Current Pharmaceutical Design - Volume 24, Issue 38, 2018

In daily practice, chemical substances called “direct oral anticoagulants” or DOACs are more convenient to administer when set beside vitamin K antagonists (VKA) due to improved pharmacologic properties, fewer drug interactions and rapid onset of action. The objective of this review was to assess whether DOACs are the alternative for VKA in subjects with mild-to-moderate chronic kidney disease (CKD). An analysis of current DOAC trials and studies was performed focusing on subjects with CKD. This review concludes that although DOACS are not recommended in the course of advanced chronic kidney disease (CrCl<30mL/min) or during dialysis, DOACS are a reasonable choice for individuals with mild to moderate CKD.

Background: Peripheral artery disease is a common manifestation of systemic atherosclerosis which strongly correlates to cardiovascular morbidity and mortality. In addition, the progression of peripheral artery disease leads to an increased risk of limb loss. In order to reduce these events, the benchmark of treatment and research over the last years has been the antiplatelet therapy which aims at inhibition of platelet aggregation. Over the last years, new studies combining antiplatelet agents in different therapeutic schemes have been proven efficacious. Unfortunately, patients remain still at high risk of CV events. Novel Oral Anticoagulants have been introduced as alternatives to warfarin, in the prevention and treatment of venous thromboembolism. The rationale of using medication which acts on platelet activation and the coagulation pathway of thrombosis has led investigators to examine the role of Noac's in preventing CV events in patients with peripheral artery disease, stable or unstable. Methods: The aim of this study is to review the current evidence with respect to recently published studies concerning the use of Novel anticoagulants in peripheral artery disease. Results: The Compass trial has shown that a combination of rivaroxaban with traditional therapy may produce promising results in reducing amputation rates, stroke, cardiac events, and mortality, however, there are still safety issues with bleeding requiring acute care. The ePAD study has provided us with insight concerning safety and efficacy after peripheral angioplasty or stenting and actually the need for further research. The Voyager Pad study, following the steps of Compass, is studying the effect and safety of the addition of rivaroxaban to traditional therapy in the highest risk population aka patients undergoing peripheral revascularization. The evidence concerning patients with concomitant atrial fibrillation appears to be insufficient, however, recent guidelines propose the use of novel oral anticoagulants. Conclusion: For the time being, novel oral anticoagulants in combination with aspirin may provide an alternative treatment in PAD, however, it is deemed necessary to identify patient subgroups who will benefit the most.

Peripheral artery disease (PAD) is the third most common manifestation of atherosclerosis after coronary artery (CAD) and cerebrovascular disease (CVD). People with PAD have plaque findings in other vascular territories as well and, thus, are at increased risk of major adverse cardiovascular or cerebrovascular events (MACCE), including myocardial infarction, and stroke. In that context, the COMPASS multicenter, randomized controlled trial showed that the risk of MACCE was significantly reduced by 24% in the rivaroxaban plus aspirin arm compared with aspirin alone (4.1% vs 5.4% respectively; HR: 0.76, 95% CI: 0.66 to 0.86). Interestingly, the rivaroxaban/aspirin arm also showed a reduction in cardiovascular death (HR: 0.78; 95% CI: 0.64-0.96]) and allcause mortality (HR: 0.82; 95% CI: 0.71-0.96) by 22% and 18%, respectively. Recently, the FDA approved the use of the dual pathway approach, rivaroxaban 2.5 mg twice daily plus aspirin 75-100mg once daily, to reduce the risk of major cardiovascular (CV) events, such as CV death, myocardial infarction and stroke, in people with CAD as well as PAD. In comparing rivaroxaban plus aspirin versus aspirin alone, a preliminary economic analysis showed that saving per patient was USD 462 for events and USD 220 for procedures with a total reduction of USD 682 per participant in the US with the combination group (rivaroxaban plus aspirin). The data from COMPASS trial suggest that low dose rivaroxaban plus aspirin may be a preferred treatment strategy in PAD patients in whom the bleeding risk is deemed to be favourable.

Background: Approximately 10–15% of patients on DOACs have to interrupt their anticoagulant before an invasive procedure every year. The perioperative management and monitoring of DOACs have proved to be challenging, as differences in patients’ status and in the invasiveness of each procedure develop different situations that need a tailored therapeutic approach to each patient’s needs. Methods: This review aims to summarize current evidence on the perioperative management of DOACs in patients undergoing a vascular surgical procedure focusing with a practical approach on three key clinical questions: (i) can we stop DOAC therapy before the vascular procedure? (ii) is bridging therapy necessary? and (iii) which is the best perioperative strategy for interruption and resumption of the anticoagulant therapy? Results: No specific data exist for the perioperative management of vascular surgery patients on DOACs, as most studies include low number of such patients. Therapeutic strategy on how to handle DOACs perioperatively must be based on their half-life, the bleeding risk of the invasive procedures, and on the thromboembolic risk of the patient. Renal function plays a crucial role in such situations, increasing thromboembolic and bleeding risk. In general, DOACs should be stopped 2 days for high bleed risk, 1 day for low risk and should be resumed 48-72 hrs after high risk, 24 hrs after low-risk procedure. Bridging is almost never needed. Conclusion: Further perioperative research studies on patients undergoing vascular surgery are needed to confirm whether currently accepted therapeutic perioperative strategy is appropriate for these patients.

In recent years, there has been an increasing interest in endovascular iliofemoral vein stenting to prevent/ alleviate symptoms related to proximal venous outflow obstruction. Maintaining long-term stent patency is one of the main challenges, and risk factors for the development of re-thrombosis are not well understood. Published data on the safety and efficacy of the procedure predominantly come from cohort studies mainly focusing on mechanical aspects relating to stent placement and flow. Aetiology of thrombus formation and thrombotic tendencies of patients due to underlying medical conditions are not captured well or linked to clinical outcomes, and the impact of choice and length of antithrombotic therapy have not been specifically investigated. Here, we review different procedure-related factors and patient characteristics that might increase the risk of re-thrombosis and the utility of antithrombotic treatment options currently available.

Introduction: Proximal aorta interventions impose significant bleeding risk. Patients on concomitant anticoagulation regimens compound the risk of bleeding in any surgery, but especially cardiothoracic interventions. The employment of direct-acting oral anticoagulants (DOAC), namely those that target clotting factors II or X, has expanded at a precipitous rate over the last decade. The emergence of their reversal agents has followed slowly, leaving clinicians with management dilemmas in urgent surgery. We discuss current reversal strategies based on the available published data and our experience with proximal aortic surgery in patients taking DOACs. Literature Search: We performed a review of literature and present three cases from our experience to offer insight into management strategies that have been historically successful. A review of literature was conducted via PubMed with the following search string: (NOAC or DOAC or TSOAC) and (aorta or aortic or (Stanford and type and a)). Case Presentation: We present three case presentations that illustrate the importance of DOAC identification and offer management strategies in mitigating associated bleeding risks in urgent or emergent surgeries. Conclusion: Treatment teams should be aware of the technical limitations of identifying and reversing DOACs. In view of the tendency toward publishing positive outcomes, more scientific rigor is required in the area of emergency DOAC reversal strategies.

Non-vitamin K oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, are increasingly used for thromboembolism prevention. Contrary to older anticoagulants, such as coumadin, when antidotes existed and were broadly used in cases of emergent surgery and bleeding, antidotes for NOACs have not been developed until recently. Moreover, the monitoring of NOAC's anticoagulant effect varies across different hospital settings and the absence of a single test that can accurately predict the degree of anticoagulation achieved increases the uncertainty. These uncertainties often result in management dilemmas for clinicians when patients who are on NOACs need a reversal of anticoagulation. Until recently, available antidotes for NOACs included only prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII and the less optimal fresh frozen plasma (FFP). Recently though, novel antidotes for NOACs have been developed, including idarucizumab, which is a monoclonal antibody fragment that binds dabigatran, and andexanet alfa, a modified decoy form of the activated factor X (FXa) that binds FXa inhibitors and AT III. Another option, ciraparantag, which is a small molecule that binds to heparin, thrombin inhibitors and FXa inhibitors, is still in phase I development. In this review, we summarize the current evidence and present the available bypassing and novel reversal agents. Finally, we propose an algorithm for the management of patients who take NOACs and present to the emergency department with either trauma and active bleeding or need for emergent surgery.

Antiplatelet pharmacotherapy for endovascular interventions has been widely adopted, with clopidogrel being one of the most common agents prescribed. A fraction of patients is resistant to clopidogrel resulting in decreased platelet inhibition despite adequate use. This finding is often termed high on-treatment platelet reactivity (HPR) and may lead to decreased patency in lower extremity arterial endovascular interventions. Current literature on HPR with lower extremity arterial endovascular interventions is limited to only a few studies. Resistance to clopidogrel is largely a result of CYP2C19 enzyme loss of function alleles. Several tests are available to measure clopidogrel resistance but light transmittance aggregometry remains the gold standard, yet direct genetic testing may be more reliable. One-year patency rates following lower extremity arterial endovascular interventions in patients with clopidogrel resistance (HPR) range between 35%-83% whereas those with the proper response to clopidogrel range between 73%-100%. Patients with decreased CYP2C19 activity show a significant decrease in one-year patency of endovascular femoropopliteal interventions (35% vs. 73%; p=0.006). Among patients tested for platelet function after in-stent thrombosis, up to 53% are resistant to clopidogrel. Lack of robust data limits our ability to predict patency in lower extremity arterial interventions for patients with HPR, but there is little doubt that longer patency seems to favor non-HPR patients. Large population, prospective trials are needed to guide our practice.

Background: Acetylsalicylic acid, clopidogrel and cilostazol are well-established agents inhibiting the normal function of platelets with known advantages and limitations. The development of novel antiplatelet agents aims to provide equal or superior outcomes for patients and simultaneously minimize side effects. Objective: The aim of this manuscript is to review the latest data on the use of novel antiplatelet agents in vascular patients. Method: Based on our 2016 review, a further search in the English medical literature has yielded a number of publications on cangrelor, prasugrel, ticagrelor, vorapaxar and a number of other – still experimental – agents (Ir- 6, UBO-QIC, W1, revacept and YM-254890). Results: Recently published data have not altered the use and indications of cangrelor, prasugrel and vorapaxar; all of them now approved by both FDA and EMA. The EUCLID trial has recently provided valuable data on the clinical use of ticagrelor, although results regarding vascular patients and administration of ticagrelor are still under scrutiny. Vorapaxar remains the only novel antiplatelet that is approved for PAD. Randomized control trials that focus on vascular patients are necessary to establish the safety and efficacy of these novel agents. Despite their positive initial results, most novel experimental antiplatelets are still in early development, thus in preclinical or early clinical phases of their trials. Research on three novel antiplatelets is currently discontinued (atopaxar, darexaban and elinogrel). Conclusion: Vorapaxar remains the only novel antiplatelet that is approved for PAD. Other novel antiplatelets demonstrate positive results, but further studies focused on vascular patients are necessary. Novel experimental antiplatelets are still in the early phases of the clinical and preclinical studies.

Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is epidemiologically associated with obesity, insulin resistance and type 2 diabetes, and is a potentially progressive condition to advanced liver fibrosis and hepatocellular carcinoma. However, there is huge interindividual variability in liver disease susceptibility. Inherited factors also play an important role in determining disease predisposition. During the last years, common variants in PNPLA3, TM6SF2, MBOAT7 and GCKR have been demonstrated to predispose to the full spectrum of NAFLD pathology by facilitating hepatic fat accumulation in the presence of environmental triggers. Other variants regulating inflammation and fibrogenesis then modulate liver disease progression in those at higher risk. Evidence is also accumulating that rare variants are involved in disease predisposition. In the future, evaluation of genetic risk factors may be exploited to stratify the risk of liver-related complications of the disease, and to guide hepatocellular carcinoma surveillance and choose pharmacological therapy.

Nonalcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. The majority of NAFLD patients do not progress to NASH and their morbidity risk is low. However, clinical and economic burden of the disease is considerable since the prevalence of the disease is estimated as high as 25% of the general population. Liver biopsy remains the current gold standard for diagnosis, despite limitations regarding sampling variability, invasive nature, and high cost. However, numerous non-invasive biomarkers, including mainly serum markers or imaging modalities, intend to detect the presence of steatosis, NASH or advanced fibrosis. To date, ultrasound is suggested as first-line screening tool for defining steatosis in a selected population, while diagnosis of NAFLD requires exclusion of other chronic liver disease etiology or other steatosis causes. A crucial step in the management of NAFLD patients is the identification of advanced fibrosis, which may be reliably excluded by using NAFLD-Fibrosis score or FIB-4 score or by performing transient elastography. The most robust modalities implement Magnetic Resonance technology and manage to accurately quantify steatosis or identify fibrosis stage, but are not yet applicable in routine practice. The most challenging endpoint has proved to be a non-invasive diagnosis of NASH since no reliable biomarkers have been found to detect or predict inflammation in NAFLD. Lately, research focuses on validating existing markers as robust diagnostic tools for clinical use and investigating novel experimental markers of disease. Current strategies concepts aim to safely diagnose NAFLD patients, aid drug development and finally, guide personalised treatment.

Background: Non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) are the most common causes of elevated liver enzymes in the general population. NASH, and to a lesser extent NAFLD have been associated with increased liver-related, cardiovascular disease (CVD), and allcause mortality. No effective treatment is widely acceptable. Objective: The purpose of this review is to summarize available data on the impact of statins on NAFLD and NASH. Method: A comprehensive review of the literature was performed to identify studies assessing the effect of statin use in NAFLD/NASH. Results: Recent reports have shown that the use of statins in patients with elevated plasma aminotransferases may be beneficial. Post hoc data from three large prospective randomized clinical trials (n>11, 000) suggest that specific statins (mainly atorvastatin) ameliorate NAFLD/NASH and reduce CVD events twice as much as in those with normal liver function. Several biopsy studies have found that rosuvastatin use is related with significant histological ameliorating effects in the setting of NASH. Statin treatment may also protect from hepatocellular carcinoma (HCC) related to NAFLD/NASH. Conclusion: Since NAFLD/NASH patients have high CVD risk, they will probably require a statin. Thus, why not select a specific statins (atorvastatin or rosuvastatin, both generic now) that offer a substantial liver- and CVDrelated adverse event reduction? The administration of statins in these patients is as safe as in the general population.

Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women during the reproductive period. True PCOS phenotype is prone to develop metabolic consequences during life. Obese PCOS women with insulin resistance are carrying a risk for developing type 2 diabetes, and influencing liver function by generating liver steatosis and nonalcoholic fatty liver disease (NAFLD). Moreover, serum testosterone of over 3 nmol/L is associated with at least two-fold higher risk for the development of NAFLD in PCOS women. Numerous genes involved in the pathogenesis of hyperandrogenism, insulin resistance and inflammation are associated with the development of NAFLD in PCOS women. Liver biopsy is not considered as the first line procedure for the diagnosis of liver damage in a prevalent condition as PCOS. Therefore, simple and reliable surrogate markers as serum aminotransferases levels or surrogate indexes (i.e. fatty liver index and NAFLD-fatty liver score) could be used for the assessment of fatty liver in PCOS women. First line therapeutic approach for NAFLD in PCOS includes a change in lifestyle that implies dietary regiment and physical activity but without well-defined protocols. Second line therapy considers addition of drugs on the established lifestyle change. Metformin remains the drug of choice for reduction of insulin resistance and liver enzymes level. Liraglutide, glucagon-like peptide-1 receptor agonists, showed favorable effects on the reduction of liver fat content and visceral adipose tissue in overweight women with PCOS. Current review analyzes the impact of metabolic risk factors, diagnostic approach and management options on NAFLD in women with PCOS.