Autosomal Recessive Hypercholesterolemia

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Nov 6, 2017 - statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was ...
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Author's Personal Copy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 71, NO. 3, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2017.11.028

Autosomal Recessive Hypercholesterolemia Long-Term Cardiovascular Outcomes Laura D’Erasmo, MD, PHD,a Ilenia Minicocci, BSC, PHD,a Antonio Nicolucci, MD,b Paolo Pintus, MD,c Janine E. Roeters Van Lennep, MD, PHD,d Luis Masana, MD, PHD,e Pedro Mata, MD,f Rosa Maria Sánchez-Hernández, MD,g Pablo Prieto-Matos, MD, PHD,h Josè T. Real, MD, PHD,i Juan F. Ascaso, MD, PHD,i Eduardo Esteve Lafuente, MD, PHD,j Miguel Pocovi, PHD,k Francisco J. Fuentes, MD, PHD,l Sandro Muntoni, MD, PHD,m Stefano Bertolini, MD,n Cesare Sirtori, MD, PHD,o Laura Calabresi, PHD,o Chiara Pavanello, PHD,o Maurizio Averna, MD,p Angelo Baldassare Cefalu, MD, PHD,p Davide Noto, MD, PHD,p Adolfo Arturo Pacifico, MD,q Giovanni Mario Pes, MD,r Mariko Harada-Shiba, MD, PHD,s Enzo Manzato, MD,t Sabina Zambon, MD,t Alberto Zambon, MD, PHD,t Anja Vogt, MD,u Marco Scardapane, MSC,b Barbara Sjouke, MD,v Renato Fellin, MD,w Marcello Arca, MDa

ABSTRACT BACKGROUND Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS We collected data for 52 patients (28 females, 24 males; 31.1  17.1 years of age; baseline LDL-C: 571.9  171.7 mg/dl). During a mean follow-up of 14.1  7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0  85.1 mg/dl (69.6% from baseline), with a better response in patients taking lomitapide (88.3%). Overall, 23.1% of ARH patients reached LDL-C of 70%. The severity of aortic valve stenosis was defined by ultrasonographic examination according to local protocols. CHD was defined as any of the following: myocardial infarction, angina pectoris, or coronary revascularization. ARH ¼ autosomal recessive hypercholesterolemia; ASCVD ¼ atherosclerotic cardiovascular disease; BMI ¼ body mass index; CHD ¼ coronary heart disease; HDL-C ¼ high-density lipoprotein cholesterol; LDLC ¼ low-density lipoprotein cholesterol.

transluminal coronary angioplasty and/or coronary artery bypass grafting; also grouped as coronary heart disease [CHD]); 4) severe (>70% stenosis) carotid atherosclerosis; 5) nonhemorrhagic stroke; and 6) cardiovascular death. The aortic valve status was evaluated by standard ultrasonographic examination as well as medical history of valve replacement. No data for safety parameters or side effects during treatment were collected. All procedures were followed in accordance with the ethical standards of the local institutional committees on human experimentation and according to tenets of the Helsinki Declaration of 1964, as revised in 2013. No specific consent was provided for this study,

but

living

patients

were

appropriately

informed and agreed to share their anonymous data for scientific purposes.

281

(SPSS Inc., Chicago, Illinois). Descriptive statistics such as mean  SD and ranges were estimated for all variables. Continuous variables were compared by Student’s t-test, whereas categorical variables were compared by chi-square or Fisher exact test. Differences in lipid levels between therapies were tested for

significance

by

using

regression

analysis,

including baseline values as covariates. To estimate the incident rate of ASCVD, the first event occurred during follow-up was considered. We estimated the time to first ASCVD event by using Kaplan-Meier survival curves. Survival curves were compared by age and previous ASCVD events by using the log-rank test. Cox proportional hazards model was applied to investigate the independent predictive role of the following characteristics: sex, age at first visit, pre-

GENETIC AND BIOCHEMICAL ANALYSES. Genetic

vious CHD event, baseline LDL-C value, and smoking.

analyses were carried out at each collaborating site by

Survival curves for aortic stenosis were not estimated

using standard sequencing protocols. Plasma lipids

due to the small number of observed events. Results

were measured by standard techniques at each site.

were expressed as hazard ratios (HR) with their 95%

LDL-C values were calculated by using the Friedewald

confidence intervals (CIs). Finally, incidence rates

formula or direct assay according to local procedures.

(IRs) for ASCVD were calculated and expressed as

No other biochemical analytes were provided.

number of events per 10,000 patient-years with their

STATISTICAL ANALYSIS. All statistical analyses were

95% CI. IRs were calculated for the whole study

performed using SPSS/WIN software version 18.0

cohort and after categorization for sex, age, and

Author's Personal Copy 282

D’Erasmo et al.

JACC VOL. 71, NO. 3, 2018

Cardiovascular Risk in ARH

JANUARY 23, 2018:279–88

previous ASCVD events. IRs in the ARH cohort were

T A B L E 2 Changes in Treatment

compared to those in the Italian general population ARH

(13). Due to the exploratory nature of our survey, we

Whole Cohort

Men

Women

did not a priori determine a specific primary

14.1  7.3

13.4  7.8

14.6  7

endpoint. Therefore, we used a 2-sided p value

No Tx

13 (26.5)

4 (19.0)

9 (32.1)

Only LA

27 (55.1)

13 (54.2)

14 (50)

Only LLM

8 (16.3)

4 (19)

4 (14.3)

LA plus LLM

1 (2.0)

0 (0.0)

1 (3.6)

NA

NA

NA

No Tx

0 (0.0)

0 (0.0)

0 (0.0)

study cohort consisted of 52 genetically defined ARH

Only LA

1 (1.9)

0 (0.0)

1 (3.6)

patients (24 men and 28 women) with complete lipid

Only LLM

24 (46.2)

7 (29.2)

17 (60.7)

and outcome data. Thirty-three subjects (63.5%) were

LA plus LLM

27 (51.9)

17 (70.8)

10 (35.7)

Rosuvastatin (mean dosage: 33.9 mg/day; range: 5–60 mg/day)

10 (19.2)

4 (16.7)

6 (21.4)

Atorvastatin (mean dosage: 55.7 mg/day; range: 20–80 mg/day)

14 (26.9)

4 (16.7)

10 (35.7)

6 (11.5)

1 (4.2)

5 (17.8)

23 (44.2)

8 (33.3)

15 (53.6)

Twelve

Lomitapide (mean dosage: 14.2 mg/day; range: 5–20 mg/day)

6 (11.5)

1 (4.2)

5 (17.9)

2 major rearrangements) in LDLRAP1 were detected;

Resins, g/day

6 (11.5)

3 (12.5)

3 (10.7)

Follow-up, yrs First evaluation

Number of medications

of 70%) and underwent revascularization. †Evaluation of aortic valve status during follow-up was available in 45 patients. IRs are reported per 10,000 person-years (95% confidence interval). Relative risk was calculated as ARH IRs/IRs general population. CABG ¼ coronary artery bypass graft; IRs ¼ incidence rates; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention; TIA ¼ transient ischemic attack; other abbreviations as in Table 1.

the remaining 3 patients, we were not able to retrieve information about the clinical management of aortic stenosis. Of note, 3 times more women than men developed

this

complication

(14.2%

vs.

4.2%,

respectively; p ¼ NS). the new ASCVD episode was 50.6  13.8 years of age

DISCUSSION

(range: 31 to 72 years). In our population, the most common incident ASCVD event was coronary revas-

The results of this study, involving a large cohort of

cularization (21.2%). For 2 patients with CHD, we did

ARH patients, highlighted 2 major findings. First, the

not have information about the treatment given;

study demonstrated the poor cardiovascular prog-

another patient who experienced CHD during follow-

nosis of these patients. During the 14-year follow-up,

up was currently treated only with medical therapy

26.9% of them had a new episode of ASCVD, and

due to the high risk associated with surgical revas-

11.5% had a new diagnosis of aortic valve stenosis,

cularization. No incident stroke was recorded. All

corresponding to an absolute risk of 1.9% per year and

fatal cardiovascular events occurred in women; 2 died

0.8% per year, respectively (Central Illustration).

of fatal coronary heart disease and 1 because of pro-

Moreover, the median ASCVD event-free survival was

gression of aortic valve stenosis. The mean age of

24 years in the overall cohort and was dramatically

death in these patients was 52.0  9.1 years.

lower (10 years) in ARH patients who had established

To estimate the actual ASCVD risk associated with

CHD at entry. Compared to the general Italian popu-

ARH, we compared the incidence rate of ASCVD in our

lation, treated ARH patients showed a 6-fold and 19-

cohort with that reported in the Italian general pop-

fold higher risk of ASCVD in men and women,

ulation standardized for a comparable follow-up

respectively. The explanation for this sex difference

period (13). Because the data in the whole general

is unclear. The apparently less aggressive LLT in

population were not available, we performed the

women seems unlikely as the percentage of LDL-C

comparison after categorization for sex (Table 3). ARH

reductions were not different between sexes. The

males showed a 6-fold and females a 19-fold higher

most plausible explanation is that ARH abolishes the

risk of incident ASCVD than individuals in the general

cardiovascular protection usually observed in pre-

population.

menopausal women.

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Cardiovascular Risk in ARH

285

F I G U R E 3 Kaplan-Meier Survival Curves for Incident ASCVD

B

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Survival Probability

Survival Probability

A

0

5

10

15

20

25

30

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

5

Years