hypertension: lower target blood pressure is better

 another large trial found a lower target blood pressure decreased cardiovascular events, the STEP trial (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients): see htn intensive rx STEP nejm2021 in dropbox or DOI: 10.1056/NEJMoa2111437 

 

Details: 

-- 8511 Chinese patients aged 60 to 80 with hypertension were enrolled in a prospective, multicenter (42 clinical centers), RCT to achieve a systolic blood pressure of 110 to 130 mmHg (intensive treatment group) versus 130 to 150 mmHg (standard treatment group), all recruited in 2017 

-- all had systolic blood pressure of 140 to 190 mmHg during three screening visits or were on antihypertensive meds 

-- mean age 66, 24% were 70 to 80 years old, 47% male, BMI 26, blood pressure 146/83 (33% >152 mmHg) 

-- baseline diabetes 19%, hyperlipidemia 37%, cardiovascular disease 6%, Framingham risk score >15% in 65% 

-- exclusions: patients with a history of ischemic or hemorrhagic stroke, secondary hypertension, hospitalization for MI within the past six months, coronary revascularization within the past year, sustained atrial fibrillation, class III or IV heart failure, uncontrolled diabetes, dilated cardiomyopathy (see supplement for full list) 

-- follow-up visits at one, two, and three months, then every three months for 48 months 

-- smart phone-based App given to all enrolled, 96% used this to transmit their home blood pressure readings, as an adjunct to office blood pressure 

-- intervention: olmesartan (an ARB), amlodipine (a CCB), and hydrochlorothiazide (not administered as initial therapy) 

-- office-based blood pressure was standardized: trained staff member (physician or nurse) had the patient rest for five minutes in a seated position and then the blood pressure was measured 3 times at one-minute intervals 

-- home-based blood pressure: used the same validated office blood pressure monitor (Omron Healthcare). Patients were trained to rest for at least five minutes in a seated position before the initial blood pressure reading and blood pressure was measured three times at least one minute apart. blood pressure was measured at least one day per week 

-- primary outcome: composite of stroke, acute coronary syndrome (acute MI or hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from a cardiovascular cause. Also measured were safety and renal outcomes 

-- secondary outcomes: individual components of the primary outcome, death from any cause, major adverse cardiac events (composite of primary outcome except for stroke), and renal outcomes (a decrease in renal function or development of end-stage renal disease) 

-- at both the third and fourth interim analyses, there was a significantly lower incidence of the primary outcome, leading to the recommendation to stop the analysis on December 31, 2020 with a median follow-up of 3.3 years instead of the planned 4 years 

 

Results: 

-- mean systolic blood pressure at one year: 127.5 mmHg in the intensive group and 135.3 mmHg in the standard group 

-- over the course of the study: mean decrease in systolic blood pressure from baseline was 19.4 mmHg in the intensive group and 10.1 mmHg in the standard treatment group (126.7 versus 135.9 mmHg) 

-- diastolic pressures were 76.4 versus 79.2 mmHg, respectively 

-- mean number of antihypertensive meds: 1.9 in the intensive group and 1.5 in the standard group 

-- home blood pressure measurements:  figure S5 in the supplement suggested a difference of 127/79 versus 135/82 mmHg, quite similar to the office-based blood pressure 

 

-- primary outcome: 

    -- intensive group: 147 patients (3.5%), 1.0% per year 

    -- standard group: 196 patients (4.6%), 1.4% for year 

        -- 36% decrease with intensive care, hazard ratio 0.74 (0.60-0.92), p=0.007 

        -- absolute difference of 1.1 percentage points 

 

-- individual components largely favored intensive treatment (review of their graphs show that the effect was evident within about 18 months of treatment and the curves splayed a bit over time with somewhat increasing benefit) 

    -- stroke: 33% decrease, HR 0.67 (0.47-0.97) 

    -- acute coronary syndrome: 33% decrease, HR 0.67 (0.47-0.94) 

    -- acute decompensated heart failure: 73% decrease, HR 0.27 (0.08-0.98) 

    -- coronary revascularization: 31% decrease, HR 0.69 (0.40-1.18), a statistical trend to decrease 

    -- atrial fibrillation: 4% decrease, HR 0.96 (0.55-1.68), not statistically different 

    -- death from cardiovascular causes: 28% decrease, HR 0.72 (0.39-1.32), not statistically different 

 

-- Prespecified subgroup analysis: benefit for the primary outcome was clear with stratification by age (60-69, 70-80), sex, baseline systolic blood pressure (<139 mmHg, 139-151 mmHg, >151 mmHg), diabetes at baseline, 10-year Framingham risk score ( <15% vs >15%), or blood pressure management (by home-based App versus usual management) 

-- diastolic blood pressure: sensitivity analysis found that those with diastolic blood pressure < 61 mmHg or pulse pressure > 60 mmHg or both within three months after randomization had similar results in the primary analysis (i.e. a low diastolic or high pulse pressure did not result in adverse primary outcomes) 

 

-- Adverse events: 

    -- only significant difference was the incidence of hypotension (3.4% versus 2.6%, p=0.03). No difference in dizziness, syncope, fractures, reduced eGFR in those with or without baseline CKD, or increase in serum creatinine 

 

Commentary: 

-- the study had similar results to the SPRINT trial, which overall showed benefit for lower target blood pressures, including those at least 75 years old (for the original study, see http://gmodestmedblogs.blogspot.com/2015/11/tighter-blood-pressure-control-sprint.html, for the subgroup of older people, see http://gmodestmedblogs.blogspot.com/2016/05/sprint-trial-elderly-subgroup-study-of.html) 

    -- however, the SPRINT trial did have some unusual/non-reproducible methods of measuring blood pressure  (see http://gmodestmedblogs.blogspot.com/2017/02/blood-pressure-guidelines-for-older.html for description), and systematically excluded diabetic patients, though those with glucose intolerance did better with lower blood pressure 

-- these results in the STEP study above were consistent across subgroups, and the only significant adverse effect was hypotension; no difference in dizziness, syncope, or fractures. it is important to note that they did not look specifically at falls, and they did not assess cognitive changes potentially associated with lower blood pressure (though these were not found in the SPRINT trial)

--one paramount concern raised over the past decade is that office-based blood pressures are not very predictive of cardiovascular events, leading the UK's NICE guidelines in 2011 to recommend ambulatory-based blood pressure measurements (ABPM) to be the primary tool to assess BP control, with the use of home-based blood pressure measurement (HBPM) as an acceptable alternative. 

    -- this was followed 4 years later by the USPSTF (for USPSTF recommendations for ABPM, see: http://gmodestmedblogs.blogspot.com/2015/10/uspstf-guidelines-on-blood-pressure.html, and https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening with their strong recommendation for ABPM and HBPM; and the Am Heart Assn support for ABPM and HBPM http://gmodestmedblogs.blogspot.com/2019/03/new-aha-blood-pressure-measurement.html

    --so, one very important finding in this study (which needs to be replicated in another large study) was that their standardized office-based blood pressure, through the methods as described above, corresponded remarkably well to the home-based pressures of the participants. The study also does describe a consistent manner of doing home blood pressure recordings, which has been done quite variably in the home blood pressure monitoring studies though still correlated pretty well with ABPM readings (see htn home based bp jcardiovascrisk2002 in dropbox, or Mule G. J Cardiovasc Risk 2002; 9: 123).  

    --The study also validates using these standardized home-based blood pressure values as an effective means to control blood pressure, with the pluses of empowering patients in their own care, as well as decreasing the need for on-site patient visits and their consequences (having to take off work, have family member accompany them to the visit, a significant time commitment to transport themselves to the office and back, potential exposure to respiratory viruses circulating in the clinical office, …). And it makes sense to train patients to do their blood pressures in a consistent and standardized manner. Prior studies have used very different approaches: some averaging 3 measurements after 5-minute rest, some discarding the first one and averaging the last 2,...

        -- One issue is the accuracy of the home blood pressure monitor. In the study, they used a specific one, the same one they used in the office, so this is not necessarily generalizable. My approach to ensure the accuracy of their blood pressure cuff has been to have the patient bring their own cuff with them for an office visit to assess how they themselves take the blood pressure, their results, and compare it to simultaneous measurements of blood pressure by myself or other office personnel 

        --for some specific studies on home-based monitoring: see http://gmodestmedblogs.blogspot.com/2016/04/home-blood-pressure-monitoring.html , http://gmodestmedblogs.blogspot.com/2018/03/home-bp-monitoring.html 

-- their use of blood pressure medicines is certainly reasonable. Notably they did not use hydrochlorothiazide as a single agent, a decision which is justified by much of the literature (see http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html, though a compilation of large databases did not find this: http://gmodestmedblogs.blogspot.com/2019/10/thiazides-best-monotherapy-for-htn.html

-- SPRINT did find that there was also a decrease in cardiovascular mortality, not found in this study. ?? why. was this study too short or not have enough people to achieve these results? a difference in cardiovascular risk factors (measured or unmeasured) in a homogenous Chinese population vs the broader one in SPRINT?

    -- of note the SPRINT trial did find increased life expectancy in those with lower blood pressure, in a secondary analysis (see http://gmodestmedblogs.blogspot.com/2020/03/bp-tight-control-increases-life.html )

 

Limitations: 

-- unclear methodologically how they computed the blood pressure. it was measured 3 times at 1-minute intervals. were the results averaged? did they ignore the first reading and average the next two?  i suspect they averaged them, though not mentioned. and the latter approach may eliminate the potential bump in the first reading that might reflect more of a "white coat" effect

-- no measurement of cognitive changes with more aggressive therapy, though these SPRINT trial did not find this to be a problem 

-- this was a homogeneous Han Chinese population, limiting generalizability of these results. However, this does complement the more diverse SPRINT trial 

-- the Framingham risk score is not necessarily as predictive in the Chinese community and may overestimate their cardiovascular risk

-- there was no multivariate adjustment made for the traditional cardiovascular risk factors (eg lipids, smoking) or others (stress, income inequality, living conditions, diet, exercise.....), though they did have subgroup analysis for diabetes

-- this study did not include those >80yo, so not generalizable to older patients. SPRINT did include those >75yo, though the mean age was 80 in this elderly group. but there was no analysis in SPRINT on the effect of lower blood pressure on those specifically in the 80-100yo range

-- and, as noted in several blogs previously, stopping the study short of the design will likely increase the perceived efficacy (which is why they stopped the study) but might limit the appearance of adverse effects

So, another large study suggesting that lower blood pressures are not only safe but protective for cardiovascular outcomes. I believe many of us are already doing this based on the SPRINT trial, and this study adds to the appropriateness of that. And a major finding was that their approach to office-based blood pressure measurement, a standardized and more broadly generalizable one, was highly predictive of clinical outcomes and not significantly different from their standardized out-of-office measurement....  

geoff

 

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