IN CONTROL II

The aim of the LoDoCo2 (Low Dose Colchicine for secondary prevention of cardiovascular disease) trial was to investigate the effect of low dose colchicine (0,5 mg once daily) on the risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. While the precise mechanism through which colchicine mitigates major cardiovascular events remains incompletely understood, it is hypothesized that its anti-inflammatory effects contribute to risk reduction among patients with established atherosclerotic disease. LoDoCo2 stands out in several respects. It represents a large-scale randomized clinical trial conducted entirely by a non-academic network of cardiologists and a consortium of pharmaceutical companies with a focus on drug repurposing. This trial underscores the potential value of older, often cost-effective medications in advancing the development of new innovative drugs. The Research Following a median follow-up period of 3 years, the addition of colchicine to standard treatment resulted in a 30% reduction in risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. Patients treated with colchicine exhibited similar side effects compared to those receiving a placebo. Furthermore, no interactions were found with other commonly used drugs such as (potent) statins. In 2021, certain international guidelines had already incorporated colchicine into the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Subsequently, in 2023, the Food and Drug Administration (FDA) approved Lodoco® (colchicine) for reducing the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular (CV) death in adult patients with established atherosclerotic disease or multiple risk factors for CV disease. This approval was based on published data regarding the effects of colchicine on cardiovascular events, along with insights from the LoDoCo2 trial. The LoDoCo2 investigators anticipate that colchicine will become the standard treatment for patients with coronary artery disease. The origin The LoDoCo2 trial is based on based on LoDoCo, a small Australian trial that assessed the benefits of administration of a low dosis colchicine on coronary artery disease (CAD). Colchicine is a relatively inexpensive medication commonly used for the treatment of inflammatory disease, e.g. gout. The LoDoCo2 trial was executed with a similar protocol in Australia and the Netherlands. LoDoCo2 is special in many ways; it is a large randomised clinical trial fully run by a non-academic network of cardiologists (WCN), funded by The Dutch Heart Foundation and ZonMw (Goed Gebruik Geneesmiddelen) and a consortium of pharmaceutical companies with focus on drug repurposing. Although the recruitment of patients already started before the start of the DCVA, the DCVA always has provided strong support, also in the route towards implementation. This drug-repurposing clinical trial shows that a collaborative statement from the DCVA and its partners is needed to change rules and regulations in order to make this effective, safe and cheap old treatment available for patients.

The SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the acute respiratory distress syndrome (ARDS). The reninangiotensin-system (RAS) plays an important role in the development of ARDS, with ACE2 (angiotensin-converting enzyme 2) being a key enzyme within this. The virus's spike protein binds to ACE2, facillitating cellular internalization. Downregulation of ACE2 results in the excessive accumulation of angiotensin II, which in turn increases pulmonary vascular permeability through stimulation of the angiotensin II type 1a receptor (AT1R), thereby exacerbating lung pathology associated with decreased ACE2 activity. Currently available AT1R blockers (ARBs) such as valsartan, have shown potential to block this pathological process mediated by angiotensin II. The Focus The primary aim of the PRAETORIAN-COVID trial is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death of COVID-19 patients. The Research Participants receiving active treatment are administered valsartan at a dosage titrated to blood pressure, with a maximum of 160 mg twice daily. Participants receiving placebo are provided with a matching placebo. The treatment duration was 14 days or until reaching the primary endpoint, or until hospital discharge, if applicable within 14 days.Two complementary mechanisms underpin the potential efficacy of angiotensin II type 1 receptor blockers (ARBs) in preventing acute respiratory distress syndrome (ARDS) and reducing morbidity and mortality: ARBs block excessive angiotensin-mediated activation of the AT1R. ARBs upregulate ACE2 expression, leading to reduced angiotensin II levels and increased production of the protective vasodilator angiotensin 1–7. Given these mechanisms, ARBs show promise in preventing ARDS development, potentially reducing the need for intensive care unit (ICU) admission and mechanical ventilation, and ultimately lowering mortality rates associated with SARS-CoV-2 infection.