Introduction:
Familial hypercholesterolemia (FH) is the most common inherited disease of the lipid
metabolism with a prevalence of approximately 1/200. It is estimated that only 15 % of
the estimated 30.000 patients in Denmark has been diagnosed. With high risk of
atherosclerotic coronary disease, it is estimated that there is a great potential
regarding cardiovascular health and health economics by early initiation of lipid
lowering treatment and cascade screening of families.
All doctors can refer to lipid clinics on the suspicion of FH. FH should be suspected
when low-density lipoprotein - cholesterol (LDL-C) is extremely elevated without any
other explanation in young individuals, or in families with premature cardiovascular
disease. The diagnosis is made from clinical scoring systems as the Simon Broome
criteria, Dutch Lipid Clinical Network criteria and the MEDPED criteria including genetic
test. The treatment is lipid-lowering drugs including statins, ezetimibe and
PCSK9-inhibitor in case of insufficient effect.
In the last 12-14 years systematic cascade screening of FH families have been used in
Denmark to track and find FH patients. The patients have since 2020 been registered in
the National clinical quality database for FH.
However FH remains an under diagnosed disease, resulting in premature ischemic
cardiovascular disease and premature cardiovascular death. Thus, there is a need for
optimized screening for FH and more projects are already initiated.
Detecting more FH patients will demand an increased attention on elevated cholesterol. A
biochemistry interpretive comment on elevated LDL-C according to the Danish FH Guideline
regarding when to suspect FH, encouraging to further investigation for secondary
dyslipidemia and successive referral to lipid clinic suspecting FH, can theoretically
increase the awareness of FH. In England a survey has shown that general practitioners
ask for interpretive comments on biochemistry analyses and 19 % of the general
practitioners demands a comment on the lipid analyses.
A minor case control study in Australia have shown that interpretive comment on lipid
profiles led to a significant reduction in LDL-C compared to controls, and increased the
rate of referral by 11.5 % in cases compared to 1 % in controls, however only a minority
was referred. The study was relatively small with 96 cases and 100 controls and an
interpretive comment was activated when LDL-C > 6.5 mmol/L. However, the study is
supported by a prospective case control study by the same research group including 231
patients with LDL-C > 6.5 mmol/L, where all doctors received an interpretive comment on
elevated the LDL-C, raising suspicion to FH, but only cases received a comment which
encouraged to referral to lipid clinic. Hereby 18 % of cases was referred compared to 8 %
of controls. This indicates that in a minor population in another country, establishment
of an interpretive comment on LDL-C could increase referral rate by 10 %. The prospective
case control study concludes that the interpretive comment increases the detection rate
of FH patients.
We want to evaluate implementation of an interpretive comment on elevated LDL-C levels in
the Region of Southern Denmark. Compared to the Australian studies we expect to get more
referrals since our cut-off for referral is lower (LDL-C 4 or 5 mmol/L depending on age).
A strength in our study is the prospective step wedge RCT design.
Purpose and scientifically question:
This study will try to optimize screening for FH by investigating the effect of a
biochemistry interpretive comment when LDL-C is significantly elevated according to the
Danish FH guideline. The comment will encourage to further investigation and referral to
local lipid clinic. The purpose is to test the effect of the interpretive comment
regarding the proportion of patients referred to the lipid clinics as the primary
endpoint. As the secondary endpoints we wish to calculate the change in LDL-C from
referral to first contact in the lipid clinic, and the proportion of new diagnosed
patients with FH at the lipid clinics in the Region of Southern Denmark.
This study will evaluate if it is possible to receive more referrals to the lipid clinics
and find more patients with FH by an interpretive comment on cholesterol levels,
encouraging to investigate for secondary dyslipidemia, and successive refer to lipid
clinic in case of no explanation of the elevated LDL-C. The study will elucidate how many
patients we have to refer, to find one patient with FH?
Method and material:
This study will through a step wedge cluster randomized controlled trial, investigate if
establishment of the interpretive comment will result in more referrals and as the
primary endpoint in more diagnosed patients with FH in the Region of Southern Denmark.
The material will consist of referred patients to the lipid clinics of Southern Denmark.
The general practitioners and medical wards in the Region of Southern Denmark will be
allocated in clusters according to the providing lab, totally 4 clusters. The clusters
will be randomised to stepwise implementation of the biochemistry interpretive comment on
cholesterol samples meeting the following criteria. FH should be suspected if LDL-C > 4
mmol/L in persons under the age of 40, or LDL-C > 5 mmol/L in persons over the age of 40
according to the Danish guideline on FH. Randomization will be dobbeltblinded to data
analyzing researchers and the general practitioners and wards receiving the interpretive
comment.
The clusters will act as their own controls, the intervention being the biochemistry
interpretive comment. The first cluster will implement the comment from the 01.12.2022
and after 12 weeks the next cluster will implement the comment. After 48 weeks all
clusters will have implemented the interpretive comment. Further 8 weeks will act as
buffer resulting in a totally study period of 52 weeks.
The Study will elucidate the proportion of referred patients and patients diagnosed with
FH in the Region of Southern Denmark, after implementation of the interpretive comment.
The study will elucidate whether the proportion of referrals and diagnosed patients
increases after implementation of the interpretive comment in the specific cluster or
between the clusters.
The proportion of referred patients will be registered through data from the electronic
patient journal system (EPJ). The reffered patients will be stratified both
geographically and according to the referring physicians electronic laboratory system to
account for bias regarding how the interpretive comment appears in the different systems,
and whether this influence referral rate. The proportion of patients diagnosed with FH
will be registered through ICD-10 codes in EPJ and crosschecked with Dutch Lipid Clinical
score from the patient journal, including lipid profile and genetics to ensure a valid
diagnosis. Furthermore HbA1c, TSH, liver- and kidney parameters and lipid profile will be
registered as patient baseline characteristic to exclude patients with secondary
dyslipidemia and to follow changes in LDL-C from referral to first lipid clinic contact.
The study will furthermore elucidate how many patients there need to be referred to find
one patient with FH.
Ethics
There is no need for information on an individual level, because the study is focusing on
an organizational level as a step wedge cluster design. The patients can always deny
further investigation or referral, and in this study we do not encourage to take blood
samples without clinical indication. Instead we encourage through the biochemistry
interpretive comment to act on blood samples already taken. The scientifically committee
of Southern Denmark finds no indication for registration of the study because it is a
study of assessing quality (Record number. S-20222000-106). The study will be registered
in the Region of Southern Denmarks list of Research projects.