Professional Documents
Culture Documents
Nephrology
American Journal of
a Katz
Family and Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller
School of Medicine, Miami, FL, USA; b Division of Population Health and Computational Medicine, Department of
Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; c Division of General Internal Medicine,
Department of Medicine, University of Miami Miller of School of Medicine, Miami, FL, USA
Keywords pirin use, and blood pressure at baseline. In the statin group,
Hypertension · Chronic kidney disease · Mortality · Statin targeting SBP to < 120 mm Hg compared to SBP < 140 mm
Hg significantly reduced the risk of all-cause mortality (ad-
justed hazard ratio [aHR] 0.44 [0.28–0.71]; event rates 1.16 vs.
Abstract 2.5 per 100 patient-years) and CV mortality (aHR 0.29 [0.12–
Background: Management of chronic kidney disease (CKD) 0.74]; event rates 0.28 vs. 0.92 per 100 patient-years) after a
patients includes efforts directed toward modifying tradi- median follow-up of 3.26 years. In the non-statin group, the
tional cardiovascular risk factors. Such efforts include opti- risk of all-cause mortality (aHR 1.07 [0.69–1.66]; event rates
mal management of hypertension together with the initia- 2.01 vs. 1.94 per 100 patient-years) and CV mortality (aHR
tion of statin therapy. Methods: In this observational study, 1.42 [0.56–3.59]; event rates 0.52 vs. 0.41 per 100 patient-
we determine the modifying effect of statins on the relation- years) were not significantly different in both SBP goal arms.
ship of systolic blood pressure (SBP) goal with mortality and Conclusion: The combination of statin therapy and intensive
other outcomes in patients with CKD participating in a clini- SBP management leads to improved survival in hypertensive
cal trial. At baseline, 2,646 CKD patients (estimated glomeru- patients with CKD. © 2019 S. Karger AG, Basel
lar filtration rate <60 mL/min/1.73 m2) were randomized to
an intensive SBP goal < 120 mm Hg or standard SBP goal
<140 mm Hg. One thousand two hundred and seventy-three
were not on statin, 1,354 were on a statin, and in 19 the use Introduction
of statin was unknown. The 2 primary outcomes were all-
cause mortality and cardiovascular disease (CVD) mortality. The association of hypertension with cardiovascular
Results: The relationships of SBP goal with all-cause mortal- disease (CVD) in chronic kidney disease (CKD) patients
ity (interaction p = 0.009) and cardiovascular (CV) mortality has been well documented in observational studies [1–
(interaction p = 0.021) were modified by the use of statin af- 3]. The systolic blood pressure (SBP) Intervention trial
ter adjusting for age, gender, race, CVD history, smoking, as- (SPRINT) demonstrated that intensive SBP control was
* 50 missing values in the non-statin group; 41 missing values in the statin group.
¶
1 missing value in the statin group.
§ 3 missing values in the statin group.
# 3 missing values in the non statin group; 5 missing values in the statin group.
+ 8 missing values in the non statin group; 10 missing values in the statin group.
BMI, body mass index; BP, blood pressure; IQR, interquartile ranges; SPRINT, systolic blood pressure intervention trial; CKD,
chronic kidney disease.
Forty-six patients died from CV events: 27 (1.99%) in mortality was not significantly different in both SBP goal
the statin group and 19 (1.49%) in the non-statin group. arms (aHR 1.42 [0.56–3.59]; event rates 0.52 vs. 0.41 per
In the Cox regression model relating CV mortality jointly 100 patient-years; Table 2; Fig. 2; online suppl. Fig. S1a).
to the SBP goal strategy and statin use at baseline, the risk The modifying effects of statins on the relationship of
of CV mortality associated to the SBP goal strategy dif- SBP goal with other outcomes were not significant (on-
fered significantly between the patients with and without line suppl. Table S4).
statin use at baseline (adjusted p for interaction = 0.021).
In the statin group, targeting a SBP to <120 mm Hg com- Sensitivity Analyses
pared to SBP <140 mm Hg significantly reduced the risk A modifying effect of statins on the relationship of
of CV mortality (aHR 0.29 [0.12–0.74]; event rates 0.28 vs. SBP goal and all-cause mortality was also appreciated
0.92 per 100 pt-ys). In the non-statin group, the risk of CV with the propensity score matched analysis (p for inter-
135
135
SBP, mm Hg
SBP, mm Hg
130 130
125 125
120 120
115
115
0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54
a Follow-up, month b Follow-up, month
Fig. 1. Separation achieved in SBP levels in the non-statin group (a) and statin group (b). The broken line depicts
the standard group; the solid line depicts the intensive group. SBP, systolic blood pressure.
action = 0.026). In the statin group, targeting a SBP to ing the risk of all-cause mortality (aHR 0.82 [0.60–1.11])
< 120 mm Hg compared to SBP < 140 mm Hg was as- and CV mortality (aHR 0.71 [0.37–1.36]) for the sub-
sociated with a reduced risk of all-cause mortality (HR group of patients not on statins.
0.39, [0.20–0.73]). In contrast, the risk of all-cause mor-
tality was not significantly different in both SBP goal SAE, CSA, and Expected Events
arms (HR 0.96 [0.58–1.59]) in the group not on statin Overall, no statistically significant differences of total
therapy. With regard to the CV mortality outcome, SAE were reported between the intensive SBP arm and stan-
while taking into account the constraints associated dard SBP arm in patients not on statin or on statin at base-
with the small number of events recorded, the results line. In the non-statin group, no significant differences of
of this sensitivity analysis also suggested a trend for an CSA and expected events were reported between the inten-
interaction effect between statin use and SBP goal on sive SBP arm and standard SBP arm. On the other hand, in
CV mortality (p for interaction = 0.064; online suppl. the statin group, patients randomized to the intensive SBP
Table S5). arm were at higher risk of developing acute kidney injury
An additional sensitivity analysis was conducted in (AKI) and hypokalemia. The risk of hypotension, syncope,
the group of patients with a 10-year ASCVD risk ≥7.5% bradycardia, injurious fall, hyponatremia, hypernatremia,
and did not show that statins modified the effect of the hyperkalemia, and orthostatic hypotension did not differ
SBP goal for the all-cause mortality outcome (p for inter- between treatment arms in the statin group (Table 3).
action = 0.103) or CV mortality (p for interaction =
0.475); however, subgroup analyses showed that target- Numbers Needed to Treat for Benefit and Harm
ing a SBP <120 mm Hg compared to <140 mm Hg sig- Estimated number needed to treat to prevent a death
nificantly reduced the risk of all-cause mortality (aHR from any cause and death from CV causes at 4.5 years of
0.55 [0.40–0.77]) and CV mortality (aHR 0.51 [0.28– follow-up were 16 (95% CI 10–35) and 33 (95% CI 20–95)
0.92]) only in the group that was on statins at base- in the statin group. The numbers needed to harm for AKI
line. Targeting a SBP to <120 mm Hg compared to SBP and hypokalemia were 17 (95% CI 10–90) and 12 (95% CI
<140 mm Hg was associated with a trend toward reduc- 6–134), respectively, in this same group [12].
HR, hazard ratio; SBP, systolic blood pressure; MI, myocardial infarction; ACS, acute coronary syndrome; CVA, stroke; aHF, acute decompensated heart failure; CVD death, death from cardiovascular causes.
interaction*
Adjusted
0.009
0.021
The prevalence of hypertension is as high as 86% in
p for
0.44 (0.28–0.71)
0.29 (0.12–0.74)
sociated with mortality [14]. Moreover, CKD patients
have an increased risk for adverse CVD outcomes [15,
16]. Consequently, one of the essential components in the
aHR*
* Adjusted for 10 covariates including: age, gender, race or ethnic group, history of subclinical/clinical CVD, aspirin use at baseline, smoking status, SBP and DBP at baseline.
optimal modification of CVD risk factors: alluding to in-
0.46 (0.29–0.74)
0.30 (0.12–0.74)
patient-
intensive (n = 657)
1.16
0.28
100
25 (3.8)
6 (0.9)
patient-
years, n
Statin (n = 1,354)
0.92
100
57 (8.2)
21 (3.0)
1.42 (0.56–3.59)
1.25 (0.50–3.10)
0.52
100
43 (6.5)
11 (1.7)
years, n
1.94
0.41
100
38 (6.2)
8 (1.3)
0.04 0.04
Cumulative hazards
Cumulative hazards
0.03 0.03
p = 0.634 p = 0.006
0.02 0.02
0.01 0.01
0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Follow-up, years Follow-up, years
Number at risk
Standard 609 584 553 378 119 697 675 657 458 138
a Intensive 664 632 612 416 132 657 634 620 424 140
0.12 0.12
0.10 0.10
Cumulative hazards
Cumulative hazards
0.08 0.08
0.04 0.04
0.02 0.02
0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Follow-up, years Follow-up, years
Number at risk
Standard 609 584 557 378 119 697 682 659 460 138
b Intensive 664 637 614 416 134 657 635 624 425 140
Fig. 2. Cumulative hazards plot for prespecified outcomes of in the statin group. Black interrupted curves represented intensive
SPRINT trial: left-sided curves depict patients with CKD in the non- arm, and solid black curves represented standard arm. a Cardiovas-
statin group, whereas right-sided curves depict patients with CKD cular mortality. b All-cause mortality. p values by log-rank test.
sively by carotid applanation tonometry and Doppler cent cholesterol guideline identifies CKD as a risk en-
velocimetry of the ascending aorta. This synergistic ef- hancer for ASCVD [23]. Evidence from randomized clin-
fect stemming from the combination of antihyperten- ical trials and meta-analysis has substantiated the effect of
sive therapy and statins appears to transcend cholesterol statins in reducing major CVD events, all-cause mortal-
reduction uniquely and suggests a more intricate form ity, and CV mortality [7, 8, 24]. The Study of Heart and
of statin-mediated vascular pleiotropic effect [21, 22]. Renal Protection trial demonstrated that the use of simv-
As previously mentioned, lipid-lowering therapy is an astatin plus ezetimibe achieved a significant 17% reduc-
important cornerstone in the management of all patients tion in the risk of CVD events [7]. Furthermore, in the
with CKD not on dialysis. Individuals with underlying Treating to New Targets trial, atorvastatin 80 mg/day
CKD are at a much higher risk for developing hard car- compared to 10 mg/day achieved a significant 32% reduc-
diovascular outcomes when compared to individuals tion in the risk of major CVD events in the subgroup of
with normal renal function. Consequently, the most re- patients with CKD [24].
Total SAEs 285 (46.8) 290 (43.7) 0.90 (0.76–1.06) 353 (50.6) 332 (50.5) 1.01 (0.87–1.18)
Conditions of interest (ER visits or SAEs)
Hypotension 20 (3.3) 23 (3.5) 1.06 (0.58–1.92) 25 (3.6) 36 (5.5) 1.52 (0.91–2.54)
Syncope 16 (2.6) 23 (3.5) 1.31 (0.69–2.48) 28 (4.0) 36 (5.5) 1.35 (0.82–2.21)
Bradycardia 21 (3.4) 15 (2.3) 0.65 (0.33–1.26) 21 (3.0) 24 (3.6) 1.20 (0.67–2.16)
Electrolyte abnormalities 28 (4.6) 35 (5.3) 1.15 (0.70–1.88) 25 (3.6) 36 (5.5) 1.54 (0.92–2.56)
Injurious fall 59 (9.7) 60 (9.0) 0.91 (0.63–1.31) 80 (11.5) 72 (11.0) 0.95 (0.69–1.31)
AKI 40 (6.6) 60 (9.0) 1.40 (0.94–2.08) 40 (5.7) 57 (8.7) 1.52 (1.02–2.28)
Expected events
Serum sodium <130 mEq/L 23 (3.8) 25 (3.8) 0.96 (0.54–1.69) 12 (1.7) 21 (3.2) 1.82 (0.89–3.71)
Serum sodium >150 mEq/L 0 (0) 1 (0.1) – 0 (0) 2 (0.3) –
Serum potassium <3.0 mEq/L 12 (2.0) 15 (2.3) 1.09 (0.51–2.33) 2 (0.3) 14 (2.1) 6.97 (1.58–30.70)
Serum potassium >5.5 mEq/L 39 (6.4) 49 (7.4) 1.10 (0.72–1.68) 37 (5.3) 51 (7.8) 1.44 (0.94–2.21)
Orthostatic hypotension
Without dizziness 127 (20.8) 141 (21.2) 0.96 (0.76–1.22) 172 (24.7) 155 (23.6) 0.94 (0.75–1.16)
With dizziness 7 (1.1) 15 (2.3) 1.78 (0.73–4.38) 15 (2.1) 9 (1.4) 0.63 (0.28–1.45)
SAE, serious adverse events; AKI, acute kidney injury; HR, hazard ratio.
Interestingly, in our propensity score-matched cohort, use were not statistically significant. Importantly, given
the use of statins alone was associated with a nonstatisti- the small number of SAE, we cannot presume that statis-
cally significant reduced risk of all-cause death (HR 0.76 tical nonsignificance implies equal between-subgroup
[0.52–1.11]) and a nonstatistically significant increased safety profiles. Patients on statin therapy assigned to the
risk of CV mortality (1.11 [0.53–2.34]). It is important to intensive SBP arm were at a 52% higher risk of develop-
mention that this analysis was underpowered and not de- ing AKI. Similarly, Rocco et al. [26] recently reported
void of bias given that statin therapy was not a random- that for SPRINT participants with CKD at baseline, tar-
ized intervention in SPRINT. geting an intensive SBP goal strategy compared to stan-
In spite of these findings, only 51% of the CKD pa- dard SBP goal strategy increased the risk of AKI to 64%.
tients enrolled in the SPRINT were using statins at base- Seventy-eight percent of those events consisted of AKI
line. Considering that the risk of cardiovascular mortality stages 1 and 2 and had an overall 95.2% partial and com-
increases with decreasing eGFR and that the 10-year risk plete resolution. Importantly, the development AKI was
for coronary death and nonfatal MI for CKD patients associated with all-cause mortality in this population. It
over the age of 50 has been noted to be consistently great- is thus recommended that renal function tests be closely
er than 10% [25], this low proportion calls into question monitored in CKD patients when intensifying BP con-
the quality of care that patients with underlying CKD trol. Characteristics such older age, nonwhite race, lower
were receiving in the primary care and specialty clinics baseline eGFR, and history of CVD warrant particular
that referred patient to the SPRINT. More importantly, attention as these have been found to confer a higher risk
this also reveals the need to improve dissemination efforts for AKI.
focusing on guideline implementation at the primary care This investigation has limitations worth mentioning.
level. First, this was a post hoc analysis of the SPRINT study.
Overall, few SAE were reported in the subgroup of Since statin use was not a randomized intervention, cau-
patients not on statins as in the subgroup of patients on sality cannot be inferred, and confirmation of these find-
statins. With the exception of a higher risk of AKI and ings would require a dedicated experimental design. Im-
hypokalemia in patients on statins and on the intensive portantly, however, our primary results were reproduced
SBP arm, differences in the risk of SAE when comparing with a propensity score-matched sensitivity analysis. This
intensive to standard SBP goals after stratifying by statin suggests that the interaction of statins with SBP interven-
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