Lipid lowering with inclisiran: a real-world single-centre experience.

OBJECTIVE: The reduction in circulating low-density lipoprotein cholesterol (LDL-c) is the primary aim of lipid-lowering therapies as a method of atherosclerotic cardiovascular disease risk reduction. Inclisiran is a new and potent lipid-lowering drug that is shown to be effective in reducing LDL-c in randomised controlled trials, however, real-world data of its use are not yet known. We sought to analyse the early effects of this drug in a tertiary centre lipid and cardiovascular risk clinic. METHODS: We performed a retrospective analysis of the first 80 patients who received a single dose of inclisiran at our lipid clinic between 1 December 2021 and 1 September 2022. Data were collected using electronic healthcare records. Baseline blood tests were taken prior to start of treatment and were repeated at 2 months follow-up. Data on adverse events were also recorded. RESULTS: At 2 months after treatment initiation, mean baseline LDL-c fell from 3.5±1.1 mmol/L by 48.6% to 1.8±1.0 mmol/L and total cholesterol from 5.7±1.3 mmol/L by 33.3% to 3.8±1.1 mmol/L (both p<0.0001). Mean high-density lipoprotein-c rose by 7.7% to 1.4±0.4 mmol/L (p=0.02) and median triglycerides fell by 31.3% to 1.1 mmol/L (IQR 0.9-2) (p=0.001). Adverse events (injection site reaction, fatigue and headache) were recorded in three patients and all had self-resolved by time of follow-up. CONCLUSION: Inclisiran use in line with National Institute for Health and Care Excellence guidelines led to significant lowering of LDL-c at 2 months, with efficacy similar to that reported in trials with good tolerability.

Investigation of low-dose ritonavir on human peripheral blood mononuclear cells using gene expression whole genome microarrays.

Ritonavir is a protease inhibitor associated with metabolic abnormalities and cardiovascular disease. We have investigated the effects of low-dose ritonavir treatment on gene expression in peripheral blood mononuclear cells (PBMC) of 10 healthy donors. Results using whole genome Illumina microarrays show that ritonavir modulates a number of genes implicated in lipid metabolism, inflammation and atherosclerosis. These candidate genes are dual specificity phosphatase 1 DUSP1), Kelch domain containing 3 (KLHDC3), neutral cholesterol ester hydrolase 1 (NCEH1) and acyl-CoA synthetase short-chain family member 2 (ACSS2). Validation experiments using quantitative PCR showed that ritonavir (at 100 mg once daily and 100 mg twice daily significantly down-regulated these 4 selected candidate genes in 20 healthy individuals. Lower expression levels of these 4 candidate genes, known to play a critical role in inflammation, lipid metabolism and atherosclerosis, may explain ritonavir adverse effects in patients.

Prevention of atherosclerosis in patients living with HIV.

INVESTIGATIONAL PRODUCT: Rosuvastatin (Crestor; Astra Zeneca). ACTIVE INGREDIENTS: Rosuvastatin (5 mg). STUDY TITLE: Prevention of Atherosclerosis in Patients Living with HIV. PHASE OF STUDY: Phase III. AIMS: PRIMARY AIM: To assess whether rosuvastatin therapy could slow the progression of the carotid intima-media thickness (C-IMT; as measured by the change in the mean IMT of the near and far walls of the distal common carotid arteries) over 2 years in HIV-infected patients (HIV-IP). SECONDARY AIMS: To assess whether rosuvastatin therapy could reduce highly sensitive C reactive protein (hs-CRP) inflammatory marker that is increased in HIV-IP.To assess the effect of rosuvastatin therapy on serum lipid levels (total cholesterol [TC], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol and triglycerides [TG]) and apolipoproteins (APO A1, APO B and APO B/A1).To assess the safety of rosuvastatin in HIV-IP through the evaluation of clinical laboratory analyses (liver function tests and creatine kinase) and adverse events (AEs). STUDY DESIGN: Two-year randomized, double-blind, placebo-controlled, parallel group study. PLANNED SAMPLE SIZE: 320 HIV-IP. SUMMARY OF ELIGIBILITY CRITERIA: HIV-IP who are aged between 30 and 60 years, with a CD4 count. greater than 200 cells/mm(3). Patients must be stable on combination antiretroviral therapy (cART) for at least 12 months and have a 10-year CVD risk of less than 20% (using the Framingham risk score). NUMBER OF STUDY CENTERS: One. DURATION OF TREATMENT: Two years (5 mg rosuvastatin or placebo once daily). DOSE AND ROUTE OF ADMINISTRATION: Oral rosuvastatin (5 mg) once daily. The incidence of cardiovascular disease (CVD) in HIV-IP is at least three times higher than in the general population and further increases each year with combination anti-retroviral therapy (cART). The carotid atherosclerosis progression rate is 10 times higher in HIV-IP than in uninfected individuals. The aim of this study is to assess whether therapy with 5 mg rosuvastatin could: 1) Slow the progression in the mean IMT of the distal common carotid arteries over two years in HIV-IP.2) Change the concentration in the inflammatory marker--hs-CRP, which is increased in HIV-IP.3) Change the concentrations of TC, LDL cholesterol, HDL cholesterol, TG, apolipoproteins (APO) B, APO A1 and APO B/A1.4) Be administered safely in the study population. Pharmacological intervention with rosuvastatin will be evaluated in a double-blind, placebo-controlled, randomized clinical trial in HIV-IP treated with cART not matching the published selection criteria for lipid-lowering therapy. For the first time, this study will investigate anti-inflammatory and anti-atherogenic effects of a pharmacological lipid-lowering agent in HIV-IP that may lead to the reduction of CVD.

Statin therapy-evidence beyond lipid lowering contributing to plaque stability.

Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and the possible mechanisms beyond lipid lowering contributing to plaque stability.

The role of anticoagulation in cancer patients: facts and figures.

Thromboembolic events contribute significantly to the morbidity and mortality in cancer. Effective and safe anticoagulation - mainstay in prevention and treatment of thrombosis - remains very challenging clinical task in oncology patients - population of high rate of treatment failure, bleeding complications and thromboembolic events recurrences. Prospective randomized clinical studies have documented that with advent of low molecular weight heparins new possibilities for thrombosis treatment and long-term prevention with more convenient and safe anticoagulation have emerged. Considerable advances have been achieved at present time in our understanding of the pathobiology of thrombogenesis in human malignancies, particularly of the interactions between coagulation cascade reactions and processes of tumor growth and dissemination. This builds up a new challenge for modern oncology - appreciation of the hypothesis of anti-malignant effects of anticoagulants, which could influence the outcome of human cancer. Antineoplastic effects of antithrombotic drugs have been reported in various experimental models. Heparins have been the most extensively studied and have been shown to reduce the primary tumour growth and its metastatic spread. Joint evidence from fundamental research and from several randomized clinical trials, observing beneficial impact of low molecular weight heparins therapy on cancer patients survival, dictate the need for further scientific steps to confirm biological effects of heparins in human malignancies. The evidence is started to accumulate, that clinically approved heparins have different abilities to influence some processes of metastasis spread. The experimental work towards development of heparin derivates with low anticoagulant activity, but with potential inhibitory effects on tumor cells migration is in progress.

Importancia de la anticoagulación en pacientes con insuficiencia cardíaca / Role of anticoagulation therapy in patients with heart failure

Heart failure represents one of the most prevalent and morbid cardiovascular condition thorough the world. It is thought, that chronic heart failure is associated with the increased incidence of thromboembolic complications, including stroke, pulmonary, coronary and peripheral embolism. However, epidemiological data on this subject is very limited. Important pathophysiological features of heart failure syndrome encompass chronic procoagulant blood state, low-grade inflammation, vessel wall structure and function abnormalities ­ all changes, predisposing to thromboembolism. The place of anticoagulant therapy in heart failure management, despite long-standing active discussions and debates, remains to be established. In fact, there is a lack of firm evidence to date, suggesting, that oral anticoagulation could be beneficent to heart failure patients, unless they have atrial fibrillation or multiple risk factors of thromboembolism, including previous thrombotic episode. However, emerging data on alternative to oral anticoagulants approaches, including direct thrombin and factor Xa inhibitors, low molecular weight heparins and antiplatelet agents opens new avenues for pharmacological antithrombotic interventions in heart failure and dictates the need to test these promising hypotheses in prospective randomised clinical trials. This paper summarises data on pathobiological background, rationale and existing evidence on thromboembolism treatment and prevention in the setting of heart failure.

La insuficiencia cardíaca representa uno de los trastornos cardiovasculares mórbidos más prevalentes en el mundo. Se piensa que la insuficiencia cardíaca crónica está asociada con el aumento en la incidencia de complicaciones tromboembólicas como el accidente cerebrovascular y los embolismos pulmonares, coronarios y periféricos. Sin embargo, los datos epidemiológicos sobre este tema son muy limitados. El síndrome de insuficiencia cardíaca comprende importantes características fisiopatológicas como el estado procoagulante crónico, la inflamación de bajo grado, la estructura de la pared vascular y anormalidades en el funcionamiento. Todos estos cambios predisponen al tromboembolismo. Aún no se estableció el lugar que ocupa la anticoagulación en el tratamiento de la insuficiencia cardíaca, a pesar de los debates y las discusiones prolongadas. De hecho, hasta la fecha se carece de pruebas que sugieran que la anticoagulación oral sea beneficiosa para los pacientes con insuficiencia cardíaca, a menos que presenten fibrilación auricular o múltiples factores de riesgo de tromboembolismo, como el antecedente de un episodio trombótico. Sin embargo, se dispone de nuevos datos acerca de enfoques alternativos a la anticoagulación oral, como los que incluyen los inhibidores directos de la trombina y del factor Xa, heparinas de bajo peso molecular y agentes antiplaquetarios, que abren nuevos caminos para la intervención farmacológica antiplaquetaria en la insuficiencia cardíaca e imponen la necesidad de probar estas hipótesis promisorias en ensayos clínicos prospectivos y aleatorizados. Este trabajo resume los datos publicados acerca de las bases teóricas, resultados actuales y la base biopatológica sobre la prevención y el tratamiento del tromboembolismo en el contexto de la insuficiencia cardíaca.

Blood coagulation in patients with chronic heart failure: evidence for hypercoagulable state and potential for pharmacological intervention.

Incidence data on thromboembolism in patients with heart failure (which may include stroke, peripheral embolism, pulmonary embolism) are limited but provide a general population range from 1-5 cases per 1000 each year, increasing with age to more than 30 cases per 1000 each year among people aged 75 years or older. However, the incidence of thromboembolism varied depending very much on what was being investigated in each of these studies. Data from subgroup analysis of the larger heart failure trials would seem to support this incidence data, although there is very little true epidemiological data and no randomised, controlled trial has been designed to specifically investigate thromboembolism in patients with heart failure. The pathophysiology of heart failure is complex. There are many well recognised factors which are associated with thrombosis in heart failure patients, such as vascular abnormalities, increased coagulability and impaired blood flow. In the past 50 years many studies have been performed to investigate if oral anticoagulation is of benefit for the prevention of thromboembolism in patients with heart failure. The use of warfarin therapy for heart failure patients has been a controversial subject. Warfarin does have a role to play in patients with myocardial infarction and those with atrial fibrillation. Furthermore, in patients with congestive heart failure secondary to coronary artery disease, warfarin reduces the occurrence of nonfatal myocardial infarction and, therefore, may reduce the chances of progression to heart failure. It has also been shown that warfarin reduces the risk of thromboembolic strokes in patients recovering from myocardial infarction. At present, there is a lack of randomised data, and the incidence of bleeding complications in patients with heart failure has caused a decrease in the use of oral anticoagulants for the prevention of thrombosis. This review summarises the incidence, potential mechanism and therapeutic approaches for management of thromboembolism in heart failure.

Induced ischemia detected by dobutamine stress echocardiography in coronary heart disease patients after myocardial re-vascularization. Experience in a District General Hospital.

Most episodes of myocardial ischemia in patients with known coronary artery disease (CHD) are asymptomatic. Silent myocardial ischemia (SMI) is an important predictor of adverse outcome in patients with proven coronary artery disease. beta-blockers are effective in suppressing ischemia, and improve clinical outcome in patients with coronary artery disease. At present, it is common practice to stop treatment with beta-blockers in clinically asymptomatic patients after coronary artery bypass graft (CABG) and/or myocardial re-vascularization (PTCA/Stent), although the possible presence of SMI/inducible ischemia after myocardial re-vascularization is not known. We examined 56 asymptomatic CHD patients after coronary artery bypass graft (n=36), percutaneous coronary angioplasty PTCA/stent (n=15), or both (n=5); therapy with beta-blockers was stopped in all of them after myocardial revascularization. All these patients underwent a dobutamine stress echocardiography test (DSE test). The DSE test was proposed to these asymptomatic CHD patients to investigate the possible presence of SMI/inducible ischemia after myocardial re-vascularization. All patients had history of myocardial infarction or evidence of mildly impaired left ventricular function at rest as assessed by cardiac catheterization. Abnormal DSE studies occurred in eight of the 56 patients (14%; 95% C.I.: 6-26%). Therapeutic approaches specifically targeted at reducing total ischaemic burden include pharmacologic therapy and myocardial revascularization. On the basis of these data, it can be concluded that asymptomatic CHD patients after myocardial re-vascularization must be re-evaluated to rule out SMI/inducible ischemia that can be treated (e.g. with beta-blockers) reducing cardiovascular morbidity and mortality.

Low molecular weight heparin (bemiparin sodium) and the coagulation profile of patients with heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with a hypercoagulable state. PATIENTS AND METHODS: A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that a prophylactic dose of low molecular weight heparin (bemiparin sodium 3500 IU/daily subcutaneously) will modify a hypercoagulable state in CHF. This study included 100 patients with CHF (New York Heart Association classification II to IV). All patients underwent 3 blood tests, at baseline (before randomization), 24 hours after randomization, and before hospital discharge or within 10 days from randomization. RESULTS: In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 24 hours, there was a significant decrease in plasma levels of D-dimer (-13.8 ng/mL; P =.01) and prothrombin fragments 1 and 2 (-0.11 nmol/L; P =.01), whereas protein C was significantly increased (+3.5%; P =.03). In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 4 to 10 days of therapy, there were significantly decreased plasma levels for factor VII:c (-3.0%; P =.01), D-dimer (-44.0 ng/mL; P =.002), and thrombin-antithrombin complex (-0.7 microg/L; P =.0001), whereas protein C was significantly increased (+16.0%; P =.03). On the other hand, in the group of patients treated with placebo after 24 hours, a significant decrease was observed of protein C (-4.0%; P =.04). After 24 hours, the changes from baseline were significantly different for some of the hemostatic factors in comparison of bemiparin sodium 3500 IU/daily and placebo (factor VII:c: -1.7 versus 0.0%; P =.04; D-dimer: -14 versus +24.3 ng/mL; P =.009; prothrombin fragments 1 and 2: -0.11 versus +0.11 nmol/L; P =.01; protein C: +3.5 versus -4.0%; P =.01). Also at discharge, the changes from baseline were different for some of the markers in comparison of bemiparin sodium with placebo (D-dimer: -44 versus 3.8 ng/mL; P =.002; thrombin-antithrombin complex: -0.70 versus +0.14 microg/L; P =.002; protein C: +16.0 versus +0.5%; P =.02). CONCLUSION: Our findings suggest that a hypercoagulable state in heart failure can be modified with bemiparin sodium therapy.