I have changed my blood pressure recommendations for a subgroup of people with criteria similar to those studied in SPRINT based on the early termination and results of this trial. Over the past 25 years a number of clinical outcome trials have evaluated the effectiveness of blood pressure reduction on cardiovascular (CV) outcomes¹. All these trials show significant CV risk reduction and especially a reduced incidence of heart failure¹.

SPRINT was designed to answer the question: ”Does a lower blood pressure level further reduce CV events and all-cause mortality in people with very high CV risk?”

SPRINT was specifically focused on people with higher CV risk than the ACCORD study, primarily driven by advanced chronic kidney disease (CKD), older age, and without diabetes. It was also a much larger trial than ACCORD in order to properly power the study to address this question. The primary analysis of ACCORD did not demonstrate a benefit of a lower BP target when reviewed in the context of aggressive glycemic control. However, the confidence limit did not exclude a benefit as large as a 27% improvement in the composite CV disease outcome. Moreover, a reanalysis of the ACCORD BP trial demonstrated that intensive BP treatment alone with usual glucose control, compared with combined standard treatment, improved major CVD outcomes (hazard ratio 0.67; 95% CI 0.50-0.91)².

SPRINT had a mean age of 68 years, with almost 29% of the 9300+ subjects with Stage 3 or higher CKD (eGFR <60 ml/min/1.73m2), a known independent CV risk factor³. Moreover, a little over 28% were over age 75. Given these demographics of very high CV risk, there was a clear benefit of CV risk reduction and all-cause mortality in the group randomized to a systolic BP of <120 mmHg.

Reviewing the specific outcomes that comprised the composite primary endpoint was quite revealing, in that the benefit was driven predominantly by heart failure, CV death and non-fatal heart failure. There was NO further benefit on reduction of ischemic type events. This is not surprising, since previous trials such as the Hypertension in Very Elderly (HYVET)⁴, and the Systolic Hypertension in elderly People (SHEP)⁵ and the Systolic Hypertension in Europe (SYST- Eur)⁶ trials all demonstrated the greatest risk reduction on heart failure events when blood pressure was lowered, albeit to much higher levels than SPRINT. In the subgroup analysis of SPRINT, everyone garnered a benefit regardless of age, sex or race, although African Americans tended not to have as great a CV risk reduction.

The interpretation of these outcomes needs careful attention. To be clear, they do NOT indicate that everyone needs to have a systolic BP <120 mmHg to reduce events. These data are generalizable only to those who have the same demographic and clinical status as defined in the inclusion criteria of the study. Contraindications to the more aggressive target include:

• Arterial stiffness. SPRINT like HYVET, recruited people who had relatively good arterial compliance. These individuals can tolerate lower pressures while people with low baseline diastolic BPs at or below 60 mmHg cannot.
• People over age 75 who have a history of falls, vertigo, orthostatic hypotension or are frail should not necessarily have their BP reduced to <120, particularly if they have a pulse pressure of >70 mmHg at baseline.

When evaluating SPRINT results, remember that the standard of care in SPRINT was the highest of any trial: cholesterol management was excellent and almost all participants were on a long acting medications. This not only ensures reduction in ischemic events but also volume events, such as heart failure. Perhaps the key element to the success of SPRINT is the ability to maintain BP control over the 24 hour period, a hallmark that is likely associated with better outcomes⁷ and not present in older trials. Clearly, those with the entry criteria for this study should be encouraged to participate in getting their BP lower to further reduce heart failure related events including death.

As a nephrologist I have to say that while the follow-up was not that long, lower pressure did not make a difference to meaningfully slow CKD progression. SPRINT now makes the fourth randomized BP level trial to show a failure of benefit of lower BP on CKD progression⁸. Thus, SPRINT provides meaningful data to help guide aggressiveness of BP lowering in older people with very high CV risk. It does not apply to people with marked arterial stiffness defined by high pulse pressures or those who met the exclusion criteria of the trial. Note that long acting thiazide-like diuretics like chlorthalidone were used in essentially everyone and hence, heart failure benefit drove the response in the lower BP group. The findings related to all-cause mortality are a mystery to me and have no plausible explanation. SPRINT MIND continues as does the follow-up of the CKD group so more data to come and hopefully provide new directions which can further reduce morbidity.

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References

1. Oliva RV, Bakris GL. Management of hypertension in the elderly population. J Gerontol A Biol Sci Med Sci 2012;67(12):1343-1351.
2. Margolis KL, O'Connor PJ, Morgan TM et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care 2014;37(6):1721-1728.
3. Fox CS, Matsushita K, Woodward M et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta- analysis. Lancet 2012;380(9854):1662-1673.
4. Beckett N, Peters R, Tuomilehto J et al. Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial. BMJ 2012;344:d7541.
5. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991;265(24):3255-3264.
6. Staessen JA, Fagard R, Thijs L et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350(9080):757-764.
7. Yano Y, Bakris GL. Recognition and management of masked hypertension: a review and novel approach. J Am Soc Hypertens 2013;7(3):244-252.
8. Upadhyay A, Uhlig K. Is the lower blood pressure target for patients with chronic kidney disease supported by evidence? Curr Opin Cardiol 2012;27(4):370-373.

Keywords: African Americans, Aged, Blood Pressure, Blood Pressure Determination, Chlorthalidone, Cholesterol, Diuretics, Diabetes Mellitus, Follow-Up Studies, Glucose, Hypertension, Hypotension, Hypotension, Orthostatic, Incidence, Renal Insufficiency, Chronic, Risk Reduction Behavior, Standard of Care, Thiazides, Vascular Stiffness, Vertigo, Secondary Prevention

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