Anticoagulation control with daily low-dose vitamin k to reduce clinically adverse outcomes and international normalized ratio variability: a systematic review and meta-analysis.

STUDY OBJECTIVES: Difficulties managing warfarin therapy have led to speculation that daily supplementation with a low dose of vitamin K might improve anticoagulation control and clinical outcomes. Thus we sought to review the available medical literature systematically examining the effectiveness of low-dose vitamin K supplementation for the reduction of clinically relevant adverse events due to vitamin K antagonist (VKA) use and for stabilization of the international normalized ratio (INR). DESIGN: We searched the Medline and Embase databases, the Cochrane Library, International Pharmaceutical Abstracts, and the U.S. National Institutes of Health clinical trials registry for randomized controlled trials of vitamin K supplementation versus placebo in patients receiving a VKA. We evaluated the outcomes of hemorrhage, thromboembolic events, and percentage of time in therapeutic range (TTR) of INRs by using the Grading of Recommendations Assessment, Development and Evaluation system for rating quality of evidence in the abstracted studies. SETTING: All randomized controlled trials studies published between 1970 and August 2012 which fitted our search strategy. PATIENTS: Patients over the age of 18 years on VKA therapy. RESULTS: Of the 624 studies we identified and screened, three studies (626 patients) were included in the meta-analysis. Most of the patients had a satisfactory TTR at baseline. We found low-quality evidence--downgraded for imprecision and risk of bias (i.e., limitation in study design and/or execution)--of no effect of vitamin K use (100 to 200 µg) on hemorrhagic events (relative risk [RR] 3.2, 95% confidence interval [CI] 0.2-64.2) and thromboembolic events (RR 2.2, 95% CI 0.1-47.5) and a significant but clinically unimportant effect on TTR with an absolute increase of 3.5% (95% CI 1.1-6.0). CONCLUSION: This meta-analysis, despite the few studies and overall low quality, suggests no beneficial role of low-dose (100 to 200 µg) vitamin K supplementation on the reduction of clinically relevant adverse events in patients taking VKAs, despite a small improvement of the TTR. Data were insufficient, however, from patients with unstable INRs.

Should vitamin K antagonist therapy be started simultaneously with parenteral anticoagulation: a meta-analysis?

For patients with an acute episode of venous thromboembolism (VTE), the optimal starting time of long-term therapy with vitamin K antagonists (VKA) and how much overlap should occur with heparin are unclear and the current guidelines and practice are not based on high-quality data. The objective of this study was to perform a meta-analysis on the evidence comparing early versus late initiation of VKA on the effectiveness and safety of anticoagulation. We searched for randomized controlled trials in Medline, EMBASE, Cochrane CENTRAL, IPA and ClinicalTrials.gov. Studies were included if they compared early initiation of VKA (within approximately 24 h) and late initiation (>4 days) of the onset of heparin therapy. Data were pooled using the Review Manager 5 software and the quality of evidence was appraised with Grading of Recommendations, Assessment, Development and Evaluation profiler. Five studies were included in the review, with a total of 840 patients. Meta-analysis of recurrence of VTE, death and major bleeding revealed no significant differences between the two treatment regimens. Minor bleeding [RR 0.65, 95% confidence interval (CI) 0.43-0.98] and hospital stay (mean difference 3.92 days, 95% CI -4.57 to -3.28) were reduced in the early VKA group (P < 0.05). The quality of evidence for each outcome except hospital stay was low. Results from this meta-analysis favour the early start of VKA (within 24 h of the initiation of heparin) based on minor bleeding and resource utilization. However, these results should be interpreted with caution, as the quality and quantity of evidence is limited.

Sodium-calcium exchange mediated contraction in left anterior descending and left ventricular branch arteries.

We tested the hypothesis that the de-endothelialized artery rings from the left anterior descending (LAD) coronary artery and its left ventricular branch (LVB) differ in their contractile responses to Na(+)-Ca(2+)-exchanger (NCX) mediated Ca(2+)-entry, muscarinic receptor activation with carbachol, and sarco/endoplasmic reticulum Ca(2+) pump (SERCA) inhibition with thapsigargin. In LVB, the force of contraction (in N/g tissue) produced by the NCX mediated Ca(2+)-entry (17.5 +/- 1.4) and carbachol (18 +/- 1.5) was only slightly smaller than that due to membrane depolarization with KCl (24.0 +/- 1.0). In contrast, in LAD the force of contraction produced with NCX (8.7 +/- 0.7) and carbachol (6.1 +/- 1.1) was much smaller than with KCl (15.7 +/- 0.7). Thapsigargin also contracted LVB with greater force than LAD. When isolated microsomes were used, the binding to the muscarinic receptor antagonist quinuclidinyl benzilate was greater in LVB than in LAD. Microsomes were also used for Western blots. The intensities of signals for both SERCA and NCX were greater in LVB than in LAD. These biochemical observations were consistent with the contractile experiments. Thus, it appears that the differences between LAD and the resistance arteries may begin as early as LVB.