Interpreting SPRINT: How low should you go?

What about patients with diabetes?

Patients were excluded from SPRINT if they were under age 50, were at low cardiovascular risk, or had diabetes, raising the question of whether the results apply to these groups as well.

The question is particularly relevant in diabetes, as the ACCORD BP study, which used the same blood pressure targets as SPRINT, did not show a significant difference in the primary cardiovascular outcome between the intensive and standard treatments in patients with diabetes (Table 3).¹³ In ACCORD BP, the rate of the primary outcome was 12% lower in the intensive treatment group than in the standard treatment group, but the 95% confidence interval was –27% to +6%, so the finding was not statistically significant. However, the wide confidence interval does not exclude the possibility of a benefit that was comparable to that observed in SPRINT.

It has been speculated that ACCORD BP was underpowered to detect significant differences in the primary outcome.²¹ An analysis combining data from both trials indicated that effects on individual outcomes were generally consistent in both trials (with no significant heterogeneity noted).²² Also, the primary composite outcome in ACCORD did not include heart failure, which is particularly sensitive to blood pressure reduction.

Additionally, ACCORD BP had a 2 × 2 factorial design involving a simultaneous comparison of intensive vs standard glycemic control, which may have influenced the effects due to blood pressure. Indeed, a post hoc analysis showed that there was a significant 26% lower risk of the primary outcome in ACCORD BP patients who received intensive systolic pressure  control plus standard glycemic control than in those receiving standard systolic control plus standard glycemic control.²³

Are more adverse events an acceptable trade-off?

Adverse events, including acute kidney injury, were more frequent in the intensive therapy group in SPRINT.

Acute kidney injury was coded as an adverse event on the basis of this diagnosis being included in the hospital discharge summary (as a primary or main secondary diagnosis) and if considered by the safety officer to be one of the top three reasons for admission or continued hospitalization. Further analysis of renal events should be forthcoming.

People in the intensive treatment group, on average, needed one more medication than those in the standard treatment group. Some of the adverse events may be related to the antihypertensive medications taken (eg, electrolyte abnormalities such as hyponatremia and hypokalemia due to diuretic use), and others may be related to blood pressure-lowering (eg, acute kidney injury due to renal hypoperfusion).

At this point, the long-term effects of these adverse events, especially on kidney function, are not known. Patients enrolled in clinical trials tend to be healthier than patients seen in clinical practice; thus, the rate of adverse events reported in the trial may be lower than one would see in the real world.

Does lower systolic pressure protect or harm the kidneys?

SPRINT included patients with stage 3 and 4 chronic kidney disease (ie, with eGFR 20–50 mL/min/1.73 m²), but it was designed to assess cardiovascular outcomes, not the progression of chronic kidney disease. The trial excluded patients with diabetic nephropathy or high degrees of proteinuria.

Only about half of hypertensive adults have their blood pressure under control, ie, < 140/90

Earlier randomized trials that focused on chronic kidney disease progression, including the MDRD²⁴ and the African American Study of Kidney Disease and Hypertension,²⁵ did not show benefit with more aggressive blood pressure-lowering (except in patients with higher degrees of proteinuria), and these trials were not powered to assess effects on cardiovascular outcomes.^24,25

The Irbesartan Diabetic Nephropathy Trial,^26,27 which was done in patients with overt diabetic nephropathy, showed that a progressively lower achieved systolic pressure down to 120 mm Hg predicted lower rates of heart failure, cardiovascular mortality, and renal events (although the trial target was ≤ 130/85 mm Hg and few participants achieved systolic pressure lower than 120 mm Hg).

IMPLICATIONS FOR MANAGEMENT

The recent estimates of hypertension prevalence and control from NHANES show that only about 53% of hypertensive adults have their blood pressure under control (defined as systolic pressure < 140 mm Hg and diastolic pressure < 90 mm Hg).² Analysis of the NHANES 2007–2012 data showed that 16.7% or 8.2 million US adults with treated hypertension meet the eligibility criteria for SPRINT.²⁸

Although the SPRINT results support the notion that “lower is better,” the risks and benefits of intensive control will need to be balanced in individual patients. Table 4 shows the number needed to treat and number needed to harm in the trial.

More aggressive management of hypertension is challenging. The median systolic pressure achieved in the intensive group in SPRINT was just over 120 mm Hg, which implies that at least half of the participants in the intensive group did not achieve the goal of less than 120 mm Hg. While it may be reasonable to aim for systolic pressure of less than 120 or 125 mm Hg in patients who fit the SPRINT criteria and can tolerate intensive blood pressure lowering, it would be prudent to aim for a more conservative goal in elderly patients who are frail and at risk for falls, considering the higher incidence of specified adverse events in the intensive group.

Results of cognitive outcomes, as well as data related to quality of life, are still awaited. Long-term renal outcomes are also unclear.

As noted above, the question of generalizability of SPRINT results to patients with diabetes is open to debate. In our opinion, with currently available evidence, it is difficult to conclusively answer the question of whether a lower systolic target provides cardiovascular benefit in diabetes. It is also unclear whether similar beneficial results would be seen with intensive treatment in a population at low cardiovascular risk. The American Heart Association and the American College of Cardiology are in the process of formulating new hypertension guidelines, and evidence from  SPRINT will inform any new recommendations.

As more medications will likely be needed for intensive systolic blood pressure control, side effects and tolerability of medications with polypharmacy and potential nonadherence with increasing complexity of medication regimens should be kept in mind. Lifestyle modifications will need to be emphasized and reinforced, with greater use of combination antihypertensive therapy.

The data from SPRINT indicate that lower systolic pressure is better, as long as untoward clinical events can be monitored and avoided or easily managed. Careful monitoring will likely entail more frequent clinic visits and more frequent assessment of renal function and electrolyte levels (participants in the intensive group in the trial were seen every month until goal was achieved). A team approach that includes pharmacists and nurse practitioners, along with optimal use of best practice algorithms and remote monitoring technology, will need to be implemented for efficient and effective care.