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.

Preventing arteriovenous shunt failure in hemodialysis patients: a population-based cohort study.

Essentials Uncertainty remains about antiplatelets for vascular access patency in hemodialysis patients. 95 971 people under hemodialysis were followed in a claims database in Taiwan. Aspirin reduced vascular access failure rate and did not increase major bleeding rate. Clopidogrel, Aggrenox, and warfarin might increase major bleeding rate. SUMMARY: Background Dialysis adequacy is a major determinant of survival for patients with end-stage renal disease. Good vascular access is essential to achieve adequate dialysis. Objectives This study evaluated the impacts of different drugs on the vascular access failure rate of an arteriovenous fistula or an arteriovenous graft and the rate of major bleeding in hemodialysis patients. Patients and methods We studied patients with end-stage renal disease registered in the Taiwan National Health Insurance program from 1 January 1997 to 31 December 2012. A total of 95 971 patients were enrolled in our study. Vascular access dysfunction was defined as the need for thrombectomy or percutaneous angioplasty. Major bleeding was defined as emergency department visits or hospitalization with a primary diagnosis of gastrointestinal bleeding or intracerebral hemorrhage. The adjusted odds ratios between person-quarters with or without antiplatelet or oral anticoagulant use were calculated using a generalized estimating equation. Results The odds ratio of vascular access failure was 0.21 (0.11-0.39) for aspirin, 0.76 (0.74-0.79) for clopidogrel, 0.67 (0.59-0.77) for dipyridamole, 0.67 (0.53-0.86) for Aggrenox and 0.96 (0.90-1.03) for warfarin. The highest odds ratio for intracerebral hemorrhage was 5.33 (1.25-22.72) in younger patients using Aggrenox. The highest odds ratio for gastrointestinal bleeding was 1.34 (1.10-1.64) for clopidogrel. Conclusion Antiplatelet agents, but not warfarin, might reduce the vascular access thrombosis rate. The gastrointestinal bleeding rate was increased in the group using clopidogrel. Aggrenox should be used with caution in young individuals because it might increase the rate of intracerebral hemorrhage.

Acute and Rapid Development of Spontaneous Spinal Epidural Hematoma Associated with Combined Aspirin-Dipyridamole Therapy: A Case Report.

CASE: Spontaneous spinal epidural hematoma (SSEH) is a known, although rare, clinical entity that may be challenging to diagnose. This case report describes the rapid development of a large SSEH in an elderly patient on aspirin-dipyridamole combination therapy after she shifted her position in bed. Magnetic resonance imaging obtained 4 hours after the onset of symptoms demonstrated a large spinal epidural hematoma that extended from T4 to L1. CONCLUSION: With early diagnosis, the patient was successfully treated with a laminectomy and evacuation of the hematoma, and there was full neurological recovery.

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.

Chemometrics Tools in Detection and Quantitation of the Main Impurities Present in Aspirin/Dipyridamole Extended-Release Capsules.

Aspirin (ASP) and dipyridamole (DIP) in combination is widely used in the prevention of secondary events after stroke and transient ischemic attack. Salicylic acid is a well-known impurity of ASP, and the DIP extended-release formulation may contain ester impurities originating from the reaction with tartaric acid. UV spectral data analysis of the active ingredients in the presence of their main impurities is presented using multivariate approaches. Four chemometric-assisted spectrophotometric methods, namely, partial least-squares, concentration residuals augmented classical least-squares (CRACLS), multivariate curve resolution (MCR) alternating least-squares (ALS), and artificial neural networks, were developed and validated. The quantitative analyses of all the proposed calibrations were compared by percentage recoveries, root mean square error of prediction, and standard error of prediction. In addition, r(2) values between the pure and estimated spectral profiles were used to evaluate the qualitative analysis of CRACLS and MCR-ALS. The lowest error was obtained by the CRACLS model, whereas the best correlation was achieved using MCR-ALS. The four multivariate calibration methods could successfully be applied for the extended-release formulation analysis. The application results were also validated by analysis of the stored dosage-form solution, which showed a susceptibility of DIP esterification in the extended-release formulation. Statistical comparison between the proposed and official methods showed no significant difference.

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.

Cost-effectiveness of antiplatelet therapy to prolong primary patency of hemodialysis graft.

INTRODUCTION: The Dialysis Access Consortium (DAC) study group previously reported that treatment with extended-release dipyridamole plus aspirin (DASA) resulted in a significant but clinically modest improvement in primary unassisted arteriovenous graft (AVG) patency. Utilizing DAC published data, the objective of this study is to evaluate the cost effectiveness of antiplatelet interventions aimed at preventing loss of primary AVG patency in hemodialysis (HD) patients. METHODS: We performed a cost-utility analysis, using a decision analysis tree model with a 12-month time horizon and a third party payer perspective. Interventions included DASA with and without concurrent aspirin, aspirin alone, and no prophylaxis. The modeled population was defined as adult (≥ 18 years of age) end-stage renal disease (ESRD) patients who had undergone placement of a new AVG in the United States. The outcomes were costs, quality-adjusted life-years (QALY), incremental cost-effectiveness ratios, and net monetary benefit. Probabilities were based upon published studies performed by the DAC Study Group while costs of medications and procedures were drawn from public sources. Utilities of health states were derived from published reports and the Short Form 6D (SF-6D) instrument. RESULTS: Aspirin alone is the most cost effective strategy for AVG pharmacologic prophylaxis, as compared to no prophylaxis or DASA with or without concurrent aspirin. The results are robust on multiple scenario analyses using both deterministic and Monte Carlo probabilistic sensitivity analyses. Accounting for both costs and QALY, using aspirin alone to prevent AVG thrombosis can potentially reduce healthcare costs by $24,679,412 per year compared to no aspirin use, at a willingness-to-pay of $50,000/ QALY. CONCLUSIONS: Aspirin monotherapy compared favorably to other strategies based on cost per QALY. Our findings support the use of aspirin prophylaxis in HD patients with a new AVG who do not have a contraindication to aspirin.

Discontinuation of antiplatelet study medication and risk of recurrent stroke and cardiovascular events: results from the PRoFESS study.

BACKGROUND: Several case control studies have reported an increased risk of cardiovascular events following discontinuation of antiplatelet agents in high-risk patients. We therefore sought to investigate the risk of recurrent stroke and cardiovascular events following discontinuation of antiplatelet study medication in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a large randomized secondary stroke prevention study. METHODS: The recurrent stroke and cardiovascular event rates following discontinuation of aspirin plus extended-release dipyridamole (ASA + ERDP) or clopidogrel were compared to the event rates in the on-treatment populations (patients who had discontinued their antiplatelet medication due to an outcome event were kept in the on-treatment population in order not to underestimate the on-treatment stroke rate). RESULTS: In 7,212 treated ASA + ERDP patients, the stroke incidence rate for the on-treatment group was 729 strokes with an average exposure of 17,048 person-years (0.12 per 1,000 person-days). For 7,864 treated clopidogrel patients, the stroke incidence rate for the on-treatment group was 737 strokes with an average exposure of 18,715 person-years (0.11 per 1,000 person-days). ASA + ERDP was discontinued in 2,843 patients (in 57.7% due to an adverse event, 28.2% noncompliance, 1.4% loss to follow-up, 4.5% withdrawal of consent and 8.1% other/nonspecified reasons) and clopidogrel was permanently discontinued in 2,176 patients (49.0% due to an adverse event, 34.2% noncompliance, 1.8% loss to follow-up, 5.3% withdrawal of consent and 9.7% other/nonspecified reasons). Within 30 days, a recurrent stroke occurred in 31 patients (0.37 per 1,000 person-days) after discontinuation of ASA + ERDP and in 15 patients (0.24 per 1,000 person-days) after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 0.77% within 30 days after discontinuation of ASA + ERDP and 0.40% within 30 days after discontinuation of clopidogrel compared with the on-treatment study populations. A combined vascular endpoint (stroke, myocardial infarction, vascular death) occurred in 68 patients (0.82 per 1,000 person-days) within 30 days after discontinuation of ASA + ERDP and in 47 patients (0.75 per 1,000 person-days) within 30 days after discontinuation of clopidogrel. This corresponds to an absolute excess risk of 2.02% within 30 days after discontinuation of ASA + ERDP and 1.83% within 30 days after discontinuation of clopidogrel compared with the on-treatment study populations. CONCLUSION: Discontinuation of antiplatelet medication after ischemic stroke should be advocated only when the risk and severity of bleeding clearly outweigh the risk of cardiovascular events.

Pharmacokinetics and pharmacodynamics of the antiplatelet combination aspirin (acetylsalicylic acid) plus extended-release dipyridamole are not altered by coadministration with the potent CYP2C19 inhibitor omeprazole.

BACKGROUND: The fixed-dose combination of aspirin (acetylsalicylic acid) 25 mg plus extended-release dipyridamole 200 mg (ASA+ER-DP) is used for long-term secondary stroke prevention in patients who have experienced non-cardioembolic stroke or transient ischemic attack. Although the theoretical risk is low that the antiplatelet activity of ASA+ER-DP will be affected by concomitant use of a proton pump inhibitor (PPI), no formal drug-drug interaction studies have been conducted. OBJECTIVE: This study aimed to determine whether the PPI omeprazole influences the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of ASA+ER-DP. STUDY DESIGN AND SETTING: This was a randomized, open-label, multiple-dose, crossover, drug-drug interaction study carried out in a clinical trial unit. PARTICIPANTS: Sixty healthy male and female volunteers aged 18-50 years were included in the study. INTERVENTION: Participants were randomized to one of two treatment sequences (ABCD or CDAB), each comprising four 7-day treatments with a washout of ≥14 days between the second and third treatments. Treatment A=ASA+ER-DP 25 mg/200 mg (Aggrenox®) twice daily (BID) alone; B=ASA+ER-DP 25 mg/200 mg BID+omeprazole (Prilosec®) 80 mg once daily (QD) following ASA+ER-DP alone for 7 days; C=omeprazole 80 mg QD alone; D=omeprazole 80 mg QD+ASA+ER-DP 25 mg/200 mg BID following omeprazole alone for 7 days. MAIN OUTCOME MEASURES: The main outcome measures were systemic PK exposure to ER-DP and ASA inhibition of arachidonic acid-induced platelet aggregation. RESULTS: Systemic exposure to ER-DP was similar with and without omeprazole, based on steady-state area under the concentration-time curve (AUC) from 0 to 12 h (AUC0-12,ss, ng·h/mL) and maximum plasma concentration (Cmax,ss, ng/mL). For the treatment comparison D versus A, the percent mean ratios were 96.38 (90% confidence interval [CI] 90.96-102.13) for AUC0-12,ss and 92.03 (86.95-97.40) for Cmax,ss. The ER-DP concentration versus time profiles were nearly superimposable. There was no effect on the PDs of the ASA component: the extent of ASA inhibition of arachidonic acid-induced platelet aggregation was almost identical with and without omeprazole, with a percent mean ratio for treatment D versus A = 99.02 (90 % CI 98.32-99.72) at 4 h after last dose. All treatments were well tolerated. CONCLUSION: The PK and PD behavior of ASA + ER-DP was not altered by concurrent administration of omeprazole.

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.

Calculation of numbers-needed-to-treat in parallel group trials assessing ordinal outcomes: case examples from acute stroke and stroke prevention.

BACKGROUND: Number-needed-to-treat describes the magnitude of the effect of an intervention, underpins health economic analyses, and is typically calculated for binary events. Ordered categorical outcomes provide more clinical information and their analysis using ordinal approaches is usually more efficient statistically. However, to date, techniques to calculate number-needed-to-treat based on ordinal outcomes for parallel group trials have had important limitations. Aims Numbers-needed-to-treat may be calculated for ordinal data from parallel group trials by using an unmatched comparison of all subjects or by generating matched pairs of patients nested within the study. METHODS: The above approaches were assessed and compared with numbers-needed-to-treat calculated for binary outcomes using individual patient data from acute and prevention stroke trials testing the effect of interventions of varying utility and efficacy. RESULTS: Numbers-needed-to-treat were generally lower numerically for ordinal vs. binary, and matched vs. unmatched analyses, and the lowest in highly efficacious interventions: hemicraniectomy, ordinal matched 2.4 vs. ordinal unmatched 2.5 vs. binary matched 12 vs. binary unmatched 9 (one trial, 12 month outcome); alteplase, 4.5 vs. 6.6 vs. 8.4 vs. 8.4 (one trial with two parts, three-months); aspirin, 42 vs. 58 vs. 76 vs. 80 (one trial, six-months); and stroke units, 3.6-5.3 vs. 6.2 vs. 4.7-5.9 vs. 6.3-7.0 (two trials, three- to 60 months). Similar trends were seen for aspirin/dipyridamole vs. aspirin in secondary prevention, 22 vs. 20 vs. 31 vs. 31 (one trial, 24 months). CONCLUSIONS: Number-needed-to-treat may be calculated for ordinal outcome data derived from parallel group stroke trials; such numbers-needed-to-treat are lower than those calculated for binary outcomes. Their use complements the use of ordinal statistical approaches in the analysis of ordered categorical data.

The Japanese aggrenox (extended-release dipyridamole plus aspirin) stroke prevention versus aspirin programme (JASAP) study: a randomized, double-blind, controlled trial.

BACKGROUND: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan. METHODS: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93-2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group. CONCLUSIONS: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).

Use of aspirin associates with longer primary patency of hemodialysis grafts.

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

Effects of Aggrenox and aspirin on plasma endothelial nitric oxide synthase and oxidised low-density lipoproteins in patients after ischaemic stroke. The AGgrenox versus aspirin therapy evaluation (AGATE) biomarker substudy.

Plasma endothelial nitric oxide synthase (eNOS), and oxidised low-density lipoproteins (oxLDL) are established biomarkers of atherosclerosis. We defined the time course and magnitude of changes of plasma eNOS and oxLDL after Aggrenox or aspirin in post-stroke patients. Baseline pretreatment eNOS levels were significantly diminished (110 ± 66pg /ml vs. 374 ± 88 pg/ml, p=0.0001), while oxLDL was twice higher (58 ± 9 mg/l vs. 23 ± 7 mg/l, p=0.004) in post-stroke survivors when compared to controls. Both Aggrenox and aspirin similarly increased plasma eNOS activity. However, oxLDL levels were static after aspirin, but inhibited late after Aggrenox. In the small randomised study, both aspirin and Aggrenox produced fast and sustained recovery of plasma eNOS levels, while only therapy with Aggrenox was associated with oxLDL inhibition late in the trial.

A multi-case report of acute renal failure in patients treated with Aggrenox.

BACKGROUND: Aggrenox is used in the secondary prevention of stroke. Acute renal failure, potentially associated with Aggrenox, has been observed in several patients. OBJECTIVE: The objective of this study was to determine if Aggrenox was associated with acute renal failure and to determine whether it was acetylsalicylic acid, dipyridamole or the combination that led to decline in renal function. METHODS: A case series of three patients suffering severe nausea, vomiting, diarrhea, renal dysfunction and clinical decline during Aggrenox therapy was examined. Serum creatinine and Blood Urea Nitrogen (BUN) were measured to evaluate renal function. RESULTS: Analysis of this patient group revealed that Patient 1 experienced nausea, emesis, anorexia, diarrhea and significant clinical decline during treatment with Aggrenox. Patients 2 and 3 also presented with complaints of nausea and emesis. Lab measurements along with clinical symptoms indicated that all three patients experienced acute renal failure, having increases in serum creatinine of 186%, 144% and 249%, respectively. Symptoms and lab work returned to baseline following discontinuation of Aggrenox. CONCLUSION: It is biologically plausible that Aggrenox may contribute to renal dysfunction in patients under certain pathophysiological circumstances.

Safety of fixed-dose aspirin-extended-release dipyridamole in patients with ischemic heart disease.

PURPOSE: The safety of fixed-dose combination aspirin-extended-release (ER) dipyridamole for stroke prevention in patients with ischemic heart disease is reviewed. SUMMARY: Randomized controlled trials have established the superiority of aspirinER dipyridamole over aspirin alone for secondary stroke prevention. One limitation of this product is the potential risk of worsening angina in patients with coronary artery disease. The English-language medical literature was searched for articles describing the cardiac safety of oral dipyridamole alone or in combination with aspirin. Meta-analyses, randomized controlled trials, observational studies, and case reports presenting information on the cardiac safety of oral dipyridamole were also reviewed. Four meta-analyses described vascular events with dipyridamole using various dosing strategies. Three trials included the endpoint of myocardial infarction in patients receiving ER dipyridamole. The meta-analyses and randomized controlled trials specifically evaluating aspirin-ER dipyridamole did not provide evidence of increased risk of vascular events. One post hoc analysis of a randomized controlled trial specifically assessed the cardiac safety of fixed-dose aspirin-ER dipyridamole and found that dipyridamole was not associated with a higher number of cardiac events compared with aspirin alone. One randomized controlled trial evaluated the efficacy of ER dipyridamole in patients with preexisting ischemic heart disease and found no evidence of increased risk of cardiac events in this population. No published reports were located describing angina with the combination product. CONCLUSION: A literature review revealed that fixed-dose aspirin-ER dipyridamole was not associated with an increased risk of cardiovascular events in patients with ischemic heart disease. However, individual patient factors merit consideration when choosing an antiplatelet agent for stroke prevention.

Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial.

BACKGROUND: Little is known about the best antiplatelet treatment immediately after ischaemic stroke or transient ischaemic attack (TIA). The EARLY trial aimed to compare outcome in patients given aspirin plus extended-release dipyridamole twice daily either within 24 h of stroke or TIA or after 7 days of aspirin monotherapy. METHODS: In 46 stroke units in Germany, patients aged 18 years or more who presented with symptoms of an acute ischaemic stroke that caused a measurable neurological deficit (National Institutes of Health stroke scale score < or =20) were randomly assigned to receive 25 mg aspirin plus 200 mg extended-release dipyridamole open-label twice daily or 100 mg aspirin monotherapy open-label once daily for 7 days. Patients were randomised by use of a pseudorandom number generator. All patients were then given open-label aspirin plus extended-release dipyridamole for up to 90 days. The primary endpoint was modified Rankin scale score as recorded by centralised, blinded assessment by telephone (tele-mRS) at 90 days. Vascular adverse events (non-fatal stroke, TIA, non-fatal myocardial infarction, and major bleeding complications) and mortality were assessed in a composite safety and efficacy endpoint. Patients were analysed as treated. This trial is registered, number NCT00562588. FINDINGS: Between July, 2007, and February, 2009, 543 patients were treated: 283 received early aspirin plus extended-release dipyridamole and 260 received aspirin plus extended-release dipyridamole after 7 days on aspirin. At day 90, 154 (56%) patients in the aspirin plus early extended-release dipyridamole group and 133 (52%) in the aspirin plus later extended-release dipyridamole group had no or mild disability (tele-mRS 0 or 1; difference 4.1%, 95% CI -4.5 to 12.6, p=0.45). 28 patients in the early initiation group and 38 in the late initiation group reached the composite endpoint (hazard ratio 0.73, 95% CI 0.44-1.19 p=0.20). INTERPRETATION: Early initiation of aspirin plus extended-release dipyridamole within 24 h of stroke onset is likely to be as safe and effective in preventing disability as is later initiation after 7 days. FUNDING: Boehringer Ingelheim.