Practice Update: Cardiology

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Warfarin Use Is Associated With Progressive
Coronary Arterial Calcification
JACC: Cardiovascular Imaging
Take-home message
• The authors of this post hoc analysis sought to determine the effect of warfarin use
on coronary percent atheroma volume (PAV) and calcium index (CaI). Using data
from 8 prospective studies, 171 patients treated with warfarin were compared with
4129 not treated with warfarin. Researchers found no difference in PAV between
individuals treated with warfarin compared with individuals not treated with warfarin.
However, individuals treated with warfarin had a significantly higher annualized CaI
increase than counterparts not receiving warfarin.
• The researchers concludes that warfarin use is associated with a significantly
greater annualized increase in the coronary calcium index. The clinical significance
of this finding is unknown, and further investigation is required to assess whether
this finding influences cardiovascular outcomes.
Abstract
OBJECTIVES This study compared serial changes
in coronary percent atheroma volume (PAV)
and calcium index (CaI) in patients with coro-
nary artery disease who were treated with and
without warfarin.
BACKGROUND Warfarin blocks the synthesis and
activity of matrix Gla protein, a vitamin K-de-
pendent inhibitor of arterial calcification. The
longitudinal impact of warfarin on serial coronary
artery calcification in vivo in humans is unknown.
METHODS In a post hoc patient-level analysis
of 8 prospective randomized trials using serial
coronary intravascular ultrasound examinations,
this study compared changes in PAV and CaI in
matched arterial segments in patients with cor-
onary artery disease who were treated with (n
= 171) and without (n = 4,129) warfarin during an
18- to 24-month period.
RESULTS Patients (mean age 57.9 ± 9.2 years; male
73%; prior and concomitant 3-hydroxy-3-methyl-
glutaryl coenzyme A reductase inhibitors (statin)
use, 73% and 97%, respectively) demonstrated
overall increases in PAV of 0.41 ± 0.07% (p =
0.001 compared with baseline) and in CaI
(median) of 0.04 (interquartile range [IQR]:
0.00 to 0.11; p < 0.001 compared with baseline).
Following propensity-weighted adjustment for
clinical trial and a range of clinical, ultrasonic,
and laboratory parameters, there was no signifi-
cant difference in the annualized change in PAV
in the presence and absence of warfarin treat-
ment (0.33 ± 0.05% vs. 0.25 ± 0.05%; p = 0.17). A
significantly greater annualized increase in CaI
was observed in warfarin-treated compared with
non-warfarin-treated patients (median 0.03; IQR:
0.0 to 0.08 vs. median 0.02; IQR: 0.0 to 0.06;
p < 0.001). In a sensitivity analysis evaluating a
1:1 matched cohort (n = 164 per group), signifi-
cantly greater annualized changes in CaI were
also observed in warfarin-treated compared with
non-warfarin-treated patients. In a multivariate
model, warfarin was independently associated
with an increasing CaI (odds ratio: 1.16; 95% con-
fidence interval: 1.05 to 1.28; p = 0.003).
CONCLUSIONS Warfarin therapy is associated with
progressive coronary atheroma calcification
independent of changes in atheroma volume.
The impact of these changes on plaque stabil-
ity and cardiovascular outcomes requires further
investigation.
Warfarin use is associated with progressive
coronary arterial calcification: insights from
serial intravascular ultrasound. JACC Cardio-
vasc Imaging 2017 Jul 13;[EPub Ahead of Print],
J Andrews, PJ Psaltis, O Bayturan, et al.
COMMENT
By James E Tisdale PharmD, BCPS, FCCP, FAPhA, FAHA
Warfarin has been used for decades as an oral anticoagu-
lant agent, exerting its effects via inhibition of synthesis
of vitamin K-dependent clotting factors. Warfarin also
inhibits synthesis and activity of matrix G1a protein (MGP), a
vitamin K-dependent protein synthesized by vascular smooth
muscle. MGP inhibits metabolism of coronary artery calcium, and
absence of MGP promotes medial calcification in experimental
models and correlates with arterial calcification in humans.
In this paper, Andrews et al hypothesized that changes in cor-
onary calcium are greater in patients taking warfarin than in
patients not treated with this anticoagulant. The investigators
analyzed eight prospective randomized trials that used serial
coronary intravascular ultrasound, and compared changes in
coronary percent atheroma volume (PAV) and calcium index
(CaI) in patients with coronary disease who were receiving war-
farin (n = 171) vs those who were not (n = 4129). After performing
propensity-weighted adjustment for clinical trial and clinical, ultra-
sound, and laboratory parameters, the investigators report the
novel finding that, although there was no significant influence of
warfarin on annualized change in PAV, significantly greater annu-
alized changes in CaI were found in warfarin-treated patients,
and warfarin was independently associated with increasing
CaI. Therefore, there was no warfarin-associated progression
in atheroma volume despite significantly greater warfarin-asso-
ciated coronary calcification.
The clinical impact of these findings remains uncertain. Although
increasing coronary artery calcification has been associated
with cardiovascular events, plaque calcification may also repre-
sent a more stable atheroma type that may be less susceptible
to plaque rupture and less likely to progress. Therefore, the
impact of warfarin-associated increased coronary calcification
with no change in atheroma volume on clinical coronary events
and overall patient outcomes requires further study. In addition,
the influence of genetic polymorphisms of vitamin K epoxide
reductase complex 1 (VKORC1, the primary target of warfarin) and
cytochrome P450 2C9 (the primary enzyme responsible for war-
farin metabolism) on the degree of warfarin-induced coronary
artery calcification and associated clinical outcome remains to
be studied. Overall, the findings of this paper are novel and set
the stage for a series of further investigations.
Dr Tisdale is Professor, College of Pharmacy, Purdue
University; Adjunct Professor, School of Medicine,
Indiana University, Indianapolis, Indiana.
EDITOR’S PICKS 11
VOL. 2 • NO. 2 • 2017