Intestinal Cholesterol Absorption, Treatment With Atorvastatin, and Cardiovascular Risk in Hemodialysis Patients

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 21, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.03.551

Intestinal Cholesterol Absorption, Treatment With Atorvastatin, and Cardiovascular Risk in Hemodialysis Patients Günther Silbernagel, MD,* Günter Fauler, PHD,y Bernd Genser, PHD,zxk Christiane Drechsler, MD, PHD,{# Vera Krane, MD,{# Hubert Scharnagl, PHD,y Tanja B. Grammer, MD,x Iris Baumgartner, MD,* Eberhard Ritz, MD,** Christoph Wanner, MD,{# Winfried März, MDyyzz

ABSTRACT BACKGROUND Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. OBJECTIVES This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin’s effectiveness to reduce cardiovascular risk in hemodialysis patients. METHODS This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n ¼ 519) or placebo (n ¼ 511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. RESULTS A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p ¼ 0.049), but not the second (HR: 0.79; p ¼ 0.225) or third tertiles (HR: 1.21; p ¼ 0.287). Atorvastatin consistently significantly reduced allcause mortality and the risk of all cardiac events in only the first tertile. CONCLUSIONS Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit. (J Am Coll Cardiol 2015;65:2291–8) © 2015 by the American College of Cardiology Foundation.

S

tatin treatment is effective in primary and sec-

impaired renal function (2–5). However, statin ther-

ondary

(CV)

apy appears to be less effective in reducing CV risk

events in patients without chronic kidney dis-

in patients with severely impaired renal function

ease (CKD) (1) and in patients with moderately

and patients on maintenance hemodialysis treatment

prevention

of

cardiovascular

From the *Division of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Switzerland; yClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; zMannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; xInstitute of Public Health, Federal University of Bahia, Salvador, Brazil; kBG Stats Consulting, Vienna, Austria; {Division of Nephrology, Department of Internal Medicine 1, University of Würzburg, Würzburg, Germany; #Comprehensive Heart Failure Centre, University of Würzburg, Würzburg, Germany; **Division of Nephrology, Department of Internal Medicine 1, University of Heidelberg, Heidelberg, Germany; yyMedical Clinic 5 (Nephrology, Hypertensiology, Endocrinology, Diabetology, and Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; and the zzSynlab Academy, Synlab Services GmbH, Mannheim, Germany. The present study was supported by Unilever R&D. Drs. Silbernagel and März have received a research grant from Unilever R&D, Vlaardingen, the Netherlands. Dr. Silbernagel was supported by a grant from the Inselspital Foundation, Bern,

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Cholesterol Absorption and Outcomes in 4D Study

ABBREVIATIONS

(5–8). Specifically, 20 mg of atorvastatin

Cholestanol was measured in 1,030 of the 1,255 par-

AND ACRONYMS

versus placebo did not significantly reduce

ticipants of the 4D study. Among the 1,030 partici-

the composite risk of CV death, nonfatal

pants with available data on cholestanol, 519 patients

myocardial infarction (MI), and stroke in

received 20 mg of atorvastatin and 511 patients

the 4D (German Diabetes Dialysis Study)

received placebo once daily. They were re-examined

study (7). Likewise, 10 mg of rosuvastatin

at 4 weeks and then every 6 months after randomi-

ECG = electrocardiogram

did not significantly reduce the composite

zation to obtain information about study endpoints or

MI = myocardial infarction

risk of death from CV causes, nonfatal MI,

serious adverse events. The study was approved by

and nonfatal stroke in the AURORA (A Study to Eval-

the local medical ethics committee, and written

uate the Use of Rosuvastatin in Subjects on Regular

informed consent was obtained from all participants

Hemodialysis: An Assessment of Survival and Cardio-

before inclusion. The data were monitored and

vascular Events) study (8). The reasons for these

collected by a contract research organization (7).

CHD = coronary heart disease CKD = chronic kidney disease CV = cardiovascular

results remain incompletely understood (9). SEE PAGE 2299

Body cholesterol, which comes from 2 sources, is either endogenously synthesized or taken up from the diet in the intestine (10). Statins inhibit cholesterol synthesis, but they do not interfere with cholesterol absorption (10). Notably, patients on maintenance hemodialysis treatment are high absorbers of intestinal cholesterol, which may account for the low effectiveness of atorvastatin to reduce CV risk in these patients (11). The present research was therefore stimulated by the question as to whether the individual cholesterol absorption rate may modify the effectiveness of atorvastatin treatment to reduce CV risk in hemodialysis patients. To answer this question, we performed a post-hoc analysis of data from the 4D study (7). Cholesterol absorption efficiency was estimated using an established biomarker, namely, the circulating cholestanolto-total cholesterol ratio (12,13).

METHODS

ENDPOINTS. The

study

endpoints

and

serious

adverse events were reported to the contract research organization. Every endpoint was adjudicated by 3 members of the endpoint committee on the basis of pre-defined criteria that were part of the study protocol. The classification by the endpoint committee was on the basis of consensus or majority vote. All committee members were blinded to the treatment assignments until August 13, 2004 (7). The primary endpoint of the 4D study was a composite of death resulting from cardiac causes, fatal or nonfatal stroke, and nonfatal MI. Death resulting from cardiac causes included sudden death, fatal MI, death caused by congestive heart failure, death resulting from coronary heart disease (CHD) during or within 28 days after an intervention, and all other deaths ascribed to CHD. Sudden cardiac death was considered death as verified by terminal rhythm disorders as seen on an electrocardiogram (ECG), witness-observed death within 1 hour after the onset of cardiac symptoms, death confirmed by autopsy, and unexpected death of presumably or possibly of cardiac origin and in the absence of an increased potassium level before the

STUDY DESIGN AND PARTICIPANTS. The design of

start of the 3 most recent hemodialysis treatment

4D has been previously reported (7,14). Briefly, 4D is a

sessions. MI was diagnosed when 2 of the following 3

prospective, randomized, double-blind, multicenter

criteria were met: typical symptoms; elevated levels

trial that included 1,255 patients with type 2 diabetes,

of cardiac enzymes (creatine kinase-MB, lactic dehy-

who were 18 to 80 years of age, and who were on

drogenase, and troponin T); or diagnostic changes on

maintenance hemodialysis treatment for <2 years.

the ECG. An ECG at rest was recorded every 6 months

Switzerland. Drs. Genser and März received a research grant from Danone Research, Palaiseau, France. Dr. Wanner received grant support from Genzyme, Cambridge, Massachusetts. These companies offer substances that interfere with cholesterol synthesis and/or absorption. Dr. März has received consulting fees, lecture fees, and research grants from Pfizer and Merck, Sharp & Dohme; and is an employee of and holding equity in Synlab Services GmbH, Augsburg, Germany, a company that offers laboratory testing, including measurement of LDL cholesterol. Dr. Wanner has received lecture fees from Pfizer and Merck, Sharp & Dohme. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Parts of this paper were presented in the late-breaking clinical trials session at the 50th European Renal Association - European Dialysis and Transplant Association Congress, held May 18 to 21, 2013, in Istanbul, Turkey, and in poster form at the 82nd European Atherosclerosis Society Congress, held May 31 to June 3, 2014, Madrid, Spain. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. You can also listen to this issue’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. Manuscript received September 30, 2014; revised manuscript received March 2, 2015, accepted March 10, 2015.

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Cholesterol Absorption and Outcomes in 4D Study

and evaluated by independent cardiologists from the

history of stroke/transient ischemic attack; peripheral

ECG monitoring board, according to the Minnesota

artery disease; congestive heart failure (predomi-

classification system for ECGs (codes 1-1-1 through 9-2

nantly presenting as New York Heart Association

for QRS complex, ST-segment, or T-wave changes).

functional class II); and arrhythmia. We then tested

An ECG that documented silent MI was considered

whether the interaction term between the treatment

evidence of a primary endpoint. When death occurred

group and the cholestanol-to-cholesterol ratio tertiles

within 28 days post-MI, as previously described,

was significantly associated with endpoints in the

it was classified as death caused by MI. Fatal MI was

entire cohort, again using time-to-event analyses (Cox

classified only as death from MI, not sudden cardiac

regression for endpoints with exclusively fatal events

death. “All cardiac events” were defined as a com-

and Andersen-Gill models for endpoints that included

posite of cardiac death, nonfatal MI, and cardiac re-

nonfatal events) (16). The model included the previ-

vascularizations. Stroke was defined as a neurological

ously mentioned covariates, the ratio tertiles, atorvas-

deficit that lasted >24 h. Computed tomographic or

tatin treatment (main effect), and the interaction term

magnetic resonance imaging of the brain was recom-

between the cholestanol-to-cholesterol ratio tertiles

mended and available in all but 16 cases (7,14). “All

and atorvastatin treatment. Goodness of fit was tested

cerebrovascular

stroke,

according to Grønnesby and Borgan (17). Next, stratified

included transient ischemic attack and prolonged

analyses were performed to test the effect of atorvas-

ischemic neurological deficit.

tatin treatment on the risk of reaching endpoints

LABORATORY PROCEDURES. Blood samples were

within the tertiles using the previously mentioned

taken before the start of dialysis and administration

adjustment, and omitting the tertiles and the interac-

of heparin or further drugs and before randomization.

tion term between the cholestanol-to-cholesterol ratio

Cholesterol was measured with enzymatic reagents

tertiles and the atorvastatin treatment. All interaction

(Wako Chemicals GmbH, Neuss, Germany) on a 30R

tests and subgroup analyses within the tertiles

analyzer (Wako Diagnostics, Richmond, Virginia) or

were performed using both the intention-to-treat and

AU640

Tokyo,

the per-protocol approach. In addition, Kaplan-Meier

Japan). Cholestanol was measured with gas chroma-

curves were plotted and log-rank tests were per-

tography and mass spectrometry using the significant

formed to test the effect of the atorvastatin treatment

ion m/z 445.4. The details of the method have pre-

within the tertiles of the cholestanol-to-cholesterol

viously been described (15).

ratio for the primary endpoint. All statistical tests

events,”

analyzer

in

(Olympus

addition

to

Corporation,

STATISTICAL ANALYSES. The baseline characteris-

tics are reported as counts (percentages) for categorical data and as means  SD for continuous data according to the atorvastatin and the placebo groups, within tertiles of the cholestanol-to-cholesterol ratio. Differ-

were 2-sided, and p values <0.05 were considered significant. Statistical analysis was conducted using the STATA statistical software package (release 13; StataCorp LP, College Station, Texas).

RESULTS

ences in the distributions of baseline characteristics between the atorvastatin and the placebo groups

Summary statistics stratified by treatment group

within these tertiles were tested for with the chi-

within cholestanol-to-cholesterol ratio tertiles are

square test for categorical data and Student t test

shown in Table 1. There were no significant differ-

and

data.

ences of any baseline characteristics across or within

The effect of atorvastatin treatment on the risk

the tertiles nor between treatment groups, except for

of reaching the endpoints in the entire cohort was

the prevalence of CAD in the second tertile and al-

tested using time-to-event analyses (Cox regression

bumin and arrhythmia in the third tertile. Potential

for endpoints with exclusively fatal events and

confounding caused by these nonbalanced variables

the Andersen-Gill model, which is an extended Cox

was controlled for by including them as covariates

regression approach that allows for multiple events,

in the time-to-event models.

analysis

of

variance

for

continuous

for endpoints that include nonfatal events) (16). The

The mean duration of follow-up was 4.1 years. Only 1

analyses were adjusted for the following: sex; age;

patient was lost to follow-up, and this patient was

phosphate; albumin; hemoglobin; glycated hemoglo-

included in the analysis until loss to follow-up (7). The

bin; ever smoking; systolic and diastolic blood

patient was allocated to the placebo group in the first

pressures; body mass index; ultrafiltration volume;

tertile. A total of 454 primary endpoints occurred. The

duration of dialysis; coronary artery disease (CAD)

absolute numbers for all endpoints by treatment

(MI, coronary artery bypass grafting, coronary inter-

groups within cholestanol-to-cholesterol ratio tertiles

vention, and angiographically documented CAD);

are shown in Table 2. By performing multivariate

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Cholesterol Absorption and Outcomes in 4D Study

T A B L E 1 Baseline Characteristics

Cholestanol-to-Cholesterol Ratio First Tertile

Second Tertile

Third Tertile

Threshold #0.77 mg/mg

Threshold >0.77 to #1.50 mg/mg

Threshold >1.50 mg/mg

Atorvastatin (n ¼ 165)

Placebo (n ¼ 178)

p Value*

Atorvastatin (n ¼ 177)

Placebo (n ¼ 166)

p Value*

Atorvastatin (n ¼ 177)

Placebo (n ¼ 167)

p Value*

Cholestanol-to-cholesterol ratio, mg/mg

0.40  0.21

0.38  0.21

0.446

1.13  0.21

1.12  0.21

0.869

4.16  7.46

3.34  5.15

0.236

Age, yrs

p Value†

66.0  8.8

65.8  9.0

0.798

66.0  7.4

65.5  7.5

0.572

66.1  8.7

67.8  7.7

0.060

Male

88 (53.3)

96 (53.9)

0.911

92 (52.0)

89 (53.6)

0.762

97 (54.8)

84 (50.3)

0.403

0.959

BMI, kg/m2

27.4  4.1

27.6  5.3

0.786

27.7  4.5

27.2  4.6

0.267

27.4  5.2

27.4  5.4

0.953

0.966

Duration of dialysis, months

17.1  8.0

18.4  8.1

0.126

18.0  8.8

19.4  8.8

0.154

17.5  8.7

18.4  87

0.318

0.278

Ultrafiltration volume, l Hemoglobin, g/dl

0.135

2.1  1.3

2.4  1.3

0.063

2.4  1.1

2.3  1.1

0.564

2.2  1.2

2.2  1.3

0.894

0.387

10.8  1.4

10.8  1.4

0.704

10.9  1.3

11.1  1.4

0.206

10.9  1.3

11.0  1.3

0.810

0.249 0.121

HbA1c, %

6.8  1.3

6.7  1.2

0.611

6.7  1.2

6.9  1.2

0.268

6.6  1.2

6.6  1.3

0.824

Fasting glucose, mg/dl

149  46

153  49

0.348

152  48

154  59

0.771

149  52

150  52

0.844

0.645

Systolic BP, mm Hg

145  23

145  19

0.918

147  23

145  24

0.414

146  21

146  23

0.982

0.852

76  11

76  11

0.731

75  11

75  10

0.694

76  11

76  12

0.692

0.258

Total cholesterol, mg/dl

217  42

218  40

0.861

221  45

218  42

0.510

219  45

223  42

0.422

0.478

LDL cholesterol, mg/dl

124  30

126  29

0.407

127  29

123  27

0.194

124  29

129  32

0.105

0.853

HDL cholesterol, mg/dl

34  12

36  13

0.189

36  13

37  14

0.580

37  13

38  13

0.743

0.088

Triglycerides, mg/dl

266  161

260  157

0.726

258  160

275  174

0.360

261  172

256  160

0.803

0.823

Phosphate, mg/dl

6.0  1.8

6.2  1.5

0.282

5.8  1.5

6.1  1.6

0.073

6.2  1.6

6.1  1.6

0.660

0.201

Diastolic BP, mm Hg

3.8  0.3

3.8  0.3

0.999

3.9  0.3

3.9  0.3

0.239

3.8  0.3

3.9  0.3

0.010

0.037

11.8  22.9

11.9  19.1

0.979

11.1  24.8

12.0  21.7

0.711

11.8  14.4

9.8  10.3

0.130

0.766

Arrhythmia

34 (20.6)

33 (18.5)

0.630

34 (19.2)

23 (13.9)

0.183

30 (17.0)

43 (25.6)

0.046

0.300

CAD

49 (29.7)

63 (35.4)

0.261

59 (33.3)

37 (22.3)

0.023

49 (27.7)

50 (29.9)

0.644

0.360

Congestive HF

61 (37.0)

64 (36.0)

0.845

73 (41.2)

55 (33.1)

0.121

55 (31.1)

67 (40.1)

0.080

0.880

Peripheral artery disease

74 (44.9)

87 (48.9)

0.455

91 (51.4)

73 (44.0)

0.168

80 (45.2)

75 (44.9)

0.957

0.761

Stroke/TIA

23 (13.9)

35 (19.7)

0.158

38 (21.5)

33 (19.9)

0.717

30 (17.0)

27 (16.2)

0.846

0.295

0.690

0.289

Never

97 (58.8)

115 (64.6)

102 (57.6)

109 (65.7)

98 (55.4)

97 (58.1)

Past

57 (34.5)

51 (28.7)

63 (35.6)

40 (24.1)

57 (32.2)

54 (32.3)

11 (6.7)

12 (6.7)

12 (6.7)

17 (10.2)

22 (12.4)

16 (9.6)

Albumin, g/dl C-reactive protein, mg/l

Smoking

Current

0.493

0.053

Values are mean  SD or n (%). *p Value for difference between atorvastatin and placebo calculated with chi-square test for categorical data and Student t test for continuous data. †p Value for difference across tertiles of cholestanol-to-cholesterol ratio calculated with chi-square test for categorical data and analysis of variance for continuous data. BMI ¼ body mass index; BP ¼ blood pressure; CAD ¼ coronary artery disease; HbA1c ¼ glycosylated hemoglobin; HDL ¼ high-density lipoprotein; HF ¼ heart failure; LDL ¼ low-density lipoprotein; TIA ¼ transient ischemic attack.

analyses, the effect of atorvastatin treatment on the

any cause, the risk of all cardiac events, and the

risk of reaching the endpoints (Table 3) was consistent

risk of cardiac death in the first tertile, but not in

with the results reported for all 1,255 participants (14).

the second or third tertiles of the cholestanol-to-

By performing intention-to-treat analyses, the

cholesterol ratio on the basis of the intention-to-treat

interaction term between the tertiles and the treat-

analyses (Table 4). For sudden cardiac death, nonfatal

ment group was significantly associated with the risk

MI, and cerebrovascular endpoints, the number of

of reaching the primary endpoint (Table 4). The prob-

events was relatively small (Table 2). Nevertheless,

ability value of the Grønnesby and Borgan (17) test

the effect of atorvastatin treatment appeared to be

confirmed satisfactory goodness of fit (Table 4). Sub-

least beneficial in the third tertile of the cholestanol-

group analyses within the cholestanol-to-cholesterol

to-cholesterol ratio for each of these endpoints

ratio tertiles showed that atorvastatin reduced the

(Table 4). These results were confirmed by per-

risk of reaching the primary endpoint in the first tertile,

protocol analyses (Online Table 1).

but did not do so in the second and third tertiles (Table 4, Central Illustration). These results were

DISCUSSION

confirmed by per-protocol analyses (Online Table 1). Consistent with the primary endpoint results,

This post-hoc analysis of the 4D trial shows that pa-

atorvastatin treatment reduced the risk of death from

tients on maintenance hemodialysis treatment with

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Cholesterol Absorption and Outcomes in 4D Study

T A B L E 2 Events by Tertiles

First Tertile

Death from all causes All cardiac events

Cardiac death Sudden cardiac death Nonfatal MI

All cerebrovascular events

Stroke

Placebo (n ¼ 178)

Atorvastatin (n ¼ 177)

Third Tertile

Event Type

4.2

4.2

4.2

4.2

3.8

3.9

First event

51 (30.9)

76 (42.7)

63 (35.6)

61 (36.7)

75 (42.4)

67 (40.1)

Second event

8 (4.8)

10 (5.6)

8 (4.5)

19 (11.4)

9 (5.1)

7 (4.2)

Total

59

86

71

80

84

74

Total

73 (44.2)

102 (57.3)

95 (53.7)

78 (47.0)

90 (50.8)

90 (53.9)

Follow-up time, yrs Primary endpoint

Second Tertile

Atorvastatin (n ¼ 165)

Placebo (n ¼ 166)

Atorvastatin (n ¼ 177)

Placebo (n ¼ 167)

First event

46 (27.9)

80 (44.9)

60 (33.9)

60 (36.1)

63 (35.6)

66 (39.5)

Second event

16 (9.7)

23 (12.9)

8 (4.5)

24 (14.5)

18 (10.2)

17 (10.2)

Total

62

103

68

84

81

83

Total

26 (15.8)

48 (27.0)

39 (22.0)

32 (19.3)

39 (22.0)

42 (25.1)

Total

17 (10.3)

25 (14.0)

29 (16.4)

18

22 (12.4)

21 (12.6)

First event

18 (10.9)

24 (13.5)

15 (8.5)

23 (13.9)

20 (11.3)

19 (11.4)

Second event

2 (1.2)

3 (1.7)

1 (0.6)

7 (4.2)

2 (1.1)

1 (0.6)

Total

20

27

16

30

22

20

First event

16 (9.7)

18 (10.1)

21 (11.9)

21 (12.7)

28 (15.8)

21 (12.6) 6 (3.6)

Second event

1 (0.6)

2 (1.1)

4 (2.3)

3 (1.8)

7 (4.0)

Total

17

20

25

24

35

27

First event

12 (7.3)

11 (6.2)

14 (7.9)

16 (9.6)

23 (13.0)

10 (6.0)

Second event

1 (0.6)

0 (0.0)

2 (1.1)

2 (1.2)

0 (0.0)

2 (1.2)

Total

13

11

16

18

23

12

Values are n (%). MI ¼ myocardial infarction.

low cholesterol absorption rates may benefit from

These data agree with findings from the 4S (Scan-

treatment with atorvastatin (Central Illustration). The

dinavian

finding is of relevance, because hemodialysis patients

beyond the obvious exception that statins appeared

Simvastatin

Survival

Study)

trial

(21),

have an extremely high CV risk (18,19). Moreover,

to be more effective in reducing CV risk in the 4S than

therapeutic strategies to reduce this risk are scarce

in the 4D study (21). In the 4S study, simvastatin

or virtually absent (9). In particular, treatment with

treatment versus placebo significantly reduced the

statins has generally not been recommended in pa-

risk of major coronary events by 38% in the lowest

tients on maintenance hemodialysis treatment (20).

quartile of the cholestanol-to-cholesterol ratio, but such treatment increased the risk of major coronary events by 17% in the highest quartile (21). Both the

T A B L E 3 Risk of Endpoints*

4S and 4D studies fit well into our current underHR (95% CI)†

p Value†

standing of cholesterol homeostasis (10): there is

Primary endpoint

0.87 (0.72–1.05)

0.145

some reason to think that treatment with statins,

Death from all causes

0.91 (0.77–1.08)

0.274

which interfere with cholesterol synthesis, is less

All cardiac events

0.77 (0.64–0.93)

0.006

effective in patients with advanced CKD who absorb

Cardiac death

0.85 (0.66–1.10)

0.213

most of their cholesterol (11). In line with this idea,

Sudden cardiac death

1.02 (0.74–1.42)

0.885

Nonfatal MI

0.74 (0.53–1.03)

0.074

All cerebrovascular events

1.06 (0.75–1.49)

0.758

in the 4D study (1.8 m g/mg) than in the LURIC

0.417

(Ludwigshafen

Stroke

1.20 (0.77–1.89)

*Comparing the atorvastatin group versus placebo group (reference) in the intention-to-treat cohort calculated with Andersen-Gill models or Cox regression. †For difference between atorvastatin treatment and placebo in the entire cohort adjusted for sex, age, phosphate, albumin, hemoglobin, HbA1c, ever smoking, systolic and diastolic BP, BMI, ultrafiltration volume, duration of dialysis, CAD (MI, coronary artery bypass grafting, coronary intervention, and angiographically documented CAD), history of stroke/TIA, peripheral artery disease, congestive HF (predominantly presenting with New York Heart Association functional class II), and arrhythmia. CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.

the mean cholestanol-to-cholesterol ratio was higher Risk

and

Cardiovascular

Health)

study (1.5 m g/mg) (15), the Framingham Offspring Study (1.4 m g/mg) (22), and especially the 4S study (1.3 mg/mg) (21). In contrast, inhibition of cholesterol absorption may be instrumental to reduce CV risk in patients with high cholesterol absorption (10). This pathophysiological background could be 1 of the reasons for the results of the SHARP (Study of Heart And Renal Protection) (23). All participants in the SHARP study had

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Cholesterol Absorption and Outcomes in 4D Study

T A B L E 4 Risk of Endpoints by Tertile*

First Tertile

Second Tertile

Third Tertile

HR (95% CI)†

p Value†

HR (95% CI)†

p Value†

HR (95% CI)†

p Value†

p Value‡

Primary endpoint

0.72 (0.52–1.00)

0.049

0.79 (0.53–1.16)

0.225

1.21 (0.85–1.74)

0.287

0.702

p Value§ p Valuek

0.042

0.140

Death from all causes

0.70 (0.52–0.96)

0.025

1.06 (0.76–1.47)

0.736

1.02 (0.73–1.43)

0.902

0.100

0.069

0.206

All cardiac events

0.65 (0.47–0.92)

0.014

0.73 (0.50–1.06)

0.097

1.07 (0.73–1.57)

0.736

0.684

0.070

0.369

Cardiac death

0.57 (0.33–0.98)

0.042

1.13 (0.67–1.90)

0.644

1.08 (0.70–1.66)

0.722

0.124

0.066

0.454

Sudden cardiac death

0.68 (0.33–1.39)

0.291

1.54 (0.82–2.90)

0.180

1.13 (0.63–2.06)

0.671

0.190

0.396

0.060

Nonfatal MI

0.81 (0.43–1.54)

0.520

0.51 (0.27–0.99)

0.040

1.10 (0.60–1.99)

0.766

0.335

0.406

0.886

All cerebrovascular events 0.92 (0.47–1.78)

0.800

0.93 (0.52–1.68)

0.814

1.28 (0.74–2.21)

0.372

0.865

0.401

0.095

Stroke

0.537

0.73 (0.33–1.62)

0.433

2.10 (1.02–4.33)

0.044

0.432

0.431

0.561

1.26 (0.60–2.67)

*Calculated with Andersen-Gill models or Cox regression. †For difference between atorvastatin treatment and placebo within the tertiles of the cholestanol-to-cholesterol ratio adjusted for sex, age, phosphate, albumin, hemoglobin, HbA1c, ever smoking, systolic and diastolic BP, BMI, ultrafiltration volume, duration of dialysis, history of stroke/TIA, CAD (MI, coronary artery bypass graft [CABG], coronary intervention, and angiographically documented CAD), peripheral artery disease, congestive HF (predominantly presenting with New York Heart Association [NYHA] functional class II), and arrhythmia. ‡For association of interaction term between tertiles and treatment group with endpoints (second tertile vs. first tertile) in the entire cohort. §For association of interaction term between tertiles and treatment group with endpoints (third tertile vs. first tertile) in the entire cohort. ‡ and § models included sex, age, phosphate, albumin, hemoglobin, HbA1c, ever smoking, systolic and diastolic BP, BMI, ultrafiltration volume, duration of dialysis, history of stroke/TIA, CAD (MI, CABG, coronary intervention, and angiographically documented CAD), peripheral artery disease, congestive HF (predominantly presenting with NYHA functional class II), arrhythmia, tertiles, atorvastatin treatment (main effect), and the interaction term between the tertiles and atorvastatin treatment. kFor goodness of fit calculated according to Grønnesby and Borgan (17) in the entire cohort. Abbreviations as in Tables 1 to 3.

CKD, and 33% of the cohort received maintenance

treatment to prevent CV complications in patients on

hemodialysis treatment. A total of 9,270 participants

maintenance hemodialysis treatment. Third, we used

were randomized to either simvastatin plus ezetimibe,

the cholestanol-to-cholesterol ratio as a measure of

a cholesterol absorption inhibitor, or placebo. The

cholesterol absorption. This estimate is less prone to

combination therapy of simvastatin and ezetimibe

confounding by diet than other biomarkers for

significantly reduced the risk of major atherosclerotic

cholesterol absorption efficiency (12,13). Fourth, the

events by 17%. The present data lend support for

laboratory personnel responsible for measuring cho-

the strategy to inhibit both cholesterol synthesis and

lestanol were blinded to all of the clinical and

cholesterol absorption, especially in hemodialysis

biochemical data of the participants. Fifth, confound-

patients. Moreover, the present post-hoc analysis of

ing due to the use of drugs that interfere with choles-

the 4D trial suggests that measurement of cholesterol

terol metabolism is unlikely. Cholestyramine, a bile

absorption may help to identify hemodialysis patients

acid sequestrant, was not used by any patient, because

who would benefit from treatment with statins. This

in Germany this medicine is regarded as contra-

would be an approach to personalized medicine,

indicated for hemodialysis patients because of it in-

which seems of particular relevance in high CV risk

creases triglycerides. Sevelamer, a phosphate-binding

hemodialysis patients on polypharmacy therapy (24).

drug with a structure similar to bile acid resins, was

However chromatography– and mass spectrometry–

approved in Germany, but not until early 2000, and

based measurement of cholestanol is still cost-

was taken by <1% of the study participants due to its

demanding, time-consuming, and only offered by

slow introduction on the market (recruitment between

specialized laboratories. Moreover, standardizing the

March 1998 and October 2002). Ezetimibe and fibrates

methods

were not taken by any patient. Sixth, the results ob-

to

measure

cholestanol

has

not

yet

concluded, and an international standardization

tained

effort is still ongoing (25).

confirmed by per-protocol analyses.

from

intention-to-treat

analyses

were

This work has major strengths. First, we report on data from the 4D study that represents 1 of only 2

STUDY LIMITATIONS. The observational character of

randomized controlled trials that investigated the

the present study might be a limitation because the

effectiveness of statin treatment to reduce CV risk only

study was a post-hoc analysis. However, we had a

in patients who received maintenance hemodialysis

clear hypothesis that was confirmed following a

treatment. The cohort is large and well characterized,

pre-defined statistical analysis plan. In addition, di-

and there was a comprehensive follow-up with a

etary intake of cholesterol or saturated fat was not

considerable amount of fatal and nonfatal events

recorded by survey or questionnaire. Finally, single

yielding high statistical power (7,14). Second, the pre-

nucleotide

sent study is the first to investigate the impact of

rs4245791, rs4299376, rs41360247, rs6576629, and

cholesterol absorption on the effectiveness of statin

rs4953023) and ABO (e.g., rs657152) genes, which

polymorphisms

in

the

ABCG8

(e.g.,

Silbernagel et al.

JACC VOL. 65, NO. 21, 2015 JUNE 2, 2015:2291–8

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Cholesterol Absorption and Outcomes in 4D Study

CENTRAL I LLU ST RAT ION Risk of Reaching the Primary Endpoint in Participants of the 4D Study on the Basis of Intestinal Cholesterol Absorption

Silbernagel, G. et al. J Am Coll Cardiol. 2015; 65(21):2291–8.

In a post-hoc analysis of hemodialysis patients participating in the German Diabetes and Dialysis Study randomized to atorvastatin or placebo group, and stratified by tertiles of the cholestanol-to-cholesterol ratio, statin effectiveness was dependent on intestinal cholesterol absorption. Those in the first tertile (A) experienced a reduction in the risk of reaching the primary endpoint, a composite of major cardiovascular events; patients in the second (B) and third (C) tertiles had no similar risk reduction.

have been implicated in cholesterol absorption and

alterations probably play a more dominant role

low-density lipoprotein cholesterol concentrations

in the regulation of cholesterol absorption than

(13), were not analyzed in the 4D study. These single

genetic variations. However, the prevalence of

nucleotide polymorphisms might help to predict the

common low-density lipoprotein cholesterol-raising

effectiveness of statin treatment to reduce CV risk.

variants

A large meta-analysis that includes several statin

be slightly higher in hemodialysis patients with

intervention trials testing for such a relationship is

a high cholestanol-to-cholesterol ratio. Moreover,

therefore encouraged.

it will be of interest to test whether the expres-

Cholesterol absorption is regulated in a complex fashion (10). In hemodialysis, specific metabolic

in

the

ABCG8

and

ABO

genes

may

sion of these genes is influenced by the uremic state.

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Cholesterol Absorption and Outcomes in 4D Study

CONCLUSIONS

PERSPECTIVES

We found that measurement of cholesterol absorption may help to identify hemodialysis patients who will benefit from treatment with statins. Beyond that, the data might argue in favor of a combination therapy that addresses both cholesterol synthesis and absorption to reduce CV risk in hemodialysis patients. REPRINT REQUESTS AND CORRESPONDENCE: Dr.

Guenther Silbernagel, Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. E-mail: guenther.

COMPETENCY IN MEDICAL KNOWLEDGE: The efficacy of atorvastatin to reduce cardiovascular risk in patients who are receiving hemodialysis is inversely related to cholesterol absorption. TRANSLATIONAL OUTLOOK: Future studies should investigate the safety and efficacy of interventions that inhibit cholesterol absorption in patients on hemodialysis with high rates of cholesterol absorption.

[email protected].

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KEY WORDS cholestanol, mortality, randomized controlled trial, statin

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A PPE NDI X For a supplemental table, please see the online version of this article.