Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit

Journal of Clinical Lipidology (2015) 9, 703–708

Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit Jing Pang, PhD, Elissa B. Poulter, MBBS, Damon A. Bell, MBChB, FRACP, FRCPA, Timothy R. Bates, MBBS, FRACP, Vicki-Lee Jefferson, MBBS, Graham S. Hillis, PhD, MBChB, Carl J. Schultz, MBChB, DPhil, Gerald F. Watts, DSc, PhD, MD, FRACP, FRCP* School of Medicine and Pharmacology, University of Western Australia, Western Australia, Australia (Drs Pang, Poulter, Bell, Bates, Jefferson, Hillis, Schultz, Watts); Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, Western Australia, Australia (Drs Bell, Bates, Watts); Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Western Australia, Australia (Dr Bell); and Department of Cardiology, Royal Perth Hospital, Western Australia, Australia (Drs Hillis, Schultz) KEYWORDS: Familial hypercholesterolemia; Screening; Coronary care unit; Prevalence

BACKGROUND: Familial hypercholesterolemia (FH) is the most common dominantly inherited cause of premature coronary artery disease (CAD). However, the diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized, this also represents a missed opportunity for screening their close family members and implementing primary prevention. OBJECTIVE: To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD. METHODS: The prevalence of FH, based on modified phenotypic Dutch Lipid Clinic Network Criteria, and the spectrum of associated CAD risk factors, were investigated in a CCU setting. Data were collected on 175 coronary care patients with onset of CAD at age ,60 years. RESULTS: The prevalence of probable/definite FH was 14.3% (95% confidence interval, 9.0%– 19.5%); 46.3% of the patients gave a family history of premature CAD and 20.6% had an untreated low-density lipoprotein cholesterol .5.0 mmol/L. Diabetes, hypertension, obesity, and smoking were common and equally prevalent in patients with and without FH. CONCLUSIONS: FH is relatively frequent among patients with a history of early-onset CAD in the CCU. Every effort should be made to detect FH in these patients and to initiate cascade testing of available family members to prevent the development of CAD in those who may be unaware that they also have the condition. Ó 2015 National Lipid Association. All rights reserved.

Introduction * Corresponding author. School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213, Perth, WA 6847, Australia. E-mail address: [email protected] Submitted April 2, 2015. Accepted for publication July 8, 2015.

1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2015.07.005

Familial hypercholesterolemia (FH) is a relatively common dominantly inherited condition resulting in markedly elevated plasma levels of low-density lipoprotein (LDL)

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cholesterol and premature coronary artery disease (CAD). The risk of CAD in FH is preventable or reversible through early detection and treatment of hypercholesterolemia.1 FH remains underdetected and undertreated in most countries.2,3 International guidelines have accordingly recommended several screening strategies for FH. An important one is the detection in coronary care units (CCUs) of potential index cases who then trigger cascade testing for the condition in close family members.2–5 The value of this integrated approach has not been adequately recognized, and, as a consequence, a key opportunity for detecting FH has not been embedded in routine clinical care. We therefore investigated the prevalence of FH using a modified and simplified version of the Dutch Lipid Clinic Network Criteria (DLCNC) among patients with earlyonset CAD in a CCU. We also assessed the spectrum of modifiable non-cholesterol risk factors in these patients.

criterion combined with a family history of early-onset CAD has also been used to diagnose FH.7 Fasting blood samples were collected in which a plasma lipid profile was assayed using standard enzymatic methods, with LDL cholesterol calculated by the Friedewald equation. Patients with secondary hypercholesterolemia (hypothyroidism and proteinuria) were excluded. In patients with triglyceride .4.5 mmol/L, LDL cholesterol was directly measured. Data were collated using Microsoft Access and Excel 2010 and analyzed using STATA 12 (StataCorp, 2011, Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). Data were compared using unpaired t tests and chi-square tests. Concordance rates and kappa statistics were also used to compare diagnostic criteria for FH. The study was approved by the Clinical Audit and Safety Unit at Royal Perth Hospital (QI Registration No: QI 120124-1).

Methods

Results

We studied 175 consecutively available patients, over 2 periods of 12 weeks each in 2011 and 2013 admitted to the CCU of the Royal Perth Hospital, Perth, Western Australia. Patients had to have been admitted with a current or prior history of CAD (acute coronary syndrome, coronary revascularization, or angina) at an age ,60 years. Clinical data were collected prospectively by a nurse from medical records and by direct interview of patients. All patients were assessed using the modified DLCNC2: premature family history of CAD (at age ,55 years for men and ,60 years for women; 1 point); personal history of CAD (2 points), personal history of stroke (1 point); and plasma LDL cholesterol .8.5 mmol/L (8 points), LDL cholesterol 6.5–8.4 (5 points), LDL cholesterol 5–6.4 mmol/L (3 points), LDL cholesterol 4–4.9 mmol/L (1 point). Individuals on statins had their plasma LDL cholesterol conservatively adjusted by a correction factor that depends on the dose and potency of specific statins to estimate pretreatment levels; the mean correction factor was 2.0, consistent with adjustments in the literature.6 FH was defined as the numerical sum to each of the previously mentioned criteria: definite, score .8; probable, score 6–8; possible, score 3–5; and unlikely, score ,3. In the present study, phenotypic FH was defined as a score .5 (probable/ definite FH). Cardiovascular risk factors, such as smoking, diabetes, hypertension, and obesity, were obtained from the medical history in the hospital records. We also assessed the prevalence of individuals with a family history of premature CAD, an LDL cholesterol .5.5 mmol/L, .5.0 mmol/L, and .4.5 mmol/L, and the prevalence of meeting both the family history and aforementioned LDL cholesterol criteria. We have evidence that an LDL cholesterol .5.0 mmol/L is predictive of a pathogenic mutation causative of FH with high sensitivity (.85%) and reasonable specificity (.60%), and this

The patients were middle-aged (50.3 6 7.1 years), 81% were men, 92% Caucasian, and 28% were on statin therapy at first review; untreated LDL cholesterol level was on average 4.13 6 1.41 mmol/L. The average DLCNC score was 3.6 6 2.0, and 21% of patients had type II diabetes, 46% hypertension, and 12% obesity. Thirty-five percent of patients were current smokers and 18% ex-smokers. Table 1 shows the prevalence of FH, defined according to different criteria. The point prevalence of probable FH was 12.0% and definite FH 2.3%, with the combined prevalence of probable/definite FH being 14.3% (95% confidence interval [CI], 9.0–19.5); over half of patients had possible FH. Excluding 6.3% of patients with angina pectoris alone, the prevalence of probable/definite FH was 15.2% (95% CI, 9.7–20.8). The prevalence estimates for FH did not differ significantly between the 2 sampling periods. Overall, 46.3% of the patients had a family history of premature CAD, but only 12.0% and 20.6% had an untreated LDL cholesterol .5.5 mmol/L and .5.0 mmol/L, respectively; 10.9% had both an untreated LDL cholesterol .5.0 mmol/L and a family history of premature CAD, a criterion which was significantly concordant with a DLCNC .5 (kappa 5 0.79; P , .001). Probable/definite FH was more common in those with CAD onset aged ,50 years compared with those aged 50 to 60 years (15.1% vs 13.3%) and more common in women than men (20.6% vs 12.8%), but the differences were not statistically significant. The prevalences of FH according to the criteria shown in Table 1 were not significantly influenced by excluding patients with hypertriglyceridemia (defined as a triglyceride concentration .2.5 mmol/L or .1.8 mmol/L). A pathogenic mutation causative of FH8 was found in 3 of 6 (50%) patients with phenotypic FH

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Screening for FH in a coronary care unit

Table 1

Prevalence of FH according to different criteria

Criteria

Prevalence, % (95% CI)

DLCNC score 3–5 (possible FH) DLCNC score .5 (probable/definite FH) DLCNC score 6–8 (probable FH) DLCNC score .8 (definite FH) Family history of premature CAD LDL cholesterol .5.5 mmol/L LDL cholesterol .5.5 mmol/L 1 family history of premature CAD LDL cholesterol .5.0 mmol/L LDL cholesterol .5.0 mmol/L 1 family history of premature CAD LDL cholesterol .4.5 mmol/L LDL cholesterol .4.5 mmol/L 1 family history of premature CAD

61.1 14.3 12.0 2.3 46.3 12.0 8.0

705

(53.8–68.4) (9.0–19.5) (7.1–16.9) (0.5–4.5) (38.8–53.7) (7.1–16.9) (3.9–12.1)

20.6 (14.5–26.6) 10.9 (6.2–15.5) 30.3 (23.4–37.2) 15.4 (10.0–20.8)

CAD, coronary artery disease; CI, confidence interval; DLCNC, Dutch Lipid Clinic Network Criteria; FH, familial hypercholesterolemia; LDL, low-density lipoprotein.

who were referred to the lipid disorders clinic for further assessment; all DNA-negative patients who were tested also had an elevated plasma level of lipoprotein(a) (Lp(a); .0.5 g/L). Table 2 shows the non-cholesterol risk factors and use of statins in patients with and without FH. The prevalence of diabetes, hypertension, and obesity was higher in those with FH than without FH, but the differences were not significantly different. The proportion of patients with FH on statins was significantly higher than those without FH; of the FH patients, 8% and 4% were treated to LDL cholesterol target levels of ,2.5 mmol/L and ,1.8 mmol/L, respectively. At discharge, 86% of the patients were on a statin (mostly atorvastatin, 40 mg or 80 mg); reasons for not prescribing a statin included intolerance, elevations in hepatic aminotransferases, and premature self-discharge.

Discussion In the present study, we show that FH is relatively common among CCU patients with history of CAD at age less than 60 years, and FH can be relatively easily identified clinically. The diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized.9 The coronary care setting is a useful environment for detecting patients likely to have FH, who should then be referred to a specialist service for confirmation of the diagnosis and family screening for the condition. We also showed a high prevalence of modifiable non-cholesterol cardiovascular risk factors among FH patients,10–13 denoting the need for a multiple risk factor prevention strategy.14 Estimates of the prevalence of FH in individuals with early-onset CAD can vary considerably (Table 3). The relatively higher estimate of FH prevalence in the present study may be a reflection of generally falling coronary rates in the rest of the population with continuing high rates among FH patients. Other reasons may be the differences in the diagnostic criteria used, populations studied, and the age-related definition for the onset of CAD. Our prevalence data and 95% CIs for FH encompass most of these results. Some of the former studies used the Simon Broome diagnostic criteria,21,22 which accord well with the DLCNC that have been validated against mutational data in FH.26 Using the DLCNC, we previously showed a comparable, but lower prevalence of FH. However, that study was retrospective, and half the sample population could not be evaluated owing to incomplete data.9 Similar limitations apply to another Australian study.23 Although we based our prevalence of probable/definite FH on the DLCNC, we also showed a comparable prevalence in the present study with a family history of premature CAD plus an untreated LDL cholesterol .5.0 mmol/L. The concordance between these 2 methods for assessing FH was statistically significant; future studies should explore the value and yield of using a simple, 2-criteria approach to detecting FH, as suggested elsewhere.7

Table 2 Age, LDL cholesterol, and frequency of non-cholesterol cardiovascular risk factors and use of statins in patients with and without FH Prevalence of FH according to different criteria

With FH (n 5 25)

Without FH (n 5 150)

P value

Age at admission to CCU, y 6 SD LDL cholesterol at admission, mmol/L 6 SD Untreated LDL cholesterol, mmol/L 6 SD Male, % (95% CI) Diabetes, % (95% CI) Hypertension, % (95% CI) Obesity, % (95% CI) Current or ex-smoking, % (95% CI) Use of statins, % (95% CI)

50.55 6 1.42 3.82 6 0.24 6.49 6 0.26 72.0 (53.1–90.9) 32.0 (12.3–51.7) 48.0 (27.0–69.0) 16.0 (5.6–31.4) 40.0 (19.4–60.6) 68.0 (48.3–87.7)

50.21 6 0.58 3.30 6 0.09 3.73 6 0.08 82.0 (75.8–88.2) 18.7 (12.4–25.0) 46.0 (37.9–54.1) 11.3 (6.2–16.5) 54.7 (46.6–62.7) 21.3 (14.7–28.0)

.826 .032 ,.001 .242 .127 .853 .506 .174 ,.001

CCU, coronary care unit; CI, confidence interval; FH, familial hypercholesterolemia; LDL, low-density lipoprotein; SD, standard deviation.

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Table 3

Published data on the prevalence of FH in individuals with CAD, present study shown for comparison

First author, year

Country/ Region

Patterson, 197215

United Kingdom

193

No age restriction

Goldstein, 197316 Goldstein, 197317

United States United States

500 176

No age restriction ,60

Nikkila, 197318

Finland

101

Koivisto, 199319 Dorsch, 200120 Bates, 20089 Rallidis, 200821 Wiesbauer, 200922 Yudi, 201223 Wald, 201524

Finland United Kingdom Australia Greece

De Backer, 201525 Present study

Diagnostic test

Criteria

3

Clinical/cholesterol

7.6

Clinical/cholesterol

Type IIa phenotype plus HC* and a firstdegree relative with type IIa phenotype plus HC* Plasma cholesterol .95th percentile

4.1

Clinical/cholesterol

,50

6

Clinical/cholesterol

150

,45

9

Genetic

Plasma cholesterol .95th percentile with a first-degree relative with HC† or premature CAD Type IIa phenotype plus HC‡ and a firstdegree relative with type IIa phenotype plus HC‡ Common LDLR mutations

292

,60

12

Clinical/cholesterol

Phenotypic Simon Broome criteria

199 135

,60 ,35

2.1 19

Clinical/cholesterol Clinical/cholesterol

Phenotypic DLCNC Phenotypic Simon Broome criteria

Austria

302

,40

8

Clinical/cholesterol

Phenotypic Simon Broome criteria

Australia United Kingdom Europe

201 231

,60 ,50

1.4 1.3

Clinical/cholesterol Genetic

Phenotypic DLCNC Common LDLR mutations

7044 2212 175

,80 ,60 ,60

8.3 15.4 14.3

Clinical/cholesterol

Phenotypic DLCNC

Clinical/cholesterol

Phenotypic DLCNC

Australia

n

Age, y

Prevalence (%)

CAD, coronary artery disease; DLCNC, Dutch Lipid Clinic Network Criteria; FH, familial hypercholesterolemia; HC, hypercholesterolemia. *HC defined as age- and gender-adjusted cholesterol .2 standard deviations above the expected level. †HC defined as cholesterol .99th percentile (age.20 y) or cholesterol .95th percentile (age #20 y). ‡HC defined as the 90th percentile of age- and gender-adjusted cholesterol in controls.

Wald et al24 demonstrated a low prevalence (1.3%) of genotypic FH among young patients with acute myocardial infarction, which falls within the 95% CI of our data, based on a definite phenotypic diagnosis of FH. However, only half of the patients in the former study underwent DNA analysis, and only a limited spectrum of LDLR mutations were investigated; APOB and PCSK9 mutations were also not tested. Although we DNA tested a small amount of phenotypic FH subjects in our clinic, half of them were found to have a pathogenic mutation. This implies that even if we had genetically tested all CCU subjects, our prevalence figure would have been higher than that reported by Wald et al.24 Of note, the study by Koivisto et al19, reporting a 9% prevalence of FH, was from North Karelia, a Finnish population with a strong founder effect. The highest prevalence of FH was reported by Rallidis et al,21 and this may relate to the very young age (,35 years) of presentation of the patients with CAD. In earlier studies undertaken in the 1970s,15–18 only survivors of myocardial infarction and their available first-degree relatives were included, suggesting an introduction of survivorship and reporting bias. In a retrospective cohort of

coronary patients, the EUROASPIRE-IV Investigators25 recently demonstrated a comparable prevalence of probable/definite FH using the DLCNC. Although there was wide variation among the 24 European countries, the overall prevalence was 8.3% and 15.4% at age ,80 and ,60 years, respectively. Although patients with FH are more likely to be taking statins than those without FH, more than 30% of the former were not on this medication at presentation, concurring with community data on FH.27 Moreover, as demonstrated elsewhere28,29 and in the present study, of the FH patients on statins, most were not treated to target. This points to a shortfall in management of FH in primary care. By contrast, at discharge, most of our CCU patients were receiving a statin. Our study has limitations. Caucasians were almost exclusively investigated; further studies of more racially diverse populations are required. As we did not routinely use DNA testing, we cannot exclude that our cases of FH had other inherited dyslipidemias, such as familial combined hyperlipidemia, polygenic hypercholesterolemia, or familial elevation of Lp(a). However, not all mutations

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Screening for FH in a coronary care unit

causing FH are at present known. The combination of polygenic hypercholesterolemia and elevated Lp(a) is an important differential diagnosis that merits further investigation in a CCU cohort. Of our cohort, 28% did not know whether they had a family history of premature CAD, which probably resulted in an underestimation of the true prevalence of FH. We did not record physical stigmata of FH, such as tendon xanthomata and arcus cornealis. However, these signs have a low sensitivity for the diagnosis of FH.2,30 Acute illness may lower plasma LDL cholesterol, and this also needs to be accounted for if the suspicion of FH based on other criteria is high. Our data demonstrate the importance of screening for FH in CCUs among patients who first present with earlyonset CAD or with a recurrent event and a previous history of premature CAD. To close this gap in coronary prevention, we recommend routine screening for FH in CCU, with referral of index cases for cascade testing of close relatives for FH. Improving awareness of FH among physicians,31 nurses and health care professionals in CCU32 combined with a simple LDL cholesterol threshold of .5.0 mmol/L coupled with a reliable family history of premature CAD and/or a modified DLCNC .5 may also have population health benefits if cascade testing is adapted effectively. The cost-effectiveness of this approach has been well documented.33,34 Finally, all efforts on improving the detection and management of FH should be integrated with primary care strategies35 to ensure continuity of care, including ensuring adherence to therapy and monitoring of the safety and side effects of cholesterol-lowering treatments. The recommended plasma LDL cholesterol targets may not be achievable in many patients with FH; however, with currently available best treatment based on statins and ezetimibe. This shortfall may be remedied by the advent of new biologics, particularly proprotein convertase subtilisin/kexin type 9 inhibitors.36

Conclusion We conclude that FH is frequent among patients with a history of early-onset CAD in a CCU setting. Routine screening for these individuals is a key strategy for increasing the detection and diagnosis of FH and simple criteria, such as a family history of premature CAD plus a pretreatment LDL cholesterol .5.0 mmoL/L, may facilitate detection. This, in turn, would allow cascade testing of available family members for primary prevention. Cardiologists and nursing staff working in CCUs can play a major role in the detection and overall care of FH.32

Acknowledgment The authors acknowledge the support from the Australian Better Health Initiative and the Department of Health

707 of Western Australia. The authors thank Lynda Southwell and Maria Vulin for nursing support.

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