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Prognostic impact of familial hypercholesterolemia on long-term outcomes in patients undergoing percutaneous coronary intervention
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Original Article
Prognostic impact of familial hypercholesterolemia on long-term outcomes in patients undergoing percutaneous coronary intervention Maximilian Tscharre, MD*, Robert Herman, BSc, Miklos Rohla, MD, PhD, Edita Piackova, MD, Kris G. Vargas, MD, Serdar Farhan, MD, Matthias K. Freynhofer, MD, Thomas W. Weiss, MD, PhD, Kurt Huber, MD 3rd Medical Department with Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria (Drs Tscharre, Rohla, Piackova, Vargas, Farhan, Freynhofer, Weiss, and Huber); Institute of Cardiometabolic Diseases, Karl Landsteiner Society, St. P€ olten, Austria (Drs Tscharre, Rohla, Weiss); and Sigmund Freud University, Medical School, Vienna, Austria (Drs Herman, Weiss, and Huber) KEYWORDS: Familial hypercholesterolemia; Percutaneous coronary intervention; Acute coronary syndrome; Stable coronary artery disease; Adverse outcomes
BACKGROUND: Patients with familial hypercholesterolemia (FH) are at increased risk for premature and subsequent cardiovascular disease. Data on long-term major adverse cardiovascular events (MACE) in patients with FH after percutaneous coronary intervention (PCI) in the era of highintensity statins are scarce. OBJECTIVE: We assessed the prognostic impact of clinically diagnosed FH on long-term MACE, a composite of all-cause death, myocardial infarction, and ischemic stroke in patients admitted for stable coronary artery disease (SCAD) or acute coronary syndromes (ACSs) undergoing PCI. METHODS: FH was diagnosed according to the Dutch Lipid Clinic Network diagnosis criteria: ‘‘Unlikely FH’’ diagnosis was defined as 0 to 2 points, ‘‘possible FH’’ as 3 to 5 points, and ‘‘probable/definite FH’’ diagnosis as 6 or higher. RESULTS: From a total of 1550 eligible patients (47.4% were admitted for SCAD and 52.6% for ACS), 77 (5.0%) were classified as probable/definite FH, 332 (21.4%) as possible FH, and 1141 (73.6%) as unlikely FH. Mean follow-up was 6.0 6 2.4 years. After adjustment for possible confounders, patients classified with probable or definite FH (hazard ratio [HR] 1.922 [95% confidence interval (CI) 1.220–2.999]; P 5 .004), but not patients with possible FH (HR 1.105 [95% CI 0.843– 1.447]; P 5 .470) faced a significant, approximately 2-fold increased risk of MACE compared with patients with unlikely FH. CONCLUSION: After adjustment for confounders, patients with probable or definite FH faced an approximate 2-fold increased risk for long-term MACE compared with patients without FH despite
Conflicts of Interest: K.H. received lecture fees from AMGEN and SANOFI AVENTIS. The rest of the authors declare no conflicts of interest. * Corresponding author. Maximilian Tscharre, MD, 3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria.
E-mail address: [email protected] Submitted April 5, 2018. Accepted for publication September 18, 2018.
1933-2874/Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association. https://doi.org/10.1016/j.jacl.2018.09.012 FLA 5.5.0 DTD JACL1387_proof 12 October 2018 4:00 pm
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the widespread use of high-intensity statins. The new option of proprotein convertase subtilisin/kexin type 9 gene inhibitors in addition to other current optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH. Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association.
Introduction
Patients and methods
Familial hypercholesterolemia (FH) is the most common autosomal dominant hereditary disorder and is characterized by severely elevated levels of cholesterol and low-density lipoprotein cholesterol (LDL-C) from birth.1 FH is most frequently attributable to mutations in the low-density lipoprotein receptor gene (LDLR) but also to mutations in the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9), all resulting in reduced hepatic capacity to clear LDL-C from the circulation.2,3 By inducing vascular inflammation, high levels of LDL-C are known to be a major risk factor for the initiation and promotion of atherosclerosis, and, as a consequence, FH patients are at an extremely high risk of premature cardiovascular disease and mortality.1,4 If left untreated, individuals with heterozygous FH (HeFH) commonly develop coronary artery disease (CAD) before the age of 55 years, and individuals with homozygous FH will manifest CAD in their childhood or adolescence and typically die by the age of 20 years.1,5 In FH patients without manifest CAD, attenuating cardiovascular risk by early initiation of lipid-lowering therapy with statins has been shown to be very effective.6,7 Unfortunately, FH (especially HeFH) remains predominately undiagnosed and undertreated, with many individuals are not being diagnosed with FH until after the occurrence of their first coronary event.1 Up to 10% of patients admitted for CAD have clinical criteria compatible with FH, which represents a prevalence of FH 10 times higher than that found in the general population.8-11 For patients with manifest CAD, only few reports concerning the prognostic impact of FH in the era of high-intensity statins are available. Regarding short-term adverse outcome, Nanchen et al. recently reported an approximately 2- to 3-fold increased risk of FH patients to suffer from a recurrent cardiovascular event within the first year after acute coronary syndrome (ACS) despite the widespread use of high-intensity statins in their cohort.12 Data on adverse outcome beyond 1 year after admission for ACS or SCAD in patients with clinically diagnosed FH is particularly limited. Therefore, we investigated the prognostic impact of FH on long-term major adverse cardiovascular events (MACE) in patients presenting with ACS or SCAD undergoing percutaneous coronary intervention (PCI).
Study population We analyzed patients undergoing successful PCI for ACS or SCAD between 2007 and 2012. ACS and SCAD were diagnosed and treated according to the recommended guidelines at that time.13,14 Implantation of drug-eluting stents or bare metal stents was under the discretion of the treating intervention. Chronic lipid-lowering treatment at the time of intervention, periprocedural details, cardiovascular comorbidities, laboratory parameters, and discharge medication for secondary prevention were documented. Patients with triglyceride levels .400 mg/dL (because of limitations to correctly estimate LDL-C), as well as patients not residing in the Vienna metropolitan region or who deceased during the initial hospital stay, were excluded from the present analysis. This study was conducted according to the Declaration of Helsinki statement, with approval by the local ethics committee (EK 17-134-VK) and informed consent by all patients. All authors had full access to the data and took responsibility for its integrity.
Diagnosis of FH FH was diagnosed according to the validated Dutch Lipid Clinic Network (DLCN) diagnosis criteria based on age, personal and family history of premature cardiovascular disease, clinical symptoms, and LDL-C levels.15 In case of chronic lipid-lowering therapy, LDL-C levels were estimated using correction factors published by Besseling et al.16 Information on clinical signs of lipid accumulation (arcus cornealis or tendon xanthoma), family history of elevated LDL-C levels, and genetic testing was not available in our study cohort and were therefore counted as zero, as done in former studies.8,12,17 Unlikely FH diagnosis was defined as 0 to 2 score points, a possible FH diagnosis as 3 to 5 score points, and a probable/definite FH diagnosis as 6 or higher according to the DLCN criteria.
Laboratory parameters Blood samples for routine laboratory parameters were collected at hospital admission (glucose, creatinine, Creactive protein [CRP] and cardiac markers) or during the first day after admission in fasting condition (total cholesterol, high-density lipoprotein cholesterol [HDL-C], and triglycerides). LDL-C was calculated using the Friedewald
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FH and outcomes after PCI
formula.18 In ACS patients, cardiac markers were monitored every 6 hours until peak values were reached. A certified clinical laboratory in our hospital performed the measurement of routine laboratory parameters.
Endpoint of interest As primary endpoint, we investigated the impact of FH on long-term MACE in all patients and in a sensitivity analysis excluding all patients without high-intensity statin therapy (atorvastatin 40 and 80 mg, rosuvastatin 20 and 40 mg). We defined MACE as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal ischemic stroke/transient ischemic attack (TIA). Patient mortality data were obtained from the Statistics Austria Institute, an independent and nonprofit federal institution under public law, which supports scientific services. Data on recurrent myocardial infarction or ischemic stroke/TIA were obtained by outpatient visits or using the common Vienna regional hospital database system. As secondary endpoint, we assessed the prevalence and management of FH in this cohort.
Statistical analysis Continuous variables after normal distribution were expressed as mean (standard deviation); otherwise, they were reported as median (25th and 75th percentiles). Normality of distribution was tested using the Kolmogorov–Smirnov–Lilliefors test. Categorical variables were expressed as absolute numbers and percentages. Continuous variables were compared by either analysis of variance or Kruskal–Wallis H-test, as appropriate; whereas c2 tests were performed for categorical variables. All statistical tests were 2-tailed, and a P-value , .05 was required for statistical significance. All statistical analyses and figures were performed with R-3.4.0.
Analysis of clinical outcome For outcome analysis, univariate and multivariable Cox proportional hazard models were applied to determine the prognostic impact of FH on long-term MACE. A Cox proportional hazard model was applied for the endpoint of interest according to the augmented backward elimination algorithm proposed by Dunkler et al., an adaption of the purposeful selection algorithm.19 As first step, all potential prognostic variables were included into a step-wise backward elimination model using a likelihood ratio test with a significance level of a . 0.2 for exclusion. In a second step, all primarily excluded variables were re-entered separately and kept in the model in case of a change-in-estimate of .5% to identify relevant confounders. Following variables were included in the primary model: DLCN classifications for diagnosis of FH, traditional cardiovascular risk factors (age, gender, body mass index, arterial hypertension, smoking, diabetes mellitus), clinical presentation (ACS/SCAD), heart failure, atrial fibrillation, estimated
3 glomerular filtration rate,20 troponin I, CRP, periprocedural details, and discharge medication.
Results In total, 1550 patients were eligible for the present analysis, of whom 47.4% were admitted for SCAD, and 52.6% for ACS. Within our cohort, 77 (5.0%) patients were classified with probable or definite FH, 332 (21.4%) with possible FH, and 1141 (73.6%) were unlikely to suffer from FH. The baseline characteristics for patients according to their DLCN classification are summarized in Table 1. Patients with probable or definite FH were younger, had better kidney function, had more often a familial background of CAD, and were more likely to be smokers when compared with patients with unlikely FH. Fifty-five (71.4%) patients with probable or definite FH, 244 (73.5%) with possible FH, and 665 (58.3%) with unlikely FH were discharged with high-intensity statins. Further use of high-dose highly effective statins in probable/definite FH patients was hindered by side effects and/or by patients’ refusal to accept such therapy.
Clinical outcome Total patient cohort After a mean follow-up of 6.0 6 2.4 years, 437 (28.0%) patients suffered from MACE, attributable to 271 (17.4%) with all-cause death, 117 (7.5%) with nonfatal MI, and 49 (3.2%) with nonfatal ischemic stroke or TIA. Unadjusted analysis revealed no significant difference between patients with probable or definite FH and unlikely FH regarding MACE (hazard ratio [HR] 0.817 [95% confidence interval [CI] 0.617–1.462], P 5.950); however, patients with possible FH had significantly lower risk compared with patients with unlikely FH (HR 0.735 [95% CI 0.571–0.947]; P 5 .017), as depicted in Figure 1 and Table 2. After adjustment for possible confounders, patients classified with probable or definite FH (HR 1.922 [95%CI 1.220– 2.999]; P 5.004), but not patients with possible FH (HR 1.105 [95%CI 0.843–1.447]; P 5 .470) faced a significant, approximately 2-fold increased risk of MACE compared with patients with unlikely FH, as shown in Figure 2. Adjusted HRs for all variables in the model are listed in Table 3. Similarly, in a sensitivity analysis including only patients discharged on high-intensity statins, patients with probable or definite FH (HR 1.982 [95% CI 1.119–3.508]; P 5 .018), but not patients with possible FH (HR 1.063 [95% CI 0.765–1.477]; P 5 .713) were at increased risk compared with patients with unlikely FH after adjustment. ACS patients In the ACS cohort, 239 (15.4%) patients suffered from MACE. From these, 143 (9.2%) were classified as all-cause death, 73 (4.7%) as nonfatal MI, and 23 (1.4%) as nonfatal stroke or TIA.
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Table 1
Baseline characteristics
Characteristics
Unlikely FH, N 5 1141 (73.6%)
Age, y 6 SD 66.3 6 11.7 Sex, n (%) Female 352 (30.9) Male 789 (69.1) Clinical presentation, n (%) SCAD 553 (48.5) NSTE-ACS 287 (25.2) STEMI 301 (26.4) Body mass index, kg/m2, median (IQR) 27.7 (24.9–30.8) Cardiogenic shock, n (%) 36 (3.2) Laboratory results, median (IQR) Total cholesterol, mg/dL 173 (148–205) LDL cholesterol, mg/dL 99 (77–127) HDL cholesterol, mg/dL 44 (36–54) Triglycerides, mg/dL 123 (93–171) Troponin I, ng/L 0.7 (0.1–15.8) C-reactive protein, mg/L 3.0 (1.3–8.0) Creatinine, mg/dL 1.0 (0.8–1.1) eGFR, mL/min/1.73 m2 76 (60–91) Cardiovascular risk factors and comorbidities, n (%) Arterial hypertension 966 (84.7) Smoking (current) 327 (28.7) Diabetes mellitus 348 (30.5) Familial history of coronary heart disease 170 (14.9) Prior myocardial infarction 236 (20.7) Prior coronary revascularization 314 (27.5) Prior stroke or transient ischaemic attack 48 (4.2) Peripheral artery disease 8 (7.1) Heart failure 141 (12.4) Atrial fibrillation 86 (7.5) Malignancy 92 (8.1) Procedural details Radial access, n (%) 134 (11.7) Use of DES, n (%) 706 (61.9) Number of affected coronary beds, n (%) 1 (1-2) Number of used stents, n (%) 1 (1-1) Total stent length, mm, median (IQR) 23 (16–32) Discharge medication, n (%) Acetylsalicylic acid 1135 (99.5) P2Y12 inhibitor 1131 (99.1) ACE-I or ARB 773 (68.1) Beta blocker 929 (81.9) Statin 1049 (92.1) High-intensity statina 665 (58.3) Ezetemibe 21 (1.8)
Possible FH, N 5 332 (21.4%)
Probable/definite FH, N 5 77 (5.0%)
P value
56.6 6 11.7
56.0 6 11.2
,.001
105 (31.6) 227 (68.4)
22 (28.6) 55 (71.4)
.870
141 96 95 27.6 7
(42.5) (28.9) (28.6) (25.2–30.9) (2.1)
40 17 20 27.3 0
(51.9) (22.1) (26.0) (25.4–29.9) (0)
.324
206 129 41 140 1.6 3.5 0.9 91
(173–235) (101–161) (35–49) (103–199) (0.1–22.3) (1.5–8.4) (0.8–1.0) (73–102)
247 162 45 137 0.7 3.0 0.9 91
(212–275) (135–199) (38–52) (98–192) (0.0–5.6) (1.9–6.1) (0.8–1.1) (71–103)
,.001 ,.001 ,.001 ,.001 .019 .761 ,.001 ,.001
267 157 74 153 69 76 12 17 38 10 20
(80.4) (47.3) (22.3) (46.1) (20.8) (22.9) (3.6) (5.1) (11.4) (3.0) (6.0)
64 33 19 42 21 25 4 8 4 1 3
(83.1) (42.9) (24.7) (54.5) (27.3) (32.5) (5.2) (10.4) (5.2) (1.3) (3.9)
.182 ,.001 .011 ,.001 .386 .126 .794 .203 .165 .002 .221
28 244 1 1 22
(8.4) (73.5) (1-2) (1-1) (16–32)
9 58 1 1 18
(11.7) (75.3) (1-2) (1-1) (15–32)
330 331 242 287 322 244 22
(99.4) (99.7) (72.9) (86.4) (97.0) (73.5) (6.6)
77 77 60 63 74 55 7
(100) (100) (77.9) (81.8) (96.1) (71.4) (9.0)
.679 .187
.010 .001 .442 .661 .047 .799 .409 .067 .144 .004 ,.001 .071
Data are presented as mean 6 SD, median (IQR), or percentage. ACE-I, angiotensin convertase enzyme inhibitor; ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; DES, drug eluting stent; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; IQR 5 interquartile range; LDL, low-density lipoprotein; SBP, systolic blood pressure; SCAD, stable coronary artery disease; SD 5 standard deviation. a Atorvastatin 40–80 mg or rosuvastatin 20–40 mg.
Unadjusted analysis revealed no significant difference between patients with probable or definite FH and unlikely FH regarding MACE (HR 1.181 [95% CI 0.673–2.072]; P 5 .562). Nevertheless, patients with possible FH had significantly lower risk compared with patients with
unlikely FH (HR 0.668 [95% CI 0.474–0.940]; P 5 .021) in the ACS cohort. After adjustment for possible confounders, patients classified with probable or definite FH (HR 2.581 [95%CI 1.440–4.624]; P 5 .001), but not patients with possible FH
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FH and outcomes after PCI
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web 4C=FPO
Tscharre et al
Figure 1 Unadjusted cumulative hazard for long-term MACE stratified for the Dutch Lipid Clinic Network (DLCN) diagnosis criteria for all patients. Probable/definite FH vs unlikely FH (hazard ratio [HR] 0.817 [95% confidence interval (CI) 0.617–1.462], P 5.950); possible FH vs unlikely FH (HR 0.735 [95% CI 0.571–0.947]; P 5 .017). FH, familial hypercholesterolemia; MACE, major adverse cardiovascular event.
(HR 1.186 [95% CI 0.827–1.702]; P 5 .353), faced a significant, approximate 2-fold increased risk of MACE compared with patients with unlikely FH, as shown in Table 2.
FH compared with patients with unlikely FH (HR 1.441 [95% CI 0.724–2.868]; P 5 .267), as shown in Table 2.
Stable CAD patients In the stable CAD (SCAD) cohort, 198 (12.6%) patients suffered from MACE, attributable to 128 (8.2%) with allcause death, 44 (2.8%) with nonfatal MI, and 26 (1.8%) with nonfatal stroke. Unadjusted analysis demonstrated no significant difference between patients with possible FH and unlikely FH (HR 0.812 [95% CI 0.558–1.182]; P 5 .812) and between patients with probable or definite FH and unlikely FH (HR 0.760 [95% CI 0.338–1.489]; P 5 .424). After adjusting for confounders, there were no significant differences among all groups; however, a trend for worse outcome was detected in patients with probable or definite
Our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, patients with probable or definite FH showed approximately the same risk for subsequent MACE as patients with unlikely FH during a 6-year period of followup, as shown in Figure 1. Only after adjustment for age and other confounders patients with probable or definite FH faced a significant, approximate 2-fold increased risk for subsequent MACE compared with patients with unlikely FH, as depicted in Figure 2.
Table 2
Discussion
Unadjusted and adjusted HRs for MACE stratified for patients according to the DLCN diagnosis criteria
Outcome All patients (N 5 1150) Unadjusted HR (95% CI) Adjusted HR (95% CI) ACS patients (N 5 816) Unadjusted HR (95% CI) Adjusted HR SCAD patients (N 5 734) Unadjusted HR (95% CI) Adjusted HR
Unlikely FH
Possible FH
Probable or definite FH
1.00 (referent) 1.00 (referent)
0.735 (0.571–0.947) 1.105 (0.843–1.447)
P 5 .017 P 5 .470
0.817 (0.617–1.462) 1.922 (1.220–2.999)
P 5 .950 P 5 .004
1.00 (referent) 1.00 (referent)
0.668 (0.474–0.940) 1.186 (0.827–1.702)
P 5 .012 P 5 .353
1.181 (0.673–2.072) 2.581 (1.440–4.624)
P 5 .562 P 5 .001
1.00 (referent) 1.00 (referent)
0.812 (0.558–1.182) 1.098 (0.7238–1.666)
P 5 .812 P 5 .660
0.760 (0.338–1.489) 1.441 (0.724–2.868)
P 5 .424 P 5 .267
ACS, acute coronary syndromes; CI, confidence interval; DLCN, Dutch Lipid Clinic Network; FH, familial hypercholesterolemia; HR, hazard ratio; MACE, major adverse cardiovascular event; SCAD, stable coronary artery disease.
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web 4C=FPO
6
Figure 2 Adjusted cumulative hazard for long-term MACE stratified for the Dutch Lipid Clinic Network (DLCN) diagnosis criteria for all patients. Probable/definite FH vs unlikely FH (hazard ratio [HR] 1.922 [95% confidence interval [CI] 1.220–2.999]; P 5 .004); possible FH vs unlikely FH (HR 1.105 [95% CI 0.843–1.447]; P 5 .470). FH, familial hypercholesterolemia; MACE, major adverse cardiovascular event.
To the best of our knowledge, this is the first investigation assessing long-term adverse outcomes of clinically diagnosed FH patients undergoing PCI for ACS or SCAD Table 3 Predictors of long-term composite MACE applying the augmented backward elimination algorithm19 Final model
HR
95% CI
P value
Unlikely FH (reference) Possible FH Probable/definite FH Age, per 1 y increase Indication for PCI eGFR, per 1 mL/min increase Troponin I, per 1 ng/L increase CRP, per 1 mg/L increase Heart failure Arterial hypertension Diabetes mellitus Current smoking ACEI or ARB Number of diseased vessels Use of drug-eluting stent
– 1.105 1.922 1.048 1.212 0.995
– 0.843–1.447 1.220–2.999 1.036–1.060 0.978–1.502 0.989–1.003
–
0.999
0.997–1.001
.226
1.003
1.001–1.005
.001
1.710 1.279 1.457 1.618 0.805 1.146
1.324–2.210 0.928–1.765 1.190–1.784 1.277–2.050 0.650–.997 1.014–1.298
,.001 .133 ,.001 ,.001 .047 .029
0.686
0.563–0.838
,.001
.470 .004 ,.001 .078 .062
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; HR, hazard ratio; MACE, major adverse cardiovascular event; PCI, percutaneous coronary intervention. Adjustment was performed for risk factors, comorbidities, procedural details, and discharge therapy. Variables entered into the model before elimination are listed in the statistical methods section.
in the era of high-intensity statins. Several investigations have previously described high rates of clinically diagnosed FH in CAD patients compared with the general population, in which the prevalence is estimated at 1:200.10 An analysis of the Swiss Special Program University Medicine-Acute Coronary Syndromes (SPUM-ACS) registry reported a prevalence of 1.6% for clinically diagnosed patients with probable or definite FH, and 4.8% for patients with premature ACS; both according to the DLCN criteria.8 An analysis of the EUROASPIRE-IV, a cohort including patients with overt CAD, reported a prevalence of 8.3% for patients with more than 6 points according to the DLCN criteria, and 15.4% for patients younger than 60 years.9 Despite these high rates of clinically diagnosed FH in patients with overt CAD, only limited knowledge regarding the prognosis of this particular patient group in the era of highintensity statins exists. Data are limited to the recent report of the SPUM-ACS registry. Similar to the present investigation, in the SPUM-ACS registry, patients with probable or definite FH had a similar risk for subsequent MACE within the first year of discharge as patients with unlikely FH, despite higher rates of high-intensity statin therapy, a younger age of approximately a decade and fewer cardiovascular risk factors. Only after adjustment for confounders, patients with probable or definite FH (compared with patients with unlikely FH) faced a significant 3.54-fold increased risk of suffering from a subsequent MACE.12 Our investigation not only confirms but also extends these previous findings. In line with results from the SPUM-ACS registry, our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, these factors did not translate into a benefit
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FH and outcomes after PCI
regarding long-term outcomes, as also observed in a sensitivity analysis excluding patients without high-intensity statin therapy. Interestingly, in our sensitivity analysis, patients with probable or definite FH on high-intensity statin appeared to have had a higher risk of MACE compared with the overall population of probable or definite FH. This phenomenon is most likely based on a higher rate of ACS patients in this subgroup and higher LDL baseline levels. These unfavorable results might be explained by the fact that although lipid-lowering therapy has improved over the last decade, the vast majority of FH patients do not achieve aimed LDL-C target levels and therefore remain at high risk for subsequent adverse cardiovascular events.21 In our cohort, no single patient with probable or definite FH presented an LDL-C level ,70 mg/dL, and only 3 patients had levels ,100 mg/dL at the time of admission. These values were observed in spite of (n 5 59) 76.6% of those patients being on statin therapy, with (n 5 33) 55.9% of them even receiving high-intensity statin therapy. Similarly, in the SPUM-ACS registry, only 4.6% of the patients with probable or definite FH reached the LDL-C target levels of ,70 mg/dL after 1 year of follow-up.12 The Spanish Familial Hypercholesterolemia Cohort Study (SAFEHEART) registry including 4132 patients with genetically diagnosed FH investigated the achievement of the target LDL-C levels over a mean followup period of 5.1 6 3.1 years. In SAFEHEART, only 1.1% of patients with known CAD reached the LDL-C target of ,70 mg/dL at time of inclusion, and only 4.4% at follow-up despite being on maximal tolerated lipid-lowering therapy with statins in combination with ezetimibe.7 Following the concept of cumulative LDL-C burden, early and rigorous lipid-lowering therapy in patients with FH is required to diminish the high atherosclerotic effects of elevated cholesterol levels in primary prevention.1 Although (n 5 59) 76.6% of our patients with probable or definite FH were treated with statins at the time of admission, only (n 5 33) 55.9% of those were on highintensity statins, resulting in 23.4% with no treatment at all, and 44.1% with insufficient lipid-lowering therapy before admission. This is particularly unfortunate as reports have shown a potential 44% to 76% risk reduction of future cardiovascular adverse events in primary prevention with moderate- or high-intensity statin therapy regimen.22,23 Our data indicate an imperative need for systematic screening for FH in CAD patients and rigorous secondary prevention, particularly with respect to lipid-lowering therapy. Despite being on high-intensity statin therapy in combination with ezetimibe, the majority of patients do not achieve the given LDL-C target levels and remain at high risk for cardiovascular disease progression. With the modern PCSK-9 inhibitors alirocumab and evolocumab, new treatment options are available for such situations. For both agents, an additional 50% to 70% LDL-C reduction of on top of a baseline lipid-lowering therapy with statins has been reported.21 For evolocumab, an additional risk reduction for subsequent cardiovascular events has been demonstrated.24
7
Limitations Our study has certain limitations. As recommended by several guidelines, the DCLN criteria were used, for clinical diagnoses of FH; however, these were not confirmed by genetic testing, and so some of our patients classified with FH may, in fact, suffer from polygenic hypercholesterolemia.1,25,26 On the other hand, potential misclassifications could have also underestimated the real cardiovascular risk of patients with true FH, as seen, for example, on the SAFEHEART registry, in which genetic confirmation did not guarantee subsequent attainments of LDL-C goals.7 Furthermore, we did not collect data on family history of high LDL-C levels or xanthomas. A strength of our study is the 100% follow-up rate, although underreporting by the Statistics Austria cannot be excluded. Moreover, this study included ACS and SCAD patients, whereas former studies were limited to ACS patient cohorts.
Conclusion Our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, these factors did not translate into a benefit regarding long-term outcomes, as also observed in a sensitivity analysis excluding patients without highintensity statin therapy. The new option of PCSK9 inhibitors in addition to other hitherto optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH.
Acknowledgments This study was supported by the Association for the Promotion of Research in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) and by the Ludwig Boltzmann Institute for Interventional Cardiology and RhythQ4 mology, Vienna, Austria. Authors’ contributions: conception and design of the study was performed by M.T. and K.H.; acquisition of data was performed by M.T., R.H., M.R., S.F., and M.K.F.; analysis and interpretation of data were performed by M.T.; drafting the article was performed by M.T., E.P., K.G.V., and K.H.; revision for intellectual content was performed by S.F., M.K.F., T.W.W., and K.H. All authors approved the final version of the article.
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2. Brown MS, Goldstein JL. Familial Hypercholesterolemia: A Genetic Defect in the Low-Density Lipoprotein Receptor. N Engl J Med. 1976;294(25):1386–1390. 3. Varret M, Abifadel M, Rabes J-P, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008;73(1): 1–13. 4. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the national lipid association expert panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5(3): S1–S8. 5. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–2437. 6. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423. 7. Perez de Isla L, Alonso R, Watts GF, et al. Attainment of LDLcholesterol treatment goals in patients with familial hypercholesterolemia: 5-year safeheart registry follow-up. J Am Coll Cardiol. 2016; 67(11):1278–1285. 8. Nanchen D, Gencer B, Auer R, et al. Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes. Eur Heart J. 2015;36(36):2438–2445. 9. De Backer G, Besseling J, Chapman J, et al. Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis. 2015;241(1):169–175. 10. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J. 2016;37(17):1384–1394. 11. Faggiano P, Pirillo A, Griffo R, et al. Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: The heredity survey. Int J Cardiol. 2018;252:193–198. 12. Nanchen D, Gencer B, Muller O, et al. Prognosis of patients with familial hypercholesterolemia after acute coronary syndromesclinical perspective. Circulation. 2016;134(10):698–709. 13. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909–2945.
14. Bassand J-P, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2007;28(13):1598–1660. 15. WHO Human Genetics Programme. Familial hypercholesterolaemia (FH): report of a second WHO consultation, Geneva, 4 September 1998. World Health Organisation; 1999Available at: http://www. Q6 who.int/iris/handle/10665/66346. 16. Besseling J, Kindt I, Hof M, Kastelein JJP, Hutten BA, Hovingh GK. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: A study of a cohort of 14,000 mutation carriers. Atherosclerosis. 2014;233(1):219–223. 17. Rerup SA, Bang LE, Mogensen UM, et al. The prevalence and prognostic importance of possible familial hypercholesterolemia in patients with myocardial infarction. Am Heart J. 2016;181:35–42. 18. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502. 19. Dunkler D, Plischke M, Leffondre K, Heinze G. Augmented backward elimination: a pragmatic and purposeful way to develop statistical models. PLoS One. 2014;9(11):e113677. 20. Levey AS, Stevens L a, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–612. 21. Catapano AL, Graham I, De Backer G, et al. ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39): 2999–3058. 22. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008;337:a2423. 23. Besseling J, Hovingh GK, Huijgen R, Kastelein JJP, Hutten BA. Statins in Familial Hypercholesterolemia. J Am Coll Cardiol. 2016;68(3): 252–260. 24. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376(18):1713–1722. 25. Amor-Salamanca A, Castillo S, Gonzalez-Vioque E, et al. Genetically confirmed familial hypercholesterolemia in patients with acute coronary syndrome. J Am Coll Cardiol. 2017;70(14):1732–1740. 26. Silva PRS, Jannes CE, Oliveira TGM, et al. Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil. Atherosclerosis. 2017;263:257–262.
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Original Article
Prognostic impact of familial hypercholesterolemia on long-term outcomes in patients undergoing percutaneous coronary intervention Maximilian Tscharre, MD*, Robert Herman, BSc, Miklos Rohla, MD, PhD, Edita Piackova, MD, Kris G. Vargas, MD, Serdar Farhan, MD, Matthias K. Freynhofer, MD, Thomas W. Weiss, MD, PhD, Kurt Huber, MD 3rd Medical Department with Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria (Drs Tscharre, Rohla, Piackova, Vargas, Farhan, Freynhofer, Weiss, and Huber); Institute of Cardiometabolic Diseases, Karl Landsteiner Society, St. P€ olten, Austria (Drs Tscharre, Rohla, Weiss); and Sigmund Freud University, Medical School, Vienna, Austria (Drs Herman, Weiss, and Huber) KEYWORDS: Familial hypercholesterolemia; Percutaneous coronary intervention; Acute coronary syndrome; Stable coronary artery disease; Adverse outcomes
BACKGROUND: Patients with familial hypercholesterolemia (FH) are at increased risk for premature and subsequent cardiovascular disease. Data on long-term major adverse cardiovascular events (MACE) in patients with FH after percutaneous coronary intervention (PCI) in the era of highintensity statins are scarce. OBJECTIVE: We assessed the prognostic impact of clinically diagnosed FH on long-term MACE, a composite of all-cause death, myocardial infarction, and ischemic stroke in patients admitted for stable coronary artery disease (SCAD) or acute coronary syndromes (ACSs) undergoing PCI. METHODS: FH was diagnosed according to the Dutch Lipid Clinic Network diagnosis criteria: ‘‘Unlikely FH’’ diagnosis was defined as 0 to 2 points, ‘‘possible FH’’ as 3 to 5 points, and ‘‘probable/definite FH’’ diagnosis as 6 or higher. RESULTS: From a total of 1550 eligible patients (47.4% were admitted for SCAD and 52.6% for ACS), 77 (5.0%) were classified as probable/definite FH, 332 (21.4%) as possible FH, and 1141 (73.6%) as unlikely FH. Mean follow-up was 6.0 6 2.4 years. After adjustment for possible confounders, patients classified with probable or definite FH (hazard ratio [HR] 1.922 [95% confidence interval (CI) 1.220–2.999]; P 5 .004), but not patients with possible FH (HR 1.105 [95% CI 0.843– 1.447]; P 5 .470) faced a significant, approximately 2-fold increased risk of MACE compared with patients with unlikely FH. CONCLUSION: After adjustment for confounders, patients with probable or definite FH faced an approximate 2-fold increased risk for long-term MACE compared with patients without FH despite
Conflicts of Interest: K.H. received lecture fees from AMGEN and SANOFI AVENTIS. The rest of the authors declare no conflicts of interest. * Corresponding author. Maximilian Tscharre, MD, 3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria.
E-mail address: [email protected] Submitted April 5, 2018. Accepted for publication September 18, 2018.
1933-2874/Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association. https://doi.org/10.1016/j.jacl.2018.09.012 FLA 5.5.0 DTD JACL1387_proof 12 October 2018 4:00 pm
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the widespread use of high-intensity statins. The new option of proprotein convertase subtilisin/kexin type 9 gene inhibitors in addition to other current optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH. Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association.
Introduction
Patients and methods
Familial hypercholesterolemia (FH) is the most common autosomal dominant hereditary disorder and is characterized by severely elevated levels of cholesterol and low-density lipoprotein cholesterol (LDL-C) from birth.1 FH is most frequently attributable to mutations in the low-density lipoprotein receptor gene (LDLR) but also to mutations in the apolipoprotein B-100 gene (APOB) and the proprotein convertase subtilisin/kexin type 9 gene (PCSK9), all resulting in reduced hepatic capacity to clear LDL-C from the circulation.2,3 By inducing vascular inflammation, high levels of LDL-C are known to be a major risk factor for the initiation and promotion of atherosclerosis, and, as a consequence, FH patients are at an extremely high risk of premature cardiovascular disease and mortality.1,4 If left untreated, individuals with heterozygous FH (HeFH) commonly develop coronary artery disease (CAD) before the age of 55 years, and individuals with homozygous FH will manifest CAD in their childhood or adolescence and typically die by the age of 20 years.1,5 In FH patients without manifest CAD, attenuating cardiovascular risk by early initiation of lipid-lowering therapy with statins has been shown to be very effective.6,7 Unfortunately, FH (especially HeFH) remains predominately undiagnosed and undertreated, with many individuals are not being diagnosed with FH until after the occurrence of their first coronary event.1 Up to 10% of patients admitted for CAD have clinical criteria compatible with FH, which represents a prevalence of FH 10 times higher than that found in the general population.8-11 For patients with manifest CAD, only few reports concerning the prognostic impact of FH in the era of high-intensity statins are available. Regarding short-term adverse outcome, Nanchen et al. recently reported an approximately 2- to 3-fold increased risk of FH patients to suffer from a recurrent cardiovascular event within the first year after acute coronary syndrome (ACS) despite the widespread use of high-intensity statins in their cohort.12 Data on adverse outcome beyond 1 year after admission for ACS or SCAD in patients with clinically diagnosed FH is particularly limited. Therefore, we investigated the prognostic impact of FH on long-term major adverse cardiovascular events (MACE) in patients presenting with ACS or SCAD undergoing percutaneous coronary intervention (PCI).
Study population We analyzed patients undergoing successful PCI for ACS or SCAD between 2007 and 2012. ACS and SCAD were diagnosed and treated according to the recommended guidelines at that time.13,14 Implantation of drug-eluting stents or bare metal stents was under the discretion of the treating intervention. Chronic lipid-lowering treatment at the time of intervention, periprocedural details, cardiovascular comorbidities, laboratory parameters, and discharge medication for secondary prevention were documented. Patients with triglyceride levels .400 mg/dL (because of limitations to correctly estimate LDL-C), as well as patients not residing in the Vienna metropolitan region or who deceased during the initial hospital stay, were excluded from the present analysis. This study was conducted according to the Declaration of Helsinki statement, with approval by the local ethics committee (EK 17-134-VK) and informed consent by all patients. All authors had full access to the data and took responsibility for its integrity.
Diagnosis of FH FH was diagnosed according to the validated Dutch Lipid Clinic Network (DLCN) diagnosis criteria based on age, personal and family history of premature cardiovascular disease, clinical symptoms, and LDL-C levels.15 In case of chronic lipid-lowering therapy, LDL-C levels were estimated using correction factors published by Besseling et al.16 Information on clinical signs of lipid accumulation (arcus cornealis or tendon xanthoma), family history of elevated LDL-C levels, and genetic testing was not available in our study cohort and were therefore counted as zero, as done in former studies.8,12,17 Unlikely FH diagnosis was defined as 0 to 2 score points, a possible FH diagnosis as 3 to 5 score points, and a probable/definite FH diagnosis as 6 or higher according to the DLCN criteria.
Laboratory parameters Blood samples for routine laboratory parameters were collected at hospital admission (glucose, creatinine, Creactive protein [CRP] and cardiac markers) or during the first day after admission in fasting condition (total cholesterol, high-density lipoprotein cholesterol [HDL-C], and triglycerides). LDL-C was calculated using the Friedewald
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FH and outcomes after PCI
formula.18 In ACS patients, cardiac markers were monitored every 6 hours until peak values were reached. A certified clinical laboratory in our hospital performed the measurement of routine laboratory parameters.
Endpoint of interest As primary endpoint, we investigated the impact of FH on long-term MACE in all patients and in a sensitivity analysis excluding all patients without high-intensity statin therapy (atorvastatin 40 and 80 mg, rosuvastatin 20 and 40 mg). We defined MACE as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal ischemic stroke/transient ischemic attack (TIA). Patient mortality data were obtained from the Statistics Austria Institute, an independent and nonprofit federal institution under public law, which supports scientific services. Data on recurrent myocardial infarction or ischemic stroke/TIA were obtained by outpatient visits or using the common Vienna regional hospital database system. As secondary endpoint, we assessed the prevalence and management of FH in this cohort.
Statistical analysis Continuous variables after normal distribution were expressed as mean (standard deviation); otherwise, they were reported as median (25th and 75th percentiles). Normality of distribution was tested using the Kolmogorov–Smirnov–Lilliefors test. Categorical variables were expressed as absolute numbers and percentages. Continuous variables were compared by either analysis of variance or Kruskal–Wallis H-test, as appropriate; whereas c2 tests were performed for categorical variables. All statistical tests were 2-tailed, and a P-value , .05 was required for statistical significance. All statistical analyses and figures were performed with R-3.4.0.
Analysis of clinical outcome For outcome analysis, univariate and multivariable Cox proportional hazard models were applied to determine the prognostic impact of FH on long-term MACE. A Cox proportional hazard model was applied for the endpoint of interest according to the augmented backward elimination algorithm proposed by Dunkler et al., an adaption of the purposeful selection algorithm.19 As first step, all potential prognostic variables were included into a step-wise backward elimination model using a likelihood ratio test with a significance level of a . 0.2 for exclusion. In a second step, all primarily excluded variables were re-entered separately and kept in the model in case of a change-in-estimate of .5% to identify relevant confounders. Following variables were included in the primary model: DLCN classifications for diagnosis of FH, traditional cardiovascular risk factors (age, gender, body mass index, arterial hypertension, smoking, diabetes mellitus), clinical presentation (ACS/SCAD), heart failure, atrial fibrillation, estimated
3 glomerular filtration rate,20 troponin I, CRP, periprocedural details, and discharge medication.
Results In total, 1550 patients were eligible for the present analysis, of whom 47.4% were admitted for SCAD, and 52.6% for ACS. Within our cohort, 77 (5.0%) patients were classified with probable or definite FH, 332 (21.4%) with possible FH, and 1141 (73.6%) were unlikely to suffer from FH. The baseline characteristics for patients according to their DLCN classification are summarized in Table 1. Patients with probable or definite FH were younger, had better kidney function, had more often a familial background of CAD, and were more likely to be smokers when compared with patients with unlikely FH. Fifty-five (71.4%) patients with probable or definite FH, 244 (73.5%) with possible FH, and 665 (58.3%) with unlikely FH were discharged with high-intensity statins. Further use of high-dose highly effective statins in probable/definite FH patients was hindered by side effects and/or by patients’ refusal to accept such therapy.
Clinical outcome Total patient cohort After a mean follow-up of 6.0 6 2.4 years, 437 (28.0%) patients suffered from MACE, attributable to 271 (17.4%) with all-cause death, 117 (7.5%) with nonfatal MI, and 49 (3.2%) with nonfatal ischemic stroke or TIA. Unadjusted analysis revealed no significant difference between patients with probable or definite FH and unlikely FH regarding MACE (hazard ratio [HR] 0.817 [95% confidence interval [CI] 0.617–1.462], P 5.950); however, patients with possible FH had significantly lower risk compared with patients with unlikely FH (HR 0.735 [95% CI 0.571–0.947]; P 5 .017), as depicted in Figure 1 and Table 2. After adjustment for possible confounders, patients classified with probable or definite FH (HR 1.922 [95%CI 1.220– 2.999]; P 5.004), but not patients with possible FH (HR 1.105 [95%CI 0.843–1.447]; P 5 .470) faced a significant, approximately 2-fold increased risk of MACE compared with patients with unlikely FH, as shown in Figure 2. Adjusted HRs for all variables in the model are listed in Table 3. Similarly, in a sensitivity analysis including only patients discharged on high-intensity statins, patients with probable or definite FH (HR 1.982 [95% CI 1.119–3.508]; P 5 .018), but not patients with possible FH (HR 1.063 [95% CI 0.765–1.477]; P 5 .713) were at increased risk compared with patients with unlikely FH after adjustment. ACS patients In the ACS cohort, 239 (15.4%) patients suffered from MACE. From these, 143 (9.2%) were classified as all-cause death, 73 (4.7%) as nonfatal MI, and 23 (1.4%) as nonfatal stroke or TIA.
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Table 1
Baseline characteristics
Characteristics
Unlikely FH, N 5 1141 (73.6%)
Age, y 6 SD 66.3 6 11.7 Sex, n (%) Female 352 (30.9) Male 789 (69.1) Clinical presentation, n (%) SCAD 553 (48.5) NSTE-ACS 287 (25.2) STEMI 301 (26.4) Body mass index, kg/m2, median (IQR) 27.7 (24.9–30.8) Cardiogenic shock, n (%) 36 (3.2) Laboratory results, median (IQR) Total cholesterol, mg/dL 173 (148–205) LDL cholesterol, mg/dL 99 (77–127) HDL cholesterol, mg/dL 44 (36–54) Triglycerides, mg/dL 123 (93–171) Troponin I, ng/L 0.7 (0.1–15.8) C-reactive protein, mg/L 3.0 (1.3–8.0) Creatinine, mg/dL 1.0 (0.8–1.1) eGFR, mL/min/1.73 m2 76 (60–91) Cardiovascular risk factors and comorbidities, n (%) Arterial hypertension 966 (84.7) Smoking (current) 327 (28.7) Diabetes mellitus 348 (30.5) Familial history of coronary heart disease 170 (14.9) Prior myocardial infarction 236 (20.7) Prior coronary revascularization 314 (27.5) Prior stroke or transient ischaemic attack 48 (4.2) Peripheral artery disease 8 (7.1) Heart failure 141 (12.4) Atrial fibrillation 86 (7.5) Malignancy 92 (8.1) Procedural details Radial access, n (%) 134 (11.7) Use of DES, n (%) 706 (61.9) Number of affected coronary beds, n (%) 1 (1-2) Number of used stents, n (%) 1 (1-1) Total stent length, mm, median (IQR) 23 (16–32) Discharge medication, n (%) Acetylsalicylic acid 1135 (99.5) P2Y12 inhibitor 1131 (99.1) ACE-I or ARB 773 (68.1) Beta blocker 929 (81.9) Statin 1049 (92.1) High-intensity statina 665 (58.3) Ezetemibe 21 (1.8)
Possible FH, N 5 332 (21.4%)
Probable/definite FH, N 5 77 (5.0%)
P value
56.6 6 11.7
56.0 6 11.2
,.001
105 (31.6) 227 (68.4)
22 (28.6) 55 (71.4)
.870
141 96 95 27.6 7
(42.5) (28.9) (28.6) (25.2–30.9) (2.1)
40 17 20 27.3 0
(51.9) (22.1) (26.0) (25.4–29.9) (0)
.324
206 129 41 140 1.6 3.5 0.9 91
(173–235) (101–161) (35–49) (103–199) (0.1–22.3) (1.5–8.4) (0.8–1.0) (73–102)
247 162 45 137 0.7 3.0 0.9 91
(212–275) (135–199) (38–52) (98–192) (0.0–5.6) (1.9–6.1) (0.8–1.1) (71–103)
,.001 ,.001 ,.001 ,.001 .019 .761 ,.001 ,.001
267 157 74 153 69 76 12 17 38 10 20
(80.4) (47.3) (22.3) (46.1) (20.8) (22.9) (3.6) (5.1) (11.4) (3.0) (6.0)
64 33 19 42 21 25 4 8 4 1 3
(83.1) (42.9) (24.7) (54.5) (27.3) (32.5) (5.2) (10.4) (5.2) (1.3) (3.9)
.182 ,.001 .011 ,.001 .386 .126 .794 .203 .165 .002 .221
28 244 1 1 22
(8.4) (73.5) (1-2) (1-1) (16–32)
9 58 1 1 18
(11.7) (75.3) (1-2) (1-1) (15–32)
330 331 242 287 322 244 22
(99.4) (99.7) (72.9) (86.4) (97.0) (73.5) (6.6)
77 77 60 63 74 55 7
(100) (100) (77.9) (81.8) (96.1) (71.4) (9.0)
.679 .187
.010 .001 .442 .661 .047 .799 .409 .067 .144 .004 ,.001 .071
Data are presented as mean 6 SD, median (IQR), or percentage. ACE-I, angiotensin convertase enzyme inhibitor; ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; DES, drug eluting stent; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; IQR 5 interquartile range; LDL, low-density lipoprotein; SBP, systolic blood pressure; SCAD, stable coronary artery disease; SD 5 standard deviation. a Atorvastatin 40–80 mg or rosuvastatin 20–40 mg.
Unadjusted analysis revealed no significant difference between patients with probable or definite FH and unlikely FH regarding MACE (HR 1.181 [95% CI 0.673–2.072]; P 5 .562). Nevertheless, patients with possible FH had significantly lower risk compared with patients with
unlikely FH (HR 0.668 [95% CI 0.474–0.940]; P 5 .021) in the ACS cohort. After adjustment for possible confounders, patients classified with probable or definite FH (HR 2.581 [95%CI 1.440–4.624]; P 5 .001), but not patients with possible FH
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Figure 1 Unadjusted cumulative hazard for long-term MACE stratified for the Dutch Lipid Clinic Network (DLCN) diagnosis criteria for all patients. Probable/definite FH vs unlikely FH (hazard ratio [HR] 0.817 [95% confidence interval (CI) 0.617–1.462], P 5.950); possible FH vs unlikely FH (HR 0.735 [95% CI 0.571–0.947]; P 5 .017). FH, familial hypercholesterolemia; MACE, major adverse cardiovascular event.
(HR 1.186 [95% CI 0.827–1.702]; P 5 .353), faced a significant, approximate 2-fold increased risk of MACE compared with patients with unlikely FH, as shown in Table 2.
FH compared with patients with unlikely FH (HR 1.441 [95% CI 0.724–2.868]; P 5 .267), as shown in Table 2.
Stable CAD patients In the stable CAD (SCAD) cohort, 198 (12.6%) patients suffered from MACE, attributable to 128 (8.2%) with allcause death, 44 (2.8%) with nonfatal MI, and 26 (1.8%) with nonfatal stroke. Unadjusted analysis demonstrated no significant difference between patients with possible FH and unlikely FH (HR 0.812 [95% CI 0.558–1.182]; P 5 .812) and between patients with probable or definite FH and unlikely FH (HR 0.760 [95% CI 0.338–1.489]; P 5 .424). After adjusting for confounders, there were no significant differences among all groups; however, a trend for worse outcome was detected in patients with probable or definite
Our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, patients with probable or definite FH showed approximately the same risk for subsequent MACE as patients with unlikely FH during a 6-year period of followup, as shown in Figure 1. Only after adjustment for age and other confounders patients with probable or definite FH faced a significant, approximate 2-fold increased risk for subsequent MACE compared with patients with unlikely FH, as depicted in Figure 2.
Table 2
Discussion
Unadjusted and adjusted HRs for MACE stratified for patients according to the DLCN diagnosis criteria
Outcome All patients (N 5 1150) Unadjusted HR (95% CI) Adjusted HR (95% CI) ACS patients (N 5 816) Unadjusted HR (95% CI) Adjusted HR SCAD patients (N 5 734) Unadjusted HR (95% CI) Adjusted HR
Unlikely FH
Possible FH
Probable or definite FH
1.00 (referent) 1.00 (referent)
0.735 (0.571–0.947) 1.105 (0.843–1.447)
P 5 .017 P 5 .470
0.817 (0.617–1.462) 1.922 (1.220–2.999)
P 5 .950 P 5 .004
1.00 (referent) 1.00 (referent)
0.668 (0.474–0.940) 1.186 (0.827–1.702)
P 5 .012 P 5 .353
1.181 (0.673–2.072) 2.581 (1.440–4.624)
P 5 .562 P 5 .001
1.00 (referent) 1.00 (referent)
0.812 (0.558–1.182) 1.098 (0.7238–1.666)
P 5 .812 P 5 .660
0.760 (0.338–1.489) 1.441 (0.724–2.868)
P 5 .424 P 5 .267
ACS, acute coronary syndromes; CI, confidence interval; DLCN, Dutch Lipid Clinic Network; FH, familial hypercholesterolemia; HR, hazard ratio; MACE, major adverse cardiovascular event; SCAD, stable coronary artery disease.
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Figure 2 Adjusted cumulative hazard for long-term MACE stratified for the Dutch Lipid Clinic Network (DLCN) diagnosis criteria for all patients. Probable/definite FH vs unlikely FH (hazard ratio [HR] 1.922 [95% confidence interval [CI] 1.220–2.999]; P 5 .004); possible FH vs unlikely FH (HR 1.105 [95% CI 0.843–1.447]; P 5 .470). FH, familial hypercholesterolemia; MACE, major adverse cardiovascular event.
To the best of our knowledge, this is the first investigation assessing long-term adverse outcomes of clinically diagnosed FH patients undergoing PCI for ACS or SCAD Table 3 Predictors of long-term composite MACE applying the augmented backward elimination algorithm19 Final model
HR
95% CI
P value
Unlikely FH (reference) Possible FH Probable/definite FH Age, per 1 y increase Indication for PCI eGFR, per 1 mL/min increase Troponin I, per 1 ng/L increase CRP, per 1 mg/L increase Heart failure Arterial hypertension Diabetes mellitus Current smoking ACEI or ARB Number of diseased vessels Use of drug-eluting stent
– 1.105 1.922 1.048 1.212 0.995
– 0.843–1.447 1.220–2.999 1.036–1.060 0.978–1.502 0.989–1.003
–
0.999
0.997–1.001
.226
1.003
1.001–1.005
.001
1.710 1.279 1.457 1.618 0.805 1.146
1.324–2.210 0.928–1.765 1.190–1.784 1.277–2.050 0.650–.997 1.014–1.298
,.001 .133 ,.001 ,.001 .047 .029
0.686
0.563–0.838
,.001
.470 .004 ,.001 .078 .062
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; FH, familial hypercholesterolemia; HR, hazard ratio; MACE, major adverse cardiovascular event; PCI, percutaneous coronary intervention. Adjustment was performed for risk factors, comorbidities, procedural details, and discharge therapy. Variables entered into the model before elimination are listed in the statistical methods section.
in the era of high-intensity statins. Several investigations have previously described high rates of clinically diagnosed FH in CAD patients compared with the general population, in which the prevalence is estimated at 1:200.10 An analysis of the Swiss Special Program University Medicine-Acute Coronary Syndromes (SPUM-ACS) registry reported a prevalence of 1.6% for clinically diagnosed patients with probable or definite FH, and 4.8% for patients with premature ACS; both according to the DLCN criteria.8 An analysis of the EUROASPIRE-IV, a cohort including patients with overt CAD, reported a prevalence of 8.3% for patients with more than 6 points according to the DLCN criteria, and 15.4% for patients younger than 60 years.9 Despite these high rates of clinically diagnosed FH in patients with overt CAD, only limited knowledge regarding the prognosis of this particular patient group in the era of highintensity statins exists. Data are limited to the recent report of the SPUM-ACS registry. Similar to the present investigation, in the SPUM-ACS registry, patients with probable or definite FH had a similar risk for subsequent MACE within the first year of discharge as patients with unlikely FH, despite higher rates of high-intensity statin therapy, a younger age of approximately a decade and fewer cardiovascular risk factors. Only after adjustment for confounders, patients with probable or definite FH (compared with patients with unlikely FH) faced a significant 3.54-fold increased risk of suffering from a subsequent MACE.12 Our investigation not only confirms but also extends these previous findings. In line with results from the SPUM-ACS registry, our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, these factors did not translate into a benefit
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regarding long-term outcomes, as also observed in a sensitivity analysis excluding patients without high-intensity statin therapy. Interestingly, in our sensitivity analysis, patients with probable or definite FH on high-intensity statin appeared to have had a higher risk of MACE compared with the overall population of probable or definite FH. This phenomenon is most likely based on a higher rate of ACS patients in this subgroup and higher LDL baseline levels. These unfavorable results might be explained by the fact that although lipid-lowering therapy has improved over the last decade, the vast majority of FH patients do not achieve aimed LDL-C target levels and therefore remain at high risk for subsequent adverse cardiovascular events.21 In our cohort, no single patient with probable or definite FH presented an LDL-C level ,70 mg/dL, and only 3 patients had levels ,100 mg/dL at the time of admission. These values were observed in spite of (n 5 59) 76.6% of those patients being on statin therapy, with (n 5 33) 55.9% of them even receiving high-intensity statin therapy. Similarly, in the SPUM-ACS registry, only 4.6% of the patients with probable or definite FH reached the LDL-C target levels of ,70 mg/dL after 1 year of follow-up.12 The Spanish Familial Hypercholesterolemia Cohort Study (SAFEHEART) registry including 4132 patients with genetically diagnosed FH investigated the achievement of the target LDL-C levels over a mean followup period of 5.1 6 3.1 years. In SAFEHEART, only 1.1% of patients with known CAD reached the LDL-C target of ,70 mg/dL at time of inclusion, and only 4.4% at follow-up despite being on maximal tolerated lipid-lowering therapy with statins in combination with ezetimibe.7 Following the concept of cumulative LDL-C burden, early and rigorous lipid-lowering therapy in patients with FH is required to diminish the high atherosclerotic effects of elevated cholesterol levels in primary prevention.1 Although (n 5 59) 76.6% of our patients with probable or definite FH were treated with statins at the time of admission, only (n 5 33) 55.9% of those were on highintensity statins, resulting in 23.4% with no treatment at all, and 44.1% with insufficient lipid-lowering therapy before admission. This is particularly unfortunate as reports have shown a potential 44% to 76% risk reduction of future cardiovascular adverse events in primary prevention with moderate- or high-intensity statin therapy regimen.22,23 Our data indicate an imperative need for systematic screening for FH in CAD patients and rigorous secondary prevention, particularly with respect to lipid-lowering therapy. Despite being on high-intensity statin therapy in combination with ezetimibe, the majority of patients do not achieve the given LDL-C target levels and remain at high risk for cardiovascular disease progression. With the modern PCSK-9 inhibitors alirocumab and evolocumab, new treatment options are available for such situations. For both agents, an additional 50% to 70% LDL-C reduction of on top of a baseline lipid-lowering therapy with statins has been reported.21 For evolocumab, an additional risk reduction for subsequent cardiovascular events has been demonstrated.24
7
Limitations Our study has certain limitations. As recommended by several guidelines, the DCLN criteria were used, for clinical diagnoses of FH; however, these were not confirmed by genetic testing, and so some of our patients classified with FH may, in fact, suffer from polygenic hypercholesterolemia.1,25,26 On the other hand, potential misclassifications could have also underestimated the real cardiovascular risk of patients with true FH, as seen, for example, on the SAFEHEART registry, in which genetic confirmation did not guarantee subsequent attainments of LDL-C goals.7 Furthermore, we did not collect data on family history of high LDL-C levels or xanthomas. A strength of our study is the 100% follow-up rate, although underreporting by the Statistics Austria cannot be excluded. Moreover, this study included ACS and SCAD patients, whereas former studies were limited to ACS patient cohorts.
Conclusion Our study shows that patients with probable or definite FH, when compared with patients with unlikely FH, were in average a decade younger, had fewer pre-existing cardiovascular comorbidities, and were more likely to receive a high-intensity statin therapy at discharge. Nevertheless, these factors did not translate into a benefit regarding long-term outcomes, as also observed in a sensitivity analysis excluding patients without highintensity statin therapy. The new option of PCSK9 inhibitors in addition to other hitherto optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH.
Acknowledgments This study was supported by the Association for the Promotion of Research in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) and by the Ludwig Boltzmann Institute for Interventional Cardiology and RhythQ4 mology, Vienna, Austria. Authors’ contributions: conception and design of the study was performed by M.T. and K.H.; acquisition of data was performed by M.T., R.H., M.R., S.F., and M.K.F.; analysis and interpretation of data were performed by M.T.; drafting the article was performed by M.T., E.P., K.G.V., and K.H.; revision for intellectual content was performed by S.F., M.K.F., T.W.W., and K.H. All authors approved the final version of the article.
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