Limitations of analyses based on achieved blood pressure: lessons from the African American study of kidney disease and hypertension trial

Abstract

Blood pressure (BP) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials. The objective of this article was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression. Participants (n=1094) in the African-American Study of Kidney Disease and Hypertension Trial were randomly assigned to either usual BP goal defined by a mean arterial pressure goal of 102 to 107 mm Hg or lower BP goal defined by a mean arterial pressure goal of ≤92 mm Hg. Median follow-up was 3.7 years. Primary outcomes were rate of decline in measured glomerular filtration rate and a composite of a decrease in glomerular filtration rate by >50% or >25 mL/min per 1.73 m(2), requirement for dialysis, transplantation, or death. Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in glomerular filtration rate or the clinical composite outcome. In contrast, the achieved BP analyses showed that each 10-mm Hg increment in mean follow-up achieved mean arterial pressure was associated with a 0.35 mL/min per 1.73 m(2) (95% CI: 0.08 to 0.62 mL/min per 1.73 m(2); P=0.01) faster mean glomerular filtration rate decline and a 17% (95% CI: 5% to 32%; P=0.006) increased risk of the clinical composite outcome. Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses, attributed in part to confounding of achieved BP with comorbidities, disease severity, and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP.

Figure 1

* Data restricted to 1065 participants with non-missing follow-up achieved MAP.

Figure 2

Mean Follow-up achieved blood pressure was defined as an average of achieved blood pressure throughout follow-up from visit 4. Data restricted to 1065 participants with non-missing follow-up achieved MAP. In the Low BP goal, 45% with mean follow-up MAP<=92, 6% with mean follow-up MAP 102–107. In usual BP goal, 6% with mean follow-up MAP<=92, 51% with mean follow-up MAP 102–107.

Figure 3

a. Intention-to-treat analysis: Mean GFR over time by randomized BP group. There was no significant difference between randomized groups in adjusted mean total GFR slope (mean = 0.25 ml/min/1.73m², 95% CI: −0.68, 0.18, p = 0.24) and adjusted mean chronic GFR slope (mean = 0.29 ml/min/1.73m², 95% CI: −0.13, 0.70, p = 0.18). b. Intention-to-treat analysis: Cumulative incidence of the clinical composite outcome by randomized BP group. Adjusted hazard ratio for the clinical composite outcome for lower vs. usual blood pressure goal was 0.98 (95% CI: 0.79, 1.22, p = 0.85). c. Achieved BP analysis relating chronic GFR slope to mean follow-up achieved MAP across all participants. Each 10 mm Hg increment in mean follow-up MAP was associated with a 0.35 (95% CI 0.08 – 0.62, p = 0.01) ml/min/1.73m² faster mean GFR decline. d. Achieved BP analysis relating risk of the clinical composite outcome to cumulative mean achieved MAP during follow-up across all participants. Plotted is adjusted hazard ratio for the clinical composite outcome for patients with cumulative mean achieved MAP=86, 104, 113mmHg vs. MAP=95 (the reference group). Each 10 mm Hg increment in mean follow-up MAP was associated with a 17% (95% CI 5% – 32%, p = 0.006) increased risk of the clinical composite outcome.

Figure 4

Estimated GFR slope, expressed in ml/min/1.73m²/ year, as a function of the patients’ randomized blood pressure group and the achieved mean follow-up MAP level based on a mixed effects linear spline model. The figure demonstrates that the relationship between GFR slope and achieved blood pressure level is influenced by factors other than the biological effect of blood pressure. The shaded region represents an achieved MAP between 102 and 107 mm Hg, which is the target range for patients assigned to the usual goal but above the target range for patients assigned to the low goal. Among the patients with similar mean follow-up MAPs within this limited range, the mean GFR slope was 0.99 ± 0.41ml/min/1.73m²/ year steeper for patients assigned to the low goal, whose MAP was above target, than for patients assigned to the usual goal despite comparable MAP levels, whose MAP was in the target range.