ABSTRACT

BACKGROUND: Cardiotoxicity occurs in 5-20% of cancer patients who receive anthracyclines. The aim of this study was to pool all the randomized controlled trials (RCTs) investigating the cardio-protective role of statins in patients treated with anthracyclines.

METHODS: PubMed and Scopus electronic databases were scanned for eligible studies up to May 3rd, 2023. A total of 5 RCTs with 808 patients were included. Efficacy endpoints were the rate of anthracycline-mediated cardiotoxicity, the incidence of hospitalization for heart failure (HF), left ventricular ejection fraction (LVEF) value after anthracycline treatment, and ∆LVEF calculated as the difference in LVEF before and after anthracycline therapy. Safety endpoints [i.e., the incidence of muscle pain and serious adverse events (SAE)] were also assessed.

RESULTS: On pooled analysis, the statin-treated group had a lower incidence of cardiotoxicity compared to the placebo group [risk ratio (RR) 0.52, 95% confidence Interval (CI) 0.33-0.83, P = 0.01; I2 = 0%], as well as higher mean LVEF [Mean difference (MD) 1.88, 95% CI 0.66-3.1, P < 0.01; I2 = 57.3%)] and a more favorable ∆LVEF during follow-up (MD 2.38, 95% CI -0.03 - +4.79, P = 0.05; I2 = 99%), despite no significant difference in terms of hospitalization for HF and rate of adverse events. Of note, severe heterogeneity affected the analyses for both LVEF and ΔLVEF.

CONCLUSIONS: The current meta-analysis of all RCTs conducted so far shows an overall beneficial effect of statins on the risk of anthracyclines induced cardiotoxicity and LVEF preservation. No difference was observed in the rate of HF hospitalization. . More powered RCTs are needed to fully investigate the impact of statins on prognosis in patients receiving anthracyclines therapy.

PMID:37527752 | DOI:10.1016/j.ijcard.2023.131219

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PubMed articles on: Cardio-Oncology

Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity

Hum Exp Toxicol. 2023 Jan-Dec;42:9603271231193392. doi: 10.1177/09603271231193392.

ABSTRACT

BACKGROUND: Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway.

METHODS: Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS.

RESULTS: Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection.

CONCLUSION: DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.

PMID:37526264 | DOI:10.1177/09603271231193392

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PubMed articles on: Cardio-Oncology

Neopetroside-B alleviates doxorubicin-induced cardiotoxicity via mitochondrial protection

Biomed Pharmacother. 2023 Jul 29;165:115232. doi: 10.1016/j.biopha.2023.115232. Online ahead of print.

ABSTRACT

Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p < 0.05) and proteins (FC > 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD+/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.

PMID:37523986 | DOI:10.1016/j.biopha.2023.115232

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PubMed articles on: Cancer & VTE/PE

Thrombophilia Gene Mutations Predict Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy

J Thromb Haemost. 2023 Aug 1:S1538-7836(23)00580-9. doi: 10.1016/j.jtha.2023.07.017. Online ahead of print.

ABSTRACT

BACKGROUND: Inherited thrombophilia and cancer both independently increase the risk of venous thromboembolism (VTE). However, whether the increased VTE risk associated with inherited thrombophilia exists in cancer patients is less clear.

OBJECTIVES: Our objective was to determine the influence of inherited thrombophilia on VTE and bleeding risk in moderate-high risk ambulatory cancer patients receiving chemotherapy.

METHODS: We conducted a post-hoc analysis using blood samples from patients enrolled in the AVERT trial to determine if previously recognized thrombophilia gene mutations (Prothrombin FII G20210A, Factor XI, Fibrinogen Gamma, Serpin Family A Member 10, Factor V K858R, Factor XIII, Factor V Leiden (FVL), and ABO blood) were associated with VTE or bleeding during the 7-months after starting chemotherapy. Logistic regression was used comparing heterozygous and homozygous mutations (combined) to wild type. VTE rates, bleeding rates and risk differences for mutations stratified by prophylactic anticoagulation use were calculated.

RESULTS: Of the 447 patients, there were 39 VTE and 39 bleeding events. The odds of VTE were significantly increased with FVL mutation and non-O blood type [OR: 5.2 (95%CI:1.9-14.7) and 2.7 (95%CI:1.2-6.1), respectively]. The use of anticoagulation prophylaxis resulted in complete protection in FVL patients whereas those not receiving anticoagulation had a VTE rate of 119 per 100 patient-years. Lower VTE rates were also observed in non-O blood type patients taking prophylactic anticoagulation. No other thrombophilia genes tested were significantly associated with VTE or bleeding.

CONCLUSIONS: Our results indicate FVL mutation and ABO blood type may be important VTE predictors in cancer patients starting chemotherapy.

PMID:37536569 | DOI:10.1016/j.jtha.2023.07.017

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PubMed articles on: Cancer & VTE/PE

Low-Molecular-Weight Heparin Versus Warfarin in Adult Cancer Patients as a Precision Medicine for Thrombosis: A Systematic Review and Meta-Analysis

Cureus. 2023 Jul 1;15(7):e41268. doi: 10.7759/cureus.41268. eCollection 2023 Jul.

ABSTRACT

Venous thromboembolism (VTE) is a condition often seen in patients diagnosed with cancer and is recognized as a predictor of poor outcomes in these patients. The probability of VTE recurring is generally higher in people with cancer than in those without; hence, addressing this issue is essential when making healthcare decisions. Therefore, our systematic review was primarily designed to compare low-weight- molecular heparin (LMWH) to warfarin in reducing recurrent VTE among cancer patients. However, other outcomes were also evaluated, such as mortality and bleeding events observed more in cancer patients. The selection of relevant articles was carried out using a database search and a manual search, which involved reviewing reference lists of articles eligible for inclusion in the current review. The methodological quality of each included study was then assessed using Cochrane's risk of bias tool in the Review Manager software (RevMan 5.4.1). Additionally, pooled results were examined using the Review Manager software and presented as forest plots. Our search of electronic databases elicited a total of 2163 articles, of which only six were deemed eligible for inclusion and analysis. Data pooled from the six studies demonstrated the effectiveness of LMWH in minimizing the reoccurrence of VTE over warfarin [risk ratio (RR): 0.67; 95% CI: 0.47 - 0.95; p = 0.03]. However, LMWH had a similar effect statistically as warfarin on the major bleeding events (RR: 1.05; 95% CI: 0.62 - 1.77; p = 0.85), minor bleeding events (RR: 0.80; 95% CI: 0.54 - 1.20; p = 0.28), and all-cause mortality (RR: 1.00; 95% CI: 0.88 - 1.13; p = 0.99). While LMWH demonstrated its effectiveness in minimizing the incidence of VTE recurrence over warfarin in cancer patients, it had no statistical difference in terms of mortality or bleeding events when compared to warfarin. Based on our findings, we recommend that LMWH continues to be used as a first-line treatment regimen to mitigate recurrent VTE in cancer patients.

PMID:37533609 | PMC:PMC10390756 | DOI:10.7759/cureus.41268

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PubMed articles on: Cancer & VTE/PE

Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis

Br J Haematol. 2023 Aug 2. doi: 10.1111/bjh.19017. Online ahead of print.

ABSTRACT

Patients with multiple myeloma (MM) are at an elevated risk of venous thromboembolism (VTE), which is further increased for those undergoing anti-myeloma therapy. Current guidelines suggest low-dose direct oral anticoagulants (DOACs) as an alternative to aspirin for primary thromboprophylaxis in this population, but data comparing these two therapies are limited. We performed a systematic review and meta-analysis to compare DOACs with aspirin for primary thromboprophylaxis in individuals undergoing outpatient anti-myeloma therapy. Studies were selected when comparing DOACs versus aspirin for thrombotic and haemorrhagic outcomes. We included 10 randomised controlled trials and observational studies comprising 1026 patients with MM who received primary thromboprophylaxis with DOACs (n = 337) or aspirin (n = 689). DOAC thromboprophylaxis was associated with a significantly lower incidence of VTE compared with aspirin (OR 0.33; 95% CI 0.16-0.68; p < 0.001). Major, clinically relevant non-major and minor bleeding event rates did not differ significantly between groups. Overall, our meta-analysis suggests that DOACs may be a preferable option to aspirin for the prevention of MM-related thrombosis. However, these results should be interpreted in the context of heterogeneous baseline population characteristics and potential bias from including observational studies. Further research is needed to evaluate the optimal thromboprophylaxis strategy, particularly in high-risk individuals.

PMID:37533165 | DOI:10.1111/bjh.19017

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PubMed articles on: Cancer & VTE/PE

Genetic insights into resting heart rate and its role in cardiovascular disease

Nat Commun. 2023 Aug 2;14(1):4646. doi: 10.1038/s41467-023-39521-2.

ABSTRACT

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

PMID:37532724 | DOI:10.1038/s41467-023-39521-2

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PubMed articles on: Cancer & VTE/PE

Prevalence of and Eligibility for Surveillance Without Anticoagulation Among Adults With Lower-Risk Acute Subsegmental Pulmonary Embolism

JAMA Netw Open. 2023 Aug 1;6(8):e2326898. doi: 10.1001/jamanetworkopen.2023.26898.

ABSTRACT

IMPORTANCE: Approximately 8% of acute pulmonary emboli are confined to the subsegmental arteries. The 2016 and 2021 American College of Chest Physicians (CHEST) guidelines and expert panel reports suggest the use of structured surveillance without anticoagulation for select ambulatory patients with subsegmental pulmonary embolism who do not have active cancer, deep vein thrombosis, impaired cardiopulmonary reserve, marked symptoms, or increased risk of recurrent venous thromboembolism; however, guideline uptake in community practice is unknown, as is the proportion of outpatients eligible for surveillance.

OBJECTIVE: To describe the prevalence of surveillance among outpatients with acute subsegmental pulmonary embolism and to estimate the proportion of patients eligible for structured surveillance using modified CHEST criteria.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted across 21 US community hospitals in the Kaiser Permanente Northern California integrated health system from January 1, 2017, to December 31, 2021. Adult outpatients with acute subsegmental pulmonary embolism were included. Patients with the following higher-risk characteristics were excluded: codiagnoses requiring hospitalization, non-low-risk vital signs (ie, systolic blood pressure <90

MAIN OUTCOMES AND MEASURES: The main outcomes were the (1) prevalence of surveillance and (2) eligibility for surveillance using 2 sets of criteria: the CHEST criteria modified by excluding patients with higher-risk characteristics or right ventricular dysfunction and a stricter set of criteria requiring age younger than 65 years and no more than 1 embolus. The prevalence of structured surveillance was calculated and the proportion of patients eligible for surveillance was estimated.

RESULTS: Of the 666 outpatients with acute subsegmental pulmonary embolism included in this study, 229 with lower-risk characteristics were examined. Their median age was 58 (IQR, 42-68) years; more than half were men (120 [52.4%]) and self-identified as non-Hispanic White (128 [55.9%]). Six patients (2.6%) were initially not treated with anticoagulants. Among the lower-risk cohort, only 1 patient (0.4% [95% CI, 0.01%-2.4%]) underwent structured surveillance, without 90-day sequelae. Thirty-five patients (15.3% of the lower-risk group and 5.3% of the full cohort) were surveillance eligible using modified CHEST criteria. Fifteen patients (6.6% of the lower-risk group and 2.3% of the full cohort) were surveillance eligible using stricter criteria.

CONCLUSIONS AND RELEVANCE: In this cohort study of lower-risk outpatients with subsegmental pulmonary embolism, few were eligible for structured surveillance, and only a small proportion of eligible patients underwent surveillance despite the CHEST guideline. If forthcoming trials find surveillance safe and effective, substantial uptake into clinical practice may require more than passive diffusion.

PMID:37531107 | DOI:10.1001/jamanetworkopen.2023.26898

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PubMed articles on: Cancer & VTE/PE

A novel risk prediction score for clinically significant bleeding in patients anticoagulated for venous thromboembolism with active cancer

Thromb Haemost. 2023 Aug 1. doi: 10.1055/a-2145-7238. Online ahead of print.

ABSTRACT

BACKGROUND: Cancer associated venous thromboembolism (Ca-VTE) treatment with anticoagulation is associated with bleeding complications and there are limited data on risk factors. Current models do not provide accurate bleeding risk prediction.

METHODS: UK Clinical Practice Research Datalink data (2008-2020) was used to generate a cohort of patients with anticoagulant initiation for first Ca-VTE. Patients were observed up to 180 days for significant bleeding including major bleeding, and clinically relevant non-major bleeding requiring hospitalisation (CRNMB-H). A scoring scheme was developed from subdistribution hazard ratios, and its discrimination (expressed by the C-statistic) estimated from cross-validation.

RESULTS: 15,749 patients with Ca-VTE and anticoagulant treatment were included. In total, 537 significant bleeding events, 161 major bleeds and 376 CRNMB-H were identified after adjudicated review in 4914 person-years of observation. Incidence rates of 3.3 and 7.7 per 100 person-years were noted for major bleeding and CRNMB-H. Independent predictors of significant bleeding were cancer of the bladder, central nervous system, cervix, kidney, melanoma, prostate and upper gastrointestinal tract. Overall C-statistic for significant bleeding was 0.70, and 0.76 and 0.67 for major bleeding and for CRNMB-H, respectively.

CONCLUSIONS: This risk score may identify patients at risk of significant bleeding, while also helping to determine treatment duration.

PMID:37527782 | DOI:10.1055/a-2145-7238

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PubMed articles on: Cancer & VTE/PE

Intravascular Tumor Extension and Pulmonary Tumor Embolism in Children With Solid Malignancies: Is There a Role for Inferior Vena Cava Filters?

J Pediatr Hematol Oncol. 2023 Jul 27. doi: 10.1097/MPH.0000000000002731. Online ahead of print.