Association of checkpoint inhibitor monotherapy with less cardiac toxicity than combination therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 671-671 ◽  
Author(s):  
Eugene Blanchard Cone ◽  
Stephen Reese ◽  
Maya Marchese ◽  
Junaid Nabi ◽  
Kerry L. Kilbridge ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Cardiac Toxicity ◽  
Checkpoint Inhibitors ◽  
Cardiac Risk ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Cardiac Events ◽  
Nccn Guidelines ◽  
Health Organization

671 Background: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting. Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p = 0.003) respectively. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.

scholarly journals Immune Checkpoint Inhibitor Monotherapy is Associated With Less Cardiac Toxicity Than Combination Therapy

2021 ◽  
Author(s):  
Eugene B. Cone ◽  
Lorine Haeuser ◽  
Stephen Reese ◽  
Maya Marchese ◽  
David-Dan Nguyen ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Pharmacovigilance Database ◽  
Health Organization

Abstract Background: Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy.Methods: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.Results: We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis(ROR 6.9, 95% CI: 5.6–8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4).Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to15.8% for ICI monotherapy (P = 0.058).Conclusions: Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy.Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.

Lower odds of cardiac events for gonadotropic releasing hormone antagonists versus agonists.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 34-34 ◽  
Author(s):  
Eugene Blanchard Cone ◽  
Maya Marchese ◽  
Stephen Reese ◽  
Junaid Nabi ◽  
Kerry L. Kilbridge ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Myocardial Infarction ◽  
Cardiac Toxicity ◽  
World Health ◽  
Reporting Odds Ratio ◽  
Gnrh Agonists ◽  
Cardiac Events ◽  
First Line ◽  
Gnrh Antagonists ◽  
Releasing Hormone

34 Background: Gonadotropic releasing hormone (GnRH) agonists and antagonists are first-line for advanced prostate cancer, but may be associated with cardiac toxicity. Observational studies show a relatively lower risk for GnRH antagonists, but a randomized trial found no difference. We compared the reporting of cardiac events for GnRH agonists and antagonists. Methods: We used VigiBase, the World Health Organization global database of case safety reports, which collects data from more than 130 countries to extract drug-adverse event (AE) pairs. Using Medical Dictionary for Regulatory Activities terminology, we identified AEs related to GnRH antagonist (degarelix) or agonist (leuprolide, goserelin, triptorelin, histrelin) therapy for prostate cancer, including myocardial infarction, heart failure, cardiomyopathies, new-onset valvular dysfunction, and other major cardiac events. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected. Results: We found 10,504 AEs for GnRH agonists, and 1,606 for GnRH antagonists; 805 (7.7%) were cardiac for agonists, and 102 for antagonists (6.4%). We found no signal for overall cardiac events or any subgrouping for GnRH antagonists, but identified a signal both for overall cardiac events (ROR 1.20, 95% CI 1.12-1.29) and myocardial infarction (1.76, 1.57-1.97) for GnRH agonists. Conclusions: Using validated pharmacovigilance methodology, we found a signal for myocardial infarction for GnRH agonists, but did not detect one for GnRH antagonists. As cardiovascular disease is the most common cause of non-cancer death in prostate cancer patients, this finding is of specific relevance in the current era of novel second-line anti-androgen therapies which may compound toxicity when added to first-line therapy. The relative cardiac toxicity of GnRH agonist therapy compared to GnRH antagonists merits renewed attention.

Association of abiraterone and higher odds of cardiac complications compared to enzalutamide.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 70-70 ◽  
Author(s):  
Eugene Blanchard Cone ◽  
Stephen Reese ◽  
Maya Marchese ◽  
Junaid Nabi ◽  
Kerry L. Kilbridge ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Standard Of Care ◽  
Individual Case ◽  
Cardiac Risk ◽  
World Health ◽  
Cardiac Complications ◽  
Reporting Odds Ratio ◽  
Cardiovascular Risks ◽  
Cardiac Events ◽  
Resistant Disease

70 Background: The standard of care for advanced prostate cancer is androgen deprivation therapy (ADT). The novel second generation agents abiraterone and enzalutamide were initially approved in castration resistant disease, but are now being used in the hormone sensitive setting. The FDA issued a 2010 warning about cardiovascular risks associated with ADT, but the risk of novel agents is less well understood, especially in comparison to each other. We sought to define the comparative cardiac risk profile of enzalutamide and abiraterone. Methods: We used VigiBase, the World Health Organization database of individual case safety reports, which collects data from more than 130 countries to identify drug associated adverse events (AE). Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac AEs related to abiraterone or enzalutamide therapy for prostate cancer. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: Vigibase contained 8203 AEs for abiraterone and 26024 for enzalutamide; 808 (9.9%) were cardiac-related for abiraterone, and 1000 for enzalutamide (3.8%). We found no disproportionality signal for cardiac events or any subtype for enzalutamide, but identified significantly higher odds of overall cardiac events (ROR 1.64, 95% CI 1.53—1.76), myocardial infarction (1.34, 1.17—1.58), arrythmia (2.09, 1.87—2.34), and heart failure (3.35, 2.92—3.85) for patients taking abiraterone. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of cardiac events for abiraterone but not for enzalutamide. Clinicians may need to consider these findings in the context of their patients’ comorbidities when prescribing ADT.

scholarly journals Immune checkpoint inhibitor-associated thyroid dysfunction: a disproportionality analysis using the WHO Adverse Drug Reaction Database, VigiBase

2020 ◽  
Vol 182 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Xuefeng Bai ◽  
Xiaoyu Chen ◽  
Xiaohong Wu ◽  
Yinqiong Huang ◽  
Yong Zhuang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Thyroid Dysfunction ◽  
Checkpoint Inhibitors ◽  
Reporting Odds Ratio ◽  
Information Component ◽  
Thyrotoxic Crisis ◽  
Medical Dictionary ◽  
Thyroid Dysfunctions

Objective Our study aimed to identify and characterize thyroid dysfunctions associated with immune checkpoint inhibitors (ICIs). Design Data were obtained from VigiBase, between January 1, 2011 to March 6, 2019. Methods All thyroid drug-adverse events are classified by group queries according to the Medical Dictionary for Regulatory Activities. Information component (IC) and reporting odds ratio (ROR) were considered as measures of disproportionality for the assessment of association between ICIs and thyroid dysfunctions. We used IC to identify meaningful drug-adverse events while using ROR to compare differences in the reporting of drug-adverse events caused by different ICI subgroups. Positive IC values are deemed significant. Results Compared with the full database, the following ICI-associated thyroid dysfunctions were over-reported: hypothyroidism (1125 reports for ICIs vs 12495 for all drugs; Information Component 4.28 (95% CI: 4.18–4.35)), hyperthyroidism (926 vs 7538; 4.66 (95% CI: 4.55–4.74)), thyroiditis (294 vs 1237; 5.40 (95% CI: 5.21–5.54)), thyrotoxic crisis (11 vs 288; 3.55 (95% CI: 2.61–4.20)). Hypothyroidism was over-reported for patients treated with ICI combination therapy versus those treated with ICI monotherapy (ROR 1.3 (95% CI: 1.1–1.7)), and the same was observed for hyperthyroidism (ROR: 1.9 (95% CI: 1.5–2.4)), thyroiditis (ROR: 3.3 (95% CI: 2.3–4.8)), thyrotoxic crisis (ROR: 11.5 (95% CI: 2.4–53.8)). All 11 thyrotoxic crisis cases were malignant melanoma patients, of which seven occurred under ICI combination therapy. Conclusions Thyroid dysfunction may occur after ICI therapies, and severe thyrotoxic crisis may even occur. Raising awareness of ICI-associated thyroid dysfunction can improve the detection and treatment of these diseases.

scholarly journals Low-dose amikacin in the treatment of Multidrug-resistant Tuberculosis (MDR-TB)

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Natasha F. Sabur ◽  
Mantaj S. Brar ◽  
Lisa Wu ◽  
Sarah K. Brode
Keyword(s):  
Hearing Loss ◽  
Adverse Events ◽  
Low Dose ◽  
Multidrug Resistant ◽  
Significant Rise ◽  
World Health ◽  
Therapeutic Drug ◽  
Successful Treatment Outcome ◽  
Mdr Tb ◽  
Health Organization

Abstract Background The World Health Organization recommends intravenous amikacin for the treatment of MDR-TB at a dose of 15 mg/kg. However, higher doses are associated with significant toxicity. Methods Patients with MDR-TB treated at our institution receive amikacin at 8–10 mg/kg, with dose adjustment based on therapeutic drug monitoring. We conducted a retrospective cohort study of patients with MDR-TB who received amikacin between 2010 and 2016. Results Forty-nine patients were included in the study. The median starting dose of amikacin was 8.9 mg/kg (IQR 8, 10), and target therapeutic drug levels were achieved at a median of 12 days (IQR 5, 26). The median duration of amikacin treatment was 7.2 months (IQR 5.7, 8), and median time to sputum culture conversion was 1 month (IQR 1,2). Six patients (12.2%) experienced hearing loss based on formal audiometry testing (95% CI 4.6–24.8%); 22.2% had subjective hearing loss (95% CI 11.2–37.1%) and 31.9% subjective tinnitus (95% CI 19.1–47.1%). Ten patients (23%) had a significant rise in serum creatinine (95% CI 11.8–38.6%), but only 5 patients had a GFR < 60 at treatment completion. 84% of patients had a successful treatment outcome (95% CI 84–99%). Conclusions Low dose amikacin is associated with relatively low rates of aminoglycoside-related adverse events. We hypothesize that low-dose amikacin can be used as a safe and effective treatment for MDR-TB in situations where an adequate regimen cannot be constructed with Group A and B drugs, and where careful monitoring for adverse events is feasible.

scholarly journals Continued low efficacy of artemether-lumefantrine in Angola, 2019

2020 ◽  
Author(s):  
Pedro Rafael Dimbu ◽  
Roberta Horth ◽  
Ana Luisa M. Cândido ◽  
Carolina Miguel Ferreira ◽  
Felismina Caquece ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Confidence Interval ◽  
Microsatellite Markers ◽  
Therapeutic Efficacy ◽  
World Health ◽  
The Third ◽  
Kaplan Meier ◽  
Late Failure ◽  
Health Organization ◽  
Parasitological Response

Background: Biennial therapeutic efficacy monitoring is a crucial activity for ensuring efficacy of currently used artemisinin-based combination therapy in Angola. Methods: Children with acute uncomplicated P. falciparum infection in sentinel sites in Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate amodiaquine (ASAQ) and followed for 28 days to assess clinical and parasitological response. Molecular correction was performed using seven microsatellite markers. Samples from treatment failures were genotyped for the pfk13, pfcrt, and pfmdr1 genes. Results: Day 3 clearance rates were ≥95% in all arms. Uncorrected Day-28 Kaplan-Meier efficacy estimates ranged from 84.2 to 90.1% for the AL arms, and 84.7 to 100% for the ASAQ arms. Corrected Day-28 estimates were 87.6% (95% Confidence interval [CI]: 81–95%) for the AL arm in Lunda Sul, 92.2% (95%CI: 87-98%) for AL in Zaire, 95.6% (95%CI: 91-100%) for ASAQ in Zaire, 98.4% (95%CI: 96-100%) for AL in Benguela, and 100% for ASAQ in Benguela and Lunda Sul. All 103 analyzed samples had wildtype pfk13 sequences. The 76T pfcrt allele was found in most (92%, 11/12) ASAQ late failure samples but only 16% (4/25) of AL failure samples. The N86 pfmdr1 allele was found in 97% (34/35) of treatment failures. Conclusion: AL efficacy in Lunda Sul was below the 90% World Health Organization threshold, the third time in four rounds that this threshold was crossed for an AL arm in Angola. In contrast, observed ASAQ efficacy has not been below 95% to date in Angola, including this latest round.

scholarly journals Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report

2019 ◽  
Vol 54 (6) ◽  
pp. 1901522 ◽  
Author(s):  
Sergey Borisov ◽  
Edvardas Danila ◽  
Andrei Maryandyshev ◽  
Margareth Dalcolmo ◽  
Skaidrius Miliauskas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Active Drug ◽  
Clinical Information ◽  
World Health ◽  
Drug Resistant ◽  
Serious Adverse Events ◽  
Resistant Tuberculosis ◽  
Drug Safety Monitoring ◽  
Grade 3 ◽  
Health Organization

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Single-Fractionated Stereotactic Radiosurgery for Intracranial Meningioma in Elderly Patients: 25-Year Experience at a Single Institution

2017 ◽  
Vol 14 (4) ◽  
pp. 341-350 ◽  
Author(s):  
Hirotaka Hasegawa ◽  
Shunya Hanakita ◽  
Masahiro Shin ◽  
Tomoyuki Koga ◽  
Wataru Takahashi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Elderly Patients ◽  
Stereotactic Radiosurgery ◽  
Therapeutic Option ◽  
Univariate Analysis ◽  
Local Tumor Control ◽  
World Health ◽  
Tumor Control ◽  
Intracranial Meningioma ◽  
Health Organization

Abstract BACKGROUND Stereotactic radiosurgery (SRS) has been accepted as a therapeutic option for intracranial meningiomas; however, the detailed data on outcomes in elderly patients remain unclear. OBJECTIVE To delineate the efficacy of SRS for meningiomas in elderly patients. METHODS The outcomes of 67 patients aged ≥65 yr who underwent SRS for benign intracranial meningioma (World Health Organization grade I) between 1990 and 2014 at our institution were retrospectively analyzed. The median age was 71 yr (range, 65-83 yr), and the mean and median follow-up were 62 and 52 mo (range, 7-195 mo), respectively. Tumor margins were irradiated with a median dose of 16 Gy, and the median tumor volume was 4.9 cm3 (range, 0.7-22.9 cm3). RESULTS Actuarial local tumor control rates at 3, 5, and 10 yr after SRS were 92%, 86%, and 72%, respectively. Previous surgery and parasagittal/falcine location were statistically significant predictive factors for failed tumor control. Mild or moderate adverse events were noted in 9 patients. No severe adverse event was observed. A higher margin dose was significantly associated with adverse events by univariate analysis. CONCLUSION SRS is one of the standard therapies for meningiomas in elderly patients, providing both favorable tumor control and a low risk of adverse events under minimum invasiveness.

scholarly journals SARS-CoV-2 Infection and Cardioncology: From Cardiometabolic Risk Factors to Outcomes in Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3316
Author(s):  
Vincenzo Quagliariello ◽  
Annamaria Bonelli ◽  
Antonietta Caronna ◽  
Gabriele Conforti ◽  
Martina Iovine ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cancer Patients ◽  
World Health ◽  
Fulminant Myocarditis ◽  
Cardiac Events ◽  
Risk Of Death ◽  
Cardiovascular Side Effects ◽  
Viral Illness ◽  
Health Organization ◽  
Gastro Intestinal Tract

The coronavirus disease-2019 (COVID-19) is a highly transmissible viral illness caused by SARS-CoV-2, which has been defined by the World Health Organization as a pandemic, considering its remarkable transmission speed worldwide. SARS-CoV-2 interacts with angiotensin-converting enzyme 2 and TMPRSS2, which is a serine protease both expressed in lungs, the gastro-intestinal tract, and cardiac myocytes. Patients with COVID-19 experienced adverse cardiac events (hypertension, venous thromboembolism, arrhythmia, myocardial injury, fulminant myocarditis), and patients with previous cardiovascular disease have a higher risk of death. Cancer patients are extremely vulnerable with a high risk of viral infection and more negative prognosis than healthy people, and the magnitude of effects depends on the type of cancer, recent chemotherapy, radiotherapy, or surgery and other concomitant comorbidities (diabetes, cardiovascular diseases, metabolic syndrome). Patients with active cancer or those treated with cardiotoxic therapies may have heart damages exacerbated by SARS-CoV-2 infection than non-cancer patients. We highlight the cardiovascular side effects of COVID-19 focusing on the main outcomes in cancer patients in updated perspective and retrospective studies. We focus on the main cardio-metabolic risk factors in non-cancer and cancer patients and provide recommendations aimed to reduce cardiovascular events, morbidity, and mortality.

scholarly journals Two Hyperparasitaemic Plasmodium Falciparum Cases Successfully Treated with Artemisinin-based Combination Therapy

2020 ◽  
Author(s):  
Benudhar Mukhi ◽  
Anupkumar R. Anvikar ◽  
Bina Srivast ◽  
Himanshu Gupta ◽  
Susanta Kumar Ghosh
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Malaria Diagnosis ◽  
World Health ◽  
Host Responses ◽  
Reference Ranges ◽  
Female Ratio ◽  
Health Organization ◽  
Complications And Mortality ◽  
Male To Female

Abstract BackgroundHyperparasitaemia is an important event in a cascade of Plasmodium falciparum severe malaria (SM) but requires host responses to cause cerebral malaria (CM) leading to death, if left untreated. Here, we report two hyperparasitaemic patients with no CM.MethodsMalaria diagnosis was performed based on thick and thin smears examination, and immunochromatographic-based rapid diagnostic test assay. Parasitaemia was calculated following World Health Organization (WHO) protocol. Haematological and biochemical investigations were also performed. ResultsThe first patient had 42% parasitaemia (100% asexual parasites). The second one had 9.5% parasitaemia comprising 46% asexual, and 54% sexual stages with 1:1 male to female ratio. On the day of admission, both had presented abnormal haematological and biochemical parameters compared to the reference ranges. Remarkably, both the patients recovered successfully with oral artemisinin-based combination therapy (ACT) and a single dose of primaquine.ConclusionThe presence of hypergametocytaemia may hinder the elimination efforts, if not treated immediately. This report also signifies the need of accurately estimating the parasitaemia in malaria patients and their timely management to prevent complications and mortality.

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