Highlights
- •A causal mediation analysis using the observational part of a large scale randomized controlled trial (RCT) is described.
- •There is no significant effect of therapy-induced low diastolic blood pressure on risk of certain cardiovascular outcomes.
- •Adjusting for mediator-outcome confounding is essential, even in RCTs.
Abstract
Background and aims
Reducing the diastolic blood pressure (DBP) below a certain threshold may lead to
inadequate organ perfusion. This raises some concerns, because pharmacotherapy reduces
both systolic and diastolic pressure. We aimed to investigate whether a pathway from
intensive systolic blood pressure (SBP) treatment influences cardiovascular outcomes
by inducing too low DBP.
Methods
We had access to data from the Systolic Blood Pressure Intervention Trial (SPRINT)
including 9361 patients with a SBP of 130 mmHg or higher and an increased cardiovascular
risk. In a formal mediation analysis, we investigated whether the effect of intense
(target SBP: 120 mm Hg) vs. standard (target SBP: 140 mmHg) intervention on a composite endpoint would be mediated
through an indirect, potentially harmful, effect through low DBP ( 60 mmHg).
Results
Adjusting for treatment, we find that low DBP per se is associated with poor cardiovascular outcomes (HR 1.90 (95% CI [1.46, 2.47]). However,
in a formal mediation analyses, we observed that the unadjusted indirect effect of
intensive blood pressure treatment going through low DBP of HR 1.12 (95% CI [1.06,
1.18]) attenuates to a statistically non-significant effect of HR 1.04 (95% CI [0.98,
1.10]) after adjustment for important covariates, suggesting that the mere association
is considerably confounded.
Conclusions
The increased risk in subjects with diastolic pressure below 60 cannot fully be explained
by the intensive treatment itself, but may be due to other measured factors. More
generally, this analysis shows that adjusting for mediator-outcome confounding is
essential, even in RCTs.
Keywords
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Article Info
Publication History
Published online: July 24, 2017
Accepted:
July 18,
2017
Received in revised form:
July 12,
2017
Received:
March 7,
2017
Identification
Copyright
© 2017 Elsevier B.V. All rights reserved.
