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\begin{document}

\title{Drug-drug interaction between warfarin and statins: A Danish cohort
study}



\author[1]{Anna Engell}%
\author[2]{Andreas Svendsen}%
\author[1]{Bent Struer Lind}%
\author[3]{Christen Andersen}%
\author[3]{John Andersen}%
\author[3]{Tora Willadsen}%
\author[4]{Frederik Persson}%
\author[5]{Anton Pottegard}%
\affil[1]{Hvidovre Hospital}%
\affil[2]{Odense Universitetshospital}%
\affil[3]{Copenhagen University Research Unit for General Practice}%
\affil[4]{Steno Diabetes Center Copenhagen}%
\affil[5]{University of Southern Denmark}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Initiation of statin treatment is suggested to increase the
international normalised ratio (INR) among warfarin users. However,
available data is limited and conflicting. We conducted a register-based
cohort study to evaluate the drug-drug interaction between warfarin and
statins. By linking data on INR measurements and filled prescriptions,
we identified warfarin users 2000-2015 initiating simvastatin (n=1,363),
atorvastatin (n=165), or rosuvastatin (n=23). Simvastatin initiation led
to an increase in mean INR from 2.40 to 2.71, with INRs peaking after 4
weeks, corresponding to a mean change of 0.32 (95\%CI 0.25-0.38).
High-dose and low-dose simvastatin led to comparable changes (mean
change 0.33 vs 0.29). Initiation of atorvastatin and rosuvastatin lead
to INR increases of 0.27 (95\%CI 0.12-0.42) and 0.30 (95\%CI
-0.09-0.69). In conclusion, initiation of simvastatin, atorvastatin, or
rosuvastatin among warfarin users led to a minor increase in INR. The
magnitude of this change is for most patients likely of limited clinical
relevance.%
\end{abstract}%



\sloppy




\textbf{Introduction}

The vitamin K antagonist warfarin is used in the treatment and
prevention of thromboembolic events.\textsuperscript{1--3} Due to its
narrow therapeutic index, use of warfarin requires close monitoring of
the international normalised ratio (INR). Warfarin is metabolized by the
cytochrome P450 (CYP) liver enzymes, especially
CYP2C9,\textsuperscript{4} which makes it highly susceptible to
drug-drug interactions (DDIs).\textsuperscript{1,4}

Due to several overlaps in indications of use, coadministration of
warfarin and statins is common.\textsuperscript{5,6} A limited number of
generally conflicting studies have reported both that statin initiation
leads to moderate INR increases,\textsuperscript{7--10} as well as,
small INR changes of limited clinical
relevance.\textsuperscript{11,12}Despite limited evidence of a
clinically relevant interaction between warfarin and statins, commonly
used online DDI guidelines consistently advise clinicians to increase
the frequency of INR monitoring and if necessary adjust the warfarin
dose, when initiating statin treatment.\textsuperscript{13--15} This
results in additional consultations and blood testing, burdening both
the patient and the health care system.

To provide additional data on this potential DDI between statins and
warfarin, we conducted a large register-based study and examined the INR
changes in warfarin users following exposure to simvastatin,
atorvastatin, and rosuvastatin.

\textbf{Methods}

\emph{Base cohort and data sources}

A base cohort was established by linking different Danish health
registries. The base cohort comprised all patients registered with at
least one INR measurement in the Copenhagen Primary Care Laboratory
(CopLab) database. The database includes laboratory test results from
primary health care patients in the Copenhagen area of Denmark from 2000
to 2015.\textsuperscript{16,17} During this period the primary health
care doctors in the Copenhagen area were served by the Elective
Laboratory of the Capital Region (ELCR). ELCR covered approximately 1.2
million inhabitants and provided a wide range of biochemical,
physiological, and cardiac tests. The CopLab database does not include
INR point of care testing (POCT) results from general practice. The ELCR
was accredited for International Organization for Standardization (ISO)
standards ISO17025 and ISO15189. Appendix A provides a detailed
description of the INR assay.

For the cohort identified via CopLab, we retrieved data about drug use
from the Danish National Prescription Registry\textsuperscript{18} as
well as hospital diagnoses from the Danish National Patient Registry
(NPR).\textsuperscript{19} Data linkage was done using the unique Danish
Civil Registration Number assigned to all Danish
residents.\textsuperscript{20}

\emph{Study population}

From the base cohort (see above) we restricted the dataset to patients
with at least two INR measurements, at least one recorded vitamin K
antagonist (VKA) dispensing, and at least one statin dispensing. Within
this cohort we identified all incident prescriptions for simvastatin,
atorvastatin and rosuvastatin, defined as a prescription with no
preceding prescription for a statin within the last 2 years. If one
individual had two such incident prescriptions for the same statin, only
the first was included. We further restricted to those with at least one
INR measurement 8 weeks before statin initiation, as well as at least
one INR measurement within 12 weeks after statin initiation. Finally, we
excluded those with no VKA prescription within 8 weeks before statin
initiation and those aged \textless{}18 years at the time of statin
initiation.

\emph{Main analysis}

The INR results were measured from 8 weeks before statin initiation to
12 weeks after statin initiation. We graphically depicted the changes in
INR values by mapping median, interquartile and
10\textsuperscript{th}and 90\textsuperscript{th} percentile during this
window. To formally assess the INR changes, we estimated the increase in
mean INR by comparing the latest INR result in the before window to the
first INR result within week 3-6 after statin initiation (if any), by
using a paired \emph{t} test. We further assessed the median effect by
estimating median changes in INR levels for all statin treated patients,
as well as those treated with a high- ([?]40mg) and low-dose
(\textless{}40mg) simvastatin in secondary analyses. Finally, we
calculated the proportion of patients with an INR above the therapeutic
interval (for most patients INR between 2-3); defined as INR
\textgreater{} 4 and \textgreater{} 5 by comparing the proportion of
patients 1-4 weeks prior to initiating simvastatin to the proportion 3-6
weeks after.

All analyses were performed using STATA Release 14.1 (Stata- Corp,
College Station, TX, USA). The study was approved by the Danish Data
Protection Agency. Since data is based on anonymized register data
neither approval from Ethics Committee nor collection of informed
consent was needed.

\emph{Supplementary and sensitivity analyses}

To assess the potential impact from other drugs interacting with
warfarin, the main analysis was repeated excluding patients filling of a
prescription for other potentially interacting drug in the observation
period (8 weeks before to 12 weeks after the date of statin initiation).
These drugs included specific antifungals, macrolides, quinolones,
metronidazole and amiodarone as described in Appendix
B.\textsuperscript{10}

Furthermore, the main analysis was repeated excluding patients with a
mechanical heart valve, identified through the NPR
\textsuperscript{21}to assess the potential influence of this patient
group with other target INR ranges than 2-3.\textsuperscript{22}

Finally, some INR measurements were labeled as imprecise (up to 5-7\%
higher than actual values) due to prolonged storage of the blood sample
before analysis of INR. We therefore conducted an analysis were these
INR measurements were discarded.

\textbf{Results}

For the analyses, we included 1,363, 165, and 23 warfarin users who had
been exposed to simvastatin, atorvastatin, and rosuvastatin,
respectively, between 2000 and 2015.

For patients treated with simvastatin, atorvastatin and rosuvastatin,
the median ages were 72 years (interquartile range (IQR) 64-79 years),
70 years (IQR 63-76), and 74 years (IQR 64-80), while the proportion of
males were 58\%, 62\%, and 47\%, respectively.

INR values increased slightly after initiation of simvastatin treatment
with a peak after about 4 weeks (Figure 1). Initiation of simvastatin
was associated with an increase in mean INR from 2.40 to 2.71,
corresponding to an increase of 0.32 (95\%CI: 0.25-0.38,
p\textless{}0.001) while the median INR change was 0.2 (IQR -0.3-0.8)
(Figure 2). During a time window of 1-4 weeks before initiation of
statin treatment, 3.4\% of patients had at least one INR measurement
above 4. This proportion increased to 9.0\% during 3-6 weeks after
initiation of statin treatment (p\textless{}0.01). Similarly, the
proportion of the patients with an INR \textgreater{} 5 increased from
1.3\% before initiation of statin treatment to 3.2\% after
(p\textless{}0.01).

When stratifying by simvastatin dosage, we found that initiation of both
high-dose ([?]40mg) simvastatin (0.33, 95\%CI 0.25-0.42) and low-dose
(\textless{}40mg) simvastatin (0.29, 95\%CI 0.20-0.38) were associated
with a similar modest increase in mean INR. The median change in INR was
0.2 (IQR -0.3-0.9) and 0.3 (IQR -0.2-0.8) for patients receiving high
and low simvastatin dose, respectively (Figure 2).

Considering atorvastatin, initiation of treatment was associated with an
increase in mean INR from 2.42 to 2.69 (change 0.27, 95\%CI 0.12-0.42,
p\textless{}0.01), while for rosuvastatin was associated with a
corresponding increase from 2.31 to 2.61 (change 0.30, 95\%CI
-0.09-0.69, p=0.121). Analyses of high dose vs. low dose were prohibited
by low statistical power for both atorvastatin and rosuvastatin.

Sensitivity analyses excluding patients filling prescriptions for other
potentially interacting drugs (n=77), and patients with a mechanical
heart valve (n=110), and INR measurements labeled as potentially
imprecise (n=81 patients with no alternative measurements) yielded
virtually unchanged estimates (data not shown).

\textbf{Discussion}

In this register-based study based on a primary health care population,
we found that initiation of simvastatin was associated with a minor, but
statistically significant increase in INR of 0.32 (95\%CI: 0.25-0.38,
p\textless{}0.001), peaking approximately 4 weeks after initiation. A
similar increase in INR was observed with atorvastatin and rosuvastatin
initiation, although failing to reach statistical significance.

The main strength of this study is the use of data obtained from daily
routine work in primary health care with limited risk of selection bias.
One limitation of this study is the assessment of drug use by
prescription data alone. The level of adherence to statin therapy cannot
be determined and neither can the precise date of initiation of statin
treatment. Early discontinuation of statins due to side effects could
minimize the effect on the change in
INR.\textsuperscript{23}Furthermore, we had no available information
about other factors that might impact the INR level e.g. lifestyle
factors, herbal medications as well as relevant diagnoses diagnosed
solely in primary health care, however, due to the within-person
comparison, most of such factors can reasonably be assumed constant.
Finally, we do not report clinical outcomes. However, increases in INR
are well known to increase the risk of severe
bleeding.\textsuperscript{1,26,27} This is supported by a study that
found initiation of statins to increase the risk of gastrointestinal
bleeding in chronic warfarin users.\textsuperscript{28}In our study the
proportion of patients with INR \textgreater{} 5 increased from 1.3 to
3.2\% after statin treatment was initiated. Importantly, however, when
scrutinizing the INR changes at the level of the individual, this
increase reflected a small overall increase and not a pronounced
increase in a subset of patients.

Our findings from primary health care in the Copenhagen area support the
recent findings from specialized anticoagulation clinics in Sweden
presented by Andersson et al, which found an increase in INR from 2.43
to 2.58 in 5637 patients on warfarin treatment initiating simvastatin,
also peaking about 4 weeks after simvastatin
initiation.\textsuperscript{10} A more pronounced increase in INR was
found in a small study, where INR increased from 2.5 at baseline to 3.2
after simvastatin initiation in 29 patients in stable warfarin
treatment.\textsuperscript{7}

The latency in the INR increase, peaking after four weeks of concomitant
treatment is surprising. Of note, a similar course was seen in the study
by Andersson et al.\textsuperscript{10} This does not correspond to
statins directly inhibiting the CYP enzymes responsible for the
metabolism of warfarin, as this would lead to a faster onset of the INR
increase, as e.g. seen for azole antinfungals.\textsuperscript{29} To
our knowledge, no alternative mechanisms have been proposed. As such,
additional work identifying the mechanism through which statin use
potentiates the effect of warfarin is warranted.

In conclusion, initiation of simvastatin, atorvastatin, and rosuvastatin
led to a minor increase in INR in patients treated with warfarin,
peaking about 4 weeks after statin initiation. The magnitude of the
change in INR is for most patients likely to be of limited clinical
relevance. Individual risk stratification including age, use of
medication and other diseases should be applied, when deciding if
increased INR monitoring should be performed during the initiation of
statin treatment.

\textbf{ACKNOWLEDGEMENTS}

The authors acknowledge Martin T. Ernst for help with data management
and Maja Hellfritszch for valuable input to the presentation of the
findings.

\textbf{CONTRIBUTORS}

A.E. was the principal author and investigator. A.P. carried out data
collection and data analysis. A.P. supervised the work. A.E. prepared
the first draft manuscript. All authors read and approved the final
manuscript.

\textbf{COMPETING INTERESTST}

F.P. reports having received research grant from AstraZeneca, Novo
Nordisk, Novartis and lecture fees from MSD, AstraZeneca, Novo Nordisk,
Novartis, Eli Lilly and Boehringer Ingelheim and have served as a
consultant for AstraZeneca, Novo Nordisk, Amgen, and MSD.

A.P. reports participation in research projects funded by Alcon,
Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Novo Nordisk,
Servier and LEO Pharma, all with funds paid to the institution where he
was employed (no personal fees) and with no relation to the work
reported in this paper.

\textbf{DATA AVAILABILITY STATEMENT}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

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\textbf{Figure legends}

\textbf{Figure 1.} Median international normalised ratio (INR), from 8
weeks before and 12 weeks after initiation of simvastatin treatment.
Grey and dashed lines illustrate the 10, 25, 75 and 90 percentiles,
respectively. INR-values were summarized in 3-day intervals.

\textbf{Figure 2.} Box and whisker plot showing median change in the
international normalised ratio (INR) for all patients treated with
simvastatin, low dose (\textless{}40mg) and high dose (\selectlanguage{english}[?]40mg) treated
patients. Upper and lower box borders illustrate the
75\textsuperscript{th} and 25\textsuperscript{th}percentiles, while
upper and lower whiskers illustrate the 10\textsuperscript{th} and
90\textsuperscript{th} percentile change in INR observed.



\textbf{Appendix A -- The International Normalised Ratio assay}

Coagulation, tissue factor-induced; rel.time (actual/norm; INR); IRP
67/40; proc.) was determined in sodium-citrate-stabilized plasma by
Stago Prothombin-complex Assay (Diagnostica Stago, Asnieres, France) on
Thrombolyzer (Behnk Elektronik, Norderstedt, Germany) and on STA-R
(Diagnostica Stago). For the Thrombolyzer assay the interserial
coefficient of variation percentage (CV\%) was 2,4 \% (at INR level 1,0)
and 2,9 \% (at INR level 2,3). For the STAR assay the interserial CV\%
was 2,1 \% (at level INR 1,00) and 2,1 \% (at INR level 2,2). The
results from the two platforms were comparable as documented by parallel
analysis of 90 human plasma samples during a period of 6 days in
December 2001 to May 2002. The equation from the parallel analysis was
STAR = 1,0186*Thrombolyzer -0,0305. The STA-R platform was used after
December 8, 2003. The INR assay was subject to external quality control
through participation in the Danish quality assessment service DEKS
(Glostrup, Denmark). The assessment schemes included 5 distributions
annually. Each distribution comprised 4 samples. The results from DEKS
confirmed the reliability of the assays, and the results from ELCR (from
2002 to 2015) deviated less than 5\% from the method mean in 89 \% of
the results (n=231). The mean deviation from the method mean was - 1,8
\% (n=196).



\textbf{Appendix B -- Codes and definitions}

Study drugs

Warfarin ATC B01AA03

Statins ATC C10AA

Simvastatin ATC C10AA01

Rosuvastatin ATC C10AA07

Atorvastain ATC C10AA05

Other drug use

Amiodarone ATC C01BD01

Fluconazole ATC J02AC01

Miconazole ATC D01AC02

Erythromycin ATC J01FA01

Ciprofloxacin ATC J01MA02

Metronidazol ATC D06BX01

Factors affecting therapeutic interval of INR

Presence of prosthetic heart valve ICD-10 Z95.2

International Classification of Diseases Tenth Revision (ICD--10),

ATC: Anatomical Therapeutic Chemical Classification System\selectlanguage{english}
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