Assessment of determining factors for severity of NeoCOVIDiabetes in India: A pan India multicentric retrospective study.

BACKGROUND AND AIMS: There is a bidirectional relationship between COVID-19 and diabetes. The primary objective of this study was to estimate the prevalence of patients newly detected to have diabetes (NDD) who recovered from COVID-19 in India whilst comparing NDD with patients without diabetes (ND) and those who have known to have diabetes (KD) in terms of glycemic status pre- and post-COVID with disease severity. MATERIALS & METHODOLOGY: There were 2212 participants enrolled from 15 sites, with 1630 active participants after the respective execution of selection criteria. Data collection was done using a specialized Case Record Form (CRF). Planned statistical analysis and descriptive statistics were concluded for significance between patient groups on various parameters. RESULT: The differences in age between the study groups were statistically significant. The average blood glucose at COVID-19 onset was significantly higher in KD than in NDD. Significantly more proportion of NDD (83%) had been hospitalized for COVID management when compared to KD (45%) and ND (55%). The NDD group received higher doses of steroids than the other two groups. On average, patients in the NDD group who received at least one vaccination (one dose or two doses) had a higher High-Resolution Computed Tomography (HRCT) score. Patients who had not been vaccinated in ND and KD groups experienced a higher HRCT score. CONCLUSION: Prospective metabolism studies in post-acute COVID-19 will be required to understand the etiology, prognosis, and treatment opportunities.

Efficacy and Safety of Pregabalin Prolonged Release-Etoricoxib Combination Compared to Etoricoxib for Chronic Low Back Pain: Phase 3, Randomized Study.

INTRODUCTION: Currently available treatments for chronic lower back pain (CLBP) do not adequately address both nociceptive and neuropathic components of pain. We evaluated efficacy and safety of fixed-dose combination (FDC) of low-dose pregabalin prolonged release 75 mg-etoricoxib 60 mg to address both pain components. METHODS: This randomized phase 3 trial conducted at 12 centres across India evaluated efficacy (based on mean change in numeric rating scale [NRS], Roland-Morris disability questionnaire [RDQ], visual analogue scale [VAS], patient global impression of improvement [PGI-I], clinical global impression of improvement [CGI-I] and rescue medication consumption) and safety of FDC in comparison to etoricoxib alone in adult patients with CLBP. Treatment duration was 8 weeks. RESULTS: Of the 371 patients screened, 319 were randomized and considered for efficacy and safety analysis. Both treatment groups had no significant difference in terms of demography and baseline disease characteristics. Significantly better outcomes with FDC compared to etoricoxib were observed at week 4 onwards. At week 8, both groups showed significant reduction in mean NRS score from baseline (- 4.00 ± 1.65 in FDC; - 2.92 ± 1.59 in etoricoxib) with mean NRS score being significantly less in the FDC group compared to etoricoxib group (3.26 ± 1.56 vs 4.31 ± 1.56; p < 0.0001). The FDC was more effective than etoricoxib in terms of significantly greater reduction in RDQ score (- 9.28 ± 4.48 vs - 6.78 ± 4.34; p < 0.0001) and VAS score (- 37.66 ± 18.7 vs - 28.50 ± 16.31; p < 0.0001) at week 8. The FDC was also better in terms of significantly more patients reporting their condition as 'very much better' (36.9% vs 5.0%; p < 0.0001) and clinicians reporting patient's condition as 'very much improved' (36.3% vs 5.7%; p < 0.0001). Overall, study medications were well tolerated. CONCLUSION: FDC of pregabalin and etoricoxib provided significant benefits in reducing pain and improving functional status compared with etoricoxib alone in patients with CLBP. Pregabalin prolonged release-etoricoxib FDC could be one of the treatment options for early and sustained pain relief and improvement in quality-of-life in treating CLBP as it addresses both neuropathic and nociceptive components of pain. TRIAL REGISTRATION: CTRI/2018/10/015886.

Low back pain is one of the most common causes of loss of productivity worldwide. About 60% of Indians suffer from low back pain at some point. Low back pain that persists for more than 3 months is classified as chronic low back pain which mostly includes both nociceptive and neuropathic components. Monotherapies, if prescribed, are not completely effective, as they generally only target either nociceptive or neuropathic components of pain. Multiple drugs are usually needed at multiple times a day, at higher doses for optimal effectiveness, and in most cases they have significant side effects if taken over prolonged periods and also add to the pill burden. To minimize treatment-associated adverse effects, and to increase treatment compliance, while addressing both the components of pain, we developed a fixed-dose combination of low-dose pregabalin prolonged release and etoricoxib. A phase 3 trial was designed to assess the efficacy and safety of the fixed-dose combination in comparison with etoricoxib alone in treating chronic low back pain. The combination demonstrated statistically and clinically significant improvement in patient-reported outcomes­pain, functionality and quality of life­as early as 4 weeks after starting the medication. No severe or serious adverse effects were reported. Thus, the combination of low-dose pregabalin prolonged release and etoricoxib could provide an option for optimal management of chronic low back pain. This would provide multiple benefits, such as addressing both nociceptive and neuropathic components of chronic low back pain, reducing drug-related adverse effects because of low dose, reducing pill burden and thereby increasing drug compliance.

A Study to Evaluate the Thyroid Function in Sero Positive Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a most common progressive, multi-systemic autoimmune disease characterized by chronic inflammation of multiple joints with associated systemic manifestations. RA has an estimated prevalence of 0.5 -1% of the adult population worldwide and is a leading cause of chronic morbidity and mortality in the industrialized world.A systematic analysis with RA showed 76% had one or more extra-articular feature. Thyroid hormone dysfunction and /or autoimmune thyroid disease were present in 6% to 33% patients with Rheumatoid Arthritis. MATERIAL: We conducted a hospital based observational, descriptive study from July 2018 until the number of sample are met. SAMPLE SIZE: 260 RA patients who are attendind OPD & IPD, that meet inclusion and exclusion criteria. OBSERVATION: The present study included the patients ranging from 15 years to above 65 years. It was observed that maximum cases were in the age group of 35-45 years (37.31%). The mean age of the study participants was 40.80±10.91years. In the present study we found that rheumatoid arthritis was more common in females 212 (81.54%) than the male cases 48(18.46%). In the present study we found that thyroid dysfunction is observed in 20% of patients. The most common thyroid dysfunction observed was overt hypothyroidism seen in 10.77% of the patients followed by subclinical hypothyroidism seen in 8.46% and subclinical hyperthyroidism 0.77% of patients. Anti-TPO antibodies were seen in 82.14% of patients with clinically overt hypothyroidism. CONCLUSION: Majority of the cases of rheumatoid arthritis are in the age group of 40.80 ±10.91 years and females account for the majority of the cases of rheumatoid arthritis. In our study thyroid dysfunction are observed in 20% of patients. Prevalence of thyroid dysfunctions in rheumatoid arthritis is high and associated with thyroid autoimmunity and suggested that all rheumatoid arthritis patients should go for thyroid functions.

Study Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio in Patient with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with synovial joint inflammation; that culminates in progressive damage of the joint, especially with persistent inflammation. The neutrophils, lymphocytes, and platelets which are an important part of the immune system have a role in the control of inflammation, while also changing secondary to inflammation. Platelets have a significant role in inflammation and immune-modulation postulated by the presence of crosstalk between markers of coagulation and the inflammatory system. MATERIAL: This was a Hospital-based, cross-sectional and comparative study. The study was conducted at SMS Medical College and Hospital (Department of Medicine), Jaipur, Rajasthan, India. OBSERVATION: Most of the RA Cases were females (63.3%), while only 11 cases (36.7%) were males. Gender matched controls were selected, thus there were more females (63.3%), and 11 (36.7%) were males. The mean neutrophil percentage was higher among RA cases (66.23 ± 10.86%) as compared to controls (52.6 ± 7.23%). CONCLUSION: The mean P: L ratio was higher among RA cases (184.88 ± 52.31) as compared to controls (115.56 ± 35.67). This difference in the P: L ratio among RA cases and controls was found to be statistically significant (p<0.001). The N: L ratio was higher among RA cases with active disease (3.31 ± 1.29) as compared to RA cases with remission (2.15 ± 0.74). This difference in N: L ratio concerning disease activity among RA cases were found to be statistically significant (p=0.007).

A Study of Procalcitonin as an Early Predictor of Severity in Acute Pancreatitis.

Acute Pancreatitis is an acute inflammation of the pancreas.Acute pancreatitis is an acute inflammatory process ranging clinically from mild discomfort with localized inflammation to severe disease involving remote organ systems. There is a continuum from the development of systemic inflammatory response syndrom, to the onset of multiple organ dysfunction (MODS), which is seen in about 24% of patients with acute pancreatitis and carries the highest mortality rate of 36%, and imaging tests showing characteristic findings of acute pancreatitis. Several inflammatory markers are being used routinely in various hospitals in India to assess the prognosis of patients with acute pancreatitis. Among these are the total and differential leukocyte counts, erythrocyte sedimentation rate, and C-reactive protein (CRP), interleukin-6, thioredoxin-1, and polymorphonuclear elastase. serum procalcitonin is one of the components to assess the severity of pancreatitis. Procalcitonin is an acute phase reactant that has been extensively investigated as early marker in systemic bacterial infection, sepsis, and multi organ failure. Because severe acute pancreatitis is associated with sepsis, infected pancreatic necrosis, and multi organ failure. Procalcitonin can be used as a useful marker in early prediction of severity. MATERIAL: a prospective observational hospital based study conducted on patients of Department of General Medicine with collaboration from Department of Biochemistry and Radio diagnosis of SMS Medical College Jaipur. Patient who were diagnosed as case of acute pancreatitis on basis of diagnostic criteria as per Atlanta classification 2013 guidelines7 were included. Total of 56 cases were included in this study. OBSERVATION: The finding observed are as under:- 1) The mean age of the population was 38.5 ±11.83 years. CONCLUSION: In present, study serum PCT was done in patients diagnosed as acute pancreatitis on basis of Atlanta classification within 48 hours of admission and was found to be increased (value is significant if it is more than 0.5ng/ml) in 23 patients out of 60, with mean of 1.94±2.4ng /ml. These 23 patients were later on found to have severe acute pancreatitis on the basis Atlanta classification and rest 37 patients who had mild pancreatitis had mean PCT 0.38±0.66ng/ml. A study conducted on 40 patients of acute pancreatitis which was confirmed by Computed tomography was conducted in Poland, where they collected blood samples on admission and 24 hour thereafter, in which they tried to evaluate the role of procalcitonin as an early predictor of course of acute pancreatitis and they found that procalcitonin concentration was significantly higher in patients of acute pancreatitis and cut off was estimated at 0.5ng/ml.79 Similarly, in this study PCT was found to be high in patients of severe acute pancreatitis only.

Microalbuminuria: As an Indicator of Sepsis and to Predict Mortality in Patients Admitted to Intensive Care Unit.

BACKGROUND: Sepsis is an important healthcare concern in India as well as globally. This study shows how the level of microalbuminuria predict mortality of patients diagnosed with sepsis and those without sepsis. METHODS: In this study total 150 patients of which 75 patients belonging to each sepsis and non-sepsis group, with age >15 years admitted in Medical Intensive Care Unit (ICU) were enroled Microalbuminuria levels were analyzed at admission and after 24 hours after admission. RESULTS: Microalbuminuria levels were significantly high in patients with sepsis as compared to non sepsis. Microalbuminuria has highest sensitivity of 90 % and specificity of 98 % to differentiate between sepsis and non sepsis in comparison to APACHE II and SOFA scores. CONCLUSION: Serial monitoring of bedside urine albumin-creatinine measurement might help in the early identification of patients with sepsis that requires early targeted therapy. The 24-hour ACR assessment predicts ICU survival and may have the potential to monitor the efficacy of therapeutic interventions delivered, such as fluid resuscitation, appropriate antibiotics, vasopressors, and ionotropes that affect the endothelium.

A preliminary clinico-epidemiological portrayal of COVID-19 pandemic at a premier medical institution of North India.

CONTEXT: The outbreak and spread of severe acute respiratory syndrome coronavirus 2 has led to a global exigency of colossal and monstrous proportions in terms of public health and economic crisis. Till date, no pharmaceutical agent is known to manage in terms of prevention and treatment of coronavirus disease 2019 (COVID-19), the disease caused by a novel virus. AIMS: The aim of the present work was to understand the underlying disease profile and dynamics that could provide relevant inputs and insight into pathophysiology and prevent further spread and evolve management strategies of COVID-19 patients from data-driven techniques. SETTINGS AND DESIGN: A retrospective observational descriptive study was conducted on 29 COVID-19 patients admitted at a premier medical institution of North India in the months of February and March 2020. METHODS: The patients were diagnosed with reverse transcription-polymerase chain reaction test. Demographic, clinical, and laboratory data were collected. RESULTS: The mean age of population was 38.8 years with male preponderance, of which two patients were residents of Italy, and others hailed from semi-arid and Western sandy arid regions of Rajasthan (urban population). The major presenting symptom complex of said COVID-19 sample population included fever (48%), cough (31%), and shortness of breath (17%). Most of the patients (83%) had no comorbidity. No clinical correlation (r) could be appreciated between the duration of test positivity and age of afflicted COVID-19 patients (r = -0.0976). CONCLUSIONS: The present evaluation of various facets of the ongoing global pandemic of COVID-19 is an attempt to portray early clinical and epidemiological parameters of the menace of COVID-19 patients admitted at SMS Medical College and Attached Hospitals, Jaipur.

Characteristics, Treatment Outcomes and Role of Hydroxychloroquine among 522 COVID-19 hospitalized patients in Jaipur City: An Epidemio-Clinical Study.

PURPOSE: The present study was undertaken to investigate epidemiological distribution, clinical manifestation, co morbid status, treatment strategy and case fatality index of emerging COVID-19 infection at SMS Medical College Hospital, Jaipur, Rajasthan. It also evaluated efficacy of hydroxychloroquine (HCQ) in treatment of patients and risk of serious adverse outcomes in patients with COVID-19 in relation to their co morbid status. MATERIALS AND METHODS: In an attempt to provide extensive information pertaining to epidemiological and clinical characteristics of COVID-19, the present study was undertaken on 522 patients. The patients were COVID-19 confirmed positive by genomic analysis through Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) at SMS Medical College and Attached Hospitals, Jaipur. The indoor admitted patient's information inclusive of demographic profile (age, sex, nationality, residence), date of confirmation for positive COVID-19 case, travel/ exposure history, date of recovery/ death, clinical features, co morbidities and treatment plan was recorded. A serial follow-up of recovered patients to evaluate infective period of the disease was also part of the study. RESULTS: A total of 522 patients of laboratory confirmed COVID-19 test by RT-PCR at SMS Hospitals, Jaipur were assessed. Among the confirmed cases, most of patients were young adult in the age group with mean age of 35.42 years. 22.41% patients were below 20 years of age, majority of patients (58.80%) were in the age range of 21 to 50 years and only 18.79% patient population was in the age range of above 50 years. Females (39.08%) were affected less than males (60.91%) with an average sex ratio of female: male being 0.64. Out of the total analyzed patients, only 24.32% patients were symptomatic, among them fever (55.90%), cough (52.75%), sore throat (49.60%) and shortness of breath (46.45%) were the most common presenting clinical manifestations while a few patients also had symptoms of headache (26.77%), chest pain (6.29%) and other symptoms (7.87%) like pain abdomen, fatigue, joints pain, altered sensorium etc. Most of symptomatic patients belonging to older age group. An average of 40.40% patient population of above 50 years of age, were symptomatic while none of the patients below 10 years of age were symptomatic. 13.98% patients had some or the other underlying co morbid disease. The most prevalent co morbidity was hypertension (42.46%) followed by Diabetes mellitus (39.72%), Old k-chest (20.54%), COPD/ Bronchial Asthma (16.43%), Coronary artery disease (13.69%), Chronic kidney disease (13.69%) and Valvular heart disease (6.84%) distributed in co morbid patients of COVID-19. 60.27% of patient population with underlying co morbid conditions were more prone to develop symptomatology complex as compared to that observed in patients with no co morbidity (18.42%). 116 patients had recovered with effective treatment till the date of data analysis. Time of recovery was counted from the date of positive report to 1st negative report of oropharyngeal sample by RT-PCR for COVID-19 with an average recovery time of 8.15 days. 23.27% patients recovered within 5 days, while 52.58% patients took about 6-10 days, 23.27% patients took 11-15 days and remaining 0.86% took more than 16 days to recover. In the present study 15 patients had died till analysis of data, among the deceased, 73.33% were above 50 year of age with a male preponderance (66.6%). Interestingly, all deceased (100%) had presented with clinical manifestations of COVID-19 and all had underlying multiple co morbid conditions. Majority of patients had early mortality after admission to hospital with two third death account in initial three days. Asymptomatic patients (cases) treated with HCQ recovered early (average recovery time =5.4 days) compared to asymptomatic patients who did not receive any treatment (control group) and had longer recovery time (average recovery time =7.6 days). CONCLUSION: The varied spectra of COVID-19 mostly affects young adult age group (third to fifth decades of life). Interestingly, early age group was also affected in significant proportion when compared with similar data from other countries. It was observed that male population seemed to be was more prone to getting infected. Majority of COVID-19 positive patients (nearly three-fourth) were asymptomatic (mostly in young age range) at the time of diagnosis, which poses a major challenge for health care workers. Fever, cough, sore throat and shortness of breath were major symptoms that could be detected in such COVID-19 patients. Symptomatic clinical manifestations were more common in old age population. Infectivity was higher in patients that had underlying co morbid disease, especially in patients with multiple co morbid conditions. Symptomatic presentation of COVID-19 was observed to be higher in patients with co morbid disease. Average recovery time from COVID-19 was 8 days with effective treatment. Mortality in COVID-19 was higher in old age population, male gender, symptomatic and co morbid patients as compared to other similarly matched group. Most of mortality was noted within first few days of admission, suggestive of early mortality due to the primary disease process. Treatment with HCQ had early recovery without effectively influencing the overall mortality.

Mortality in H1N1: A comparison of patient attributes in outbreaks due to A/California/7/2009 and A/Michigan/45/2015 strains.

INTRODUCTION: The resurgence of epidemic of Influenza A (H1N1) pdm 09 was phenomenal in 2015 and has become an annual phenomenon. Antigenic drift and reassortment is the rule rather than exception, conferring survival benefit to the virus. As this disease has high mortality, we compared the clinico-epidemiological profile of patients expired in the year 2015 due to "A/California/7/2009" strain with those of expired in the year 2018 due to "A/Michigan/45/2015" strain. MATERIAL AND METHOD: We collected data of all expired patients in our institute in the year 2015 from 1st January to 30th may as well as 2018 in the same time period. The data of 116 patients who expired in 2015 due to "A/California/7/2009" H1N1 strain were compared with similar data of 30 patients expired in 2018 due to "A/Michigan/45/2015" strain of H1N1. Patients of pneumonia, having age >18 years, positive for H1N1by real-time reverse-transcriptase-polymerase- chain-reaction (RT-PCR) and died in our hospital were included in this study. Clinical features and laboratory data were obtained from the hospital records of the patients. Data analysis was done using SPSS software. RESULT: In 2015 total number of hospitalized patients due to "A/California/7/2009" strain were 571 and 116(20.31%) out of them died, in 2018 those due to "A/Michigan/45/2015" total admission were 177 and 30(16.94%) out of them died (p-0.032). Though it was not statistically significant but it is lesser than in 2015 despite the fact that more patients with co morbidities were affected in 2018. Duration in ICU was significantly longer in 2018(MS) group [5(1-7)] compared to 2015 (CS) group [3(1-17)] with p value of 0.017 (i.e. < 0.05). But both groups were not different in terms of duration on mechanical ventilator. (p-0.257).The 2015 (CS) group had 74.1% with other co-morbidities versus 96.7% of those in 2018 (MS) group (p- 0.015). This implies that the mortality with "A/Michigan/45/2015" infection was mainly seen in the patients who already had one or more co-morbidities unlike "A/California/7/2009" infection.The 2018 (MS) group had significantly higher proportion (60%) of patients with acute kidney injury compared to 34.5% in 2015(CS) (p-0.019). 50% of dead patients in 2018(MS) had anemia compared to 11.2% in 2015(CS) (p<0.001). Deranged liver function test was seen in 46.7% patients in 2018(MS) compared to only 15.5% patients in 2014(CS) (p<0.001).The only reverse trend was shown in case of diabetes, A/California/7/2009 strain affected 27% diabetics compared with 6.7% affected by A/Michigan/45/2015 strain (p=0.030) (Table 5). CONCLUSION: The study showed that though "A/Michigan/45/2015" affected higher number of patients with co morbidities compared to "A/California/7/2009" but had slightly lesser mortality.

Dengue Fever as a Rare Cause of Acute Pancreatitis.

Dengue is an arthropod borne viral infection endemic in tropical and subtropical climate. Here we report an unusual presentation of Dengue fever as acute pancreatitis. Timely recognition of such atypical complication can reduce the morbidity and mortality.

Severe Hyponatremia as an Uncommon Presenting Feature of Pituitary Macroadenoma.

Hyponatremia is a common electrolyte disturbance, but less commonly utilized and require a thorough evaluation to unmask etiology. It has variety of causes and is rarely due to hypopituitarism. Hyponatremia is a very early complication of pituitary tumor. Here, we report a case, who presented to us with hyponatremia and eventually thorough work-up led us to a diagnosis of Non-functioning pituitary macroadenoma.

Progressive Disseminated Histoplasmosis with Coomb's Positive Hemolytic Anemia in an Immunocompetent Host.

Progressive Disseminated Histoplasmosis (PDH) is mainly described in immuno-compromised individuals and rare in immuno-competent subjects. Here we report a case of progressive disseminated histoplasmosis with Comb's positive hemolytic anemia, which is infrequently reported from a country like India where histoplasmosis is not an endemic mycosis.

Profiling the Mortality due to Influenza A (H1N1) pdm09 at a Tertiary Care Hospital in Jaipur during the Current Season--January & February 2015.

BACKGROUND: The onset of winter of 2014-2015 saw an alarming spurt in influenza A (H1N1) pdm 09 leading to a significant mortality. Rajasthan was one of the foremost affected state bearing the frontal attack in which majority of deaths occurred early and in the young. OBJECTIVE: To sketch out the mortality profile with respect to demographic and clinical progression with an aim to identify the groups, this virus conspicuously picked up with a perspective to control some of the avoidable factors. METHODS: We analyzed the epidemiological data in 76 RT-PCR confirmed deaths of H1N1 patients that occurred between 1st January 2015 and 28 February 2015 over a period of 59 days at SMS Medical College Hospital, Jaipur. RESULTS: A total of 412 patients got hospitalized during two months period from 1st January 2015 to 28th February 2015, out of which 76 fatal cases presenting with category C symptoms along with radiological evidence of bilateral pneumonia were analyzed. 48.6% deaths occurred in the 18-40 years of age group. The mean age being 44.01 ± 15.07 years. Females had a marginally increased mortality rate (F: M-1.23:1). The mean time of onset of symptoms to hospitalization was 6.79 ± 4.63 days. Fifty-one (67.1% 0) patients were from urban areas, whereas 25 (32.89%) belonged to rural areas. Only 7.83% patients presented within 24 - 48 hours whereas 46% presented within 5 days of onset of symptoms. 66.9% succumbed within 5 days of hospitalization, despite of starting Oseltamivir in a dose of 150 mg/bd on the day of admission. 64.5% had predisposing risk factors. Bilateral pneumonia was observed in all the 76 patients, septicemia in 21.12%, MODS in 30.26% and AKI in 9.21%. CONCLUSIONS: The in-hospital mortality of 17.79% despite of starting Oseltamivir has raised concern about identifying the so called "Rapid Progressors" [66.9% succumbing within 5 days of hospitalization]. As a corollary of this analysis the authors are of the opinion that a rejig of the existing guidelines to identify and treat influenza like illness be made available at the national level. What factors promote rapid progression especially in a group without any predisposing risk condition should form the focus of future studies. As risk group individuals formed a major chunk of deaths, the need to vaccinate this group should form a scaffold on which future directions and interventions have to be built up to combat the morbidity and mortality.

Rivaroxaban: a novel anticoagulant.

For more than 50 years, warfarin has single-handedly ruled the world of anti-coagulation without any competition, whatsoever! The anticoagulant was made available in 1940 and since then no other anti-coagulant has ever been able to match it in the clinical arena. But it looks like that the advances in the field of anti-coagulation, for the first time, have seriously started to erode its base. This review takes a look at rivaroxaban, a direct factor Xa inhibitor and one of the most foremost competitors of warfarin.