Resumption of anticoagulant therapy after anticoagulant-related gastrointestinal bleeding: A systematic review and meta-analysis.

INTRODUCTION: Oral anticoagulation (OAC) is permanently discontinued in up to 50% of patients following a gastrointestinal (GI) bleed. A previous meta-analysis showed a reduced risk of thromboembolism and death, and a non-statistically significant increased risk of re-bleeding associated with resumption. We conducted an updated meta-analysis to determine the risks of recurrent GI bleeding, thromboembolism, and death in patients who resumed OAC compared to those who did not. MATERIALS AND METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials for new references from January 2014 to September 2017. Randomized controlled trials and observational studies involving adults with OAC-related GI bleeding were included. Risk of bias was assessed using the Cochrane Collaboration's ROBINS-I tool. Pooled relative risk (RR) ratios were calculated using a random-effects model. RESULTS: We identified 12 observational studies involving 3098 patients. There was an increased risk of recurrent GI bleeding (RR 1.91, 95% CI 1.47-2.48, I2 = 0%, 11 studies), and a reduced risk of thromboembolism (RR 0.30, 95% CI 0.13-0.68, I2 = 59.8%, 9 studies) and death (RR 0.51, 95% CI 0.38-0.70, I2 = 71.8%, 8 studies) in patients who resumed OAC compared to those who did not. Eleven studies were judged to be at serious risk of bias due to confounding. CONCLUSIONS: Resuming OAC after OAC-related GI bleeding appears to be associated with an increase in recurrent GI bleeding, but a reduction in thromboembolism and death. Further prospective data are needed to identify patients for whom the net clinical benefit favours OAC resumption and the optimal timing of resumption.

An evaluation of the potential drug interaction between warfarin and levothyroxine.

BACKGROUND: Drug interaction references report that initiation of levothyroxine potentiates the effects of warfarin, and recommend more frequent International Normalized Ratio (INR) monitoring, but the mechanism is not well understood. OBJECTIVE: To assess the impact of levothyroxine initiation on INR response. PATIENTS/METHODS: A retrospective, self-controlled study was performed on patients aged ≥ 18 years receiving chronic warfarin therapy who were started on levothyroxine between 1 January 2006 and 30 June 2013, and who were followed for 90 days prior to and after levothyroxine initiation. The included patients had at least one elevated thyroid-stimulating hormone laboratory value in the pre-period, continuous warfarin therapy for 100 days prior to levothyroxine initiation, no purchases of medications known to interact with warfarin, no procedures requiring warfarin interruption, and no bleeding or thromboembolic event during the study period. The primary outcome was a comparison of the warfarin dose/INR ratio recorded before the initiation of levothyroxine with the ratio recorded during the post-period after two consecutive INRs with no warfarin dose change. RESULTS: One hundred and two patients were included in the primary outcome. The mean warfarin dose/INR ratios in the pre-period and post-period were equivalent (P = 0.825). Although the mean warfarin dose was numerically lower in the post-period than in the pre-period, this difference did not reach statistical significance (P = 0.068). CONCLUSION: No difference in the mean warfarin dose/INR ratio before and after initiation of levothyroxine was detected. The results suggest that there is not a clinically significant interaction between warfarin and levothyroxine, and so additional monitoring may not be necessary.

Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users.

BACKGROUND: For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible. OBJECTIVE: To identify patients with stable INRs (INR values exclusively within the INR range) and comparator patients (at least one INR outside the INR range), compare occurrences of thromboembolism, bleeding and death between groups, and identify independent predictors of stable INR control. METHODS: The study was a retrospective, longitudinal cohort study using data extracted from electronic databases. Patient characteristics and risk factors were entered into multivariate logistic regression models to identify variables that independently predict stable INR status. RESULTS: There were 533 stable and 2555 comparator patients. Bleeding and thromboembolic complications were significantly lower in stable vs. comparator patients (2.1% vs. 4.1% and 0.2% vs. 1.3%, respectively; P < 0.05). Independent predictors of stable INR control were age >70 years, male gender and the absence of heart failure. Stable patients were significantly less likely to have target INR > or =3.0 or chronic diseases. CONCLUSION: A group of patients with exclusively therapeutic INR values over 12 months is identifiable. In general, these patients are older, have a target INR <3.0, and do not have heart failure and/or other chronic diseases. Our findings suggest that many patients whose INR values remain within the therapeutic range over time could be safely treated with INR recall intervals >4 weeks.

Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy.

BACKGROUND AND AIMS: To assess the effect of warfarin anticoagulation therapy (AC) on the incidence of colon bleeding after elective colonoscopy with polypectomy and to identify independent predictors of post-polypectomy colon bleeding. METHODS: This was a retrospective cohort analysis. Patients interrupting warfarin AC therapy for polypectomy (AC group) were matched on age (+/- 3 years) with up to two patients who underwent polypectomy but were not receiving AC (non-AC group). Data were extracted from electronic medical, pharmacy and laboratory claims and records and manual medical chart review. Incidence rates of colon bleeding requiring hospitalization, other gastrointestinal bleeding, thrombosis and death in the 30 days post-polypectomy were compared between groups. Multivariate regression techniques were used to identify independent predictors of post-polypectomy colon bleeding. RESULTS: A total of 425 AC group patients were matched to 800 non-AC group patients. Post-polypectomy colon bleeding occurred more often in AC group patients (2.6% vs. 0.2%, P = 0.005). There were no differences in the rates of other outcomes (P > 0.05). Independent predictors of colon bleeding included AC group status [adjusted odds ratio (AOR) = 11.6; 95% confidence interval (CI) = 2.3-57.3], number of polyps removed (AOR = 1.2; 95% CI = 1.1-1.4) and male gender (AOR = 9.2, 95% CI = 1.1-74.9). CONCLUSIONS: The incidence of post-polypectomy colon bleeding was higher in patients receiving AC even although warfarin was interrupted for the procedure. Independent predictors of colon bleeding were identified as: receiving AC, removal of multiple polyps and male gender. Our findings suggest that additional methods to reduce the likelihood of post-polypectomy colon bleeding in AC patients should be investigated.

Testosterone and sexual experience alter levels of plasma membrane binding sites for progesterone in the male rat brain.

Physiological levels of progesterone act in conjunction with androgens to facilitate copulatory behavior in male rats, mice, and lizards. Radiolabeled progesterone conjugated to bovine serum albumin measured specific binding sites in membrane fractions from male rats that were gonadectomized and testosterone treated, or remained gonadally intact, to determine the role of gonadal steroids on mPR binding. To determine whether behavioral experience could alter binding levels, males either remained sexually naïve or became sexually experienced. In sexually naïve males, the highest levels of specific binding occurred in the dorsal portions of the medial preoptic area, with only moderate levels of binding in ventral portions of the medial preoptic area and the dorsal and ventral medial hypothalamus. However, conjugated progesterone binding in these brain regions did not change as a function of testosterone or behavioral manipulations. In contrast, the amygdala responded to behavioral experience with significantly (4-fold) increased binding in gonadectomized, T-treated males with sexual experience. These data indicate that the neuronal plasticity for membrane-associated progesterone binding is regionally specific, being regulated by sexual experience following the reinstatement of testosterone levels, thus suggesting a functional role for plasma membrane activity of progesterone in male rat reproduction.

Phase transitions for flat anti-de Sitter black holes.

We reexamine the thermodynamics of anti-de Sitter (adS) black holes with Ricci flat horizons using the adS soliton as the thermal background. We find that there is a phase transition which is dependent not only on the temperature but also on the black hole area, which is an independent parameter. As in the spherical adS black hole, this phase transition is related via the adS/conformal-field-theory correspondence to a confinement-deconfinement transition in the large- N gauge theory on the conformal boundary at infinity.

Effectiveness and economic impact associated with a program for outpatient management of acute deep vein thrombosis in a group model health maintenance organization.

BACKGROUND: Controlled clinical trials have demonstrated that outpatient administration of low-molecular-weight heparin to patients with acute deep vein thrombosis (DVT) provides safety and efficacy equivalent to that of traditional inpatient therapy with unfractionated heparin. Whether favorable results reported in controlled clinical trials are achievable in clinical practice is an important consideration. METHODS: Appropriate patients with objectively diagnosed DVT were treated as outpatients with low-molecular-weight heparin and warfarin sodium according to an approved guideline. The primary end point for analysis consisted of objectively diagnosed symptomatic recurrent thromboembolism or major bleeding within a 90-day evaluation period. The incremental cost incurred by the organization while using the outpatient DVT treatment guideline was determined. Incremental cost savings of the outpatient DVT treatment program were determined based on the cost that would have accrued had the patient been admitted to the hospital for treatment with unfractionated heparin. RESULTS: We enrolled 391 patients (91.4%) in the outpatient DVT treatment program. Of these, 373 (95.4%) completed 90 days of therapy without reaching the primary end point. The percentage of patients reaching the primary outcome measure (4.6%) fell within the range of patients enrolled in controlled clinical trials (3.5%-9.4%). During the 2-year program evaluation, total cost savings of $1,108,587 were realized. CONCLUSIONS: Outpatient treatment of acute DVT can be managed safely and effectively in clinical practice. The potential savings associated with outpatient DVT treatment are substantial. Arch Intern Med. 2000;160:2926-2932

Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation.

STUDY OBJECTIVE: To compare the efficacy of managing excessive anticoagulation in the absence of bleeding by either omitting warfarin therapy alone or administering oral phytonadione in addition to omitting warfarin therapy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Clinical pharmacy anticoagulation service in a group model health maintenance organization. SUBJECTS: Thirty nonbleeding patients with international normalized ratios (INRs) ranging from 6.0-10.0. INTERVENTIONS: Patients were randomized to receive either a single oral dose of phytonadione 2.5 mg or placebo. Both groups omitted warfarin doses until the INR became less than or equal to 4.0. MEASUREMENTS AND RESULTS: The mean calculated time to reach an INR of 4.0 was significantly greater in the placebo than the phytonadione group (2.6 vs 1.4 days, p=0.006). Overcorrection of anticoagulation was significantly more common in patients receiving phytonadione. Overt warfarin resistance was not observed in either group after reinitiating warfarin therapy. No major bleeding or thromboembolic complications occurred, and minor bleeding episodes were similar in both groups. CONCLUSION: The addition of oral phytonadione 2.5 mg reduced the time to achieve an INR of 4.0 by approximately 1 day compared with omitting warfarin therapy alone. Adverse events did not differ between the two groups. Both strategies were effective in managing asymptomatic patients with INRs of 6.0-10.0. Oral phytonadione may be most appropriate for patients at high risk for bleeding in whom the benefit of prompt INR reduction would outweigh the thromboembolic risk associated with INR overcorrection.

Peer reviewed: monitoring endocrine-disrupting chemicals.

Novel strategies are providing a more comprehensive and refined basis for understanding the occurrence and effects of endocrine disrupters.

Clinical pharmacy anticoagulation services in a group model health maintenance organization.

The clinical pharmacy anticoagulation service (CPAS) at a large group model health maintenance organization is described. The service has expanded dramatically from a local service providing anticoagulation monitoring for the patients of a single physician to a regional service staffed by seven full-time employees who monitor over 3,000 patients. The structure and operations of the CPAS are described as well as the processes used to manage anticoagulation therapy complications. A program for treating patients with deep vein thrombosis in the outpatient setting using enoxaparin is also described.

Evaluation of excessive anticoagulation in a group model health maintenance organization.

BACKGROUND: The fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy recently published guidelines that included recommendations regarding the management of excessive anticoagulation. Limited data are available to support these recommendations. OBJECTIVES: To assess management and outcomes of excessive anticoagulation in a group model health maintenance organization, compare management with the published guidelines, and analyze the cost of treatment strategies. METHODS: A search of computerized laboratory information identified patients with an international normalized ratio (INR) of greater than 6.0 during the 9-month study. Pertinent data were collected through a retrospective medical record review. Information was concurrently collected for cost analyses. RESULTS: The analysis included 301 episodes of excessive anticoagulation among 248 patients. Most (83%) episodes of elevated INRs were managed conservatively by a temporary discontinuation of warfarin sodium therapy until the INR was in a therapeutic range. Conservative management resulted in no sequelae in 212 (85.1%) of 249 episodes. Two episodes (0.8%) of major bleeding evolved in patients managed conservatively. No sequelae were documented in 23 (44%) of 52 episodes of phytonadione (vitamin K1) administration. Sixteen (31%) episodes of major bleeding were documented, but bleeding occurred before phytonadione administration in all cases. Administering phytonadione resulted in hospital admission for 3 patients--2 (3.8%) because of thromboembolism and 1 (1.9%) for the administration of heparin sodium. Cost-effectiveness analysis determined that treatment with phytonadione is 7 times more costly than conservative management when INRs are between 6.0 and 10.0. CONCLUSIONS: Most episodes of excessive anticoagulation were not managed per consensus guidelines. The higher the INR, the more likely were interventions to adhere to the guidelines. Administering phytonadione to patients with a moderate elevation of INRs (6.0-10.0) may be unnecessary. Based on this study, conservative management is a viable option.

Controversies surrounding estrogen use in postmenopausal women.

OBJECTIVE: To provide an overview of controversies regarding the use of estrogen in postmenopausal women. DATA SOURCES: A MEDLINE search was conducted to identify pertinent literature published since 1990. Recently published textbooks devoted to the subjects of menopause and women's health were also reviewed, particularly their bibliographies. The bibliographies of selected review articles were also reviewed. STUDY SELECTION: Due to the vast amount of literature, only the most relevant published studies were reviewed. Review articles and book chapters authored by researchers of international reputation were also reviewed. DATA EXTRACTION: Identified studies from the primary literature and selected reviews were carefully reviewed. Information regarding the use of estrogen in postmenopausal women was extracted. Particular attention was given to areas of controversy commonly dealt with in the lay media. DATA SYNTHESIS: The number of postmenopausal women in the US will approach 60 million in the next decade. Despite numerous potential benefits, many women elect to not take estrogen due to fear of cancer or poor understanding of the long-term consequences of menopause and the beneficial effects of estrogen replacement therapy. Many women rely on the news media for information about hormone therapy and subsequently become confused regarding the benefits and risks. Estrogen relieves climacteric symptoms such as hot flushes and symptoms related to genitourinary tissue atrophy. Outcomes from controlled clinical trials are lacking, but numerous epidemiologic studies document clinically significant decreases in cardiovascular disease and osteoporotic morbidity and mortality. Unopposed estrogen increases the risk for endometrial cancer, but addition of a progestin for at least 10 days per cycle effectively reduces this risk to that of women who do not take estrogen. The association between postmenopausal estrogen use and breast cancer remains controversial, despite the results of numerous observational studies. This uncertainty regarding estrogen replacement and breast cancer risk can actually be reassuring when placed in proper perspective. CONCLUSIONS: Until some of the controversies surrounding postmenopausal hormone use are resolved, an objective discussion with a knowledgeable healthcare professional regarding the potential benefits and risks will help women make informed decisions regarding estrogen replacement therapy in the postmenopausal years.

Dornase alfa: a new option in the management of cystic fibrosis.

Recombinant human DNase I, or dornase alfa, is the first new therapy developed specifically for cystic fibrosis in almost 30 years. It selectively digests extracellular DNA and reduces the viscosity of purulent sputum. In clinical trials dornase alfa modestly improved pulmonary function, slightly decreasing the number of respiratory exacerbations requiring parenteral antibiotics compared with placebo. Phase III studies suggest that patients receiving dornase alfa also spend slightly fewer days in the hospital than those treated with placebo. The aerosolized preparation is safe and generally well tolerated. Voice alteration and sore throat are the most commonly reported adverse effects. Further research is necessary to determine the optimum time to initiate therapy and to evaluate the agent's pharmacoeconomic impact on the treatment of cystic fibrosis. Aerosolized dornase alfa should always be given in conjunction with standard cystic fibrosis therapies including antibiotics, chest physiotherapy, and pancreatic enzyme supplementation.

Progesterone modulation of androgen-dependent sexual behavior in male rats.

The present study examines the effects of physiological levels of progesterone (P) on copulatory behavior in sexually naive male rats. Two weeks after gonadectomy males were implanted with either empty Silastic capsules (BL) or Silastic capsules containing testosterone (T), P, or both (P+T). When tested with an estrous female, all of the gonadally intact males (intact) and none of the BL controls exhibited mounting/intromission behaviors. Mounting was observed in 75% of the T-alone males. More than half (64%) of the P-alone males and 100% P+T males exhibited mounting. In most cases, mounting was followed by intromission responses. Subsequently, intact and gonadectomized males received daily injections of the P antagonist RU486 along with hormone treatment. After receiving RU486, only 63% of the intact males and 71% of the T-alone males mounted successfully. The facilitatory effects of P on copulatory behavior were completely abolished by RU486 treatment. The present studies provide the first evidence in mammals suggesting that P-dependent mechanisms influence neurochemical pathways involved in copulation.

Strategies for cell biological studies in oxytocinergic neurons.

Hypothalamic magnocellular neurons expressing the neurohypophysial peptides, oxytocin (OT) and vasopressin (AVP), have historically served as valuable models for cell biological studies of peptidergic neurons. This is because of the relative ease with which the perikarya, axons, and nerve terminals of these cells can be isolated for anatomical, biochemical, and physiological analysis. A popular strategy is to harness the regulatory elements in the OT and AVP genes in order to target specific molecules to these cells in vivo, so as to elucidate various cell biological issues, e.g., pacemaker, prohormone processing, axonal transport, and secretion mechanisms. The peptide genes are good sources for regulatory controls since they are relatively abundantly and specifically expressed in these neurons in the CNS. The major problem has been to identify the critical regulatory elements in these genes which are responsible for the cell-specific expression. Recent transgenic studies have implicated various 3'-untranslated nucleotide sequence regions in the OT and AVP genes which appear to contain these regulatory elements. A structural analysis of these regions in the mouse genes will be discussed. A second problem has been the availability of appropriate model systems to test constructs for "cell-specific" expression. Transgenic mice have been effective models in this regard but are costly and labor-intensive. An alternative approach using biolistic techniques to transfect slice-explants containing the primary OT and AVP neurons in culture will be described.

Oxytocin and rodent sociosexual responses: from behavior to gene expression.

In most mammals, gonadal steroid hormones are required for the expression of species-typical reproductive behavior. Over the past few years it has become evident that neuropeptides, such as oxytocin (OT) and vasopressin (AVP), also play a key role in the regulation of both social and sexual behavior. Through studies of gonadal steroid/neuropeptide interactions, we have been able to discover species differences in behavioral and physiological responses to OT that may be associated with species-specific distributions of OT receptors or differential levels of OT gene expression in the central nervous system (CNS). However, the characterization of OT's behavioral effects has been conducted primarily in rats and the neural mechanisms underlying these behaviors are not clearly understood. The present paper will describe and discuss the biological significance of OT-mediated behavioral responses in both female and male prairie voles and rats, speculate on the neural mechanisms (OT receptor regulation) and reproductive physiology involved in species-specific sociosexual behavior, and present new methodologies for studying signal transduction mechanisms involved in OT gene expression in the CNS.

Lack of interaction between glipizide and co-trimoxazole.

To identify the effects of co-trimoxazole on the elimination and disposition kinetics of glipizide, eight healthy male volunteers were studied in an unblinded, randomized, cross-over trial with two phases (no treatment or co-trimoxazole 160/800 mg twice a day). During each phase, subjects were treated at home for 7 days with one of the treatment regimens, followed by a 24-hour hospitalization for a single-dose challenge with 10-mg oral glipizide and detailed blood studies. A 7-day washout period was interspersed between the phases. Pharmacokinetic and pharmacodynamic parameters were determined and compared using the Student's t-test for paired observations. Glipizide area under the curve (AUC), clearance, and half life for treatment and control phases were 5758 +/- 1874 versus 5176 +/- 1505 micrograms/L/hour (P = .21), 0.41 +/- 0.15 versus 0.45 +/- 0.14 mL/min/kg (P = .27), and 5.13 +/- 2.10 versus 3.95 +/- 1.37 hours (P = .04), respectively. Twenty-four-hour glucose AUCs for treatment and control phases were 112.24 +/- 8.76 versus 114.86 +/- 11.98 mmol/L/hour (P = .55), respectively. The only parameter reaching statistical significance was glipizide half life, but the difference is of doubtful clinical significance because of difficulty in identifying a clear elimination phase in several subjects. It is concluded that co-trimoxazole administration did not significantly alter glipizide disposition and elimination kinetics in this study population.

Increased Fos expression in oxytocin neurons following masculine sexual behavior.

Induction of the c-fos protein product (Fos) was used to immunocytochemically identify oxytocin (OT) neurons that may be activated during copulatory interactions. Fos induction was quantified in sexually-experienced male rats after either (a) exposure to a testing arena recently vacated by an estrous female, (b) copulatory interactions such as mounting and intromission without ejaculation, or (c) mounting and intromissions culminating in ejaculation. In the parvocellular regions of the paraventricular nucleus of the hypothalamus (PVN), the number of neurons expressing Fos increased following either intromission (53%) or ejaculation (124%). Significant, but less striking, increases in the number of cells expressing Fos were noted in magnocellular regions of the PVN where intromission resulted in a 13% increase and ejaculation in a 49% increase in Fos. The number of perikarya immunoreactive for OT and AVP did not differ as a function of increasing sexual contacts. In control (novel arena) males, 33-73% of the Fos labeling occurred in OT cells. Sexual interactions did not enhance the number of double-labeled cells in most parvocellular regions. However, in lateral parvocellular regions located in the most caudal aspects of the PVN, 31% of the Fos-positive cells occurred in OT neurons in ejaculated males, while in control males none of the OT cells were double-labeled. This PVN subdivision is known to consist of neurons that project to the brain stem and spinal cord at lumbar levels which contain motor neurons that regulate penile reflexes. The present data suggest a possible neurochemical circuit which incorporates oxytocinergic neurons in the mediation of masculine sexual responses.

Progesterone and sexual behavior in males.

Previous investigations into the effects of progestins on copulatory behavior have suggested that progesterone inhibits the expression of androgen-dependent sexual behaviors in males. However, virtually all of those studies utilized pharmacological dosages of progesterone. Such experiments, although essential for understanding the behavioral effects of progesterone, yield little insight into the function of endogenous progesterone in masculine sexual responses. In this brief review, attention is focused on the role of physiological levels progesterone in copulatory behavior in male reptiles and mammals. Efforts are made to promote a reevaluation of the behavioral effects of progestins in males, similar to ongoing studies which are reexamining neural mechanisms involved in progestin-mediated reproductive behavior in the female.