Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease

William Herrington, Natalie Staplin, Parminder K Judge, Marion Mafham, Jonathan Emberson, Richard Haynes, David C Wheeler, Robert Walker, Charlie Tomson, Larry Agodoa, Andrzej Wiecek, Sarah Lewington, Christina A Reith, Martin J Landray, Colin Baigent, SHARP Collaborative Group, William Herrington, Natalie Staplin, Parminder K Judge, Marion Mafham, Jonathan Emberson, Richard Haynes, David C Wheeler, Robert Walker, Charlie Tomson, Larry Agodoa, Andrzej Wiecek, Sarah Lewington, Christina A Reith, Martin J Landray, Colin Baigent, SHARP Collaborative Group

Abstract

Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11-1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00125593.

Keywords: blood pressure; chronic kidney disease; epidemiology; troponin; vascular disease.

© 2016 The Authors.

Figures

Figure 1.
Figure 1.
Association between troponin-I (TnI) and risk of cardiovascular events (A) overall and (B) by renal replacement therapy status. Analyses restricted to those without previous cardiovascular disease at baseline. The reference group in A is those with a TnI ≤0.01 ng/mL and in B, it is those not on dialysis at baseline with a TnI ≤0.01 ng/mL. Hazard ratios adjusted for age, sex, ethnicity, country, education, smoking status, previous diabetes mellitus, estimated glomerular filtration rate, renal replacement therapy status (A only), body mass index, treatment allocation, and blood pressure are quoted (above squares) with number of events (below squares). CI indicates confidence interval.
Figure 2.
Figure 2.
Association between (A) systolic blood pressure (SBP), (B) diastolic blood pressure (DBP), and (C) pulse pressure (PP) and cardiovascular events overall. For each plot, categories of blood pressure contain similar numbers of events. Hazard ratios (HRs) adjusted for age, sex, ethnicity, country, education, smoking status, previous cardiovascular disease, previous diabetes mellitus, estimated glomerular filtration rate, renal replacement therapy status, body mass index, and treatment allocation are quoted (above squares) with numbers of events (below). Exclusions as per Table.*HRs per 10 mm Hg higher usual blood pressure are presented for associations where there is no evidence of deviation from a loglinear relationship. CI indicates confidence interval.
Figure 3.
Figure 3.
Association between systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) and cardiovascular events, subdivided by self-reported history of previous cardiovascular disease (A, C, E) and by baseline troponin-I concentration (B, D, F). For each plot, categories of blood pressure contain similar numbers of events. Hazard ratios adjusted for age, sex, ethnicity, country, education, smoking status, previous diabetes mellitus, estimated glomerular filtration rate, renal replacement therapy status, body mass index, and treatment allocation are quoted (above squares) with numbers of events (below). Exclusions as per Table. *Hazard ratios per 10 mm Hg higher usual SBP/PP are presented for associations where there is no evidence of deviation from a log–linear relationship. CI indicates confidence interval; CVD, self-reported history of cardiovascular disease; HR, hazard ratio; and TnI, troponin-I (ng/mL).
Figure 4.
Figure 4.
Association between (A) systolic blood pressure (SBP), (C) diastolic blood pressure (DBP), and (E) pulse pressure (PP) and atherosclerotic cardiovascular events and association between (B) SBP, (D) DBP, and (F) PP and nonatherosclerotic cardiovascular events, subdivided by evidence of previous cardiovascular disease. Conventions as per Figure 3. CI indicates confidence interval; CVD, self-reported history of cardiovascular disease; HR, hazard ratio; and TnI, troponin-I (ng/mL).
Figure 5.
Figure 5.
Association between systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) and cardiovascular events, subdivided by evidence of previous cardiovascular disease, for those not on dialysis (A, C, E) and on dialysis (B, D, F). Conventions as per Figure 3. CI indicates confidence interval; CVD, self-reported history of cardiovascular disease; HR, hazard ratio; and TnI, troponin-I (ng/mL).

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