Author + information
- aDepartment of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana
- bDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama
- ↵∗Reprint requests and correspondence:
Dr. Paul K. Whelton, Department of Epidemiology #8318, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Room 2018, New Orleans, Louisiana 70112.
Event-based clinical trials are designed to provide internal validity and sufficient power to identify a treatment benefit if one exists while minimizing a finding due to chance (1), and they are therefore usually conducted in selected high-risk populations. For many trials with good internal validity, a major challenge is understanding how much the findings should be generalized. This is the case for SPRINT (Systolic Blood Pressure Intervention Trial). SPRINT was a large, randomized controlled trial that reported a reduced incidence of cardiovascular disease (CVD) events and all-cause mortality by more intensive treatment to a lower systolic blood pressure (SBP) goal (<120 mm Hg), compared with a conventional goal (<140 mm Hg) (2). SPRINT was conducted in U.S. adults ≥50 years of age with hypertension (HTN), baseline SBP of 130 to 180 mm Hg, and at least 1 additional indication of CVD risk. Diabetes, stroke, congestive heart failure (ejection fraction <35%), polycystic kidney disease, heavy proteinuria (>1 g/day), advanced chronic kidney disease (estimated glomerular filtration rate <20 ml/min/1.73 m2), and adherence concerns were all reasons for exclusion. An estimate based on National Health and Nutrition Examination Survey data suggested that approximately 16.8 million U.S. adults meet SPRINT eligibility criteria (6.6 million with SBP 130 to 139 mm Hg and 10.2 million with SBP ≥140 mm Hg) (3). This finding represents about 30% of the 55.7 million adults with SBP of 130 to 139 mm Hg (26.6 million) or ≥140 mm Hg (29.1 million). How broadly SPRINT findings should be generalized is an important and challenging consideration for clinicians, guideline committees, and policy decision makers.
In this issue of the Journal, Ko et al. (4) used 2 databases to explore questions that pertain to management of high BP and CVD risk in the Republic of Korea. Using nationally representative survey data, they report that a much smaller percentage of adults with HTN (defined as physician-diagnosed and patient-reported HTN or SBP ≥130 mm Hg) met the SPRINT treatment goal of <120 mm Hg compared with the proportion that met 2014 JAMA guideline treatment goals (11.9% vs. 70.8%, respectively) (5). Using a Framingham Heart Study risk prediction model and a Korean-derived coronary heart disease (CHD) risk prediction model, they found that the 10-year predicted risk of CVD events was considerably higher (about 24%) in those with a BP below the 2014 JAMA guideline recommendations but above the SPRINT BP goal than in those who met the SPRINT goals. In a separate analysis, based on an average follow-up of 6.6 years in the Korean National Health Insurance Service health examinee cohort (n = 67,965), there was a statistically significant trend for progressively higher risk of major CVD events (a composite of nonfatal myocardial infarction [MI], nonfatal stroke, or fatal CVD), nonfatal MI, and nonfatal stroke in participants with increasing SBP. The CVD event rate was highest in Korean adults whose SBP exceeded the goals recommended in the 2014 JAMA guidelines and lowest in those whose SBP was below the SPRINT goal.
None of these findings (4) are surprising. They do provide quantitative estimates of the extent to which SPRINT BP goals and 2014 BP recommendations were being achieved in Korea, as well as potential estimates of the CVD risk implications associated with various decisions for diagnosis and effective treatment of HTN in Korean adults. Changing the target for HTN treatment to SBP <120 mm Hg for all Korean adults would require considerable effort and would almost certainly result in a substantial reduction in HTN control rates, but these data suggest that more intensive reduction in SBP may also result in substantial reduction in CVD risk.
The findings of Ko et al. (4) must be interpreted with caution. The survey data estimates of BP levels during HTN treatment were collected before publication of both the SPRINT main results paper and the 2014 BP recommendations paper, at a time when Korean guidelines for HTN management recommended much less intensive reduction in BP than would meet SPRINT goals (6). This study provides CVD event rate estimates based on experience in all Korean adults with HTN, whereas the SPRINT experience was derived from a much more restricted sample of older U.S. adults with HTN and a high risk of CVD. The estimates for reduction of CVD risk associated with lowering SBP below the SPRINT goals compared with the 2014 JAMA guidelines were based on observational studies rather than on direct experience in a randomized clinical trial. There were also important differences between the definition of CVD in the Korean studies and SPRINT. The Framingham and Korean-derived risk models used to predict CVD risk in this study were restricted to CHD risk (7,8). In SPRINT, the primary outcome was a composite of MI, acute coronary syndrome (non-MI acute coronary syndrome), stroke, acute decompensated heart failure, and CVD-related death. Heart failure and CVD-related death were the components most affected by more intensive reduction in BP (hazard ratios of 0.62 [p = 0.002] for heart failure and 0.57 [p = 0.005] for CVD-related death). In contrast, the hazard ratios for MI and non-MI acute coronary syndrome were 0.83 (p = 0.19) and 1.00 (p = 0.99), respectively.
Additional observational research using the Korea National Health and Nutrition Examination Survey and the Korean National Health Insurance Service could aid in interpreting the potential applicability of the SPRINT results. In the present analysis by Ko et al. (4), the SPRINT SBP treatment goal was applied to all Korean adults. Focusing only on those who meet the SPRINT eligibility criteria would provide the greatest confidence for generalizing the results. There may be other subgroups of Korean adults with HTN who do not meet the SPRINT eligibility criteria but could potentially benefit from more intensive lowering of their BP, especially those at high risk for CVD. Determining the potential reduction in population-attributable risk associated with more intensive BP treatment in a SPRINT-eligible population and other population subgroups could inform decisions regarding intensity of antihypertensive treatment. An additional unanswered question is how to manage patients with hypertension but low CVD risk. It would be useful to understand the reasons for the reported discrepancy between the Framingham and Korean risk modeling instruments. Ko et al. reported that the mean 10-year predicted CVD risk when using the Framingham score was 7.65% for Korean adults meeting the 2014 JAMA guidelines but not the SPRINT target goals. However, the 10-year CHD risk was only 1.67% when the Korean risk score model was applied. Imprecision in the calibration of CVD risk scores could lead to overestimation or underestimation of CVD risk. Intensive BP reduction in patients at low risk for CVD would result in little if any risk reduction benefit, at least in the short term. This scenario underscores the importance of ensuring that CVD risk–estimating instruments provide an accurate estimate for the population in which they are being applied, especially when they are used to guide clinical decision making.
The analyses by Ko et al. (4) underscore the need for conduct of SPRINT-like trials in populations that differ from those included in the initial study. In countries such as Korea, stroke plays a much more important role as a cause of CVD morbidity and mortality compared with the role it plays in the United States (9). A substantial proportion of adults with HTN reside in countries where stroke is the dominant type of CVD experienced (10), and nonatherosclerotic hemorrhagic stroke is more common than in high-income countries such as the United States (11). In addition, a well-powered trial is urgently needed to resolve the question of whether more intensive reduction in BP in patients with diabetes mellitus is beneficial (12). Until these and other SPRINT-like trials have been completed, guideline committees and the practice community must use caution when generalizing SPRINT results to adults with a profile that differs from the participants in the parent study.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Whelton serves as chair of the SPRINT steering committee. Dr. Muntner has received grant support from Amgen Inc. unrelated to the topic of the current paper.
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