Practice Update: Cardiology

EDITOR’S PICKS 11

Warfarin Use Is Associated With Progressive Coronary Arterial Calcification JACC: Cardiovascular Imaging

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. www.practiceupdate.com/c/56095

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

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).

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,

COMMENT By James E Tisdale PharmD, BCPS, FCCP, FAPhA, FAHA W arfarin 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.

VOL. 2 • NO. 2 • 2017