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Circulation Jan 2024There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety of Switching From a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial.
BACKGROUND
There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC).
METHODS
We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min·1.73 m or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events.
RESULTS
Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61).
CONCLUSIONS
Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications.
REGISTRATION
URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study).
Topics: Humans; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Frail Elderly; Frailty; Thromboembolism; Vitamin K; Administration, Oral; Stroke
PubMed: 37634130
DOI: 10.1161/CIRCULATIONAHA.123.066485 -
Clinical Microbiology and Infection :... Sep 2023The timing of the switch from intravenous (i.v.) to oral antibiotic therapy for orthopaedic bone and joint infections (BJIs) is debated. In this narrative article, we... (Review)
Review
OBJECTIVES
The timing of the switch from intravenous (i.v.) to oral antibiotic therapy for orthopaedic bone and joint infections (BJIs) is debated. In this narrative article, we discuss the evidence for and against an early switch in BJIs.
DATA SOURCES
We performed a PubMed and internet search investigating the association between the duration of i.v. treatment for BJI and remission of infection among adult orthopaedic patients.
CONTENT
Among eight randomized controlled trials and multiple retrospective studies, we failed to find any minimal duration of postsurgical i.v. therapy associated with clinical outcomes. We did not find scientific data to support the prolonged use of i.v. therapy or to inform a minimal duration of i.v.
THERAPY
Growing evidence supports the safety of an early switch to oral medications once the patient is clinically stable.
IMPLICATIONS
After surgery for BJI, a switch to oral antibiotics within a few days is reasonable in most cases. We recommend making the decision on the time point based on clinical criteria and in an interdisciplinary team at the bedside.
Topics: Adult; Humans; Administration, Intravenous; Administration, Oral; Anti-Bacterial Agents; Retrospective Studies; Randomized Controlled Trials as Topic
PubMed: 37182643
DOI: 10.1016/j.cmi.2023.05.008 -
American Journal of Cardiovascular... Jul 2023Direct oral anticoagulants (DOACs) are recommended for the prevention of thromboembolism in patients with atrial fibrillation (AF), and are now preferred over vitamin K... (Review)
Review
Direct oral anticoagulants (DOACs) are recommended for the prevention of thromboembolism in patients with atrial fibrillation (AF), and are now preferred over vitamin K antagonists due to their beneficial efficacy and safety profile. However, all oral anticoagulants carry a risk of gastrointestinal (GI) bleeding. Although the risk is well documented and acute bleeding well codified, there is limited high-quality evidence and no guidelines to guide physicians on the optimal management of anticoagulation after a GI bleeding event. The aim of this review is to provide a multidisciplinary critical discussion of the optimal management of GI bleeding in patients with AF receiving oral anticoagulants to help physicians provide individualized treatment for each patient and optimize outcomes. It is important to perform endoscopy when a patient presents with bleeding manifestations or hemodynamic instability to determine the bleed location and severity of bleeding and then perform initial resuscitation. Administration of all anticoagulants and antiplatelets should be stopped and bleeding allowed to resolve with time; however, anticoagulant reversal should be considered for patients who have life-threatening bleeding or when the bleeding is not controlled by the initial resuscitation. Anticoagulation needs to be timely resumed considering that bleeding risk outweighs thrombotic risk when anticoagulation is resumed early after the bleeding event. To prevent further bleeding, physicians should prescribe anticoagulant therapy with the lowest risk of GI bleeding, avoid medications with GI toxicity, and consider the effect of concomitant medications on potentiating the bleeding risk.
Topics: Humans; Atrial Fibrillation; Anticoagulants; Gastrointestinal Hemorrhage; Thromboembolism; Blood Coagulation; Administration, Oral; Stroke
PubMed: 37145342
DOI: 10.1007/s40256-023-00582-9 -
Annual Review of Pharmacology and... Jan 2024Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and... (Review)
Review
Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.
Topics: Humans; Aged; Warfarin; Anticoagulants; Hemorrhage; Atrial Fibrillation; Renal Insufficiency, Chronic; Administration, Oral
PubMed: 37758192
DOI: 10.1146/annurev-pharmtox-032823-122811 -
Blood Feb 2024The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and...
The direct oral anticoagulants (DOACs) rivaroxaban and dabigatran are newly licensed for the treatment and prevention of venous thromboembolism (VTE) in children and mark a renaissance in pediatric anticoagulation management. They provide a convenient option over standard-of-care anticoagulants (heparins, fondaparinux, and vitamin K antagonists) because of their oral route of administration, child-friendly formulations, and significant reduction in monitoring. However, limitations related to therapeutic monitoring when needed and the lack of approved reversal agents for DOACs in children raise some safety concerns. There is accumulating experience of safety and efficacy of DOACs in adults for a broad scope of indications; however, the cumulative experience of using DOACs in pediatrics, specifically for those with coexisting chronic illnesses, is sparse. Consequently, clinicians must often rely on their experience for treating VTE and extrapolate from data in adults while using DOACs in children. In this article, the authors share their experience of managing 4 scenarios that hematologists are likely to encounter in their day-to-day practice. Topics addressed include (1) appropriateness of indication; (2) use for special populations of children; (3) considerations for laboratory monitoring; (4) transition between anticoagulants; (5) major drug interactions; (6) perioperative management; and (7) anticoagulation reversal.
Topics: Humans; Child; Venous Thromboembolism; Anticoagulants; Dabigatran; Rivaroxaban; Blood Coagulation; Administration, Oral
PubMed: 37390311
DOI: 10.1182/blood.2022018966 -
Archives of Gynecology and Obstetrics Oct 2023To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency (ferritin < 30 µg/L).
METHODS
In a single-centre, open-label, randomised controlled trial at a Danish hospital, women with persistent iron deficiency after routine oral iron treatment were allocated to receive 1000 mg IV iron (single-dose) or 100 mg elemental oral iron daily. Outcomes were assessed during an 18-week follow-up period. The primary endpoint was the proportion of non-anaemic (haemoglobin [Hb] ≥ 11 g/dL) women throughout follow-up. Other outcomes included changes in haematological parameters, patient-reported fatigue, and quality of life (QoL). Safety was assessed by recording adverse events.
RESULTS
From July 2017 to February 2020, 100 women were randomised to IV iron and 101 to oral iron. Throughout follow-up, 91% of women were non-anaemic in the IV iron group compared with 73% in the oral iron group (18% difference [95% confidence interval 0.10-0.25]; p < 0.001). The mean Hb increase was significantly greater with IV iron versus oral iron at Weeks 6 (0.4 versus - 0.2 g/dL; p < 0.001), 12 (0.5 versus 0.1 g/dL; p < 0.001), and 18 (0.8 versus 0.5 g/dL; p = 0.01). Improvements in fatigue and QoL were greater with IV iron versus oral iron at Weeks 3 and 6. The incidence of treatment-related adverse events was comparable between treatment groups.
CONCLUSION
IV iron was superior in preventing anaemia compared with oral iron in pregnant women with persistent iron deficiency; biochemical superiority was accompanied by improved fatigue and QoL.
CLINICAL TRIAL REGISTRATION
European Clinical Trials Database: EudraCT no.: 2017-000776-29 (3 May 2017); ClinicalTrials.gov: NCT03188445 (13 June 2017). The trial protocol has been published: https://dx.doi.org/10.1186%2Fs13063-020-04637-z .
Topics: Humans; Female; Pregnancy; Ferric Compounds; Anemia, Iron-Deficiency; Administration, Oral; Administration, Intravenous; Trace Elements; Pregnancy Trimester, Second; Denmark; Treatment Outcome; Adult
PubMed: 36107229
DOI: 10.1007/s00404-022-06768-x -
Nutrients Aug 2023Alpha-lipoic acid (ALA) was found to improve the symptoms in patients with diabetic sensorimotor peripheral neuropathy (DSPN) by reducing oxidative stress and... (Meta-Analysis)
Meta-Analysis Review
Alpha-lipoic acid (ALA) was found to improve the symptoms in patients with diabetic sensorimotor peripheral neuropathy (DSPN) by reducing oxidative stress and ameliorating microcirculation. Our meta-analysis is aimed at evaluating the effects of oral-administered ALA versus a placebo in patients with DSPN and determining the optimal dosage for this treatment. We systematically reviewed randomized controlled trials (RCTs) in the PubMed, Embase, and Cochrane databases to determine the efficacy of oral ALA for patients with DSPN. The primary outcome was total symptoms' score (TSS), and secondary outcomes were the neurological disability score (NDS), neuropathy impaired score (NIS), NIS-lower limb (NIS-LL), vibration perception threshold (VPT), nerve conduction study (NCS) results, and global satisfaction. A subgroup analysis of the ALA dosage (600, 1200, and 1800 mg/day) was also conducted. Ten RCTs (1242 patients) were included. ALA treatment produced favorable results for TSS (a dose-related trend was observed), NDS, and the global satisfaction score. For VAS, VPT, NIS-LL, and NCS results, ALA did not produce favorable results. ALA treatment had favorable effects on DSPN by reducing sensory symptoms, and it resulted in a dose-dependent response relative to the placebo for TSS and the global satisfaction score. The use of ALA to prevent neurological symptoms should be further researched.
Topics: Humans; Diabetic Neuropathies; Thioctic Acid; Administration, Oral; Databases, Factual; Lower Extremity; Diabetes Mellitus
PubMed: 37630823
DOI: 10.3390/nu15163634 -
Expert Opinion on Drug Delivery 2023Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins... (Review)
Review
INTRODUCTION
Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes.
AREAS COVERED
This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies.
EXPERT OPINION
Although most current studies on oral protein delivery rely on and animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.
Topics: Animals; Humans; Drug Delivery Systems; Administration, Oral; Proteins; Peptides
PubMed: 37450427
DOI: 10.1080/17425247.2023.2237408 -
Biomaterials Nov 2023Biologics are unaffordable to a large majority of the global population because of prohibitively expensive fermentation systems, purification and the requirement for... (Review)
Review
Biologics are unaffordable to a large majority of the global population because of prohibitively expensive fermentation systems, purification and the requirement for cold chain for storage and transportation. Limitations of current production and delivery systems of biologics were evident during the recent pandemic when <2.5% of vaccines produced were available to low-income countries and ∼19 million doses were discarded in Africa due to lack of cold-chain infrastructure. Among FDA-approved biologics since 2015, >90% are delivered using invasive methods. While oral or topical drugs are highly preferred by patients because of their affordability and convenience, only two oral drugs have been approved by FDA since 2015. A newly launched oral biologic costs only ∼3% of the average cost of injectable biologics because of the simplified regulatory approval process by elimination of prohibitively expensive fermentation, purification, cold storage/transportation. In addition, the cost of developing a new biologic injectable product (∼$2.5 billion) has been dramatically reduced through oral or topical delivery. Topical delivery has the unique advantage of targeted delivery of high concentration protein drugs, without getting diluted in circulating blood. However, only very few topical drugs have been approved by the FDA. Therefore, this review highlights recent advances in oral or topical delivery of proteins at early or advanced stages of human clinical trials using chewing gums, patches or sprays, or nucleic acid drugs directly, or in combination with, nanoparticles and offers future directions.
Topics: Humans; Pharmaceutical Preparations; Administration, Topical; Proteins; Biological Products; Administration, Oral
PubMed: 37690380
DOI: 10.1016/j.biomaterials.2023.122312 -
Genes Dec 2023Globally, oral diseases are common, pose an economic burden, and significantly decline the quality of life of affected individuals. Recently, researchers have...
BACKGROUND
Globally, oral diseases are common, pose an economic burden, and significantly decline the quality of life of affected individuals. Recently, researchers have substantially highlighted the effect of depression on oral disease incidence and development. In this study, we elucidated the correlation between depression and oral diseases.
METHODS
Using two-sample Mendelian randomization (MR), the association between depression and the risk of 17 oral diseases was evaluated. Three methods were used to perform MR analysis: the inverse variance-weighted, weighted median, and MR-Egger methods. Furthermore, Cochran's Q test, MR-Egger intercept test, MR Pleiotropy RESidual Sum and Outlier test, and leave-one-out analysis were performed to analyze sensitivity.
RESULTS
After implementing multiple test corrections, we observed that genetic susceptibility to depression was associated with an increased risk of mouth ulcers, toothache, loose teeth, bleeding gums, painful gums, chronic periodontitis, chronic tonsil and adenoid diseases, peritonsillar abscess, and excessive tooth attrition. However, a causal relationship between depression and other oral diseases was not observed. Sensitivity analysis confirmed the robustness of the results.
CONCLUSIONS
We confirmed the causal relationship between depression and several oral diseases, thereby providing a novel viewpoint on the prevention and treatment of oral diseases. Our findings suggest the integration of depression control into routine clinical care to enhance the effectiveness of oral disease treatment.
Topics: Humans; Depression; Mendelian Randomization Analysis; Quality of Life; Administration, Oral; Causality
PubMed: 38137013
DOI: 10.3390/genes14122191