CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD).

BACKGROUND: Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. METHODS: GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. CONCLUSION: The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

The oncological and surgical safety of robot-assisted surgery in colorectal cancer: outcomes of a longitudinal prospective cohort study.

BACKGROUND: Colorectal cancer is one of the most common cancers worldwide. Laparoscopic colorectal surgery (LCRS) is a frequently used modality. A new development in minimally invasive surgery is robot-assisted colorectal surgery (RACRS). METHODS: Prospectively collected data of 378 consecutive patients who underwent RACRS or LCRS for stage I-III colorectal cancer from Dec 2014 to Oct 2017 were analyzed. Primary outcome was oncological outcome (radical margins, number of retrieved lymph nodes, locoregional recurrence). Secondary outcomes were distant metastases, overall and disease-free survival, operation time, conversion, length of hospital stay, and intra- and post-operative complications. RESULTS: 206 RACRS (129 colon and 77 rectal) and 172 LCRS (138 colon and 34 rectal) procedures were included. Baseline characteristics were similar. Overall median follow-up time was 15 months (0.2-36). Oncological outcome was similar. In colon cancer, radical margins were achieved in 99.3% in RACRS group versus 98.6% in LCRS group (p = 0.60), the average number of harvested lymph nodes was 16 ± 6 versus 18 ± 7 (p = 0.16), and locoregional recurrence rate in 24 months was 3.8% vs 3.8% (p = 0.99), respectively. In rectal cancer, radical margins were achieved in 89.6% in RACRS group versus 94.3% in LCRS group (p = 0.42), the average number of harvested lymph nodes was 16 ± 8 versus 15 ± 4 (p = 0.51), and locoregional recurrence rate in 24 months was 9.5 versus 5.6% (p = 0.42), respectively. Incidence of metastasis, survival rates, operation time, length of hospital stay, and number of severe post-operative complications measured by Clavien-Dindo scores did not differ between RACRS and LCRS groups. Conversion and intra-operative complication rates were significantly lower in the RACRS group as compared to the LCRS group (3% vs 9%, p = 0.008 and 2% vs 8%, p = 0.003, respectively). CONCLUSION: RACRS is safe in the treatment of patients with stage I-III colorectal cancer. Oncological outcome did not differ between RACRS and LCRS groups. RACRS had lower conversion and intra-operative complication rates.