Editor's Note: This is Part II (Cons) of a two-part Expert Analysis. Go to Part I (Pros).

The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients aged 50 years or more who had a systolic blood pressure (SBP) equal or greater than 130 mm Hg and a high cardiovascular risk to an antihypertensive treatment aimed at achieving an SBP of <120 mm Hg (intensive treatment) or <140 mm Hg (standard treatment).¹ From an average initial value of about 139 mm Hg, the antihypertensive drugs employed lowered SBP to 121 and 136 mm Hg in the two groups, respectively. This went on for more than three years, after which the trial was stopped because of a lower rate of the primary composite cardiovascular outcome in the intensive as compared to the standard treatment patients (-25%, P ≤ 0.001). The intensive treatment group also showed a reduction in the risk of all-cause death (-27%, P = 0.003), the favourable effects of the greater SBP lowering including both genders and all races, with an extension to elderly patients, patients with chronic kidney disease and individuals with or without CVD history.

SPRINT is an important trial which suggests that when cardiovascular risk is high, antihypertensive treatment might be initiated in individuals with an SBP in the high-normal range. It further conveys the strong message that in these patients, treatment should pursue an aggressively low BP target, with no conservative attitude in the elderly as compared to younger patients. This challenges current hypertension guidelines,^2-4 which recommend antihypertensive treatment to: 1) start only if patients have a SBP ≥140 mm Hg; 2) aim at a SBP goal of <140 mm Hg, regardless the level of cardiovascular risk; and 3) adopt higher systolic BP thresholds and targets in elderly patients. However, before accepting SPRINT as the source of an indisputable new evidence that will modify treatment of the most important cardiovascular risk factor worldwide in a much more interventional fashion,⁵ possible drawbacks and difficulties of interpreting its data and extending them to clinical practiced should be mentioned and discussed.

My first consideration is that more than 90% of the SPRINT patients were under antihypertensive drug treatment at baseline. This means that their original SBP was not in the high-normal range, as found by the measurement performed before randomization, but presumably in grade 1 or perhaps even grade 2 hypertension, given that many patients were taking two drugs and, thus, being under a clearcut BP-lowering influence. This will represent a strong counter-argument to an interpretation of the results as supportive of initiation of antihypertensive drug treatment at <140 mm Hg SBP in both middle-aged and elderly patients in whom current charts or scores quantify cardiovascular risk as high.

My second consideration is that SPRINT excluded patients with diabetes mellitus. This fails to provide information on individuals in whom high BP is extremely common⁶ and the protective effect of BP-lowering treatment well documented.⁷ Unfortunately, it also prevents comparisons between the SPRINT favourable findings and the negative findings obtained in the large number of diabetic patients of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,⁸ in which an antihypertensive treatment that lowered SBP to values similar to those achieved in SPRINT did not affect cardiovascular outcome and all-cause mortality compared to patients remaining at an SBP similar to that of the SPRINT standard-treatment group. At present no convincing hypothesis can explain this puzzling discrepancy. What seems to be obvious, however, is that the difference between the results of SPRINT and ACCORD cannot be simplistically interpreted to mean that intensive BP reductions are protective when cardiovascular risk is high, except when the high risk is due to diabetes. This clashes with the large body of evidence that the relationship between treatment-induced BP reductions and events is at least qualitatively similar in non-diabetic and diabetic patients.⁹ And that in both conditions BP reduction "per se" (i.e., irrespective of the drug employed) plays a substantial protective role.¹⁰

A third consideration is that a reduced development of heart failure (-38%, P = <0.002) largely drove the overall cardiovascular benefit accompanying the intensive BP reduction in SPRINT. This is in line with the marked protective effect of antihypertensive treatment on heart failure recently shown by a meta-analysis of a large number of trials,¹¹ albeit for BP reductions smaller and on-treatment BP levels much higher than those of the SPRINT trial. However, although the SPRINT criteria employed to diagnose heart failure were by no means worse than in other trials, it is undeniable that in its incipient phase (i.e., the phase aimed at by antihypertensive treatment trials) diagnosis of heart failure has a subjective symptom-related component that makes it softer than other cardiovascular outcomes. It would be important to discuss whether this might have increased the size of the heart failure benefit, also considering that SPRINT investigators were unblinded to patients belonging to one or the other group, and there was a greater use of diuretics in the intensive treatment patients, which might have masked the symptoms of heart failure rather than preventing it.

Apart from the size of the heart failure benefit apart, it is highly surprising that the intensive BP reduction in SPRINT brought about no significant benefit on the risk of either myocardial infarction or stroke. Previous data have raised the possibility that at low achieved BP values a J-curve phenomenon increases the incidence of myocardial infarction and, thus, offsets the coronary benefit of smaller BP reductions.¹² However, stroke has almost invariably been shown to be markedly reduced by treatment-induced BP reductions,¹³ the protective effects being well visible shortly after initiation of antihypertensive drug administration in the setting of both secondary and primary prevention (i.e., in patients with but also without a history of cerebrovascular disease such as those recruited for SPRINT). Furthermore, at variance from heart failure and coronary disease, stroke has been the outcome more frequently and clearly reduced with a progressive reduction of SBP down to 120 mm Hg or below,^14-17 a latest example being the observation made on the diabetic patients of the ACCORD trial.⁸ Because the type of antihypertensive treatment employed does not affect the linear relationship between BP and stroke reductions, drug differences between SPRINT and other studies hardly offer a credible explanation. Thus, this remains a puzzling finding of the SPRINT trial.

In SPRINT, the marked SBP drop achieved in the intensive treatment group was accompanied by a marked increase in the incidence of side effects, such as hypotension, syncope, and electrolyte abnormalities. Kidney injuries and failures were also significantly increased, presumably because of the ischemic effect of an excessive reduction of renal perfusion gradient. On this count, the SPRINT data are remarkably similar to those of ACCORD, in which patients with an achieved SBP of about 120 mm Hg exhibited an almost three-fold increase of serious side effects compared to patients remaining at an on-treatment SBP of about 133 mm Hg.⁸ Thus, one may draw the conclusion that achieving a low BP target is invariably associated with a substantial worsening of antihypertensive treatment tolerability. This has important adverse implications. The greater number of side effects in SPRINT did not lead to a more common drop-out (patients' close follow-up and high motivation minimize drop-out in trials). However, in real life, serious side effects dramatically increase treatment discontinuation and favor low long-term adherence to the prescribed antihypertensive drug regimens¹⁸ with a substantial loss of their protective effects.^19,20 The protective effect of an aggressive antihypertensive treatment strategy may, thus, face a substantial attenuation when transferred to medical practice.

Finally, I would like to consider an element of the design of the SPRINT trial – namely, the decision to limit the investigation to two groups of patients with a widely different achieved BP target. Compared to trials in which the compared groups were divided by few mm Hg only,²¹ this may have favored outcome differences. However, it also leaves us with no information as to whether the SBP at which the greater protective effect occurs is right or close to the SBP of the intensive treatment group, at an SBP only slightly less than that of the standard treatment group, or somewhere in-between, in the latter two cases with perhaps a more favourable tolerability profile and chance of real-life implementation. The two-group design also does not allow one to determine whether there is an intermediate SBP at which the protective effect is greater than at the lowest extreme (i.e., a J-curve phenomenon to avoid). This will be addressed by the ongoing Optimal Blood Pressure and Cholesterol Targets for Preventing Recurrent Stroke in Hypertensives (ESH-CHL-SHOT) trial, which explores the protective effect of three different SBP treatment targets in patients with a history of stroke, including patients with diabetes.²² Hopefully, the results of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment (ESH-CHL-SHOT) will complement the important findings of SPRINT and answer some of the questions that SPRINT has raised.

References

1. The SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16
2. Mancia G, Fagard R, Narkiewicz K, et al. 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;31:1281-357.
3. 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;311:507-20.
4. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) 2014;16:14-26.
5. Ezzati M, Riboli E. Behavioral and dietary risk factors for noncommunicable diseases. N Engl J Med 2013;369:954-64.
6. Parving HH, Tarnow L, Rossing P. Renal protection in diabetes: an emerging role for calcium antagonists. J Hypertens Suppl 1996;14:S21-25.
7. Zanchetti A, Ruilope LM. Antihypertensive treatment in patients with type 2 diabetes mellitus: what guidance from recent controlled randomized trials. J Hypertens 2002;20:2099-110.
8. ACCORD Study Group, Cushman WC, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
9. Redon J, Mancia G, Sleight P, et al. Safety and efficacy of low blood pressures among patients with diabetes: subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). J Am Coll Cardiol 2012;59:74-83.
10. Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. J Hypertens 2011;29:1253-69.
11. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and meta-regression analyses of randomized trials. J Hypertens 2014;32:2285-95.
12. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006;144:884-93.
13. Kjeldsen SE, Fossum E, Reims HM, Høieggen A. Hypertension treatment and stroke prevention. Blood Press 2003;12:264-8.
14. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006;24:1201-8.
15. Mancia G, Schumacher H, Redon J, et al. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET). Circulation 2011;124:1727-36.
16. Mancia G, Kjeldsen SE, Zappe DH, et al. Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial. Eur Heart J 2015 Nov 20. [Epub ahead of print]
17. Zanchetti A, Thomopoulos C, Parati G .Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal. Circ Res 2015;116:1058-73.
18. Ambrosioni E, Leonetti G, Pessina AC, Rappelli A, Trimarco B, Zanchetti A. Patterns of hypertension management in Italy: results of a pharmacoepidemiological survey on antihypertensive therapy. Scientific Committee of the Italian Pharmacoepidemiological Survey on Antihypertensive Therapy. J Hypertens 2000;18:1691-9.
19. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia G. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens 2011;29:610-8.
20. Simpson SH, Eurich DT, Majumdar SR, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 2006;333:15.
21. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755-62.
22. Zanchetti A, Liu L, Mancia G, et al. Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial. J Hypertens 2014;32:1888-97.

Keywords: Aged, Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Cardiovascular Diseases, Cholesterol, Coronary Artery Disease, Diabetes Mellitus, Diuretics, Electrolytes, Follow-Up Studies, Goals, Hypertension, Hypotension, Incidence, Middle Aged, Motivation, Myocardial Infarction, Primary Prevention, Random Allocation, Reference Values, Renal Insufficiency, Chronic, Research Personnel, Risk Factors, Stroke, Syncope, Secondary Prevention

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