Introduction: Anticoagulation with vitamin K antagonists (VKA) requires monitoring of their effect, traditionally with the prothrombin time (PT) that is affected by VKA influence on coagulation ...factors (F) II, VII and X. Rapid fluctuations in factor VII, which has a short half-life, contribute to the PT (INR) variation but not to the antithrombotic effect that depends mainly on reductions of FII and FX. This was lately confirmed by the Fiix-trial that showed that monitoring warfarin with Fiix-PT (affected only by FII and FX) improved anticoagulation stability. Here, we assessed anticoagulation variability in relation to the occurrence of thromboembolism and bleeding in patients monitored with Fiix-PT or PT.
Methods and materials: This is a subgroup analysis of the Fiix-trial, a single-center, double blind, prospective, randomized controlled clinical trial, comparing outcomes in patients in whom warfarin was monitored with either Fiix-PT/Fiix-INR (Fiix-warfarin patients) or PT/INR (PT-warfarin patients). Patients on warfarin, 18 years and older, with target INR range of 2.0 - 3.0, were randomized and assessed for occurrence of clinically relevant vascular events (CRVE), i.e. thromboembolism (TE), major bleedings (MB) and other non-major clinically relevant bleedings. Using an intention-to-monitor method, we assessed test parameters, dosing, time in range (TTR) and the variance growth rate (VGR) of the INR (an INR fluctuation index) in relation to occurrence of CRVE.
Results: The median observation time was 1.4 years in 572 patients managed with Fiix-warfarin and 571 with PT-warfarin. CRVE occurred in 115 Fiix-warfarin patients and 132 PT-warfarin patients (PNI=0.0066). MB and TE occurred in 19 vs. 21 (PNI=0.0142) and 10 vs. 19 (PNI=0.0002) patients, respectively. There were 11,026 monitoring tests in the Fiix-arm and 11,499 in the PT-arm. Patients suffering CRVE had significantly more frequent monitoring tests and shorter intervals between tests than those without. Patients with CRVE also had significantly greater dose changes (p<0.0001 in both arms). The median TTR was lower with PT-warfarin than with Fiix-warfarin and patients with CRVE had lower TTR than those without in both study arms (Fiix-warfarin 79% vs. 82%, p=0.0441 vs. PT-warfarin 75% vs. 80%, p=0.0004). The lowest median TTR was observed in PT-warfarin patients suffering from MB (73%) or TE (62%). There was consistently more INR-fluctuation (higher VGR, here shown by B1 method measuring INR jumps from one test to the next) with PT-warfarin than with Fiix-warfarin. Also, patients with CRVE had VGR of 0.35 vs. 0.21 (p=0.0643) and without CRVE 0.21 vs. 0.17 (p=0.0146), respectively. The fluctuation was particularly high in both PT-warfarin and Fiix-warfarin patients suffering from MB (0.59 and 0.31, n.s.). PT-warfarin patients with TE had VGR 0.50 vs. 0.20 with Fiix-warfarin (p=0.0051). Finally, the median INR observed at the time of major events corresponded to the risk of bleeding and TE in the Fiix arm, and with risk of TE in the PT arm.
Conclusions: Fiix-warfarin is a more stable anticoagulant than PT-warfarin. The significantly lower INR variation in Fiix-warfarin patients with TE is in agreement with the reduced long-term thromboembolism observed in the Fiix-trial. Monitoring warfarin with the Fiix-PT (Fiix-INR) instead of the PT (INR) and paying particular attention to patients demonstrating anticoagulation instability could improve the clinical outcome of patients on warfarin further.
Gudmundsdottir:Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.
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Introduction: Experiments suggest that the anticoagulation effect of warfarin is mainly influenced by a reduction in coagulation factor (F) II and X activity and that FVII may have relatively ...little effect. Due to the short half-life of FVII but its strong influence on the prothrombin time (PT), monitoring warfarin using PT may therefore confound warfarin dosing. The Fiix-prothrombin time is specially designed to circumvent measuring FVII activity and is only sensitive to the activity of FII and FX in the sample. The Fiix-trial was a single center randomized prospective and blinded non-inferiority clinical trial that examined monitoring warfarin with the Fiix-PT compared to the PT.
Methods: All community dwelling patients 18 years and older with an INR target of 2-3 managed by our center´s anticoagulation management service were eligible for participation. A PT ratio adapted for thromboplastin sensitivity (INR) was calculated for both tests and results were reported by the laboratory as R-INR (“research INR”) to the dosing staff that was blinded to each patient´s test method. Warfarin dosing was software assisted using the DAWN anticoagulation software. Protocols designed for monitoring with PT were used, including a recommended maximum six week interval between tests. The major efficacy endpoint was fatal and non-fatal thromboembolism (TE) rate and the major safety endpoint was major bleeding per patient year (ppy). Surrogate efficacy parameters included number of tests, tests in range, time within target range 2-3 (TTR), monitoring test interval and dose adjustment rate.
Results: After exclusion of 4 patients in each group, 573 patients were evaluable in the Fiix-PT arm and 575 in the control arm. About 69% had atrial fibrillation (AF) and 21% had venous thromboembolism (TE). The median monitoring time was 1.7 (IQR 1.1-1.9) years per patient in both study arms. The TE rate was similar in the first six months but thereafter the event curves diverged (Figure 1) and therefore we specially examined events occuring after six months in a secondary analysis. In the primary analysis of events during days 1-720, the TE rate ppy was 1.2% in the Fiix-arm vs 2.3% in controls (-48%, p = 0.09) demonstrating at least non-inferiority of Fiix-PT monitoring compared to the PT in reducing TE. The major bleeding rate did not differ; 2.2% and 2.5%, respectively (p = n.s., non-inferior). In the secondary analysis, after excluding the first six observation months, the Fiix-PT lead to a superior long-term reduction in TE (1.1% vs 2.2% annual rate, -50%, p = 0.03) with major bleeding rate of 1.5% vs 2.3% respectively (p = 0.8). A subanalysis of patients with AF yielded similar results. The intracranial hemorrhage (ICH)/intracerebral hemorrhage rate was 0.26%/0.13% ppy in the Fiix-arm and 0.64%/0.38% ppy in the PT-arm. In the first six months the test volume was the same in both arms but therafter a 5.8% reduction occurred in the Fiix-arm. The dose adjustment rate was reduced 12% overall and 18% during long term monitoring (4.1 vs 5.0 ppy, p = 0.01). At six month intervals, the median percent TTR was 84.9 (79.9-86.7) in the Fiix-arm vs 80.3 (78.5-81.3%) in the PT-arm.
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Conclusion: Monitoring warfarin with Fiix-PT is non-inferior and possibly superior to the PT in reducing long-term recurrent TE. Bleeding is not increased despite omitting FVII activity in the monitoring test. With the Fiix-PT, the warfarin effect fluctuates less than with standard PT as manifested by a higher TTR and reduced dose-adjustment need. Overall, the results suggest that the fluctuation typically observed during warfarin treatment is partly caused by the traditional prothrombin time itself.
Onundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Gudmundsdottir:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.
Objective. In this study we tested the hypothesis that α-2 adrenergic antagonism could facilitate induction of previously non-inducible ventricular tachycardia (VT) during acute ischemia. Previous ...reports suggest that VT during ischemia may be modulated by α-2 adrenergic agonists. Design. The left anterior descending artery was occluded after instrumentation of the ischemic risk zone with 21 multipolar plunge needles, each recording 6 bipolar electrograms. Three dimensional mapping characterized the mechanism of VT induced with extrastimuli. Results. Of 16 non-inducible dogs included, eight which were given the α-2 adrenergic antagonist yohimbine all had inducible VT, while all eight in the control group remained non-inducible (p <0.05). Six of the VTs were of focal Purkinje origin. The cycle length of the VT was 119±4 ms. Mean arterial pressure (81±8 to 82±8 mmHg, p =ns), ventricular effective refractory period (146±6 to 144±5 ms, p =ns) and ischemic zone size (55±6% vs. 61±4%, p =0.45) were not altered by yohimbine indicating minimal central or pre-junctional effects of the drug. Conclusions. Yohimbine facilitates induction of VT, especially those with focal Purkinje fiber origin, suggestive of an effect mediated through antagonism of post-junctional α-2 adrenoceptors on Purkinje fibers.
Indications for implantable cardioverter defibrillator (ICD) implantation have expanded considerably in recent years, resulting in steadily growing numbers of ICD recipients worldwide. The aim of ...this study was to review the overall experience with ICDs in Iceland.
This was a retrospective single centre study set at the University Hospital in Iceland. Data on all ICD implantations in Iceland from the first implantation in 1992 till the end of 2002 was reviewed.
Sixty-two patients (71% male) received an ICD during this period. There was an increase in the number of implants by year and the number of new implants in 2001 and 2002 amounted to 56 and 38 per million, respectively. The mean age at implantation was 58 (+/-14) years. Forty patients (65%) had coronary artery disease. The most common indications for ICD implantation were cardiac arrest, 32 (52%) and another 26 (42%) had experienced ventricular tachycardia without cardiac arrest. The most common adverse event was inappropriate shocks. Twenty-eight patients (45%) received therapy from their ICDs, with the majority receiving appropriate therapy. Of the thirteen patients deceased before or during the study period, no case of sudden arrhythmic death was observed.
This study shows that the experience with ICDs in Iceland is in most respects similar to other Western countries.
Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We ...performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in
, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in
results in exon skipping. We also observe an association with a missense variant in
(OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
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