Degree project, 30 ECTS August 26, 2020
Low-density Lipoprotein Lowering in Patients with
Familial Hypercholesterolemia – A Retrospective
Study from the Dyslipidemia Unit at Karlstad
Central Hospital
Author: David Fresnais, Bachelor of Medicine School of Medical Sciences Örebro University Örebro Sweden Supervisor: Payam Khalili, MD PhD Department of Cardiology, Karlstad Central Hospital
Karlstad Sweden Word count
Abstract: 249 Manuscript: 2839
Abbreviations
CI – Confidence interval IQR – Inter-quartile range OR – Odds ratio
SD – Standard deviation
FH – Familial hypercholesterolemia
ASCVD – Atherosclerotic cardiovascular disease LDL-C – Low-density lipoprotein cholesterol LLT – Lipid-lowering treatment
PCSK9-i – Proprotein convertase subtilisin/kexin type 9 inhibitor DLCNS – Dutch Lipid Clinic Network criteria score
ICD – International Classification of Disease
Abstract Introduction
Familial hypercholesterolemia (FH) is a genetic disease affecting 1 in 300 individuals, leading to elevated low-density lipoprotein cholesterol (LDL-C). Early diagnosis and initiation of lipid lowering treatment (LLT) – mainly statins and a new type of LLT; PCSK9-inhibitors – are essential to prevent atherosclerotic cardiovascular disease (ASCVD). The Dyslipidemia Unit at Karlstad Central Hospital (DCSK) was started in October 2018 to optimize
identification and treatment of FH-patients. Aim
The main aim of this study was to investigate whether a specialized outpatient unit for FH could significantly lower patients’ LDL-C by changing the treatment strategy. The secondary aim was to study whether smoking, genetically verified FH, and treatment with PCSK9-inhibitors affected the treatment efficacy in terms of lowering LDL-C.
Methods
A retrospective review of medical records from 24 patients treated for FH at DCSK between October 2018 and November 2019 was performed. Wilcoxon signed rank-test was used to compare LDL-C at admission to LDL-C at follow-up visit (median time until follow-up: 7 months). Mann-Whitney U-tests were used to determine whether smoking, genetically verified FH, and treatment with PCSK9-inhibitors affected LDL-C.
Results
LDL-C was significantly reduced when comparing levels at admission to levels after
changing treatment strategies at DCSK; mean reduction was 1.2 mmol/L. The level of LDL-C reduction was not affected by smoking, treatment with PCSK9-inhibitors, or genetically verified FH.
Conclusion
The present study shows that patients’ LDL-C was effectively lowered after treatment modifications at DCSK. However, more aggressive LLT is needed since none of the patients were able to meet European treatment guidelines for FH.
Introduction
Familial hypercholesterolemia (FH) is an autosomal dominant disorder of low-density lipoprotein cholesterol (LDL-C) metabolism, resulting in premature mortality and morbidity from atherosclerotic cardiovascular disease (ASCVD) (1,2). FH has a population prevalence of approximately 1 in 300 (3,4). The etiology of FH is most commonly due to known
mutations in the hepatic LDL-receptor, and mutations in apolipoprotein B-100, proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as LDL-receptor adaptor protein (5,6). FH is considered as a significantly underdiagnosed condition, and it is estimated that 1.8-4.5 million people are affected in Europe, of whom 75% are not diagnosed (7). Identification of FH is mandatory for initiation of adequate treatment.
Early diagnosis and treatment are important since the mean age of coronary heart disease onset in men with FH is 45 years, and 55 years in women with FH (1,4). Early and sustained reduction of LDL-C in FH patients can significantly reduce the risk for ASCVD (5,8–10).
Diagnosis of FH is currently made either by using clinical scoring criteria or by DNA-analysis (if clinical diagnosis is not evident). One of the recommended clinical criteria available for diagnosis is the Dutch Lipid Clinic Network Score (DLCNS). These criteria are based on patients’ cholesterol levels, family history of premature ASCVD, physical
examination, and genetic testing. Additionally, DNA-based cascade screening is used to identify relatives of the index patient (6,11).
Once patients have been identified, lipid-lowering therapy (LLT) using statins alone or in combination with other LLT’s such as ezetimibe, can be initiated. FH-patients with a major cardiovascular risk factor – such as severe hypertension, ASCVD, chronic kidney disease, and diabetes – are considered as very-high-risk patients whereas FH patients without these major risk factors are considered high-risk patients. The new European
treatment guidelines recommend LDL-C treatment goals of <1.4 mmol/L- and <1.8 mmol/L + >_50% total reduction in LDL-C for very-high-risk- and high-risk patients, respectively (11). A new treatment approach using a monoclonal antibody that binds PCSK9 and has been shown to lower LDL-C by 60%, has recently been approved (12,13). PCSK9-inhibitors are recommended in patients with very-high-risk of cardiovascular disease, if acceptable LDL-C reduction is not achieved on high-dose statin treatment in combination with ezetimibe (11).
The Dyslipidemia Unit at Karlstad central hospital (DCSK) was started in October 2018 to optimize the identification and treatment of FH-patients. Patients are
diagnosis of FH 2) optimization of LLT with the possibility to prescribe PCSK9-inhibitors or adjust the current LLT, and 3) cascade screening.
Aim
The main aim of this study was to investigate whether a specialized outpatient unit for FH, such as the DCSK, could significantly lower patients’ LDL-C levels by adjustment of
treatment strategy. The secondary aim was to study the effect of smoking, genetically verified disease, and treatment with PCSK9-inhibitors might affect treatment efficacy in terms of lowering LDL-C. Smoking and genetically verified disease are well known cardiovascular risk factors, while treatment with PCSK9-inhibitors could be hypothesized to confer additional LDL-C lowering.
Methods
A retrospective review of medical records from patients referred to DCSK between October 2018 and November 2019 was performed. Information on age, gender, family history of FH or ASCVD, and smoking status was obtained from scanned forms filled in by the patients at admission. Information on LDL-C levels, BMI, diabetes, ASCVD, and results from genetic testing was obtained from patient records. Patients diagnosed with FH by International Classification of Disease (ICD) 10th revision code: E78.0A (either through positive genetic testing or clinical diagnosis through DLCNS), were included in this study. Patients who did not prove to have FH – either after clinical investigation and Dutch Lipid Clinic Network scoring or genetic testing – were excluded. The study population consisted of both patients who were referred from primary care and who were identified through genetic cascade testing by DCSK. It has also been possible for patients with suspected FH to refer themselves for evaluation at DCSK. The proportion between these have not been examined for this study.
LDL-C levels were recorded at two times: (1) At admission to DCSK and (2) at follow-up after an average of 7 months (standard deviation (SD): 4 months), after treatment adjustments.
Statistics
Shapiro-Wilk test was used to test for the normality of the LDL-C dataset. Since data did not follow a normal distribution, Wilcoxon signed rank-test was used to analyze and compare LDL-C at admission to LDL-C at follow-up. Mann-Whitney U-tests were performed to determine the roles of smoking, genetically verified disease, and treatment with
PCSK9-inhibitors on LDL-C lowering. The difference between LDL-C at admission and at follow-up was used in the analyses using Mann-Whitney U-test. LDL-C was treated as a continuous variable, while smoking, treatment with PCSK9-inhibitors and results from genetic testing were treated as categorical variables. All analyses were performed in IBM SPSS Statistics 22.
Ethical considerations
Ethical approval has not been obtained because the project has been considered a quality assessment of the outpatient unit. All information extracted from the medical records was gathered after obtaining the approval of the chief executive at the Department of Cardiology in Karlstad and was used for this project exclusively. A note stating the reason for entering patient records was made for each patient included in the study. To ensure that no data could be linked to individual patients, all variables extracted from medical records were coded numerically and the personal identification numbers in the data processing file were replaced by serial numbers (information regarding the relationship between the personal identification numbers and serial numbers was stored in a separate, code protected file).
Results
In total, 55 patients were referred to the DCSK and were identified during the study inclusion period. Of those, 25 were excluded since they did not prove to have FH after investigation (based on genetic testing and/or DLCNS). Of the 30 eligible patients, 6 were not qualified for further analysis due to loss of follow-up. The dropout was likely random due to patients who had not yet been called for a return visit given the short follow-up time.
All 24 patients included in the analyses had been diagnosed- and treated for FH at DCSK. At admission, the median DLCNS was 13.5 (inter-quartile range; IQR: 8). Twelve patients had been previously diagnosed with ASCVD, 14 had hypertension, 2 had diabetes mellitus type II, and 4 were smokers. Baseline characteristics and co-morbidities of the study population are summarized in Table 1.
Table 1. Baseline characteristics (N = 24)
Age; mean (±SD) 54.3 (17) Men; N (%) 10 (42) Women; N (%) 14 (58) BMI; mean (±SD) 28.0 (5) Smoking; N (%) 4 (17) ASCVD; N (%) 12 (50) Diabetes; N (%) 2 (8) Hypertension; N (%) 14 (58) DLCNS; median (IQR) 13.5 (8)
Positive genetic test* (of tested); N (%) 14 (74)
DLCNS = Dutch Lipid Clinic Network Score, ASCVD = Atherosclerotic cardiovascular disease, SD = Standard deviation, IQR = Interquartile range.
Nineteen out of 24 patients were already on LLT prior to admission to DCSK. In 18 of 19 patients, a modification of their treatment was made. Modifications in treatment and treatment after modifications are presented in Table 2.
Table 2. Lipid-lowering treatment and modifications in treatment at DCSK
New treatment in treatment-naïve patients 5
Initiation of statins and/or ezetimibe 4 Initiation of PCSK9-i treatment 1
Treatment modifications**:
No changes in treatment; N (%) 1 (5) Increased dose of current treatment; N (%) 1 (5) Addition of statin and/or ezetimibe; N (%) 10 (53) Addition of PCSK9-i; N (%) 9 (47)
Treatment after modifications:
Statin and/or ezetimibe; N (%) 15 (62.5)
PCSK9-i*; N (%) 9 (37.5)
Table 2: Modifications in LLT after admission, and LLT after modifications.
PCSK9-i = Proprotein convertase subtilisin/kexin type 9 inhibitor, LLT = Lipid-lowering treatment *either in monotherapy or in addition to treatment with statins
LDL-C at admission and follow-up are presented as whisker-diagrams in Figure 1. Analysis with Wilcoxon signed rank-test showed a significant LDL-C reduction when comparing LDL-C at admission to LDL-C at follow-up (p < 0.01). Mean LDL-C reduction was 1.23 mmol/L (95% CI = 0.63 – 1.82). A sensitivity analysis was performed excluding the 5 patients who were not on LLT prior to admission to DCSK, and a significant LDL-C
reduction of 1.03 mmol/L (CI = 0.47 – 1.59) was observed (p < 0.01).
Figure 1: LDL-C at admission and follow up after 7 months (SD = 4 months), presented as whisker-diagrams. LDL-C = low-density lipoprotein.
In subgroup analyses (smokers vs. non-smokers; patients with positive vs. negative genetic test results; treatment with PCSK9-inhibitors vs. statin and/or ezetimibe), there was no additional impact on the magnitude of LDL-C lowering among smokers (p = 0.26; Fig 3.1), patients with genetically confirmed disease (p = 0.24; Fig 3.2), or patients treated with PCSK9-inhibitors (p = 0.20; Fig 3.3), respectively.
0 1 2 3 4 5 6 7 8 9 Admission Follow-up
Figure 1. LDL-C at admission and follow-up
LDL-C (mmol/L)
Figure 2.1, 2.2, and 2.3: LDL-C at admission and follow-up after 7 months (SD = 4 moths) presented as whisker-diagrams for: Smokers and non-smokers, patients with positive- vs. negative genetic test results, patients treated with PCSK9-inhibitors and those receiving conventional treatment*.
LDL-C = Low-density lipoprotein, PCSK9-inhibitor = Proprotein subtilisin/kexin type 9 inhibitor. * Conventional treatment = Statin and/or ezetimibe.
0 1 2 3 4 5 6 7 8 9
Smokers; admission Smokers; follow up Non-smokers; admission Non-smokers; follow-up
Figure 2.1: LDL-C at admission and follow-up; smokers compared to non-smokers
LDL-C (mmol/L) 0 2 4 6 8 10
Positive test; admission Positive test; follow-up Negative test; admission Negative test; follow-up
Figure 2.3: LDL-C at admission and follow-up; positive- compared to negative genetic test results
LDL-C (mmol/L) 0 1 2 3 4 5 6 7 8 9
PCSK9; admission PCSK9; follow-up Conventional; admission Conventional; follow-up
Figure 2.2: LDL-C at admission and follow-up; PCSK9 inhibitor compared to conventional treatment
LDL-C (mmol/L)
Discussion
The present study showed that a specialized outpatient unit for FH, such as the DCSK, could significantly lower patients’ LDL-C through optimizing the treatment approach. Although limited by small sample size, our study could not find any difference on the magnitude of LDL-C lowering between smokers and non-smokers, patients with positive genetic test results compared to those who tested negative, and patients treated with PCSK9-inhibitors compared to those receiving conventional treatment.
The observed LDL-C lowering is likely attributed to medication changes made by the DCSK, since no other interventions with comparable effect on LDL-C were made during the follow-up time (although the DCSK plans to work with a dietician in the future). Eighteen out of 24 patients had their LLT modified at admission to DCSK, and all of them had reduced their LDL-C at follow-up, except 1 patient who could not tolerate the prescribed treatment due to adverse effects. These LLT’s have been shown to effectively lower LDL-C and are in line with treatment recommendations from current European guidelines for management of dyslipidemia in FH-patients (9,11,12).
Nineteen out of 24 patients were already on LLT prior to admission. The five patients who were not on LLT prior to admission were either relatives to FH-patients
identified through cascade screening, or patients who could not tolerate treatment offered by primary care due to adverse effects. In these patients, an LDL-C reduction would be expected from initiation of any LLT (if treatment was tolerated), leading to a possible overestimation of treatment results in the overall cohort. To account for this factor, a sensitivity analysis was performed without these patients, and the LDL-C reduction remained significant.
The LDL-C reduction observed in this study is only a surrogate for clinically-relevant outcomes, such as ASCVD, but it could be considered as significant from a clinical perspective since LDL-C reduction in patients with FH can reduce the risk of ASCVD (5,9,10). In fact, several epidemiological and randomized studies, have consistently
demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD (14,15). A meta-analysis of data from 170,000 participants in 26 randomized trials showed that more intense statin treatment leads to further reduction in the incidence of major cardiovascular events, and that the risk decreases by more than 20% for every 1 mmol/L decrease in LDL-C (16). Although our study results cannot be directly compared to the previous studies due to the differences in sample size, the LLT used, and the causes of dyslipidemia among the study cohorts, the LDL-C lowering by more than 1 mmol/L in the present study implies a potentially clinically important reduced risk for ASCVD as well.
In primary prevention for individuals with FH at very-high risk, an LDL-C goal of <1.4 mmol/L and a more than 50% reduction in LDL-C from baseline is recommended, whereas for high-risk patients an LDL-C goal of <1.8 mmol/L should be considered (11). These treatment goals were not met in any of the 24 patients studied. Several observational studies have reported similar difficulties in meeting the recommended target treatment goals despite the use of LLT (17–19). A large cross-sectional study including 1249 patients with FH conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals in the Netherlands, reported that only 20% of patients reached the LDL-C treatment target of < 2.5 mmol/L (20), which is less strict than recommendations from current guidelines. Although the target LDL-C level attainment appears to be low, one study found that the likelihood of reaching LDL-C treatment targets increases with duration of specialized care (21). These results emphasize the need for improved monitoring and utilization of available treatments in FH-patients to further decrease LDL-C levels. Specialized care units could play a central role towards this goal by improving monitoring of treatment, and by consistently detecting new cases through cascade-screening (6,7,11).
In the present study, smoking did not affect the efficacy of LLT. Smoking is known to accelerate atherosclerosis of blood vessels and is, thus, a strong risk factor for ASCVD, especially in high-risk groups (22,23). The association between smoking and LDL-C is not fully understood, but studies have demonstrated an adverse effect on the lipid-profile of patients (24,25). The results indicate that a multifactorial approach is necessary for
treatment of patients with FH and risk factors for cardiovascular disease. It is not possible to draw any firm conclusions regarding the effect of smoking on LDL-C reduction from the current results due to the limited number of patients and because lifestyle factors that can affect LDL-C such as exercise, diet, and social background (11) were not taken into account.
The addition of a PCSK9-i, either alone or in combination with other LLT’s, did not provide a statistically significant further reduction of LDL-C in our study cohort.
Although, the small number of patients treated with PCSK9-i in the study cohort can preclude the presence of significance, other potential explanations can also be considered, including the possibility that PCSK9-inhibitors have comparative treatment efficacy to conventional
treatment in FH patients, incorrect indication for treatment with PCSK9-i, or the risk that patients with indication for PCSK9-i treatment are more resistant to LLT. In clinical trials, PCSK9-inhibitors have repeatedly been shown to significantly reduce LDL-C. In the ODYSSEY- and FOURIER trials, addition of a PCSK9-i to statin therapy reduced patients’ LDL-C levels by more than half (12,13,26). While these studies looked at patients with
heterogenous causes of dyslipidemia, a large cohort of 1257 FH-patients showed that PCSK9-inhibitors have similar effectiveness in FH patients (27).
The lack of significant difference in LDL-C reduction when comparing the groups with positive- vs. negative genetic test results, can be explained by the small sample size but can also be a true lack of association due to the presence of unknown mutations causing FH or the possibility that LLT may be effective regardless of underlying cause (28,29).
Limitations
The major limitations of this study are the limited study population, the short follow-up of the patients, and that LDL-C lowering was used as a surrogate marker for cardiovascular disease risk-reduction instead of clinically relevant outcomes such as cardiac events. A strong and reliable difference was found for the primary aim, however, results from analyses of the secondary aims were not clear enough to make any firm conclusions. Also, the study did not account for other ASCVD-risk factors presented, such as diabetes and hypertension, mainly due to the limited study population.
Conclusion
The present study showed that patients’ LDL-C was effectively lowered after treatment modifications at a specialized outpatient care unit for identification and management of FH-patients. Whether this reduction could lead to a reduced risk for ASCVD can be speculated but cannot be confirmed by the present study. Considering that LDL-C lowering is the most important intervention to prevent ASCVD in FH-patients, more aggressive LLT is needed since none of the patients were able to meet European treatment guidelines for FH. Smoking, genetically verified disease, and treatment with PCSK9-i did not affect the magnitude of LDL-C lowering, although the small study population might preclude the presence of significance. Further studies investigating the role of specialized outpatient units for FH, using prospective study design with a larger number of patients, longer follow-up, and clinically relevant outcomes, such as the incidence of cardiac events, are necessary.
Conflict of interest
Payam Khalili has a current employment at Karlstad Central Hospital and is engaged in work at the hospital’s Dyslipidemia Unit. Payam Khalili has not received additional research
funding for conducting this project and has no other commercial, legal, financial, or any other opposing interests that may affect this study.
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Populärvetenskaplig sammanfattning
Familjär hyperkolesterolemi (FH) är en ärftlig sjukdom som leder till höga nivåer av skadligt LDL-kolesterol i blodet. En av 300 personer beräknas vara drabbade. Obehandlat leder sjukdomen till för tidig sjuklighet och död i hjärtkärlsjukdom, där medelåldern för insjuknande i hjärtkärlsjukdom är ca 45 år för män och 55 år för kvinnor. Insättande av kolesterolsänkande medicinering är därför av största vikt efter att diagnos fastställts. För att upptäcka patienter med FH och erbjuda bästa möjliga behandling finns speciella
dyslipidemienheter runt om i landet. En sådan enhet är dyslipidemienheten i Karlstad, som startades i oktober 2018.
Den aktuella studien har undersökt hur nivåerna av LDL-kolesterol hos 24 patienter med FH påverkats av modifieringar i lipidsänkande behandling på den nämnda enheten. Resultaten visar att patienterna minskat sina nivåer av LDL-kolesterol med 25% efter en genomsnittlig uppföljningstid på ca 7 månader jämfört med värden tagna vid ankomst till enheten.
Trots den betydande kolesterolsänkningen hade inga av patienterna som deltog i studien tillräckligt låga kolesterolvärden efter uppföljningstiden för att uppfylla målen enligt gällande europeiska behandlingsriktlinjer. Det visar att aggressivare kolesterolsänkande behandling troligtvis är nödvändig för denna patientgrupp i framtiden.
Cover letter
August 7, 2020
Dear Editor,
We would like to submit an original research article entitled “Low-density Lipoprotein Lowering in Patients with Familial Hypercholesterolemia – A retrospective study from the Dyslipidemia Unit at Karlstad Central Hospital” to be considered for publication by
Atherosclerosis. This is an original work and has not been published, nor is it currently under consideration for publication elsewhere.
This retrospective review of medical records has investigated the effect on low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH) after admission to- and treatment at a specialized dyslipidemia unit in Sweden. After an average follow-up time of 7 months, LDL-C was reduced by 25% compared to admission, after modifications in lipid-lowering therapy (LLT). Although LDL-C was significantly reduced, none of the patients fulfilled treatment goals according to current European guidelines. These results suggest that more aggressive LLT might be needed to meet the current treatment goals for patients with FH.
We believe that this manuscript is appropriate for publication to Atherosclerosis since it provides information with a potential impact on the way the healthcare system is organized regarding FH since it supports the role of specialized care units.
We have one conflict of interest to disclose: Payam Khalili has a current employment at Karlstad Central Hospital and is engaged in work at the hospital’s Dyslipidemia Unit, where the current study was performed.
Thank you for your consideration of this manuscript.
Sincerely,
David Fresnais, Bachelor of Medicine School of Medical Sciences
Örebro University Örebro
Sweden
Etisk reflektion
Inför utförandet av den aktuella studien har inget etiskt godkännande erhållits. Beslutet togs efter noggrant etiskt övervägande och reflektion. Studien behandlar resultat från genetisk testning av patienter, vilket är ett viktigt verktyg (som ibland även innefattar släktingar till patienter) som ingår i utredning och diagnosticering av patienter med misstänkt familjär hyperkolesterolemi. Därför övervägdes insatser för att respektera juridiska- och etiska principer för autonomi och integritet så långt som möjligt i designandet av studien. Resultat från DNA-analyser av släktingar till forskningspersoner behandlades inte. För att säkerställa att inga uppgifter kunde kopplas till enskilda patienter kodades alla variabler som
extraherades från journalerna numeriskt och personnummer i databehandlingsfilen ersattes av serienummer (information om förhållandet mellan personnummer och serienummer lagrades i en separat kodskyddad fil).
Samtycke till att extrahera information ur patienternas journaler har inte inhämtats, men samlades in efter att ha fått godkännande av verksamhetschefen för Hjärt-akutmedicin kliniken i Karlstad (där dyslipidemienheten ingår). För varje patient som ingick i studien gjordes ett kort diktat som angav skälet till att man gått in i journalen. All data som extraherades har använts enbart för utförandet av den aktuella studien.
Vi har bedömt att den här studien inte på något sätt har kunnat påverka varken patienten eller patientens behandling negativt eftersom det är en retrospektiv studie.
