ABSTRACT

BACKGROUND: Filgotinib (FIL) is a selective JAK1 inhibitor with an affinity 30-fold higher than JAK2, approved to treat moderate to severe active rheumatoid arthritis (RA), in adults with inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

METHODS: We conducted a retrospective, multicentric study in order to evaluate efficacy and safety of FIL 200 mg daily therapy, after 3 and 6 months, in 120 patients affected by RA, managed in Tuscany and Umbria rheumatological centers. The following clinical records were analyzed: demographical data, smoking status, previous presence of comorbidities (Herpes zoster -HZ- infection, venous thromboembolism -VTE-, major adverse cardiovascular events -MACE-, cancer, diabetes, and hypertension), disease duration, presence of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), number of biological failures, and prior csDMARDs utilized. At baseline, and after 3 (T3) and 6 (T6) months of FIL therapy, we evaluated mean steroid dosage, csDMARDs intake, clinimetric indexes (DAS28, CDAI, HAQ, patient and doctor PGA, VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and body mass index (BMI).

RESULTS: At baseline, the mean disease duration was 9.4 ± 7.5 years; the prevalence of previous HZ infection, VTE, MACE, and cancer was respectively 4.12%, 0%, 7.21%, and 0.83%, respectively. In total, 76.3% of patients failed one or more biologics (one biological failure, 20.6%; two biological failures, 27.8%; three biological failures, 16.5%; four biological failures, 10.3%; five biological failures, 1.1%). After 3 months of FIL therapy, all clinimetric index results significantly improved from baseline, as well as after 6 months. Also, ESR and CRP significatively decreased at T3 and T6. Two cases of HZ were recorded, while no new MACE, VTE, or cancer were recorded during the observation time.

CONCLUSION: Despite the limitations of the retrospective study and of the observational period of only 6 months, real-life data on the treatment of RA patients with FIL demonstrate that this Jak inhibitor therapy is safe in terms of CV, VTE events, and occurrence of cancer, and is also effective in a population identified as "difficult to treat" due to failure of previous b-DMARD therapy.

PMID:37763071 | PMC:PMC10532886 | DOI:10.3390/jpm13091303

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PubMed articles on: Cancer & VTE/PE

Oral Anticoagulants Beyond Warfarin

Annu Rev Pharmacol Toxicol. 2023 Sep 27. doi: 10.1146/annurev-pharmtox-032823-122811. Online ahead of print.

ABSTRACT

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. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37758192 | DOI:10.1146/annurev-pharmtox-032823-122811

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PubMed articles on: Cardio-Oncology

Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction

Int J Mol Sci. 2023 Sep 7;24(18):13826. doi: 10.3390/ijms241813826.

ABSTRACT

The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy.

PMID:37762130 | PMC:PMC10531061 | DOI:10.3390/ijms241813826

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Cardiotoxicity News

PubMed articles on: Cancer & VTE/PE

A case report: A patient rescued by VA-ECMO after cardiac arrest triggered by trigeminocardiac reflex after nasal surgery

Medicine (Baltimore). 2023 Sep 29;102(39):e35226. doi: 10.1097/MD.0000000000035226.

ABSTRACT

RATIONALE: Cardiac arrest (CA) caused by trigeminocardiac reflex (TCR) after endoscopic nasal surgery is rare. Hence, when a patient suffers from TCR induced CA in the recovery room, most doctors may not be able to find the cause in a short time, and standard cardiopulmonary resuscitation and resuscitation measures may not be effective. Providing circulatory assistance through venous-arterial extracorporeal membrane oxygenation (VA-ECMO) can help healthcare providers gain time to identify the etiology and initiate symptom-specific treatment.

PATIENT CONCERNS: We report a rare case of CA after endoscopic nasal surgery treated with VA-ECMO.

DIAGNOSES: We excluded myocardial infarction, pulmonary embolism, allergies, hypoxia, and electrolyte abnormalities based on the relevant examination results. Following a multidisciplinary consultation, clinical manifestation and a review of previous literature, we reasoned that the CA was due to TCR.

INTERVENTIONS: VA-ECMO was established to resuscitate the patient successfully during effective cardiopulmonary resuscitation.

OUTCOMES: ECMO was successfully evacuated a period of 190 minutes of therapy. The patient was discharged home on day 8.

LESSONS: TCR is notable during endoscopic nasal surgery. Our case indicates that CA in operating room is worth prolonged CCPR. The ideal time for ECPR implementation should not be limited within 20 minutes after CCPR.

PMID:37773828 | DOI:10.1097/MD.0000000000035226

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PubMed articles on: Cardio-Oncology

Early Echocardiography and ECG Changes Following Radiotherapy in Patients with Stage II-III HER2-Positive Breast Cancer Treated with Anthracycline-Based Chemotherapy with or without Trastuzumab-Based Therapy

Med Sci Monit. 2023 Sep 20;29:e941754. doi: 10.12659/MSM.941754.

ABSTRACT

BACKGROUND Cardiotoxicity from radiotherapy and anti-cancer therapies have been reported in patients with breast cancer. This study aimed to investigate the early echocardiography and ECG changes following radiotherapy in 68 patients ages 30-78 years with stages II-III HER2-positive breast cancer treated with anthracycline-based chemotherapy with or without trastuzumab-based therapy from 2015 to 2021. MATERIAL AND METHODS We analyzed data of 68 breast cancer patients aged 30-78 years, predominantly in AJCC stages II-III (61) and HER2-positive (58), treated and monitored from 2015 to 2021. Cardiac function was assessed using echo- and electrocardiography. We employed univariate logistic models to gauge associations between pre-existing cardiac conditions, treatment modalities, and changes in cardiac function. RESULTS A decrease in the left ventricle ejection fraction (EF) by >5% was associated with heart doses >49.3 Gy and with maximum and average doses to the left anterior descending artery (LAD) exceeding 46.9 Gy and 32.7 Gy, respectively. An EF drop of ≥10% was correlated with anti-HER2 therapy, pre-existing ECG changes, and the onset of conditions in the left ventricle, major vessels, and valves. Conditions were exacerbated in patients with prior echocardiographic abnormalities, while some emerged concurrent with the EF decline. CONCLUSIONS This research emphasizes the importance of personalized heart monitoring and care for breast cancer patients undergoing multimodal therapies. Significant and potentially irreversible EF declines can result from radiation and anti-HER2 treatments.

PMID:37772333 | DOI:10.12659/MSM.941754

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PubMed articles on: Cancer & VTE/PE

Venous Thromboembolism Chemoprophylaxis Adherence Rates After Major Cancer Surgery

JAMA Netw Open. 2023 Sep 5;6(9):e2335311. doi: 10.1001/jamanetworkopen.2023.35311.