Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease.

Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.

Clinical evaluation of liposome-based gel formulation containing glycolic acid for the treatment of photodamaged skin.

Background: Long contact of UV causes skin damage. Glycolic acid (GA) as an alpha hydroxy acid is used to treat photodamaged skin. However, GA leads to side effects including; burning, erythema and peeling.Purpose: The aim of this study was to develop a controlled delivery systems loading GA in order to increasing its efficacy and lowering its side effects.Methods: Liposomes were evaluated for encapsulation efficiency, size and morphology. Optimized formulation was dispersed in HPMC gel bases and drug release kinetics were also studied. Clinical efficacy and safety of GA-loaded liposomal gel and GA gel formulation were evaluated in patients with photodamaged skin.Results: The EE% and average particle size of liposomes were 64 ±2.1 % and 317±3.6 nm, respectively. SEM image showed that liposomes were spherical in shape. In vitro release kinetics of GA from both formulations followed Weibull model. Clinical evaluation revealed that GA-loaded liposomal gel was more effective than GA gel formulation. Treatment with GA-loaded liposomal gel resulted in a statistically significant reduction in the scores of hyperpigmentation, fine wrinkling and lentigines. Moreover, liposomal gel formulation was able to minimize side effects of GA.Conclusion: According to the obtained results, the liposome-based gel formulation can be used as potential drug delivery system to enhance permeation of GA through skin layers and also reduce its side effects.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Evaluating the role of intravenous pentoxifylline administration on primary percutaneous coronary intervention success rate in patients with ST-elevation myocardial infarction (PENTOS-PCI).

Ischemia reperfusion injury can lead to further myocardiocyte damage in patients with ST-elevation myocardial infarction (STEMI). Pentoxifylline is a methylxanthine derivative with known anti-inflammatory, antioxidant, vasodilator, and rheological properties which can be a promising agent in preventing reperfusion injury. PENTOS-PCI is a single-center, randomized, double-blind, placebo-controlled trial which evaluated the efficacy and safety of preprocedural administration of intravenous pentoxifylline in patients undergoing primary percutaneous coronary intervention (PCI). Patients with acute STEMI who were eligible for PCI were randomized to receive either 100-mg intravenous infusion of pentoxifylline or placebo, prior to transferring to catheterization laboratory. Overall, 161 patients were included in our study of whom 80 patients were assigned to pentoxifylline and 81 to the control groups. Per-protocol analysis of primary endpoint indexing PCI's success rate as measured by thrombolysis in myocardial infarction (TIMI) flow grade 3 was not significantly different between pentoxifylline and placebo (71.3% and 66.3% respectively, P = 0.40). In addition, pentoxifylline could not improve secondary angiographic endpoints including myocardial blush grade 3 (87.5% and 85.2%, P = 0.79) and corrected TIMI frame count (22.8 [± 9.0] and 24.0 [± 5.1], P = 0.33) in the intervention and placebo groups respectively. The rates of major adverse cardiac and treatment emergent adverse effects were not significantly different between the two groups. Administration of intravenous pentoxifylline before primary PCI did not improve the success rate of the procedure in patients with STEMI. Intravenous administration of pentoxifylline was well tolerated, and there were no significant differences regarding adverse drug reactions in the two groups. Panel A, background: pentoxifylline is a methylxanthine derivative with known anti-inflammatory, antioxidant, vasodilator, and rheological properties which can be a promising agent in preventing reperfusion injury. Panel B: study design and main results of the PENTOS-PCI trial. cTFC corrected TIMI frame count, ED emergency department, IRI ischemia reperfusion injury, MBG myocardial blush grade, PCI percutaneous coronary intervention, PPCI primary PCI, PTX pentoxifylline, ROS reactive oxygen species, SD standard deviation, STEMI ST-elevation myocardial infarction, TIMI thrombolysis in myocardial infarction.

A stepwise approach to prescribing novel lipid-lowering medications.

Dyslipidemia is a major modifiable risk factor for developing atherosclerotic cardiovascular disease. Despite increasing high intensity statin prescription and adherence to statin therapy, a considerable number of patients will not reach the guideline directed goals due to statin intolerance, lack of adherence or treatment efficacy. Several new lipid lowering medications have received approval by regulatory agencies in the past decade including proprotein convertase subtilisin/kexin type 9 modulators, ATP-citrate lyase inhibitors, angiopoietin-like 3 inhibitors, lomitapide, and icosapent ethyl. Although approved by regulatory agencies, these medications are still under-prescribed worldwide which may be related to cost issues, lack of cardiovascular outcome results, or clinicians not being familiar with their use. In this review, we propose a practical stepwise approach including each class' efficacy, place in therapy, adverse effects, warnings and precautions, and monitoring parameters. This information can help the clinicians to prescribing these novel lipid lowering medications to achieve treatment goals and reduce the risk of atherosclerotic cardiovascular disease. The aim is to shift the paradigm for high-intensity statins from watch and wait to initial combination therapy for high-risk patients.

Preprocedural Colchicine in Patients With Acute ST-elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention: A Randomized Controlled Trial (PodCAST-PCI).

ABSTRACT: Primary percutaneous coronary intervention (PPCI) is the gold standard of treatment in patients with acute ST-elevation myocardial infarction (STEMI). The no-reflow phenomenon (NRP) is a detrimental consequence of STEMI. Colchicine is an anti-inflammatory drug that may help prevent the NRP and improve patient outcomes. In a randomized, double-blind, placebo-controlled clinical trial, 451 patients with acute STEMI who were candidates for PPCI and eligible for enrollment were randomized into the colchicine group (n = 229) and the control group (n = 222). About 321 patients were eligible to participate; 161 patients were assigned to the colchicine group, whereas 160 patients were assigned to the control group. Colchicine was administered 1 mg before PCI and 0.5 mg daily after the procedure until discharge. NRP, measured by angiographic findings including the thrombolysis in myocardial infarction flow grade and the thrombolysis in myocardial infarction myocardial perfusion grade, was reported as the primary outcome. Secondary end points included ST resolution 90 minutes after the procedure, P-selectin, high-sensitivity C-reactive protein, and troponin levels postprocedurally, predischarge ejection fraction, and major adverse cardiac events (MACE) at 1 month and 1 year after PPCI. NRP rates did not show a significant difference between the 2 groups ( P = 0.98). Moreover, the levels of P-selectin, high-sensitivity C-reactive protein, and troponin were not significantly different. MACE and predischarge ejection fraction were also not significantly different between the groups. In patients with STEMI treated by PPCI, colchicine administered before PPCI was not associated with a significant reduction in the NRP and MACE prevention (trial registration: IRCT20120111008698N23).

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Use of novel antithrombotic agents for COVID-19: Systematic summary of ongoing randomized controlled trials.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies. OBJECTIVES: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. METHODS: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19. RESULTS: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. CONCLUSION: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19.

Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials.

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Pharmacologic Prevention of Myocardial Ischemia-Reperfusion Injury in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

ABSTRACT: Establishing efficient perfusion into the myocardium is the main purpose in patients with acute coronary syndrome, but the process of reperfusion is not without risk and can damage the myocardium paradoxically. Unfortunately, there is no effective treatment for reperfusion injury, and efforts to find an efficient preventive approach are still ongoing. In the past 3 decades, there have been many successful animal studies on how to prevent reperfusion injury; nonetheless, translation to the clinical setting has almost always proven disappointing. In this article, we review clinical studies on the prevention of reperfusion injury in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention in a pharmacologic-based approach. We categorize all the agents that are evaluated for the prevention of myocardial reperfusion injury based on their mechanisms of action into 5 groups: drugs that can reduce oxidative stress, drugs that can affect cellular metabolism, rheological agents that target microvascular obstruction, anti-inflammatory agents, and agents with mixed mechanisms of action. Then, review all the clinical studies of these agents in the setting of primary percutaneous coronary intervention. Finally, we will discuss the possible reasons for the failure in translation of studies into practice and propose potential solutions to overcome this problem.

Cardiovascular Complications of COVID-19: Pharmacotherapy Perspective.

Coronavirus disease of 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly the world over. The disease was declared "pandemic" by the World Health Organization. An approved therapy for patients with COVID-19 has yet to emerge; however, there are some medications used in the treatment of SARS-CoV-2 infection globally including hydroxychloroquine, remdesivir, dexamethasone, protease inhibitors, and anti-inflammatory agents. Patients with underlying cardiovascular disease are at increased risk of mortality and morbidity from COVID-19. Moreover, patients with chronic stable states and even otherwise healthy individuals might sustain acute cardiovascular problems due to COVID-19 infection. This article seeks to review the latest evidence with a view to explaining possible pharmacotherapies for the cardiovascular complications of COVID-19 including acute coronary syndrome, heart failure, myocarditis, arrhythmias, and venous thromboembolism, as well as possible interactions between these medications and those currently administered (or under evaluation) in the treatment of COVID-19.