been published previously (Powles et al. BMJ Open 2013; 3(12): e003733)

- Our model estimated sodium consumption with the use of 24-hour urine collections as the reference standard.

- To make our data comparable to data from prior regional surveys and blood pressure trials in which urinary sodium levels were measured, we did not adjust our analyses for sodium loss due to factors other than urinary excretion (e.g., sweat).

Effects of Reduced Sodium Intake on Blood Pressure

- Two recent Cochrane meta-analyses evaluated randomized trials of the effect of reduce sodium intake on blood pressure. (He et al. Cochrane Database Syst Rev

2013; 4: CD004937; Graudal et al. Cochrane Database Syst Rev 2011;11: CD004022)

- These meta-analyses did not determine whether blood-pressure lowering was linear across a range of sodium intakes and did not simultaneously quantify heterogeneity according to age, race, and the presence or absence of hypertension

- We performed a new meta-analysis evaluating all randomized interventions identified in these articles (Section S1 in Supplementary Appendix).

- Using data from these trials, we evaluated whether the effects of reduced sodium intake on blood pressure were linear.

- We evaluated the potential heterogeneity in this effect by taking into account population characteristics, including age, the presence or absence of hypertension, and race, as well as the duration of the intervention.

- We also assessed whether, apart from the presence or absence of hypertension, the effects of reduced sodium intake on blood-pressure lowering were blunted by the use of antihypertensive medication.

Effects of Blood-Pressure Levels on Cardiovascular Mortality

- To calculate the effects of systolic blood pressure on deaths from cardiovascular causes, we combined results from two large international projects (totaling 99 cohorts, 1.38 million participants, and 65,000 cardiovascular events) that pooled individual-level data, consistently adjusted for confounding.

- We accounted for regression dilution bias based on serial blood-pressure measures over time.

- We interpolated and extrapolated age-specific proportional effects (relative risks) of systolic blood pressure on cardiovascular mortality in 10-year age groups across the pooling projects (see Section S2 and Fig. S3 in the Supplementary Appendix).

- We used the same estimates of relative risk according to sex and race, on the basis of evidence of generally similar proportional effects of blood pressure on cardiovascular events according to sex and race in trials of antihypertensive drugs and observational studies of blood pressure and cardiovascular events.

Reference Levels of Sodium Consumption

- To define reference levels of sodium consumption, we conducted a search of published survey data, cohort studies, controlled trials, and dietary recommendations.

- We determined levels of sodium consumption that were associated with the lowest blood-pressure levels in ecologic studies and in randomized trials and with the lowest risk of disease in meta-analyses of prospective cohort studies

- We also considered at least theoretical feasibility based on the lowest national mean levels of consumption globally.

- Finally, we considered the consistency of our identified reference intake levels with major dietary guidelines.

- Details are provided in Section S4 in the Supplementary Appendix

Current Blood-Pressure Levels and Cause-Specific Mortality

- Data on current blood-pressure levels and cardiovascular mortality, each according to country, age, and sex, were compiled as part of the Global Burden of Disease Study 2010

- Data on blood pressure (from 786 country-years and 5.4 million participants) were obtained from published and unpublished health examination surveys and epidemiologic studies from around the world.

- Data on causes of death were obtained for 187 countries from 1980 through 2010; these data were obtained from vital-registration systems, verbal autopsies, mortality surveillance, census data, surveys, hospitals, police records, and mortuaries.

- Details of data collection and the statistical modeling used to estimate mean systolic blood pressure and causespecific mortality are provided in Table S1 and Sections S5 and S6 in the Supplementary Appendix

Cardiovascular Mortality Associated with Sodium Consumption above the Reference Level

- We estimated disease burdens using comparative risk assessment, capturing geographic and demographic variations in sodium intake, blood pressure, cardiovascular mortality, and corresponding uncertainties (details are provided in Table S1 and Section S7 in the Supplementary Appendix).

- We incorporated age-specific and sex-specific sodium intake, blood-pressure level, relative risk, and mortality data for each country to model the fraction and numbers of deaths estimated to be attributable to sodium intake above the reference level.

- The population-attributable fraction was estimated in a two-step process.

- First, we used the effects of sodium consumption on blood pressure according to age, the presence or absence of hypertension, and race to calculate the change in mean systolic blood pressure that would be expected from reducing sodium consumption to reference levels as defined above.

- Second, we used the age-specific effects of blood pressure on cardiovascular mortality to calculate the resulting change in risk.

- Estimated numbers of deaths attributable to sodium intake above the reference level were calculated by multiplying the population-attributable fraction by the absolute number of deaths in each country, age, and sex stratum.

RESULTS

Global Sodium Consumption

- We estimated that in 2010, the mean level of consumption of sodium worldwide was 3.95 g per day, and regional means ranged from 2.18 to 5.51 g per day (Fig. S1 in the Supplementary Appendix).

- Overall, 181 of 187 countries — 99.2% of the adult population in the world — had estimated mean levels of sodium intake exceeding the World Health Organization recommendation of 2.0 g per day, and 119 countries — 88.3% of the adult population in the world — exceeded this recommended level by more than 1.0 g per day.

Effects of Reduced Sodium Intake on Blood Pressure

- In our primary analysis of reduced sodium intake and blood pressure, we found strong evidence of a linear dose–response relationship (P < 0.001 for linearity and P = 0.58 for nonlinearity) (Fig. 1A).

- When the data were evaluated with the use of inverse-variance weighted meta-regression, each reduction of 2.30 g of sodium per day was associated with a reduction of 3.82 mm Hg (95% confidence interval [CI], 3.08 to 4.55) in blood pressure (Fig. 1B).

- The effects of dietary sodium on blood pressure were modified according to population characteristics, with larger reductions in blood pressure among (Fig. S2 in the Supplementary Appendix):

i) older persons >  younger persons

ii) blacks > whites,

iii) hypertensive > normotensive persons.

- For a white, normotensive population at 50 years of age, each reduction of 2.30 g per day in sodium intake lowered systolic blood pressure by 3.74 mm Hg (95% CI, 2.29 to 5.18).

- We did not find evidence of substantial blunting of the blood-pressure–lowering effects of sodium restriction by antihypertensive drugs, although the data available to address this question were limited. Further details are provided in Section S1 in the Supplementary Appendix

Effects of Blood Pressure on Cardiovascular Mortality

- The pooled analyses of blood pressure and cardiovascular mortality showed a log-linear (proportional) dose–response relationship, with no evidence of a threshold as low as a systolic blood pressure of at least 115 mm Hg (see Section S2 and Fig. S3 in the Supplementary Appendix).

- The relative magnitude of the effect on blood pressure decreased with age, in a manner similar to that seen with other cardiovascular risk factors.

Reference Levels of Sodium Consumption

- Potential reference levels of sodium consumption according to various definitions are shown in Table S3 in the Supplementary Appendix

- The lowest mean intake associated with both lower systolic blood pressure and a lower positive relationship between higher age and blood pressure in ecologic studies was 614 mg of sodium per day.

- In large, well-controlled, randomized feeding trials, the lowest tested sodium intake for which reductions in blood-pressure levels were clearly documented was 1500 mg per day.

- In prospective observational studies, the lowest mean sodium intake associated with a lower risk of cardiovascular events ranged from 1787 to 2391 mg per day.

- We also considered observed mean levels of sodium intake that have been associated with the lowest risk of stomach cancer (1245 mg per day).

- Levels of sodium intake associated with the lowest risk ranged from 614 to 2391 mg per day, depending on the type of evidence and the outcome.

- According to national data on sodium consumption, the estimated lowest observed mean national intake level was approximately 1500 mg per day.

- The maximum level of sodium intake recommended in major dietary guidelines ranged from 1200 to 2400 mg per day

Estimated Cardiovascular Mortality Attributed to Sodium Consumption

- On the basis of the correlations between sodium intake and blood pressure and between blood pressure and cardiovascular mortality that are described above, and using a reference level of sodium intake of 2.0±0.2 g per day, we found that 1.65 million deaths from cardiovascular causes (95% uncertainty interval, 1.10 million to 2.22 million) worldwide in 2010 were attributable to sodium consumption above the reference level (Table 1, and Table S4 in the Supplementary Appendix).

Of these deaths,

- 687,000 (41.7%) were due to coronary heart disease,

- 685,000 (41.6%) were due to stroke, and

- 276,000 (16.7%) were due to other cardiovascular disease.

- Globally, 40.4% of these deaths occurred prematurely (i.e., in persons younger than 70 years of age) (see Section S8 and Fig. S4 in the Supplementary Appendix).

- Four of every 5 sodium-associated deaths from cardiovascular causes (84.3%) occurred in low-income and middle-income countries.

- In sum, approximately 1 of every 10 deaths from cardiovascular causes worldwide (9.5%) (95% uncertainty interval, 6.4 to 12.8) and nearly 1 of every 5 (17.8%) premature deaths from cardiovascular causes were attributed to sodium consumption above the reference level.

- Across nine regions of the world, the absolute rate of sodium-associated deaths from cardiovascular causes was highest in Central Asia and Eastern and Central Europe (Fig. 2A, and Fig. S5 and Table S4 in the Supplementary Appendix).

- Proportional cardiovascular mortality was high in all regions: among younger adults, it exceeded 10% in nearly all regions and it exceeded 20% in Central Asia and Eastern and Central Europe, East Asia, and Southeast Asia (Fig. 2B).

- Among older adults, who have a higher absolute risk and more competing risk factors, proportional sodium-associated cardiovascular mortality approached or exceeded 10% in Central Asia and Eastern and Central Europe, East Asia, and Southeast Asia.

- Most sodium-associated cardiovascular deaths were due to coronary heart disease, except in East Asia, Southeast Asia, and sub-Saharan Africa, where most deaths from cardiovascular causes were due to stroke, especially hemorrhagic and other nonischemic strokes (Table S4 and Fig. S5 in the Supplementary Appendix). 

- Across individual nations, substantial variation was evident.

- Sodium-associated cardiovascular mortality was highest in the country of Georgia (1967 deaths per 1 million adults per year; 95% uncertainty interval, 1321 to 2647) and lowest in Kenya (4 deaths per 1 million adults per year; 95% uncertainty interval, 3 to 6) (Fig. 3).

- Proportional cardiovascular mortality ranged from 27.4% in Mauritius (95% uncertainty interval, 18.8 to 35.9) to 0.3% in Kenya (95% uncertainty interval, 0.2 to 0.4) (Fig. 4).

-Among the 30 most populous nations (Fig. S6 in the Supplementary Appendix), the highest sodium-associated cardiovascular mortality was in Ukraine (1540 deaths per 1 million adults per year; 95% uncertainty interval, 1017 to 2099), and the highest proportional mortality was in China (15.3% of all cardiovascular deaths; 95% uncertainty interval, 10.5 to 20.2).

- Detailed information about individual nations is provided in Section S9 and Table S5 in the Supplementary Appendix.

- In sensitivity analyses, lowering the definition of the reference intake level from 2.0 to 1.0 g of sodium per day increased the number of deaths from cardiovascular causes in the world that were attributed to sodium consumption by approximately 40%, to 2.30 million (95% uncertainty interval, 1.55 million to 3.07 million) (Tables S6 and S7 and Fig. S7 and S8 in the Supplementary Appendix).

- When we estimated effects attributable only to sodium intake above 4.0±0.4 g per day, 512,901 worldwide deaths from cardiovascular causes (95% uncertainty interval, 333,710 to 704,773) were attributed to such consumption (Tables S8 and S9 in the Supplementary Appendix).

- This was the estimated number of deaths that were potentially preventable if only the nations with the highest level of sodium consumption lowered their intake to just the current mean intake in the world.

- If we altered our model so that the estimated benefits of blood-pressure lowering did not continue below 125 mm Hg, 1.55 million deaths from cardiovascular causes in the world (95% uncertainty interval, 1.10 million to 2.10 million) were attributed to sodium consumption above a level of 2.0 g per day.

DISCUSSION

Main Findings

- Globally, 1.65 million deaths from cardiovascular causes in 2010 — about 1 of 10 deaths from cardiovascular causes — were attributed to sodium consumption of more than 2.0 g per day.

- Notably, 4 of 5 of these deaths occurred in low and middle-income countries, and 2 of 5 of these deaths occurred prematurely (before the age of 70 years).

Regional Findings

- Our findings also show and quantify the heterogeneity in disease burden attributed to sodium according to region, age, and type of cardiovascular disease.

- Yet, we also found that no region and few countries were spared.

- Whereas estimated sodium-associated cardiovascular mortality was highest in Central Asia, it was high (more than 750 deaths per 1 million adults who were 70 years of age or older) in all regions.

- The estimated number of proportional sodium-associated deaths was also high, approaching or exceeding 15% of premature deaths from cardiovascular causes in most regions

Dose-response relationship between sodium intake and blood pressure

- Our meta-analysis of 107 randomized interventions in 103 trials showed a linear dose–response relationship between reduced sodium intake and blood pressure, jointly modified according to age, race, and the presence or absence of hypertension.

- These findings are consistent with the findings of a meta-analysis, published after submission of this article, that included fewer trials (34 trials).

- Larger effects in older adults and hypertensive persons would be consistent with decreasing vascular compliance and renal filtration; in blacks, larger effects would be consistent with differences in renal handling of sodium.

- We used randomized trials of reduced sodium intake and blood pressure to estimate the more conceptually appropriate effect of lifetime differences in intake, because direct evidence on lifetime effects, which may be larger, is available only from ecologic comparisons and experiments involving nonhuman primates

Possible controversy

- Some researchers have argued that it may not be possible to directly extrapolate the effects of sodium on blood pressure to cardiovascular risk.

- However, the effect on cardiovascular disease is supported by extensive experimental and ecologic evidence, data on cardiovascular events from some trials of reduced sodium intake, and evidence of the cardiovascular benefits of blood-pressure lowering across multiple interventions (see Section S3 in the Supplementary Appendix).

- A meta-analysis of prospective cohort studies showed that higher sodium consumption was associated with a higher rate of death from coronary heart disease (relative risk, 1.32; 95% CI, 1.13 to 1.53) and death from stroke (relative risk, 1.63; 95% CI, 1.27 to 2.10), the two main end points in our analysis.

- Although concerns have been raised that reduced sodium intake may cause physiological harm, a meta-analysis of 37 trials showed no significant adverse effects on blood lipid levels, catecholamine levels, or renal function

Results from observational studies

- There is mixed evidence from observational data on the relationship between very low sodium intake and cardiovascular events.

- A recent Institute of Medicine report concluded that, if restricted to studies of clinical cardiovascular events, there is insufficient evidence that lowering sodium intake further beyond 2.30 g per day either increases or decreases the occurrence of cardiovascular disease.

- Yet the report further concluded that the entirety of the evidence, “when considered collectively, indicates a positive relationship between higher levels of sodium intake and [the] risk of cardiovascular disease.”

- Although precise targets for sodium reduction remain controversial, various organizations tasked with reviewing all the evidence have arrived at target levels ranging from 1200 to 2400 mg per day (Table S3 in the Supplementary Appendix).

Limitations

- Causality cannot be proved, although every effort was made to maximize validity, minimize error and bias, and incorporate heterogeneity and uncertainty,

- Dietary sodium was estimated based on 24-hour urine collections, which reflect approximately 90% of intake and also can be limited by incomplete collection.

- Data on sodium intake were not available across all countries or years - increased statistical uncertainty and the risk that some data could reflect sampling bias.

- Dietary sodium is also associated with nonfatal cardiovascular disease, kidney disease, and gastric cancer, the second-leading fatal cancer worldwide – may underestimate the full global health effects of dietary sodium.

- No data on potassium consumption – also influences blood pressure and the risk of stroke.

- Specific approaches or timelines for reduced sodium intake was not incorporated.

CONCLUSION

- On the basis of currently available data on sodium consumption, dose–response effects on blood pressure and cardiovascular mortality, and cause-specific deaths, we estimate that in 2010, a total of 1.65 million deaths from cardiovascular causes were attributable to consumption of more than 2.0 g of sodium per day.

Mozaffarian et al. N Engl J Med 2014;371:624-34. DOI: 10.1056/NEJMoa1304127

Supplementary Material

Correspondence (Comment by other experts and the authors' reply)

Editorial

Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years. A Randomized Clinical Trial

INTRODUCTION

- In the United States, 75% of persons older than 75 years have hypertension, for whom cardiovascular disease complications are a leading cause of disability, morbidity, and mortality

- European guideline committees have recommended treatment initiation only above 160 mm Hg for persons aged 80 years or older

- US guideline, a report from the panel appointed to the Eighth Joint National Committee (JNC 8), recommended a SBP treatment target of 150 mm Hg for adults aged 60 years or older.

- However, a report from a minority of the members argued to retain the previously recommended SBP treatment goal of 140 mm Hg, highlighting the lack of consensus

- Whether treatment targets should consider factors such as frailty or functional status is also unknown

- Observational studies have noted differential associations among elevated blood pressure (BP) and cardiovascular disease, stroke, and mortality risk when analyses are stratified according to measures of functional status.

- A recent secondary analysis of the Systolic Hypertension in the Elderly Program showed that the benefit of antihypertensive therapy was limited to participants without a self-reported physical ability limitation.

- In contrast, analyses from the Hypertension in the Very Elderly Trial (HYVET) showed a consistent benefit with antihypertensive therapy on outcomes irrespective of frailty status.

The Systolic Blood Pressure Intervention Trial (SPRINT) recently reported that participants assigned to an intensive SBP treatment target of less than 120 mm Hg vs the standard SBP treatment goal of less than140mmHg had a 25% lower relative risk of major cardiovascular events and death, and a 27% lower relative risk of death from any cause.

- This trial was specifically funded to enhance recruitment of a prespecified subgroup of adults aged 75 years or older, and the study protocol (appears in Supplement 1) also included measures of functional status and frailty.

- This article details results for the prespecified subgroup of adults aged 75 years or older with hypertension.

OBJECTIVE

To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes.

METHODOLOGY

Population

Inclusion:

- Increased risk for cardiovascular disease (based on a clinical or subclinical cardiovascular disease, chronic kidney disease [CKD], a 10-year Framingham General cardiovascular disease risk ≥15%, or age ≥75 years).

Exclusion:

- had type 2 diabetes, a history of stroke, symptomatic heart failure within the past 6 months or reduced left ventricular ejection fraction (<35%), a clinical diagnosis of or treatment for dementia, an expected survival of less than 3 years, unintentional weight loss (>10% of body weight) during the preceding 6 months, an SBP of less than 110 mm Hg following 1 minute of standing, or resided in a nursing home.

Study Measurements

- Sociodemographic data were collected at baseline, whereas both clinical and laboratory data were obtained at baseline and every 3 months

- Race and ethnicity information was obtained via self-report.

- Blood pressure was determined using the mean of 3 properly sized automated cuff readings, taken 1 minute apart after 5 minutes of quiet rest without staff in the room.

- Gait speed was measured via a timed 4-m walk performed twice at the participant’s usual pace from a standing start.

- The use of an assistive device was permitted if typically used by the participant to walk short distances.

- The faster of the 2 gait speeds (measured in meters/second) was used in the analysis.

- Frailty status at randomization was quantified using a previously reported 37-item frailty index.

Clinical Outcomes

- A committee unaware of treatment assignment adjudicated the protocol-specified clinical outcomes.

- The primary cardiovascular disease outcome was a composite of: nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes.

- Secondary outcomes: all-cause mortality and the composite of the SPRINT primary outcome and all-cause mortality.

- The primary renal disease outcome was assessed in participants with CKD at baseline (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m² based on the 4-variable

Modification of Diet in Renal Disease equation). It was based on the composite incidence of either a decrease in eGFR of 50% or greater (confirmed by subsequent laboratory test ≥90 days later) or the development of end-stage renal disease requiring long-term dialysis or transplantation.

- Secondary renal disease outcome (assessed in participants without CKD at baseline) was based on incidence of a decrease in eGFR from 30% or greater at baseline to a value less than 60 mL/min/1.73 m² (also confirmed by a subsequent test ≥90 days later).

Definition of Serious Adverse Events

- Serious adverse events (SAEs) were defined as events that were fatal or life threatening, resulted in significant or persistent disability, required hospitalization or resulted in prolonged hospitalization, or medical events that the investigator judged to be a significant hazard or harm to the participant and required medical or surgical intervention to prevent any of these.

- The following conditions of interest were reported as adverse events if they were evaluated in an emergency department: hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia.

- Episodes of acute kidney injury (or acute renal failure) were monitored if they led to hospitalization and were reported in the hospital discharge summary.

Statistical Analysis

- Power to detect a 25% treatment effect for the primary outcome within the subgroup of participants aged 75 years or older was estimated assuming an enrollment of 3250.With a 2-year recruitment period, maximum follow-up of 6 years, and annual loss to follow-up of 2%, power was estimated to be 81.9%, assuming an event rate of 3.25%per year in the standard treatment group (Appendix B in Supplement 1).

- Linear-mixed models with an unstructured covariance matrix, assuming independence across participants, were used to model longitudinal differences in SBP between treatment groups

- Fixed effects in the model were BP at randomization and a treatment group indicator.

- The time to first occurrence of the primary composite outcome, all-cause mortality, primary composite outcome plus all-cause mortality, SAEs, and loss to follow-up or withdrawing consent were compared between the 2 randomized groups using Cox proportional hazards regression models with the baseline hazard function stratified by clinic site (participants were recruited at 100 clinics).

- Follow-up time was censored on the date of last event ascertainment on or before August 20, 2015, the date on which the National Heart, Lung, and Blood Institute director decided to stop the intervention.

- Exploratory secondary analyses were conducted to examine modification of the treatment effect by frailty status and gait speed.

- Neither frailty status nor gait speed was a prespecified subgroup in the trial protocol.

We fit separate Cox regression models:

- for frailty status classified as fit (frailty index ≤0.10), less fit (frailty index >0.10 to ≤0.21), or frail (frailty index >0.21), and

- for gait speed classified as 0.8m/s or greater (normal walker), less than 0.8 m/s (slow walker), or missing.

- Interactions between treatment group, frailty status, and gait speed were formally tested by including interaction terms within a Cox regression model (ie, using likelihood ratio tests to compare with a model that did not allow the treatment effect to vary by frailty status or gait speed).

- For the primary cardiovascular disease composite outcome, sensitivity analyses accounting for the competing risk of death were conducted using the sub-distribution hazard model of Fine and Gray.

- All hypothesis tests were 2-sided at the 5%level of significance

- Additional analyses compared the total burden of SAEs between the randomized groups (allowing for recurrent events) using the mean cumulative count estimator (standard errors computed using bootstrap resampling).

- Hazard ratios (HRs) were computed to compare the randomized groups using the gap-time formation of the Prentice, Williams, and Peterson recurrent events regression model.

- All analyses were performed using SAS version 9.4 (SAS Institute Inc) and the R Statistical Computing Environment (http://www.r-project.org)

RESULTS

Baseline characteristics and Study Retention

- The treatment groups were similar for most characteristics with the exception of frailty status and aspirin use (Table 1).

- Overall, 815 participants (30.9%) were classified as frail and 1456 (55.2%) as less fit (Table 1).

- A total of 2510 (95.2%) participants provided complete follow-up data.

- In the intensive treatment group, 440 participants (33.4%) were classified as frail compared with 375 participants (28.4%) in the standard treatment group.

- A total of 740 participants (28.1%) were classified as slow walkers (<0.8m/s).

- There was no baseline treatment group difference in the proportion of participants classified as slow walkers or in performance on the Montreal Cognitive Assessment screening test

- Even though participants who were less fit, frail, or with reduced gait speed exhibited higher rates of loss to follow-up or withdrawal of consent, there were no significant differences between the treatment groups for frailty or low gait speed (eTable 1 in Supplement 2).

- The frequency at which participants discontinued the intervention but continued follow-up was 6.2% in the intensive treatment group vs 6.4% in the standard treatment group (P = .87).

Blood Pressure Levels

Throughout follow-up,

Mean SBP:

- Intensive treatment group: 123.4 mm Hg

- Standard treatment group: 134.8 mm Hg

- Between group difference: 11.4 mg (95% CI, 10.8-11.9 mm Hg)

Mean Diastolic BP:

- Intensive treatment group: 62.0 mm Hg

- Standard treatment group: 67.2 mm Hg

- On average, participants in the intensive treatment group required 1 more medication to reach the achieved lower BP (eTable 2 and eFigure 1 in Supplement 2).

- Within the intensive treatment group, mean SBP during follow-up was higher for participants classified as less fit or frail compared with those considered fit.

- Differences in mean SBP by treatment group differed by frailty status (P = .01), with frail participants exhibiting smaller inter-treatment group differences (10.8 mm Hg) compared with less fit participants (11.3 mm Hg) and fit participants (13.5 mm Hg).

- Treatment group differences in SBP were similar across subgroups defined by gait speed.

Clinical Outcome

- A primary composite outcome event was observed for 102 participants (2.59% per year) in the intensive treatment group and for 148 participants (3.85% per year) in the standard treatment group (HR, 0.66 [95% CI, 0.51-0.85]; Table 3).

- Results were similar for all-cause mortality (there were 73 deaths in the intensive treatment group and 107 deaths in the standard treatment group; HR, 0.67 [95% CI, 0.49-0.91]).

- Inference for the primary outcome was unchanged when non-cardiovascular disease death was treated as a competing risk (HR, 0.66 [95% CI, 0.52-0.85]).

- At 3.14 years, the number needed to treat (NNT) estimate for the primary outcome was 27 (95% CI, 19-61) and for all-cause mortality was 41 (95% CI, 27-145).

 - Because the treatment effect estimate was not statistically significant for cardiovascular disease death, the NNT estimate (using the abbreviations of Altman) was an NNT_Benefit of 116 (NNT_Harm of 544 to ∞ to NNT_Benefit of 68).

- In participants without CKD at the time of randomization, more participants in the intensive treatment group compared with the standard treatment group experienced the secondary CKD outcome (a 30% decrease in eGFR from baseline to an eGFR <60 mL/min/1.73 m2 [1.70% vs 0.58% per year, respectively]; HR, 3.14 [95% CI, 1.66-6.37]).

- There were no significant treatment group differences in the primary renal outcome in those with baseline CKD; however, power to detect differences was limited due to low numbers of events.

Exploratory Subgroup Analyses

- Results stratified by baseline frailty status showed higher event rates with increasing frailty in both treatment groups (Table 4 and Figure 2).

- However, within each frailty stratum, absolute event rates were lower for the intensive treatment group (P = .84 for interaction).

- Results were similar when participants were stratified by gait speed (P = .85 for interaction), with the HRs in favor of the intensive treatment group in each gait speed stratum (eFigure 2 in Supplement 2).

Serious Adverse Events (SAEs)

- Detailed information regarding SAEs appears in eTable 3 and eTable 4 in Supplement 2.

- In the intensive treatment group, SAEs occurred in 637 participants (48.4%) compared with 637 participants (48.3%) in the standard treatment group (HR, 0.99 [95% CI, 0.89-1.11]; P = .90).

- The absolute rate of SAEs was higher but was not statistically significantly different in the intensive treatment group for hypotension (2.4%vs 1.4% in the standard treatment group;

For each specific SAE:

- Hypotension: 2.4% (intensive group) vs 1.4% (standard group) (HR, 1.71 [95% CI, 0.97-3.09])

- Syncope: 3.0% (intensive group) vs 2.4% (standard group) (HR, 1.23 [95% CI, 0.76-2.00])

- Electrolyte abnormalities: 4.0% (intensive group) vs 2.7% (standard group) (HR, 1.51 [95% CI, 0.99-2.33])

- Acute kidney injury: 5.5% (intensive group) vs 4.0% (standard group) (HR, 1.41 [95% CI, 0.98-2.04])

- Injurious falls: 4.9% (intensive group) vs 5.5% (standard group) (HR, 0.91 [95% CI, 0.65-1.29])

[Note from ZYL: To see whether the group differences are significant, we look at the 95% confidence interval (CI) of the hazard ratio (HR): If the CI pass did not pass through the value ‘1’, then it is significant; if the CI passed through value ‘1’, then it is not significant (The reason why we look at ‘1’ is because ‘1’ means null effect in ratio).

From the results, all of the CI of the serious adverse events reported passed through the value ‘1’, therefore the serious adverse events between groups were not significantly difference. However, it must be noted that there is a trend that the intensive group had more hypotension, electrolyte abnormalities and acute kidney injury (the lower CI is very near to 1)

- Even though the SAE rates were higher with greater frailty or slower walking speed, these rates were not statistically different by treatment group when stratified by frailty status or gait speed.

DISCUSSION

Main Findings

- These results extend and detail the main SPRINT study findings in community-dwelling persons aged 75 years or older, demonstrating that a treatment goal for SBP of <120 mm Hg reduced incident cardiovascular disease by 33% (from 3.85% to 2.59% per year) and total mortality by 32% (from 2.63% to 1.78% per year)

- Number needed to treat: strategy of intensive BP control for 3.14 years would be expected to prevent 1 primary outcome event for every 27 persons treated and 1 death from any cause for every 41 persons treated.

- These estimates are lower than those from the overall results of the trial due to the higher event rate in persons aged 75 years or older.

- Exploratory analysis also suggested that the benefit of intensive BP control was consistent among persons in this age range who were frail or had reduced gait speed.

Serious Adverse Events

- The overall SAE rate was comparable by treatment group, including among the most frail participants.

- There were no differences in the number of participants experiencing injurious falls or in the prevalence of orthostatic hypotension measured at study visits – complement results from other trials demonstrating improved BP control reduces risk for orthostatic hypotension and has no effect on risk for injurious falls

Limitations

- Randomization was not stratified by categories of age

- Did not enroll older adults residing in nursing homes, persons with type 2 diabetes or prevalent stroke (because of concurrent BP lowering trials) and individuals with symptomatic heart failure due to protocol differences required to maintain BP control in this condition – cannot be generalized to these groups of patients. Individuals with these conditions also represent a subset of older persons at increased risk for falls.

Exploratory Analysis

- No other chronic conditions were excluded from this trial, and the frailty index applied in this study combined with the assessment of gait speed contribute to assessing possible effect modification by comorbidity and functional status.

- In exploratory analyses, there was no evidence of heterogeneity for the cardiovascular benefit of intensive BP management by frailty or gait speed.

- However, these analyses should be interpreted cautiously.

- The analyses were not prespecified in the trial protocol and were possibly underpowered because SPRINT was designed to consider only the ability to detect a treatment effect in participants aged 75 years or older as a whole

Representativeness of the trial participants

- Despite excluding some chronic conditions, 30.9% of participants aged 75 years or older in this trial were categorized as frail at baseline, and the distribution of frailty status parallels that estimated for ambulatory, community living populations of similar age.

- In addition, the proportion of US adults aged 75 years or older who have hypertension and meet the study entry criteria has been estimated to represent 64% of that population using the 2007-2012 National Health and Nutrition Surveys (approximately 5.8 million individuals).

- Therefore, participants aged 75 years or older in this trial are representative of a sizeable fraction of adults in this age group with hypertension

Compare with the HYVET Trial

- Randomized 3845 patients aged 80 years or older within Europe and Asia (mean age, 83 years [3 years older than SPRINT]; mean entry SBP, 173mmHg [31 mm Hg higher than SPRINT]) to either therapy with indapamide, with or without the angiotensin-converting enzyme inhibitor perindopril, or placebo with an SBP treatment goal of <150 mm Hg.

- The 2-year between-group SBP difference was 15 mm Hg (the active treatment group achieved a mean SBP of 143mm Hg, slightly higher than the SPRINT baseline SBP).

- Similar to SPRINT, HYVET was terminated early (at a median follow-up time of 1.8 years) due to significant reductions in the incidence rate of total mortality.

- A retrospective analysis of the HYVET population conducted to determine its frailty status identified that (1) the cohort’s frailty status was similar to that of community living populations of similar age and (2) the treatment benefits were similar even in the most frail participants.

- Taken together, current results from SPRINT also reinforce and extend HYVET’s conclusions that risk reductions in cardiovascular disease events and mortality from high BP treatment are evident regardless of frailty status

SAEs related to Acute Kidney Injury

- Among all participants aged 75 years or older, the SAEs related to acute kidney injury occurred more frequently in the intensive treatment group (72 participants [5.5%] vs 53 participants [4.0%] in the standard treatment group).

- The differences in adverse renal outcomes may be related to a reversible intrarenal hemodynamic effect of the reduction in BP and more frequent use of diuretics, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers in the intensive treatment group.

- Although there is no evidence of permanent kidney injury associated with the lower BP goal, the possibility of long-term adverse renal outcomes cannot be excluded and requires longer-term follow-up

Implications of the study

- Considering the high prevalence of hypertension among older persons, patients and their physicians may be inclined to underestimate the burden of hypertension or the benefits of lowering BP, resulting in under-treatment.

- On average, the benefits that resulted from intensive therapy required treatment with 1 additional antihypertensive drug and additional early visits for dose titration and monitoring.

- Future analyses of SPRINT data may be helpful to better define the burden, costs, and benefits of intensive BP control.

- However, the present results have substantial implications for the future of intensive BP therapy in older adults because of this condition’s high prevalence, the high absolute risk for cardiovascular disease complications from elevated BP, and the devastating consequences of such events on the independent function of older people

CONCLUSIONS

- Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause
- The overall serious adverse events rate was comparable by treatment group, including among the most frail participants.

Williamson et al. JAMA. 2016;315(24):2673-2682.doi:10.1001/jama.2016.7050

Supplemental Content

Editorial

A Randomized Trial of Intensive versus Standard Blood-Pressure Control

 INTRODUCTION

- Hypertension affects approximately 1 billion adults worldwide.

- Among persons 50 years of age or older, isolated systolic hypertension is the most common form of hypertension, and systolic blood pressure becomes more important than diastolic blood pressure as an independent risk predictor for coronary events, stroke, heart failure, and end-stage renal disease (ESRD).

- Elevated blood pressure is the leading risk factor,among 67 studied, for death and  disability-adjusted life-years lost during 2010.

- Clinical trials have shown that treatment of hypertension reduces the risk of cardiovascular disease outcomes, including incident stroke (by 35 to 40%), myocardial infarction (by 15 to 25%), and heart failure (by up to 64%).

- However, the target for systolic blood-pressure lowering is uncertain

- Observational studies have shown a progressive increase in cardiovascular risk as systolic blood pressure rises above 115 mm Hg, but the available evidence from randomized, controlled trials in the general population of patients with hypertension only documents the benefit of treatment to achieve a systolic blood pressure target of less than 150 mm Hg, with limited data concerning lower blood-pressure targets

- In a trial involving patients with type 2 diabetes mellitus, the rate of major cardiovascular events was similar with a systolic blood pressure target of <120 mm Hg and the commonly recommended target of < 140 mm Hg, though the rate of stroke was lower with the target of <120 mm Hg (Cushman et al. N Engl J Med 2010; 362: 1575-85)

- A recent trial involving patients who had had a stroke compared treatment to lower systolic blood pressure to less than 130 mm Hg with treatment to lower it to less than 150 mm Hg and showed no significant benefit of the lower target with respect to the overall risk of another stroke but a significant benefit with respect to the risk of hemorrhagic stroke (Benavente et al. Lancet 2013; 382: 507-15)

- The hypothesis that a lower systolic blood pressure goal (e.g., <120 mm Hg) would reduce clinical events more than a standard goal was designated by a National Heart, Lung, and Blood Institute (NHLBI) expert panel in 2007 as the most important hypothesis to test regarding the prevention of hypertension-related complications among patients without diabetes.

- The current article describes the primary results of the Systolic Blood Pressure Intervention Trial (SPRINT), which compared the benefit of treatment of systolic blood pressure to a target of less than 120 mm Hg with treatment to a target of less than 140 mm Hg

METHODS

Study Design

- Randomized, controlled, open-label trial

Setting

- Conducted at 102 clinical sites (organized into 5 clinical center networks) in the United States, including Puerto Rico

Study Administration

- A trial coordinating center served as a data and biostatistical core center and supervised the central laboratory, the electrocardiography reading center, the magnetic resonance imaging reading center, and the drug-distribution center.

- The coordinating center was responsible for analysing the data.

- An independent data and safety monitoring board monitored unblinded trial results and safety events.

Study Population

- Inclusion Criteria: Age ≥ 50, systolic blood pressure of 130 to 180 mm Hg and increased risk of cardiovascular events

[Increased cardiovascular risk was defined by one or more of the following: clinical or subclinical cardiovascular disease other than stroke; chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate (eGFR) of 20-<60 ml/minute/1.73 m² of body surface area, calculated with the use of the four-variable Modification of Diet in Renal Disease equation; a 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framingham risk score; or an age ≥ 75]

- Exclusion Criteria: Patients with diabetes mellitus and previous stroke

Study Conduct and Intervention

- Intensive treatment: target systolic blood pressure at <120 mm Hg

- Standard treatment: target systolic blood pressure at < 140 mm Hg

- Randomization was stratified according to clinical site

- Blinding: Participants and study personnel were aware of the study-group assignments, but outcome adjudicators were not

- After the participants underwent randomization, their baseline antihypertensive regimens were adjusted on the basis of the study-group assignment.

- The treatment algorithms were similar to those used in the Action to Control Cardiovascular

Risk in Diabetes (ACCORD) trial.

- These algorithms and our formulary are listed in Figures S1 and S2 and Table S1 in the Supplementary Appendix

- All major classes of antihypertensive agents were included in the formulary and were provided at no cost to the participants

- The protocol encouraged, but did not mandate, the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes, including thiazide-type diuretics (encouraged as the first-line agent), loop diuretics (for participants with advanced chronic kidney disease), and beta-adrenergic blockers (for those with coronary artery disease).

- Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calciumchannel blocker

- Azilsartan and azilsartan combined with chlorthalidone were donated by Takeda Pharmaceuticals International and Arbor Pharmaceuticals; neither company had any other role in the study.

- Participants were seen monthly for the first 3 months and every 3 months thereafter

- Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of <120 mm Hg.

- For participants in the standard-treatment group, medications were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits.

- Dose adjustment was based on a mean of three blood-pressure measurements at an office visit while the patient was seated and after 5 minutes of quiet rest; the measurements were made with the use of an automated measurement system (Model 907, Omron Healthcare).

- Lifestyle modification was encouraged as part of the management strategy.

- Retention in the study and adherence to treatment were monitored prospectively and routinely throughout the trial.

Study Measurement

- Demographic data were collected at baseline.

- Clinical and laboratory data were obtained at baseline and every 3 months thereafter

- A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes.

- Although the interviewers were aware of the study-group assignments, they used the same format for interviews in the two groups to minimize ascertainment bias.

- Medical records and electrocardiograms were obtained for documentation of events.

- Whenever clinical site staff became aware of a death, a standard protocol was used to obtain information on the event

- Serious adverse events were defined as events that were fatal or life-threatening, that resulted in clinically significant or persistent disability, that required or prolonged a hospitalization, or that were judged by the investigator to represent a clinically significant hazard or harm to the participant that might require medical or surgical intervention to prevent one of the other events listed above

- A short list of monitored conditions were reported as adverse events if they were evaluated in an emergency department: hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia

- We also monitored occurrences of acute kidney injury or acute renal failure if they were noted on admission or occurred during a hospitalization and were reported in the hospital discharge summary as a primary or main secondary diagnosis.

- The Medical Dictionary for Regulatory Activities was used to classify the safety events. Coding was performed at the coordinating center, and up to three codes were assigned to each safety event.

- The relationship of serious adverse events to the intervention was assessed by the trial safety officer and reviewed monthly by the safety committee.

Study Outcomes

- Definitions of study outcomes are outlined in the Supplementary Appendix.

- A committee whose members were unaware of the study-group assignments adjudicated the clinical outcomes specified in the protocol.

- The primary hypothesis was that treatment to reach a systolic blood-pressure target of less than 120 mm Hg, as compared with a target of less than 140 mm Hg, would result in a lower rate of the composite outcome of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes

- Secondary outcomes included the individual components of the primary composite outcome, death from any cause, and the composite of the primary outcome or death from any cause.

- We also assessed renal outcomes, using a different definition for patients with chronic kidney disease (eGFR <60 ml per minute per 1.73 m²) at baseline and those without it.

- The renal outcome in participants with chronic kidney disease at baseline was a composite of a decrease in the eGFR of 50% or more (confirmed by a subsequent laboratory test) or the development of ESRD requiring long-term dialysis or kidney transplantation.

- In participants without chronic kidney disease at baseline, the renal outcome was defined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m².

- Incident albuminuria, defined for all study participants by a doubling of the ratio of urinary albumin (in milligrams) to creatinine (in grams) from less than 10 at baseline to greater than 10 during follow-up, was also a prespecified renal outcome

Prespecified subgroup analysis

- defined according to status with respect to cardiovascular disease at baseline (yes vs.

no), status with respect to chronic kidney disease at baseline (yes vs. no), sex, race (black vs. nonblack), age (<75 vs. ≥75 years), and baseline systolic blood pressure in three levels (≤132 mm Hg, >132 to <145 mm Hg, and ≥145 mm Hg).

- We also planned a comparison of the effects of systolic blood-pressure targets on incident dementia, changes in cognitive function, and cerebral small-vessel ischemic disease; these results are not presented here.

Statistical Analysis

- We planned a 2-year recruitment period, with a maximum follow-up of 6 years, and anticipated a loss to follow-up of 2% per year

- With an enrolment target of 9250 participants, we estimated that the trial would have 88.7% power to detect a 20% effect with respect to the primary outcome, assuming an event rate of 2.2% per year in the standard-treatment group

- Primary Analysis: Time to the first occurrence of a primary outcome event between the two study groups with intention-to-treat approach for all randomly assigned participants.

- Statistical Test: Cox proportional-hazards regression with two-sided tests at the 5% level of significance, with stratification according to clinic. Follow-up time was censored on the date of last event ascertainment.

- Interactions between treatment effect and prespecified subgroups were assessed with a likelihood-ratio test for the interaction with the use of Hommel-adjusted P values

- Interim analyses: performed for each meeting of the data and safety monitoring board, with group-sequential stopping boundaries defined with the use of the Lan-DeMets method with an O’Brien-Fleming-type spending function.

- Sensitivity analysis: Fine-Gray model for the competing risk of death 

RESULTS

Study Participants

- A total of 9361 participants were enrolled between November 2010 and March 2013.

- Descriptive baseline statistics are presented in Table 1.

- On August 20, 2015, the NHLBI director accepted a recommendation from the data and safety monitoring board of the trial to inform the investigators and participants of the cardiovascular-outcome results after analyses of the primary outcome exceeded the monitoring boundary at two consecutive time points (Fig. S3 in the Supplementary Appendix), thus initiating the process to end the blood-pressure intervention early.

- The median follow-up on August 20, 2015, was 3.26 years of the planned average of 5 years

Blood Pressure

- The two treatment strategies resulted in a rapid and sustained between-group difference in systolic blood pressure (Fig. 2).

At 1 year

- Mean systolic blood pressure

Intensive-treatment group: 121.4 mm Hg

Standard-treatment group: 136.2 mm Hg

Average Difference: 14.8 mm Hg

- Mean diastolic blood pressure

Intensive-treatment group: 68.7 mm Hg

Standard-treatment group: 76.3 mm Hg

Throughout the 3.26 years of follow-up

- Mean systolic blood pressure

Intensive-treatment group: 121.5 mm Hg

Standard-treatment group: 134.6 mm Hg

Mean number of blood pressure medication: 2.9

- The relative distribution of antihypertensive medication classes used was similar in the two

groups, though the use of each class was greater in the intensive-treatment group (Table S2 in the Supplementary Appendix)

Clinical Outcome

Primary Outcome

- A primary outcome event was confirmed in 562 participants -- 243 (1.65% per year) in the intensive-treatment group and 319 (2.19% per year) in the standard-treatment group (hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001) (Table 2).

[Note from ZYL: 
If HR=1, means null effect; 
If HR<1, means the intensive-group had lower rate of primary outcome event (protective effect); 
If HR>1, means the intensive-group had higher rate of prumary outcome event (harmful effect)
If the 95% CI pass through the value '1', the group difference is not significant (because the CI pass through the null effect).
In this case, HR 0.75 means that intensive treatment group had 25% reduction in risk of primary outcome events, and this result is significant because the CI does not pass through '1'.]

- Separation in the primary outcome between the groups was apparent at 1 year (Fig. 3A).

- The between-group differences were consistent across the components of the primary outcome and other prespecified secondary outcomes (Table 2).

Mortality outcome

- A total of 365 deaths occurred --155 in the intensive-treatment group and 210 in the standard-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003).

[Quiz: What do HR 0.73 means here? Which group had lower risk of death? Is the difference significant?]

- Separation in mortality between the groups became apparent at approximately 2 years (Fig. 3B)

- Causes of death are provided in Table S3 in the Supplementary Appendix

- The relative risk of death from cardiovascular causes was 43% lower with the intensive intervention than with the standard treatment (P = 0.005) (Table 2).

Numbers needed to treat

- The numbers needed to treat to prevent a primary outcome event, death from any cause, and death from cardiovascular causes during the median 3.26 years of the trial were 61, 90, and 172, respectively.

Subgroup analysis

- The effects of the intervention on the rate of the primary outcome and on the rate of death from any cause were consistent across the prespecified subgroups. (Fig. 4, and

Fig. S5 in the Supplementary Appendix).

Interaction and Sensitivity Analysis

- There were no significant interactions between treatment and subgroup with respect to the primary outcome or death from any cause.

- When death was treated as a competing risk in a Fine-Gray model, the results with respect to the primary outcome were virtually unchanged (hazard ratio, 0.76; 95% CI, 0.64 to 0.89).

Renal outcome

- Among participants who had chronic kidney disease at baseline, no significant between-group difference in the composite outcome of a decrease in the eGFR of 50% or more or the development of ESRD was noted, though the number of events was small (Table 2).

- Among participants who did not have chronic kidney disease at baseline, the incidence of the outcome defined by a decrease in the eGFR of 30% or more to a value of less than 60 ml per minute per 1.73 m² was higher in the intensive-treatment group than in the standard-treatment group (1.21% per year vs. 0.35% per year; hazard ratio, 3.49; 95% CI, 2.44 to 5.10; P<0.001).

Serious Adverse Events

- Serious adverse events occurred in 1793 participants in the intensive-treatment group (38.3%) and in 1736 participants in the standard-treatment group (37.1%) (hazard ratio with intensive treatment, 1.04; P = 0.25) (Table 3, and Table S4 in the Supplementary Appendix). - Serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure, but not injurious falls or bradycardia, occurred more frequently in the intensive-treatment group than in the standard-treatment group.

- Orthostatic hypotension as assessed during a clinic visit was significantly less common in the intensive-treatment group.

- A total of 220 participants in the intensive-treatment group (4.7%) and 118 participants in the standard-treatment group (2.5%) had serious adverse events that were classified as possibly or definitely related to the intervention (hazard ratio, 1.88; P<0.001) (Table S5 in the Supplementary Appendix).

- The magnitude and pattern of differences in adverse events according to treatment assignment among participants 75 years of age or older were similar to those in the overall cohort (Table S6 in the Supplementary Appendix).

DISCUSSION

Main Findings

- SPRINT showed that among adults with hypertension but without diabetes, lowering systolic blood pressure to a target goal of less than 120 mm Hg, as compared with the standard goal of less than 140 mm Hg, resulted in significantly lower rates of fatal and nonfatal cardiovascular events and death from any cause

- Trial participants assigned to the lower systolic blood-pressure target (intensive-treatment group), as compared with those assigned to the higher target (standard-treatment group), had a 25% lower relative risk of the primary outcome;

- In addition, the intensive-treatment group had lower rates of several other important outcomes, including heart failure (38% lower relative risk), death from cardiovascular causes (43% lower relative risk), and death from any cause (27% lower relative risk).

- During the follow-up period of the trial (median, 3.26 years), the number needed to treat with a strategy of intensive blood-pressure control to prevent one primary outcome event was 61, and the number needed to treat to prevent one death from any cause was 90. These benefits with respect to both the primary outcome and death were consistent across all prespecified subgroups, including participants 75 years of age or older.

Why the intensive-treatment group had worse renal outcome?

- Owing in part to a lower-than-expected decline in the eGFR and to the early termination of the trial, the number of renal events was small

- Among participants who did not have chronic kidney disease at baseline, a decrease in

the eGFR of 30% or more to a value < 60 ml/min/1.73m² occurred more frequently in the intensive-treatment group than in the standard-treatment group

- Among all participants, acute kidney injury or acute renal failure occurred more frequently in the intensive-treatment group than in the standard-treatment group

- The differences in adverse renal outcomes may be related to a reversible intrarenal hemodynamic effect of the greater reduction in blood pressure and greater use of diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers in the intensive-treatment group

- With the currently available data, there is no evidence of substantial permanent kidney injury associated with the lower systolic blood-pressure goal; however, the possibility of a long-term adverse renal outcome cannot be excluded.

- These observations and hypotheses need to be explored further in analyses that incorporate more clinical outcomes and longer follow-up.

Lower blood pressure target is better in most patients with hypertension, even among the elderly

- The results of SPRINT add substantially to the evidence of benefits of lowering systolic blood pressure, especially in older patients with hypertension

-Trials such as the Systolic Hypertension in the Elderly Program trial, the Systolic Hypertension in Europe trial, and the Hypertension in the Very Elderly Trial showed the benefits of lowering systolic blood pressure below 150 mm Hg

- However, trials evaluating systolic blood-pressure levels lower than those studied in these trials have been either underpowered or performed without specific systolic blood-pressure targets

- A major component of the controversy regarding the selection of the systolic blood-pressure goal in this population has resulted from inadequate data on the risks versus benefits of systolic blood-pressure targets below 150 mm Hg

- SPRINT now provides evidence of benefits for an even lower systolic blood-pressure target than that currently recommended in most patients with hypertension.

SPRINT vs ACCORD

- Both SPRINT and ACCORD examined identical systolic blood-pressure targets (<120 mm Hg vs. <140 mm Hg).

- In contrast to the findings of SPRINT, the cardiovascular and mortality benefits observed in the ACCORD trial were not statistically significant and were of a lesser magnitude.

- Several important differences between these trials should be noted.

- The ACCORD trial enrolled participants with diabetes exclusively, whereas SPRINT excluded participants with diabetes;

- The sample size of the ACCORD trial was only half that of SPRINT (4733 vs. 9361).

- SPRINT enrolled an older cohort (mean age, 68 years, vs. 62 years in the ACCORD trial), with 28% of participants 75 years of age or older, and also included participants with chronic kidney disease.

- The ACCORD trial showed a (nonsignificant) 12% lower risk of its primary composite cardiovascular outcome, with a 95% confidence interval that included the possibility of a 27% lower risk, which is consistent with the cardiovascular benefit observed in SPRINT

- The ACCORD trial also used a factorial design that included comparisons of standard and intensive glycemic and lipid treatment targets in the same trial.

- A secondary analysis of the ACCORD results showed that, as compared with the combined standard glycemia and blood-pressure treatments, intensive blood-pressure treatment alone reduced major cardiovascular outcomes by 26% without additional benefit from combining the two intensive treatments.

- Thus, the difference in results between the trials could be due to differences in study design, treatment interactions, or the play of chance.

- An inherent difference in the cardiovascular benefits of systolic blood-pressure lowering between the population with diabetes and the population without diabetes seems unlikely but cannot be ruled out.

Stroke outcome

- In the Secondary Prevention of Small Subcortical Strokes trial (intensive systolic blood-pressure goal <130 mm Hg) and in the ACCORD trial (intensive systolic blood-pressure goal <120 mm Hg), the lower blood-pressure target was associated with a nonsignificant 19% lower incidence of stroke (P = 0.08) and a significant 41% lower incidence of stroke, respectively, than the incidence with higher targets.

- The intensive-treatment group in SPRINT had a nonsignificant 11% lower incidence of stroke, though SPRINT also excluded persons with prevalent stroke or transient ischemic attack at baseline.

Serious Adverse Events

- In SPRINT, significant between-group differences were noted in some adverse effects that were attributed to the intervention (Table S5 in the Supplementary Appendix).

- Orthostatic hypotension as assessed during a clinic visit (Table 3) was observed less frequently in the intensive-treatment group than in the standard-treatment group (P = 0.01), but syncope was more common among participants in the intensive-treatment group than among those in the standard-treatment group (3.5% vs. 2.4%, P = 0.003), as was hypotension (3.4% vs. 2.0%, P<0.001).

- There was no between-group difference in injurious falls (hazard ratio, 1.00; P = 0.97).

- There was a higher rate of acute kidney injury or acute renal failure in the intensive-treatment group, as noted above.

- These adverse events need to be weighed against the benefits with respect to cardiovascular events and death that are associated with intensive control of systolic blood pressure.

Strengths

- Large sample size

- Diversity of the population (including a large proportion of patients age ≥75)

- Success in achieving the intended separation in systolic blood pressure between the two intervention groups throughout the trial.

Limitations

- Lack of generalizability to populations not included in the study-such as persons with diabetes, those with prior stroke, and those younger than 50 years of age

- Older adults residing in nursing homes or assisted-living facilities were also not enrolled.

- Effects of the lower blood pressure on the central nervous system and kidney cannot be reasonably interpreted until analysis of these end points has been completed.

Practical issues raised

- Hypertension control to a blood pressure of less than 140/90 mm Hg is achieved in only about 50% of the general population in the United States, which suggests that control to even that level is challenging

- We excluded patients with more severe hypertension, and control of systolic blood pressure to less than 120 mm Hg required, on average, one additional antihypertensive drug.

- In addition, the median systolic blood pressure in the intensive-treatment group was just above 120 mm Hg, which indicates that more than half the participants had a systolic

blood pressure above the 120 mm Hg target.

- These observations suggest that achieving a systolic blood-pressure goal of < 120 mm Hg in the overall population of patients with hypertension would be more demanding and time-consuming for both providers and patients than achieving a goal of 140 mm Hg, and would necessitate increased medication costs and clinic visits.

CONCLUSIONS

- Targeting a systolic blood pressure of < 120 mm Hg, as compared with < 140 mm Hg, in patients at high risk for cardiovascular events but without diabetes resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

- However, some adverse events occurred significantly more frequently with the lower target (syncope, hypotension, worse renal outcome)

- These adverse events need to be weighed against the benefits with respect to cardiovascular events and death that are associated with intensive control of systolic blood pressure.

The SPRINT Research Group. N Engl J Med 2015;373:2103-16. DOI: 10.1056/NEJMoa1511939

Supplementary Materials 

Editorial 1, Editorial 2 (Words from the Editors)

Clinical Decision (A case study is presented with experts debate on whether to maintain current treatment or modify treatment to lower blood pressure)

Correspondence
(Comment from other experts and reply from the authors, very important to take note)