Discussion
This systematic review identified eight studies exploring the effect of
statin initiation on the degree of anticoagulation in VKA users.
Overall, initiation of simvastatin treatment in warfarin users lead to a
slight increase in mean INR ranging from 0.15-0.65, which seemingly
peaks about 4 weeks after initiation.[13, 14],[19] For the other
studied statins (atorvastatin, pravastatin, rosuvastatin, and
fluvastatin) the same tendency of slightly increased anticoagulation was
also present, described as INR increases, reduced doses of VKA and
increased risk of hospitalization with GI bleeding.
The primary strength of our study is the multiple broad systematic
search strategies designed to include original data. All literature was
assessed by two persons, ensuring validity of the literature selection.
While all the included studies concerned patients in VKA treatment
initiating treatment with statins, the studies showed considerable
heterogeneity, with regard to type of statin and statin dose.
Furthermore, the included studies concerned patients in VKA treatment
with warfarin, phenprocomarol and acenocoumarol treatment. Finally, the
patient population in the included studies also differed. While most
studies excluded patients taking other medication that could interact
with VKA and coagulation,[13,14],[16-19] two studies did not
report whether these patients were excluded or not.[15, 20] In the
two included clinical trials, treatment with rosuvastatin and
atorvastatin was initiated in patients without any clinical indication
requiring cholesterol lowering therapy.[15, 16] It is possible that
the pharmacological response to statins and the interaction with VKA in
patients with normal cholesterol levels differs from patients with
elevated cholesterol levels. Further, for some studies, the lack of
information regarding the type of statin[20] and the possible use of
statins in the control group[18] result in difficulties, when
interpreting the findings of the studies. Among the six studies where
outcome was change in INR/PTT,[20] only half provided any analytical
characterization of the INR/PTT tests used in the studies.[15, 16,
19] This missing laboratory information might explain at least in part
the differences in the observed increases in INR.[21] Due to the
heterogeneity of the studies, a direct comparison by meta-analysis was
not considered feasible.
The pharmacological mechanism of the potential interaction between VKA
and statins is to our knowledge not fully described. In vitro data
suggests that statins have the potential to enhance the pharmacological
activity of warfarin by competitively inhibiting its CYP-dependent
metabolism.[14] However, considering the substantial delay in the
drug-drug interaction (~four weeks) and the unspecific
effect of several statins on warfarin effectiveness, this drug-drug
interaction might not be mediated through cytochrome P450 inhibition,
which would be expected to lead to a faster onset of INR increase, as
e.g. seen for azole antifungals.[22] An alternative explanation for
the observed associations could be related to the effect of changes in
cholesterol levels on warfarin metabolism. Cholesterol levels stabilize
about four weeks after initiation of statins [23, 24] coinciding
with the maximum impact of statin initiation on INR among patients
treated with VKA. However, further data is required to support this
hypothesis.