Results
We screened 8,623 titles and abstracts and selected 80 studies for
full-text screening. Of these, eight studies were included
(Figure 1 ). The most common reason for excluding studies during
full-text screening was due to the studies not concerning newly
initiated statin treatment (n = 29). A full overview of the included
studies can be found in Table 1 . Out of the eight included
studies, four studies investigated the effect of a specific statin
(simvastatin[13, 14], rosuvastatin[15], and
atorvastatin[16]), while three studies investigated the effect of
more than one statin type.[17-19] Finally, one study did not specify
which statin type the patients were initiating treatment with.[20]
Concerning the VKA-treatment, seven studies included patients in
warfarin treatment only,[13-16],[18-20] whereas one study
concerned patients in phenprocoumon and acenocoumarol treatment.[17]
The size of the included population ranged from 7 to 5,637 patients in
six of the studies, while one study did not report the size of the study
population.[20] Although all eight studies met our inclusion
criteria, only seven studies focused specifically on the effect of
initiating statin treatment on coagulation activity,[13-19] while
one study addressed several drug interactions with warfarin, including
statins.[20] Two of the included studies were prospective controlled
drug trials, comprising patients in stable warfarin treatment receiving
statin treatment only due to the trial, and not due to any known medical
condition.[15, 16]
The three studies that focused on simvastatin initiation in patients
treated with warfarin, all reported a small increase in mean INR. The
largest study, including data from 5,637 warfarin users, found an
increase in mean INR from 2.43 at baseline to 2.58, four weeks after
initiation of simvastatin treatment.[13] Similarly, another large
register-based cohort study including 1,363 patients found an increase
in mean INR from 2.40 to 2.71 also peaking approximately four weeks
after initiation of simvastatin treatment.[19] Furthermore, it was
shown that high-dose (>40 mg) and low-dose simvastatin
(< 40 mg) led to comparable changes in INR (increase of 0.33
vs 0.29).[19] A smaller study (n=29) reported an increase in mean
INR from 2.50 at baseline to 3.15 after initiation of simvastatin
treatment.[14] In this study, the INR values were obtained from the
patient’s visit to the anticoagulation clinic prior to initiating
simvastatin treatment and from the subsequent clinic visit after
simvastatin had been initiated, with no information about the number of
days/weeks in between.[14] Two studies reported a mean reduction of
the daily warfarin dose following statin initiation of 7% and 9%,
respectively.[13, 14] An observational case-control study assessed
whether initiation of fibrates or statins in chronic warfarin users
increased the risk of hospitalization due to gastrointestinal (GI)
bleeding.[13] The study included warfarin patients initiating
treatment with fluvastatin (n = 16), simvastatin (n = 277), atorvastatin
(n = 499) and pravastatin (n = 113). Each patient case with GI bleeding
was matched with up to 50 controls, whom had initiated treatment with
the same type of statin as the case, but had not been hospitalized due
to GI bleedings. In chronic warfarin users, the risk of GI bleeding was
highest 31-60 days after simvastatin initiation with an Odds Ratio (OR)
of 1.60 (95% CI 1.07-2.39), and for atorvastatin the risk of GI
bleeding was highest 1-30 days after initiating treatment with an OR of
1.39 (95% CI 1.07-1.81). Concerning fluvastatin treatment, there were
too few cases to obtain reliable estimates. No increased risk of GI
bleeding was observed, when initiating treatment with the chosen
reference drug; pravastatin, as
pravastatin is not metabolized by
CYP enzymes and therefore was not expected to interact with
warfarin.[18]
A pilot study of warfarin-associated drug interactions did not find any
changes in INR related to initiation of statin treatment, when patients
with INR >1.8 and <3.2 in the period of 60 days
prior to initiation of statin treatment, were categorized in four groups
according to the change in INR. The four groups compromised: nonevents
(2.0<INR<3.0), increasing (INR≥4.0), decreasing
(INR≤1.5) and residual. Most patients were in the nonevent group
(67.9%), while 7.8% and 7.1% experienced increased and decreased INR
levels, respectively, and 17.3% patients were in the residual group in
between the other three groups.[20] No specification of the type of
the included statins was stated, and neither were the size of the
exposed population of warfarin users, therefore this study was
considered to have lesser relevance to the evaluation of the effect of
initiation of statin treatment on level of coagulation.
In another study, the immediate (on average 1 week after initiation of
statin treatment) and long-term (6-12 weeks after initiation of statin
treatment) effects of statins on INR in 435 patients in phenprocoumon
treatment and 303 patients in acenocoumarol treatment were
studied.[17] The patients treated with phenprocoumon (n = 435) and
acenocoumarol (n = 303), respectively, initiated treatment with the
statins simvastatin, atorvastatin, pravastatin, rosuvastatin or
fluvastatin. For all statins, the immediate effect on INR was an
increase of 0.1 among phenprocoumon users, while no effect was observed
for acenocoumarol. VKA dose was decreased with 0.02 mg/day in
phenprocoumon users and 0.04 mg/day in acenocoumarol users within the
first six weeks after initiation of statin treatment, and reduced
furthermore with 0.07 mg/day and 0.11 mg/day respectively after 12 weeks
of statin treatment.[17]
Finally, two prospective clinical studies investigated the potential
drug interaction between rosuvastatin and warfarin and atorvastatin and
warfarin, respectively. One study investigated the effect of initiation
and dosage increasement of rosuvastatin in seven patients in stable
warfarin treatment. Initiation of treatment with 10 mg rosuvastatin per
day in a period of up to 14 days resulted in an INR > 4 in
two out of the seven patients. Four out of the remaining five patients
experienced an INR > 4 within the next 14 days, when
rosuvastatin dosage was increased to 80 mg.[15] A small study with
12 patients in warfarin treatment described the change in mean
prothrombin time the first 15 days after initiation of atorvastatin
treatment. The mean prothrombin time remained unchanged except for a
small yet statistically significant decrease of 1.6 seconds from day 3-5
after initiation of atorvastatin treatment. However, the decrease was
not considered therapeutically important.[16]