A randomized controlled trial to evaluate outcomes with Aggrenox in patients with SARS-CoV-2 infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients. METHODS: In an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge. RESULTS: From October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05). CONCLUSION: In this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

Congenital Degos Disease: Case Report and Dermoscopic Findings.

Pediatric Degos disease is rare, with only 36 cases reported in the medical literature. Classically the diagnosis has been established according to pathognomonic histopathologic findings, but when these features are not present, there may be a delay in diagnosis. We report the second congenital case of Degos disease, highlighting the clinical and dermoscopic findings.

Perioperative Management of Antiplatelets and Anticoagulants Among Patients Undergoing Elective Transurethral Resection of the Prostate--A Single Institution Experience.

PURPOSE: To evaluate current practice in the perioperative management of antiplatelets (AP) and anticoagulants (AC) among men undergoing elective transurethral resection of the prostate (TURP), as well as the associated perioperative bleeding and thromboembolic complications. PATIENTS AND METHODS: Retrospective review of consecutive elective TURP patients in a single tertiary institution from January 2011 to December 2013 (n = 293). Data on the regular use of AP/AC and the perioperative management approach were collected from patients' electronic medical records. Bleeding and thromboembolic complications were assessed up to 30 days postoperative. Association between AP/AC use and perioperative complications was assessed using the Kruskall-Wallis test (continuous variables) and the Fisher exact test (categoric variables). RESULTS: There were 107/293 (37%) patients receiving long-term AP while there were 25/293 (9%) patients receiving long-term AC. A total of 72/107 (67%) patients ceased AP on an average of 7.6 days preoperatively, while 35/107 (33%) continued receiving AP. Patients with coronary stents (62%) and coronary bypass graft (67%) were significantly more likely to continued receiving AP (P < 0.001). AC was ceased in all patients preoperatively, with 16/25 (64%) receiving enoxaparin bridging. Overall, there were 31 (10%) incidents of bleeding complications and 5 (2%) thromboembolic events. AC users who had enoxaparin bridging had significantly higher risk of bleeding complications (44%), compared with non-AP/AC users (8%), AP users who ceased AP (4%), AP users who continued receiving AP (17%), and AC users who did not receive enoxaparin bridging (0%) (P < 0.001). AC users who received enoxaparin bridging also reported significantly higher thromboembolic complications (17%; P < 0.001) and prolonged hospital stay (mean 5.4 days) (P = 0.002), compared with other patients. CONCLUSION: Perioperative management of AP/AC should be based on the indications and the American College of Chest Physicians thromboembolic risk stratification. Regular AC users who had enoxaparin bridging are at increased risk of both perioperative bleeding and thromboembolic complications.

Spray drying as a fast and simple technique for the preparation of extended release dipyridamole (DYP) microparticles in a fixed dose combination (FDC) product with aspirin.

INTRODUCTION: Recent advances have proven that the combinational therapy of extended release dipyridamole (DYP) and fast release aspirin (ASP) can improve clinical indices of heart failure in several vascular disorders. Although pharmaceutical industries always supported fast, simple and cost saving techniques in their productions, there is no simple reported method available for this purpose. The aim of this study was to check the possibility of preparing a FDC product, containing individual dosage units of extended release DYP microparticles and fast release ASP, using the spray-drying technique as a practice compatible with pharmaceutical industries. MATERIALS AND METHOD: Solid dispersions of DYP in different polymeric substances (ethyl cellulose, carnauba wax, and Eudragit PO 100), were prepared using the spray-drying method. The physicochemical properties and structure of the prepared microparticles were analyzed using different techniques, such as the particle size analyzer (PSA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X ray diffraction (XRD), and USP dissolution tester. ASP tablets were prepared individually and tested according to pharmacopeia. RESULTS AND DISCUSSION: Results showed that prepared microparticles measured about 2.3 µm in size. Statistical analysis of the release data revealed that there is no significant difference in the mean release amount of the selected formulation compared to the innovative brand (Aggrenox®). CONCLUSION: Findings proposed a new formulation (F7) as an alternative to innovative brand and proved spray drying as a practice compatible with pharmaceutical industries and as a successful method for sustaining the DYP release rate from prepared microparticles in a FDC dosage form.

Prevalence of ex vivo high on-treatment platelet reactivity on antiplatelet therapy after transient ischemic attack or ischemic stroke on the PFA-100(®) and VerifyNow(®).

BACKGROUND: The prevalence of ex vivo high on-treatment platelet reactivity (HTPR) to commonly prescribed antiplatelet regimens after transient ischemic attack (TIA) or ischemic stroke is uncertain. METHODS: Platelet function inhibition was simultaneously assessed with modified light transmission aggregometry (VerifyNow; Accumetrics Inc, San Diego, CA) and with a moderately high shear stress platelet function analyzer (PFA-100; Siemens Medical Solutions USA, Inc, Malvern, PA) in a pilot, cross-sectional study of TIA or ischemic stroke patients. Patients were assessed on aspirin-dipyridamole combination therapy (n = 51) or clopidogrel monotherapy (n = 25). RESULTS: On the VerifyNow, HTPR on aspirin was identified in 4 of 51 patients (8%) on aspirin-dipyridamole combination therapy (≥ 550 aspirin reaction units on the aspirin cartridge). Eleven of 25 (44%) patients had HTPR on clopidogrel (≥ 194 P2Y12 reaction units on the P2Y12 cartridge). On the PFA-100, 21 of 51 patients (41%) on aspirin-dipyridamole combination therapy had HTPR on the collagen-epinephrine (C-EPI) cartridge. Twenty-three of 25 patients (92%) on clopidogrel had HTPR on the collagen-adenosine diphosphate (C-ADP) cartridge. The proportion of patients with antiplatelet HTPR was lower on the VerifyNow than PFA-100 in patients on both regimens (P < .001). CONCLUSIONS: The prevalence of ex vivo antiplatelet HTPR after TIA or ischemic stroke is markedly influenced by the method used to assess platelet reactivity. The PFA-100 C-ADP cartridge is not sensitive at detecting the antiplatelet effects of clopidogrel ex vivo. Larger prospective studies with the VerifyNow and with the PFA-100 C-EPI and recently released Innovance PFA P2Y cartridges (Siemens Medical Solutions USA, Inc) in addition to newer tests of platelet function are warranted to assess whether platelet function monitoring predicts clinical outcome in ischemic cerebrovascular disease.

[Current issues of anticoagulation therapy in the course of dental treatment and oral surgery]. / Véralvadásgátló gyógyszerek alkalmazásának aktuális kérdései a fogorvosi és szájsebészeti kezelések során.

More and more patients receiving anticoagulant therapy or other drugs modifying the coagulation mechanism require dental or oral surgical treatment nowadays. The reason is that in Hungary the various forms of thrombosis are on the first place of morbidity and mortality lists. More than 50 per cent of all the mortality is due to thromboembolism. In view of all this it is not surprising that in the past years the indications, application and dosage of anticoagulant and platelet aggregation inhibitor drugs have changed. Decades-old principles have been modified. It is important for dentists and oral surgeons to know the risk of interventions in patients receiving anticoagulant or platelet inhibitory therapy.

Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack: a randomized, single-blind, 30-day trial.

BACKGROUND: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens. OBJECTIVE: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA). METHODS: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States. Eligible patients were aged 40 years and had a diagnosis of type 2 diabetes and a history of TIA. Patients were allocated to receive ER-DP+ASA 200/25 mg BID, clopidogrel 75 mg/d, or clopidogrel 75 mg/d plus ASA 81 mg/d. Multiple platelet bio-markers were assessed at baseline, day 15, and day 30 using aggregometry, cartridge-based platelet function analyzers, and flow cytometry. The primary end point was the change in platelet receptor expression after 30 days of therapy. Compliance and tolerability were monitored by measuring plasma dipyridamole levels and recording all episodes of headache and vomiting. RESULTS: The study enrolled 60 consecutive patients (20 per treatment arm), all of whom completed the study. There were no significant differences between treatment arms, although the ER-DP+ASA group had a numerically greater mean age, higher proportion of men, and a greater prevalence of vascular disease and smoking compared with the other groups. There were no deaths or serious adverse events during the study, including symptoms attributable to cerebral ischemia, worsening of diabetes, or cerebral or systemic bleeding. Three patients in the ER-DP+ASA group and 1 in the clopidogrel plus ASA group reported headache during the first several days of therapy; 1 patient in the clopidogrel monotherapy group experienced transitory nausea and vomiting. ER-DP+ASA was associated with a significantly delayed (day 30) reduction in expression of glyco-protein (GP) Ilb/IIIa activity (P = 0.02), platelet-endothelial cell adhesion molecule 1 (PECAM-1) (P = 0.03), GP Ib (P = 0.001), vitronectin (P = 0.001), P-selectin (P = 0.001), lysosome-associated membrane protein 1 (P = 0.001), and cluster of differentiation 40 ligand (P = 0.01), as well as significant inhibition of the intact (P = 0.01) and cleaved (P = 0.01) epitopes of protease-activated receptor 1. Clopidogrel monotherapy, on the other hand, was associated with significant inhibition of adenosine diphosphate-induced platelet aggregation (P = 0.001), closure-time prolongation (P = 0.01), and reduction in measurements on the rapid platelet function assay-ASA at day 15 (P = 0.001). Expression of PECAM-1 (P = 0.03) and GP IIb/IIIa activity (P = 0.01) was reduced at day 15 in clopidogrel-treated patients. The addition of ASA to clopidogrel was associated with significant inhibition of collagen-induced platelet aggregation (P = 0.001) and diminished formation of platelet-monocyte microparticles at days 15 (P = 0.02) and 30 (P = 0.03). CONCLUSIONS: In these patients with type 2 diabetes and a history of TIA, patterns of platelet inhibition differed significantly according to whether treatment was with ER-DP+ASA or clopidogrel with or without ASA. The antiplatelet activity of clopidogrel was more potent and occurred earlier (15 days), whereas ER-DP+ASA was associated with moderate downregulation of multiple activation-dependent platelet receptors that occurred later (30 days).

Influence of antiplatelet therapy on cerebral micro-emboli after carotid endarterectomy using postoperative transcranial Doppler monitoring.

AIM: To study the effect of different antiplatelet regimens (APT) on the rate of postoperative TCD registered micro-embolic signals (MES) following carotid endarterectomy (CEA). DESIGN: Prospective, randomised, double-blinded, pilot study. METHODS: The study group of 102 CEA patients (76 men, mean age 66.8 years) was randomised to routine Asasantin (Dipyridamole 200mg/Aspirin 25mg) twice daily (group I; n=39), Asasantin plus 75 mg Clopidogrel once daily (group II; n=33), or Asasantin plus Rheomacrodex (Dextran 40) 100g/L iv; 500 ml (group III; n=30). TCD monitoring of the ipsilateral middle cerebral artery for the occurrence of MES was performed intra-operatively and during the second postoperative hour following CEA. Primary endpoints were the rate of postoperative emboli and the occurrence of cerebrovascular complications. Secondary endpoint was any adverse bleeding. RESULTS: There were no deaths or major strokes. We observed 2 intraoperative TIA's (group II and III) and 1 postoperative minor stroke (group I). In comparison with placebo, Clopidogrel or Rheomacrodex in addition to Asasantin produced no significant reduction in the number of postoperative MES. There was no significant difference between the number of postoperative MES and different antiplatelet regimens. The incidence of bleeding complications was not significantly different between the 3 APT groups. CONCLUSION: In the present study, we could not show a significant influence of different antiplatelet regimens on TCD detected postoperative embolization following CEA.

Aggrenox-associated acute interstitial nephritis.

Acute interstitial nephritis (AIN) associated with the administration of the combination drug Aggrenox ( acetylsalicylic acid 25 mg and dipyridamole 200 mg) has not been previously reported. This is an 83-year-old man who presented with nausea, vomiting, weakness, and non-oliguric renal failure. He started to have these complaints four days after starting Aggrenox one tablet daily. There were no recent medication changes aside from the addition of Aggrenox. The patient had normal serum creatinine one year prior to this event. The renal biopsy showed acute interstitial nephritis (AIN). The Aggrenox was stopped and the patient received saline intravenously. The serum creatinine rose from 494 mmol/L on admission to a peak of 798 mmol/L on day 5 then decreased gradually to 179 mmol/L over four months. The serologic investigations for common infectious and immune causes of AIN were negative. In conclusion, this patient suffered AIN associated with the administration of Aggrenox and improved with discontinuation of this drug. Further investigation may be needed to evaluate the prevalence of AIN associated with Aggrenox.

Design of the Dialysis Access Consortium (DAC) Aggrenox Prevention Of Access Stenosis Trial.

BACKGROUND: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis. RESULTS: This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial.

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox than either for aspirin or dipyridamole alone. To test whether Aggrenox has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox and aspirin provided fast and sustained platelet inhibition. Aggrenox(R), however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox. In 61 of 90 direct comparisons, aspirin and Aggrenox were equivalent. Aggrenox was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox compared with Aspirin in preventing recurrent stroke.

Rapid platelet inhibition after a single capsule of Aggrenox: challenging a conventional full-dose aspirin antiplatelet advantage?

Aggrenox is a novel combination of 25 mg of aspirin with 200 mg of sustained release dipyridamole. In a recent large trial (ESPS-2), Aggrenox was twice as effective for secondary stroke prevention as either aspirin or dipyridamole alone, suggesting superior platelet inhibition for combination therapy. We sought to compare the time course of platelet inhibition with Aggrenox compared with escalating doses of non-enteric coated aspirin. Data from 10 healthy volunteers were analyzed. Fasting subjects sequentially ingested aspirin in the following order: 325 mg, 81 mg, 25 mg, and then one pill of Aggrenox after a 3-week interval for aspirin washout. Platelet function was assessed at baseline, 15, 30, 60, and 120 min post-medication with 5 microM epinephrine and 5 microM ADP using conventional aggregometry. Aspirin provided significant (P < 0.01) reduction of platelet aggregation at 15 min post 325 mg, 30 min post 81 mg, and unexpectedly within 60 min after taking 25 mg of aspirin. A single pill of Aggrenox also inhibited platelet aggregation within 1 hr after administration. Aspirin inhibits platelets remarkably fast. Both Aggrenox and a matching dose of aspirin (25 mg) exhibit significant antiplatelet properties within 60 min after ingestion. These findings could be relevant for the optimal balance between the reduction of vascular events via sufficient and rapid platelet inhibition and low risk of bleeding complications associated with the Aggrenox therapy.

Aggrenox: a fixed-dose combination of aspirin and dipyridamole.

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of a fixed-dose combination of aspirin and extended-release (ER) dipyridamole indicated for the secondary prevention of stroke. DATA SOURCES: Published articles and abstracts were identified from a MEDLINE search (1966-December 1999) using the search terms dipyridamole, aspirin, antiplatelet, antiaggregation, and stroke prevention. Pertinent articles written in English were considered for review. Additional articles were identified from the references of retrieved literature. STUDY SELECTION AND DATA EXTRACTION: Studies including a combination of aspirin/dipyridamole in human subjects were evaluated. Emphasis was placed on randomized, controlled trials. DATA SYNTHESIS: Aspirin is a platelet inhibitor that works by inhibiting platelet cyclooxygenase, which reduces the production of thromboxane A2. Dipyridamole is a platelet inhibitor that is thought to work in part by inhibiting platelet cyclic-3',5'-adenosine monophosphate and cyclic-3',5'-guanosine monophosphate phosphodiesterase. The active metabolite of aspirin, salicylic acid, is highly bound to plasma protein and has a plasma half-life of two to three hours. Dipyridamole is also highly bound to plasma proteins, and the ER formulation has a plasma half-life of 13 hours. The first European Stroke Prevention Study (ESPS-1) found the combination of aspirin/dipyridamole to be superior to placebo in the prevention of stroke and transient ischemic attack (TIA). The ESPS-1, however, did not include an aspirin-only treatment arm. Therefore, it was unclear whether the combination of aspirin/dipyridamole was superior to aspirin alone. As a result, a second trial was conducted that included treatment arms of aspirin alone, ER dipyridamole alone, combination therapy, and placebo. The combination of aspirin 25 mg plus ER dipyridamole 200 mg twice daily was shown in the ESPS-2 to be significantly better than either agent given individually in preventing stroke and TIAs (p < 0.001). CONCLUSIONS: The American College of Chest Physicians (ACCP) recommends aspirin 50-325 mg/d to be the initial antiplatelet of choice for the prevention of atherothrombotic cerebral ischemic events. However, with the favorable results of the ESPS-2, it may be appropriate to substitute aspirin/ER dipyridamole for aspirin alone as the drug of choice. This combination appears to have a favorable adverse effect profile. The relative effectiveness of aspirin/ER dipyridamole compared with clopidogrel and ticlopidine has yet to be determined. If alternative antiplatelet therapy is needed, the ACCP recommends clopidogrel rather than ticlopidine because of its lower incidence of adverse effects. The ACCP further states that the combination of aspirin plus dipyridamole may be more effective than clopidogrel; these agents have a similarly favorable adverse effect profile.