Is there a circannual variation in the anticoagulation control of warfarin?

BACKGROUND: The literature regarding the seasonal variation in the therapeutic response to warfarin is somewhat contradictory, with several discrepancies. We assessed the influence of seasons on various pharmacodynamic indices of warfarin. METHODS: A retrospective study was carried out in adults receiving warfarin for at least 6 months. Details of their demographic characteristics, duration and dose of warfarin therapy and values of prothrombin time international normalised ratio (PT-INR) were retrieved. Standard definitions were followed for defining various seasons, time in therapeutic range (TTR), log-INR variability and warfarin sensitivity index (WSI). National Institute for Health and Care Excellence (NICE) criteria were used for defining TTR into good (≥65%) and poor (<65%) anticoagulation control. RESULTS: Two hundred and four patients were recruited. Only a subtle statistically significant difference was observed between the numbers of patients in the various PT-INR categories. However, no significant intra-individual differences were observed in mean TTR. Similarly, the proportion of patients with poor anticoagulation control, high INR variability and high WSI was not significantly different between summer, transition period 1, winter and transition period 2. CONCLUSION: No clinically significant seasonal variations were observed in the therapeutic response to warfarin.

Supra-therapeutic Anticoagulation with Warfarin: A Cross-sectional Study.

AIMS: To identify the extent and associated factors for patients with prolonged prothrombin time, international normalized ratio (PT-INR), and the dosage modifications were carried out with warfarin. BACKGROUND: Studies evaluating patients on warfarin with supratherapeutic anticoagulation are limited. It is vital to understand the management strategies for patients receiving warfarin who are bleeding and those with only supratherapeutic PT-INR. OBJECTIVE: To evaluate the factors associated with supratherapeutic anticoagulation without bleeding with warfarin. METHODS: A cross-sectional study was carried out on patients receiving long-term warfarin with at least one PT-INR value > 3.2. Percent time in therapeutic range (TTR) was calculated and National Institute for Health and Care Excellence (NICE) guidelines were adhered to defining anticoagulation control into good (> 65%) and poor (< 65%). RESULTS: One hundred and forty-four patients were recruited. Nearly half of the study population had PT-INR values between 3.2 and 3.9. On average, individuals had at least 4 times PT-INR values in the supratherapeutic range. Elderly patients were observed with a significant trend of supratherapeutic INR. Duration of therapy was significantly correlated with the risk of PT-INR > 4. Lower TTR was observed in patients with frequent PT-INR > 4 and those patients had significantly poor anticoagulation control. Duration of warfarin therapy and HAS-BLED scores were observed to be significant predictors of supratherapeutic INR. Large variations were observed in the modifications of warfarin dose carried out at various supratherapeutic INR values and consequently PTINR values. CONCLUSION: We observed that the majority of patients with supratherapeutic INR had their INR values between 3.2 and 3.9. Elderly patients, with higher HAS-BLED scores and prolonged duration of warfarin therapy, were observed with an increased risk of supratherapeutic anticoagulation. Careful dosage modifications are needed particularly in high-risk categories as mentioned above.

Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study.

BACKGROUND: Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability. METHODS: A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA's recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM). RESULTS: The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allele in VKORC1. Groups' II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2. CONCLUSION: The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

Does fasting during Ramadan influence the therapeutic effect of warfarin?

WHAT IS KNOWN AND OBJECTIVES: The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. METHODS: Patients receiving warfarin for at least 1 year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1 month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. RESULTS AND DISCUSSION: One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3 months (pre-Ramadan, Ramadan and post-Ramadan periods). WHAT IS NEW AND CONCLUSION: Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.

Evaluation of pharmacokinetics of warfarin from validated pharmacokinetic-pharmacodynamic model.

Background: Pharmacokinetics of warfarin has not been described in our population. We derived the pharmacokinetic parameters from a validated pharmacokinetic-pharmacodynamic model. Methods: Patients receiving warfarin for at least 6 months were recruited and their demographic characteristics, prothrombin time international normalized ratio (PT-INR), warfarin doses and concomitant drugs were collected. Using a validated pharmacokinetic-pharmacodynamic model, we predicted maximum plasma concentration (C max), total clearance (C L), volume of distribution (V d) and elimination rate (k). Warfarin sensitive index (WSI) and warfarin composite measures (WCM) were estimated from the dose and INR values. Liver weight was predicted using validated formula. Results: Two-hundred and twenty patients were recruited. The following were the predicted pharmacokinetic parameters: C max (mg/L) was 5.8 (0.4); k (L/day) was 1 (0.1); CL (L/day) was 2.1 (0.2); and V d (L) was 7.6 (0.2). Patients with C max and elimination rate outside the mean+1.96 SD had significantly lower WSI and higher WCM. Significant correlations were observed between C max with CL, V d, and k of warfarin. Significant correlations were also observed between CL and V d of warfarin with liver weight of the study participants. Conclusion: We predicted pharmacokinetic parameters of warfarin from the validated pharmacokinetic-pharmacodynamic model in our population. More studies are needed exploring the relationship between various pharmacodynamic indices of warfarin and pharmacokinetic parameters of warfarin.

Evaluation of Stable Doses of Warfarin in a Patient Cohort.

BACKGROUND: Definitions for stable dose of warfarin varies in the reported studies. International warfarin pharmacogenetic consortium (IWPC) algorithm was generated from the data based on these definitions. OBJECTIVE: In the present study, we primarily evaluated whether any significant differences exist between the definitions for stable warfarin dose. METHODS: A prospective cross-sectional study in adults receiving warfarin for at least 3 months was carried out. Stable doses of warfarin as defined in previous studies were compared with the standard definition. Bland-Altman plots, Pearson's correlation and intra-class coefficients (ICC) were used to assess the correlation, reliability and agreements between the doses. RESULTS: Sixty-four patients were recruited. Twenty definitions were obtained from the previous studies. We observed that all but one showed very high or high positive correlations; and either excellent or good ICC. No significant differences between the doses initiated and predicted by IWPC algorithm. CONCLUSION: We observed similar stable doses between the definitions except for one. Hence, IWPC algorithm may not have any bias associated with inclusion of any studies with variable definitions for stable warfarin dose.

Evaluation of inter-patient variability in the pharmacodynamic indices of warfarin.

OBJECTIVES: Warfarin exhibits huge inter-individual variability in therapeutic response. We assessed the extent and the factors affecting inter-individual variability in the anticoagulation control using pre-validated pharmacodynamic indices. METHODS: Patients receiving warfarin for at least 6 months were recruited. CHA2DS2-VASc, HASBLED, SAMe-TT2R2 scores, warfarin sensitive index (WSI), log-INR variability, and warfarin composite measure (WCM) were assessed. National Institute for Health and Care Excellence (NICE) guideline was adhered for assessing the anticoagulation control using time in therapeutic range (TTR) (TTR < 65%-poor; and TTR ≥ 65%-good). Odds ratio [95% confidence interval] was the effect estimate measure. RESULTS: Eighty-seven (39.5%) of the patients were poorly anticoagulated. Those with lower HASBLED [OR: 0.3; 0.1, 0.6] and SAMe-TT2R2 scores [OR: 0.2; 0.04, 0.7] and higher CHA2DS2-VASc score [OR: 1.8; 1.1, 1.3] predicted good anticoagulation control. Thirty-five (15.9%) patients had high INR variability. Lower TTR, shorter duration of therapy, and higher WSI were observed in patients with high INR variability, and presence of drugs with potential interaction significantly predicted high INR variability. CONCLUSION: Significant numbers of our patients on warfarin had poor anticoagulation control and high INR variability. We have identified duration of therapy, CHA2DS2-VASc score, and WSI as reliable predictors for anticoagulation control and INR variability.

The surprise pathology-Primary squamous cell carcinoma of the colon-A case report.

INTRODUCTION: Primary squamous cell carcinomas are rare in the colon. Identified as colonic growths causing obstructive or ulcerative features, they are treated like usual colonic adenocarcinomas until the surprise findings on histopathology. A thorough search for possible primary with colonic metastasis is warranted prior to confirmation of diagnosis. They can coexist with adenocarcinomas and ulcerative colitis. We present this case with intent to add to existing literature the presentation and catastrophic clinical course of the disease in our patient. CLINICAL FINDINGS: The patient presented with obstructive pattern of a colonic growth with rapid weight loss. There was no family history of colonic disease and the patient did not suffer from inflammatory bowel disease. DIAGNOSIS AND THERAPEUTIC INTERVENTION: CT Scan of the abdomen revealed the growth which was infiltrating the abdominal musculature causing micro abscess formation. Colonoscopy was inconclusive as the growth was not passable enough to obtain enough biopsy for pathology. The patient underwent surgery for removal of tumor and the histopathology revealed the squamous cell carcinoma. Through the course of patient's recovery in hospital thorough evaluation was done to identify primary in sites mainly the urogenital tract. The patient was discharged and unfortunately succumbed to her disease at home before definitive treatment could be given. CONCLUSION: Squamous cell carcinomas in the colon warrants extensive search for the primary and coexistent adenocarcinomas or ulcerative colitis. In patients who recover from surgery, chemoradiation directed towards the pathology should be initiated to prevent rapid deterioration as in our case. Its presentation may be exophytic infiltrating surrounding structures and micro abscesses or perforations may also be encountered. We add our case report to the existing literature of primary squamous cell colon carcinoma series.

Health-related quality of life in patients receiving oral anti-coagulants: a cross-sectional study.

OBJECTIVES: Patients receiving long-term anticoagulants were reported with varied health-related quality of life (HrQoL). We assessed HrQoL in patients receiving either warfarin or dabigatran from a tertiary care hospital. METHODS: A cross-sectional study was carried out following consent from patients on oral anticoagulants. Demographics, prothrombin time international normalized ratio (PT-INR), and drug-related details were collected. A validated Arabic version of the perception of anticoagulant treatment questionnaire (PACT-2) was used to assess HrQoL under three dimensions: convenience; burden of disease; and treatment satisfaction. RESULTS: One-hundred and fifty patients were recruited. Overall good quality of life was observed as indicated by the average score of 80.3 in the warfarin group and, moderate in the dabigatran (average score of 68). Highly adherent and elderly patients receiving warfarin were significantly more likely to have good quality of life. Therapeutic PT-INR and high medication adherence were the primary domains significantly associated with good quality of life amongst patients with warfarin. CONCLUSION: We observed good quality of life in patients receiving warfarin particularly those in the categories of elderly, with therapeutic PT-INR and high medication adherence. Small sample size with dabigatran precludes any firm conclusions.

Ventricular arrhythmia and tachycardia-induced cardiomyopathy in Gitelman syndrome, hypokalaemia is not the only culpable.

Gitelman syndrome (GS) is an autosomal recessive tubulopathy recently implicated in cases with ventricular arrhythmias (VAs), the latter being considered linked to electrolytes' imbalance. However, a direct causal relationship is considered to be an oversimplification for a complex molecular dysfunction. Recent work has suggested a degree of microvascular dysfunction in patients with GS that might be attributed as a mechanism of arrhythmia. We report a case of GS presenting with VAs complicated by cardiomyopathy. The high load of premature ventricular contractions that were attributed to the hypokalaemia has masked the presence of the left ventricular (LV) outflow tract tachycardia. Her LV systolic function recovered after successful electrophysiology ablation procedure. Atrioventricular nodal re-entry tachycardia was discovered incidentally during the study and was ablated successfully.

Left circumflex artery injury postmitral valve surgery, single center experience.

The left circumflex (LCX) artery is located close to the mitral valve (MV), making it susceptible to injury during MV surgery. We are reporting our experience in the diagnosis and management of this complication. We retrospectively reviewed our surgical and coronary angiography databases for patients with documented LCX artery injury during MV surgery between January 2000 and December 2016. The complication was associated with MV replacement (9/1313, 0.7%) but not MV repair (0/393, 0.0%). Eight patients (88.9%) were female and the mean age was 40.4 ±â€¯14.2 years. There was roughly similar distribution of left and right dominant coronary circulations (5 and 4 patients, respectively). Eight patients (88.9%) had ischemic changes on electrocardiogram and ventricular arrhythmias were documented on six patients (66.7%). Three patients (33.3%) were treated with percutaneous coronary intervention while six patients (66.7%) required redo surgery to graft the LCX artery. The 30-day mortality was high (33.3%). A high index of suspicion is required to diagnose this injury. At the moment, no consensus is available on the optimal treatment strategy. We propose percutaneous approach as the first option to spare the patients from undergoing open-heart surgery for the second time.

Transcatheter versus surgical valve replacement for a failed pulmonary homograft in the Ross population.

BACKGROUND: Patients who undergo the Ross procedure are at increased risk of pulmonary valve (PV) homograft dysfunction. For those who require reintervention on the homograft, transcatheter PV replacement (tPVR) provides a less invasive therapeutic option than surgical PVR (sPVR). We examined the outcomes following tPVR versus sPVR in a cohort of patients who underwent the Ross procedure. METHODS: We performed a retrospective analysis of Ross patients age ≥14 years who underwent tPVR (n = 47) or sPVR (n = 41) at our institution. The patients' clinical and echocardiographic data were reviewed. RESULTS: Baseline parameters, including demographic data and left ventricular and right ventricular (RV) systolic function, were similar in the 2 groups. The mean follow-up was 56 ± 24 months for the tPVR group and 89 ± 46 months for the sPVR group (P < .001). No procedure-related mortality was noted in either group. At 6-year follow-up, there was no significant between-group difference in event-free survival (tPVR, 79% ± 7% vs sPVR, 91% ± 4%; P = .15) or PV reintervention (tPVR, 26% ± 9% vs sPVR, 8% ± 5%; P = .31). PV-associated infective endocarditis (IE) was significantly more common with tPVR (tPVR, 13% vs sPVR, 0%; P = .04), with an annualized rate of 2.98% per patient-year. In addition, there was a trend toward more valve dysfunction following sPVR (sPVR, 67% ± 8% vs tPVR, 35% ± 8%; P = .08). CONCLUSIONS: In Ross patients who require reintervention on the PV homograft, both tPVR and sPVR provide low procedural mortality and comparable midterm outcome with no significant difference in mortality or PV reintervention. However, IE is more common following tPVR. A larger randomized study is needed to determine the role of each procedure in patient management.

Peripartum cardiomyopathy, what if your patient plans to reconceive?

Patients with peripartum cardiomyopathy (PPCM) often express a desire to conceive again, and the risk of relapse in future pregnancies should be disclosed. No consensus is available that can determine that risk. Adequate contractile reserve, evidenced by a stress echocardiogram (exercise or dobutamine), can identify those with lower relapse risk.

Tricuspid stenosis: An emerging disease in cardiac implantable electronic devices era. Case report and literature review.

Tricuspid valve dysfunction and in particular tricuspid stenosis has recently been described secondary to cardiac implantable electronic devices. The valve is subjected to different mechanisms of injury related to the endocardial lead passing through its plane. The lead can form a loop or perforate one of the leaflets and initiate inflammatory response and fibrotic changes. Multimodality cardiac imaging is required to diagnose this clinical entity and decide on the best treatment plan. Here we present a case of a young female who developed tricuspid stenosis secondary to permanent pacemaker lead that was implanted 24 years before. We performed a review for all cases reported in the literature with a similar condition and various treatment approaches. .

The Echocardiographic "Spike and Dome"--Obstruction It Is But Where?

Spectral Doppler interrogation of the descending thoracic and abdominal aorta provides valuable information regarding cardiac and vascular hemodynamics. An abnormal aortic Doppler profile is encountered in pathological conditions that affect the aorta and its branches, the aortic valve, the left ventricle, and the pericardium. Characteristic findings on Doppler interrogation of the aorta are often noted in individuals with obstructive atherosclerotic disease of the aorto-iliac system including severe stenosis or occlusion of the distal aorta and/or iliac arteries. In this manuscript, we highlight the findings on spectral Doppler that led to the identification of occlusive disease in the distal aorta.

Spectral Doppler of the Hepatic Veins in Rate, Rhythm, and Conduction Disorders.

Doppler interrogation of blood flow in the hepatic veins (HVs) provides valuable information regarding a wide spectrum of pathological processes that affect the right heart. Systematic analysis of the direction, velocity, and phasicity of the HV waveforms allows one to distinguish normal from abnormal patterns and provides important diagnostic information. Abnormalities in heart rate, rhythm, and intracardiac conduction are commonly encountered during echocardiographic studies. Sinus bradycardia and tachycardia, bradyarrhythmias and tachyarrhythmias as well as atrioventricular conduction disturbances influence the flow pattern in the HVs and may pose a challenge to the correct interpretation of the HV Doppler. Alterations in HV flow that are induced by the electrical abnormalities may mimic right heart pathology. Awareness of these alterations allows one to avoid misinterpretation of the HV signal, helps diagnose the underlying rhythm or conduction abnormality, and permits assessment of the impact on right heart hemodynamics.

Progressive coronary aneurysms in Behçet disease, a journey through surgical and percutaneous treatment: A case report.

Behçet disease is a systemic autoimmune disease that causes inflammation within the vascular tree. Coronary arteries are rarely involved with stenosis, arteritis or aneurysm formation. Treatment is mainly directed to reduce the burden of inflammation systemically with steroid and immunosuppressive medications. However, patients might present in critical conditions requiring interventions in the form of percutaneous therapy or surgical bypass grafting. We present the case of a 34-year-old male who presented with acute coronary insult and was later found to have Behçet disease. His course was aggressive, as he required bypass graft surgery for rupture coronary aneurysm and cardiac tamponade. Later on, he required percutaneous intervention with cover stents for multiple coronary aneurysms that he developed afterward despite being on medical therapy. .

Spectral Doppler of the Hepatic Veins in Noncardiac Diseases: What the Echocardiographer Should Know.

In most instances, the flow profile in the hepatic veins (HVs) reflects the fluctuation of pressure within the right atrium. Thus, interrogation of blood flow in the HVs is highly useful for the evaluation of right heart hemodynamics and has become an integral part of any routine echocardiographic examination. However, flow in the HVs is also affected by the state of the liver parenchyma and by the fluctuation of pressure within the thoracic cavity. Therefore, liver and pulmonary pathologies influence the flow pattern in the HVs and may lead to its dissociation from right heart hemodynamics. Echocardiographers should familiarize themselves with the findings on HV Doppler in noncardiac diseases to avoid misinterpretation and incorrect diagnosis.

The various hemodynamic profiles of the patent ductus arteriosus in adults.

The patent ductus arteriosus (PDA) has diverse clinical and hemodynamic manifestations depending on its size and the degree of the ensuing left-to-right shunt. A small PDA that causes minor shunting has no major hemodynamic consequences. Conversely, a large PDA with a significant left-to-right shunt may lead to various hemodynamic abnormalities. These include left-sided volume overload that may result in heart failure and/or pulmonary hypertension, the latter being a flow-dependent and mostly reversible phenomenon. The most feared complication is the development of severe and irreversible pulmonary hypertension (Eisenmenger physiology). In this manuscript, we provide examples of the various hemodynamic profiles of PDA as assessed by echocardiography in the adult population.