A SPRINT to lower blood pressure targets?



by E. L. Schiffrin, Canada

Ernesto L. SCHIFFRIN, MD, PhD
Lady Davis Institute for Medical
Research, and Department of
Medicine, Sir Mortimer B.
Davis-Jewish General Hospital
McGill University
Montreal, QC, CANADA

The recent findings of SPRINT (Systolic blood PRessure INtervention Trial), a landmark trial in hypertension, suggest that there are significant benefits in targeting a systolic blood pressure lower than 120 mm Hg in patients at high cardiovascular risk, rather than the classic target of lower than 140 mm Hg. Following this trial, the medical world continues to debate these benefits. This article reviews current evidence for and against lower blood pressure targets, the potential impact of this evidence on lowering blood pressure targets in future guidelines, the importance of the method of measuring blood pressure if one is to intensify antihypertensive treatment to achieve these new lower blood pressure goals for treatment, and the role that initiation with combination therapy may have in reaching these lower targets.

SPRINT (Systolic blood PRessure INtervention Trial) was developed to investigate whether hypertensive patients at high cardiovascular risk benefited from being treated to a systolic blood pressure (BP) lower than 120 mm Hg, in contrast to the usual target systolic BP of 140 mm Hg.1 Previous trials in this population (SHEP [Systolic Hypertension in the Elderly Programme],2 Syst-Eur [Systolic Hypertension in Europe],3 and HYVET [HYpertension in the Very Elderly Trial],4 the latter only in subjects aged more than 80 years old) had demonstrated efficacy in prevention of cardiovascular events when systolic BP was lowered to below 150 mm Hg (HYVET) or close to or below 140 mm Hg (in the other trials). There was no evidence on whether lowering systolic BP much below 140 mm Hg would produce additional benefits. Accordingly, there was equipoise between a standard therapy group treated to below 140 mm Hg, and an intensive therapy group treated to a systolic BP of less than 120 mm Hg.

The trial recruited individuals aged more than 50 years old, already treated or not with antihypertensive agents.5 Subjects were required to have systolic BP between 130 and 180 mm Hg, and another risk factor for cardiovascular events. This risk factor could be age above 75 years (28% of subjects), chronic kidney disease (CKD) patients with estimated glomerular filtration rate (eGFR) 20-59 mL/min/1.73 m2 (28%), clinical or asymptomatic cardiovascular disease, or a Framingham Risk Score for 10-year cardiovascular disease risk ≥15%. Because diabetic patients were part of the ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial,6 which was taking place when the SPRINT trial was being designed, and the same applied to patients with prior stroke in the SPS3 (Secondary Prevention of Small Subcor- tical Strokes) trial,7 these patients were excluded. Also excluded were CKD patients with eGFR <20 mL/min/1.73 m2 and patients with congestive heart failure, polycystic kidney disease, proteinuria >1 g/day, orthostatic hypotension with systolic BP <110 mm Hg, or adherence concerns. Excluded as well were individuals residing in nursing homes or those with a diagnosis of dementia. The study was funded by the US National Institutes of Health through the National Heart, Lung and Blood Institute.

For SPRINT, 14 692 subjects were screened, and 9361 were randomized into an intensive therapy group with a target systolic BP of less than 120 mm Hg (4678 subjects) or a standard therapy group with a target systolic BP of less than 140 mm Hg (4683 subjects). On August 20, 2015, the National Heart, Lung and Blood Institute ordered the study stopped after a mean duration of 3.26 years because of dramatic benefit in the intensified therapy group. The results were presented on November 8, 2015, at the scientific sessions of the American Heart Association and published that day online in the New England Journal of Medicine and in print the following December.5 The systolic BP of 121.5 mm Hg in the intensive therapy group versus 134.6 mm Hg in the standard therapy group in SPRINT was associated with a 25% relative risk reduction of the primary end point (all myocardial infarction, non– myocardial infarction acute coronary syndrome, all stroke, all heart failure, and cardiovascular death).

Of interest, among the components of the primary outcome, heart failure experienced a significant relative risk reduction of 38% and cardiovascular death of 43%, whereas myocardial infarction, acute coronary syndrome, and stroke were not significantly reduced. There was a significant relative risk reduction of all-cause mortality of 27%. Benefits occurred consistently across all prespecified groups, including those with or without prior CKD, age older or younger than 75 years, female or male, African-American or not, prior cardiovascular disease or not, and systolic BP at entry ≤132, >132 to <145 mm Hg, or ≥145 mm Hg. There was a trend toward greater benefit with lower systolic BP at entry, although this was not statistically significant. Whether this may have resulted from allowing BP to drift upward in those patients entering the study with lower baseline systolic BPs who were randomized to standard therapy and who accordingly had to be down titrated, which might have harmed high cardiovascular risk patients whose BP had previously been intensively controlled, will need to be clarified. Patients with CKD and those without CKD did not differ with respect to renal outcomes on either treatment, although among those without CKD at baseline, significantly more subjects under intensified therapy than in the standard group exhibited a more than 30% reduction in eGFR to a value of less than 60 mL/min/1.73 m2, a change whose significance remains unclear.

In a more recent publication, it was shown that the subjects older than 75 years of age benefited as much as the total group if they were in the intensive therapy group, whether or not they were fit or less fit.8 This result is particularly important considering that some guidelines have allowed target systolic BP for elderly subjects over 60 years of age to drift upward to less than 150 mm Hg,9 and most others have recommended a goal systolic BP of less than 150 mm Hg for the very elderly above 80 years old, based on HYVET.10-12

Serious adverse effects occurred with relatively low frequency in both the intensified and the standard therapy group.5 Hypotension, syncope, electrolyte abnormalities (such as hyponatremia and hypokalemia), acute kidney injury, and acute renal failure occurred with low frequency, but to a greater extent in the intensified therapy group. Interestingly, orthostatic hypotension was more frequent, but rare, in the standard therapy group. There was no difference in injurious falls between the groups.

The conclusions to be drawn from SPRINT are that more intensive treatment of BP leads to a reduction in cardiovascular events and all-cause mortality, with no difference in serious adverse events, and that treatment benefit is consistent across prespecified subgroups. The SPRINT findings are consistent with meta-analyses that suggest the benefits of more intensive treatment. In a meta-analysis of 123 studies including 623 815 subjects, Ettehad et al13 showed that BP lowering significantly reduces vascular risk across various baseline BP levels and comorbidities, providing support for lowering systolic BP to less than 130 mm Hg. These results suggest that BP-lowering treatment should be provided to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and/or CKD. Further supportive data for this position come from a meta-analysis of 14 studies by Xie et al14 comprising 43 483 subjects, a followup of 3.8 years, and a mean BP reduction of 7 mm Hg. These authors showed that intensive BP lowering provided greater vascular protection than standard regimens. In high-risk patients, there were additional benefits from more intensive BP lowering, including for those with systolic BP below 140 mm Hg. The number-needed-to-treat in the high-risk population trials was 94 and in lower risk trials, 186.14

In contrast to SPRINT,5 ACCORD6 failed to prove that intensive BP lowering was superior to standard BP lowering for diabetic subjects. Since diabetic persons are at high risk of cardiovascular events—in many ways similar to SPRINT patients— why did the two studies produce differing results? For one, the results actually went in the same direction, but ACCORD was probably underpowered. Secondly, it could be that the factorial design, with a hypoglycemic and a lipid-lowering arm, could have contributed to the absence of a positive outcome. So perhaps a new, adequately powered study in diabetic patients will now be needed to know how low to go with BP in diabetes.

Based on the quite dramatic results of SPRINT, Hypertension Canada has already introduced a SPRINT-based recommendation for new goals and intensified treatment of hypertensive patients with high cardiovascular risk.15 We recently published our arguments for this recommendation that essentially replicates the inclusion and exclusion criteria of SPRINT and recommends a systolic BP goal of 120 mm Hg or less for SPRINT like patients.16 However, it should be noted that Hypertension Canada guidelines recommend automated office blood pressure (AOBP) measurement as the preferred method for measuring BP.15 Several studies have shown that when measuring BP with a manual technique, BP values are 10-15 mm Hg higher than those obtained using AOBP measurement.17 In fact, simply having the health-care professional leave the side of the patient while BP is being measured with AOBP (unattended or unobserved AOBP) will result in lower BP values.18 Since unattended AOBP measurement was part of the protocol in SPRINT, and generally seems to have been carried out during the study, Hypertension Canada’s recommendation for intensified treatment goals (systolic BP ≤120 mm Hg) requires the use of unattended AOBP measurement.15 For this reason, the International Society of Hypertension has issued the following recommendation: “The practical message from the International Society of Hypertension is to strive for a systolic BP target of 130 mm Hg in most patients with hypertension.12 This is especially important considering that BP measurements in the community worldwide are not likely to be performed using the SPRINT protocol. Advocating a target of <120 mm Hg is not justified in clinical practice, and in any case would incur the costs of increased clinic visits, more intensive health care, and more medications. This applies particularly to low- and middle-income countries with resource poor health-care systems.”12

Do we need a new definition of hypertension after SPRINT? We have made some recommendations in this regard.19 Since AOBP measurement is not yet 100% available, when BP is measured with manual BP instruments, the definition of hypertension should remain BP ≥140/90 mm Hg, with a target for treatment in general <140/90 mm Hg, although the goal in most patients should be close to 130/80 mm Hg. The target BP in high cardiovascular risk, including CKD, elderly, patients with a Framingham Risk Score of ≥15%, and probably diabetic subjects,11,15 should be <130/80 mm Hg. However, if BP is measured with guideline-directed unattended AOBP following a 5-minute rest period, as in SPRINT, the definition of hypertension should be BP ≥130/80 mm Hg. In high cardiovascular risk subjects the threshold for treatment should be BP ≥130/80 mm Hg, with a target systolic BP of ≤120 mm Hg.15,19 For those subjects that do not fit the SPRINT criteria, including uncomplicated hypertension without target organ damage (although without any evidence and as an extrapolation from SPRINT), target BP should be <130/80 mm Hg when measuring BP with unattended AOBP.

I believe that the major conclusions to be derived from SPRINT for management of hypertension are that with the increase in research and popularity as well as use of AOBP measurement, after more than 100 years we finally have an approach to reliably and accurately measure BP in the office. Beyond the SPRINT target BP, one of the more important conclusions to draw from this trial is the idea that intensifying treatment will improve outcomes, including in the elderly.

The question now remains, how do we intensify treatment and overcome the hurdle that multiple pills represent for adherence to treatment?20 This is particularly so for high cardiovascular risk patients who need, in addition to BP medications, lipid-lowering agents and other additional drugs, for example antidiabetic agents. Diabetic subjects often require several hypoglycemic medications, which adds up to many medications (and sometimes more pills) to be taken daily. We know that in SPRINT the group receiving intensified therapy took an average of 2.8 antihypertensive agents compared to the standard therapy group that only took an average of 1.8 medications.5 This is similar to other trials where in order to achieve greater control of BP, it has been necessary to give two to four agents. However, it has been shown that combining two drugs at half the standard dose of each is superior to monotherapy, and that additive BP-lowering effects of two drugs are not associated with additive adverse effects.21,22

We also know that the more medications there are, the lower the adherence to treatment.23 The answer to this is single pill combinations for the treatment of hypertension, including in some cases drugs for the treatment of dyslipidemia as well. The most frequent reason for resistance to treatment relates to medication-related causes, including a suboptimal regimen of drugs leading to nonadherence.23 Frequent changes in drugs, so called therapeutic turbulence,23 and therapeutic inertia24 both lead to poor BP control. As a consequence, this has led to studies that showed that combining antihypertensive drugs may result in greater antihypertensive benefits than intensifying monotherapy, with a lower incidence of adverse events.21,22 Following these studies it was demonstrated that initiating treatment of hypertension with combination therapy resulted in fewer BP-related complications, including cardiovascular, coronary, and cerebrovascular outcomes.25,26 Use of low-dose combinations was effective in rapidly controlling BP in the STITCH (Simplified Treatment Intervention To Control Hypertension) trial.27 In fact, the STITCH trial was able to demonstrate more rapid BP control using half doses of antihypertensive agents in combination than using a guideline- directed protocol,27 which could result in a reduction of cardiovascular events. Combination therapy has indeed been shown to have a better tolerability profile than individual antihypertensive agents.28

In conclusion, measuring BP accurately (preferably with AOBP), intensifying treatment, and using single-pill combinations to address both adherence and tolerability concerns will go a long way to improving outcomes and preventing cardiovascular events in patients with hypertension. ■

References
1. Ambrosius WT, Sink KM, Foy CG, et al; SPRINT Study Research Group. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials. 2014;11:532-546.
2. SHEP Cooperative Research Group. 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). JAMA. 1991;265: 3255-3264.
3. Staessen JA, Fagard R, Thijs L, et al; Systolic Hypertension in Europe (Syst- Eur) Trial Investigators: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-764.
4. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. Engl J Med. 2008;358:1887- 1898.
5. Wright JT Jr, Williamson JD, Whelton PK, et al; SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2116.
6. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585.
7. Benavente OR, Coffey CS, Conwit R, et al; SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382:507-515.
8. Williamson JD, Supiano MA, Applegate WB, et al; SPRINT Research Group. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315: 2673-2682.
9. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311: 507-520.
10. Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31: 1281-1357.
11. Quinn RR, Hemmelgarn BR, Padwal RS, et al; Canadian Hypertension Education Program. The 2010 Canadian Hypertension Education Program (CHEP) recommendations for the management of hypertension: part I – Blood pressure measurement, diagnosis, and assessment of risk. Can J Cardiol. 2010; 26:241-248.
12. Weber MA, Poulter NR, Schutte AE, et al. Is it time to reappraise blood pressure thresholds and targets? A statement from the International Society of Hypertension-a global perspective. Hypertension. 2016;68:266-268.
13. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387:957-967.
14. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435-443.
15. Leung AA, Nerenberg K, Daskalopoulou SS, et al; CHEP Guidelines Task Force. Hypertension Canada’s 2016 Canadian Hypertension Education Program guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2016;32:569-588.
16. Padwal R, Rabi DM, Schiffrin EL. Recommendations for intensive blood pressure lowering in high-risk patients, the Canadian viewpoint. Hypertension. 2016; 68:3-5.
17. Myers MG, Godwin M, Dawes M, Kiss A, Tobe SW, Kaczorowski J. Measurement of blood pressure in the office: recognizing the problem and proposing the solution. Hypertension. 2010;55:195-200.
18. Martin CA, Cameron JD, Chen SS, McGrath BP. Measurement of blood pressure in the office. Hypertension. 2010;56:e11.
19. Schiffrin EL, Calhoun DA, Flack JM. Do we need a new definition of hypertension after SPRINT? Am J Hypertens. 2016;29:1127-1129. Editorial.
20. Garg JP, Elliott WJ, Folker A, Izhar M, Black HR; RUSH University Hypertension Service. Resistant hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens. 2005;18:619-626.
21. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427.
22. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
23. Caro JJ, Speckman JL, Salas M, Raggio G, Jackson JD. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. Can Med Assoc J. 1999;160:41-46.
24. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension. 2006;47:345-351.
25. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. ypertension. 2011;58:566-572.
26. Gradman AH, Parisé H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension. 2013;61:309-318.
27. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53:646-653.
28. Laurent S, Parati G, Chazova I, et al. Randomized evaluation of a novel, fixeddose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a first-step treatment in hypertension. J Hypertens. 2015;33:653-661.

Keywords: SPRINT; systolic blood pressure; intervention; lower blood pressure target; measurement method; treatment initiation; combination therapy; automated office blood pressure measurement