This report illustrates the challenges of using analyses of achieved BP to guide treatment recommendations. The AASK trial is one of a few studies that directly compared different BP goals and is ideally suited to this evaluation. In this paper, we document that analyses based on achieved BP lead to markedly different inferences than ITT analyses. Specifically, ITT analyses comparing randomized groups documented that the rate of decline in kidney function did not differ between the lower and usual BP goal groups. However, in analyses based on achieved BP, lower levels of BP were associated with more favorable renal outcomes. Further analyses documented that the likely reason for this discrepancy was confounding of achieved BP with co-morbidities and adherence. When results were stratified by achieved MAP, participants in the lower BP group who were above goal had a faster decline in renal function than did participants in the usual BP group who were within goal but had the same achieved MAP. However, this group also had poorer prognostic factors at baseline and worse adherence during follow-up.
This pattern has been seen in other trials comparing the effect of BP goals on clinical outcomes. A similar discrepancy between the ITT comparison of randomized BP groups and analyses of achieved BP occurred in the Modification of Diet in Renal Disease (MDRD) trial, in which participants were randomized to lower BP goal group (MAP ≤ 92mmHg) or a usual BP goal group (MAP ≤ 107 mmHg, < 113 mmHg in those age > 61). (21
) As in the AASK analyses, when the randomized groups were combined and analyzed by achieved mean MAP, there was an association between higher levels of mean MAP during follow-up and decline in GFR, even after controlling for baseline characteristics.(18
No difference in CVD or renal outcomes was noted in the overall cohort in the Hypertension Optimal treatment Trial (HOT), a large clinical trial (n=18,790) which included a subset of hypertensive participants with mild renal disease at baseline randomized to one of three diastolic BP goal groups, (≤90 mmHg, <85 mmHg and, ≤80 mmHg).(30
) In contrast to the ITT analysis, lower levels of achieved diastolic BP were associated with a reduced risk of CVD in this trial, though not a significant difference in serum creatinine after 3.8 years of follow-up. Of note, this study randomized participants based on diastolic rather than systolic BP goals, and only two serum creatinine measurements were available (baseline and final visit).(30
The limitations of as-treated analyses, in which outcomes are related to treatment received rather than randomized treatment assignment, have been documented in the nephrology and general clinical trials literature.(29
) This report demonstrates these limitations in the setting of analyses of achieved blood pressure. Recently, the Action to Control Cardiovascular Risk in Diabetes Trial (ACCORD) documented that a SBP goal <120 mmHg did not significantly lower the rate of composite or cardiovascular events compared to a traditional SBP goal of < 140 mmHg in patients with type 2 diabetes.(34
) Such results will likely encourage post-hoc analyses to identify those that may have benefited from the lower SBP goal. However, in view of results from AASK, we urge caution, especially if analyses based on achieved BP are conducted. A trial similar to ACCORD, the Systolic Blood Pressure Invention Trial (SPRINT), in non diabetic hypertensive patients (40% with CKD) which is underway by NHLBI will offer similar appeal.
An important issue is the extent to which confounding may account for the relationship of blood pressure with clinical outcomes in observational studies. Our sense is that the problem of confounding, while potentially present in observational studies, is magnified in the setting of achieved BP analyses conducted in the setting of a clinical trial. Although their effects might be reduced, the confounding relationships demonstrated in the AASK as-treated analyses seem likely to also occur in the observational setting, where national and international standards stipulate maximum acceptable BP levels. If such a bias does exist, then regardless of where BP targets are set, patients with higher observed BP levels may always seem to do worse. When BP level is explicitly targeted, as in the AASK Trial, variations in co-morbidities and behavioral factors may account for a greater proportion of the variation in achieved BP than in the observational setting, where observed BP level also depends on variations in practice patterns, access to treatment, and other factors. Thus, the degree of confounding in achieved BP analyses from the AASK Trial is likely amplified due to the controlled conditions of the trial. Nonetheless, residual confounding likely occurs in observational analyses, especially recent studies in which there are substantial efforts to control BP to recommended BP goals.
The AASK Trial, with distinct randomly assigned BP goals but partially overlapping achieved BP levels, provided a unique opportunity to investigate potential biases in analyses of achieved BP by comparing patients with similar BP levels who were in-goal for one treatment arm but out of goal for the other. Potential limitations include reduced statistical power in analyses based on subgroups of participants. However, major strengths include a well-characterized study population with extensive data on potential confounders, both at baseline and during follow-up; a long duration of follow-up; and a large, sustained contrast in BP between randomized groups.
In summary, analyses based on achieved BP can lead to markedly different inferences than traditional intention-to-treat analyses. A major reason for this discrepancy appears to be confounding of achieved BP with co morbidities, disease severity and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP.