Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT

Background - The randomized, placebo-controlled COLchicine Cardiovascular Outcomes Trial (COLCOT) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post-hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods - There were 1522 participants of European descent from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular (CV) endpoint was defined as for the main trial, as time to first occurrence of CV death, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina requiring coronary revascularization. The safety endpoint was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study (GWAS) in colchicine-treated patients. Results - None of the genetic variants passed the GWAS significance threshold for the primary CV endpoint conducted in 702 patients in the colchicine arm who were compliant to medication. The GWAS for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found two significant association signals, one with lead variant rs6916345 (hazard ratio (HR)=1.89, 95% confidence interval (CI) 1.52-2.35, P=7.41×10 -9 ) in a locus which colocalizes with Crohn's disease, and one with lead variant rs74795203 (HR= 2.51, 95% CI 1.82-3.47; P=2.70×10 -8 ), an intronic variant in gene SEPHS1 . The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions - We found two genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

Early discontinuation and dose reduction of adjuvant chemotherapy in stage III colon cancer patients

Background: The benefit of chemotherapy in colon cancer patients is well documented but depends largely on whether patients complete the planned treatment regimen. We evaluated predictors of early discontinuation (EDChemo) and dose reduction of chemotherapy, especially the role of adverse treatment effects, in stage III patients who received adjuvant chemotherapy. Methods: Stage III colon cancer patients who were diagnosed in 2003–2014 and recruited into a population-based study in Germany and received FOLFOX [5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin], capecitabine monotherapy (CapMono), or 5-FU/LV were included. We assessed determinants of EDChemo and dose reduction using multivariable logistic regression. Also, we estimated proportions of EDChemo and dose reduction that are attributable to adverse effects using attributable fractions. Results: EDChemo and dose reduction rates were 52% and 17% for FOLFOX, 28% and 9% for CapMono, and 45% and 6% for 5-FU/LV, respectively. Predictors of EDChemo were low-grade tumor and treatment in a medium-volume hospital (for FOLFOX), obesity (for CapMono), and increasing age, T4 stage, and treatment in a medium-volume hospital (for 5-FU/LV). Adverse effects were particularly strongly associated with EDChemo and contributed to about 63%, 51%, and 32% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Of the various adverse effects, gastrointestinal events showed the strongest associations with EDChemo and accounted for about 7%, 26%, and 20% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Adverse effects were, moreover, a strong determinant of dose reduction and accounted for about 82% of all cases. Conclusions: EDChemo is common in stage III colon cancer patients receiving chemotherapy and more than half of the cases of EDChemo and dose reduction are due to adverse treatment effects. Further research should address the potential for reducing EDChemo and dose reduction rates by close monitoring of patients for early signs and enhanced management of adverse effects, especially gastrointestinal events.

Clofazimine: Can it be Useful in COVID 19?

Clofazimine is a riminophenazine dye originally used as an antitubercular agent after its first synthesis in 1954, just few years after it was administered as a treatment for leprosy by YT Chang. In the following years, also an anti-inflammatory effectiveness on erythema nodosum leprosum was recognized [1]. In the ‘70s, its therapeutic activity on discoid lupus erythematosus and pyoderma gangrenosum was documented [2]. The safety of Clofazimine is good with a median frequency of the most reported adverse event (skin discoloration and gastrointestinal events) of 5.1% and a requiring discontinuation of the treatment in 0.1% of cases [3].

No Differences in Gastrointestinal Bleeding Risk among Clopidogrel-, Ticagrelor-, or Prasugrel-Based Dual Antiplatelet Therapy

The risk for gastrointestinal bleeding from dual antiplatelet therapy (DAPT) with new antiplatelets (prasugrel/ticagrelor) compared to clopidogrel is unclear. Aim: To determine the risk and type of major (gastrointestinal bleeding requiring hospitalization) and minor (anemia and iron deficiency) gastrointestinal events with different types of DAPT. Methods: Retrospective observational cohort study of patients who started DAPT after percutaneous coronary intervention. Follow-up was censored after 12 months of DAPT, when a major gastrointestinal event occurred, or when DAPT was discontinued. Results: Among 1,327 patients (54.03% were treated with clopidogrel-based DAPT, 38.13% with ticagrelor-based DAPT, and 7.84% with prasugrel-based DAPT), 29.5% had at least one gastrointestinal event. Patients taking clopidogrel-DAPT were older, with more comorbidities, and higher gastrointestinal risk compared to those taking other DAPT regimens. Adjusted hazard ratios (HRs) showed no between-group differences in the risk for major (clopidogrel vs. new antiplatelets: HR 0.996; 95% confidence interval 0.497–1.996) and minor (HR 0.920; 0.712–1.189) gastrointestinal events. Most patients received proton pump inhibitors while on DAPT (93.3%) and after withdrawal (83.2%). Conclusion: Prasugrel- or ticagrelor-based DAPT was not associated with increased gastrointestinal bleeding risk when compared to clopidogrel-DAPT. New antiplatelets do not necessarily need to be restricted to patients with low gastrointestinal risk.