‘J-Curve’ in Hypertension May Be Explained by Differences in Patient Characteristics

In an analysis of two large blood pressure (BP)-lowering trials, straying too far from a treatment target, whether it’s on the high or low side of conventional or more aggressive treatment goals, increases the risk of adverse clinical outcomes.

However, this so-called J-curve phenomenon, where adverse events are observed among patients with too low or too high systolic BP, is likely attributable to differing patient characteristics rather than the achieved blood-pressure targets. 

Looking at pooled data from the SPRINT and ACCORD BP trials, researchers led by Deborah Kalkman, MD (Academic Medical Center, Amsterdam, the Netherlands), showed that the J-curve was present and shaped similarly regardless of whether patients were randomized to intensive BP control aiming for a systolic of less than 120 mm Hg or to more conventional treatment targeting less than 140 mm Hg.

Thus, it is likely that patients who either can’t get down to goal or go too far below are inherently sicker than those who hover around the BP goal, whatever that may be, Kalkman told TCTMD. “I think that’s the reason why we see the J-curve.”

As Kalkman et al state in their study published online September 22, 2017, ahead of print in Circulation: “Our results show that differences in patient characteristics are an important determinant of the association between achieved blood pressure and adverse outcomes and that the benefit or risk associated with intensive blood pressure-lowering treatment can only be established via randomized clinical trials.”

Explaining the Mystery

The ideal BP level remains one of the major questions in hypertension—as well as the subject of ongoing and heated debate—and the answer is complicated by observational studies showing that cardiovascular risk is elevated at both high and low systolic readings.

Guidelines generally recommend aiming for a systolic goal of less than 140 mm Hg, but the SPRINT trial—reported nearly 2 years ago—showed that aiming for less than 120 mm Hg instead of the standard goal reduces the risk of adverse outcomes in nondiabetic patients at high cardiovascular risk. That benefit is accompanied by an increase in some adverse events, including hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure.

The ACCORD BP trial, which randomized diabetic patients to the same systolic goals used in SPRINT, did not show a significant benefit from intensive control for the primary composite outcome, although stroke risk was reduced.

The findings from both trials conflicted with observational data supporting higher risks at both higher and lower achieved systolic BP.

“While SPRINT and ACCORD BP were randomized controlled trials, the increased risk of cardiovascular events observed in participants with lower [systolic BP] and [diastolic BP] values from studies that did not randomize to different blood pressure targets may have been confounded by other covariates, including differences in patient characteristics,” Kalkman et al explain.

They explored that possibility by pooling individual patient data from the two trials. The analysis included 194,875 on-treatment systolic measurements in 13,946 patients.

During a median follow-up of 3.3 years, composite cardiovascular events occurred in 7.3% of patients and 3.7% died. More intensive BP control was associated with a significant reduction in composite cardiovascular events (HR 0.82; P = 0.002) but not all-cause mortality (HR 0.86; P = 0.10).

The researchers found nearly identical J-curves for each treatment arm, with the lowest event rates observed for on-treatment systolic readings about 3 mm Hg below each treatment goal.

“Consequently, deviations from target blood pressure values may be a marker of unfavorable patient characteristics and unmeasured confounding,” the investigators write. “This challenges causal explanations in the association between low on-treatment blood pressure and adverse clinical outcomes in trial patients.”

Kalkman concluded: “We can partially, I think, explain this mystery that is called the J-curve phenomenon in hypertension.”