Extended-release Dipyridamole Research Articles

Aspirin-Dipyridamole in Fluctuating Small Vessel Disease Ischemic Strokes (P7-5.013)

<h3>Objective:</h3> Short-term inpatient use of aspirin-dipyridamole (Aggrenox) in small vessel disease (SVD) ischemic strokes (IS) may reduce neurologic fluctuations, leading to better functional outcomes. This single-center retrospective case-control study aims to compare outcomes in patients diagnosed with SVD IS who received Aggrenox versus standard antiplatelet therapy. <h3>Background:</h3> Aggrenox is a fixed-dose combination of aspirin, an antiplatelet, and extended-release dipyridamole, which acts both to impair platelet function and cause vasodilation. Previous studies showed Aggrenox to be safe and effective for secondary stroke prevention. We suspect that early use of Aggrenox could be effective for stroke prevention and functional outcomes due to its vasodilatory properties. <h3>Design/Methods:</h3> A retrospective analysis of patients diagnosed with SVD IS between January 2016–December 2020 was completed. We plan to enroll patients admitted through September 2022. Patients with age ≥18, who received a minimum of four doses of Aggrenox during hospitalization, will be matched with control patients who did not receive Aggrenox. Study end points include discharge NIHSS compared hospital day 1 and discharge mRS compared to admission. REDCap is being used for data collection and generation of descriptive statistics. <h3>Results:</h3> Thus far, 49 patients have qualified for inclusion into the Aggrenox cohort, with data collection still in progress. Subject pool has mean age 55; 49% male; 82% African American; 49% diabetic; 37% received tPA; mean length of time from admission to administration of Aggrenox of 26 hours; mean duration of Aggrenox 4 days; mean NIHSS on admission 5.7; mean NIHSS on discharge 5.1; mean mRS at admission 0.6; mean mRS at discharge 2.7; 41% of patients discharged home, 57% to inpatient rehabilitation, and 2% to a skilled nursing facility. <h3>Conclusions:</h3> Data in the Aggrenox population shows a trend toward improvement in NIHSS throughout hospitalization. Once control group data is collected, comparative statistics will be used to analyze outcomes between the two groups. <b>Disclosure:</b> Dr. Moran has nothing to disclose. Dr. March has nothing to disclose. Dr. Nearing has nothing to disclose.

Navigating Antiplatelet Treatment Options for Stroke: Evidence-Based and Pragmatic Strategies.

The benefit of using antiplatelet monotherapy in acute ischemic stroke and secondary stroke prevention is well established. In the last few years, several large randomized trials showed that the use of short-term dual antiplatelet therapy in particular stroke subtypes may reduce the risk of recurrent ischemic events. The aim of this article is to provide a critical analysis of the current evidence and recommendations for the use of antiplatelet agents for stroke prevention. Long-term therapy with aspirin, clopidogrel, or aspirin plus extended-release dipyridamole is recommended for secondary stroke prevention in patients with noncardioembolic ischemic stroke. Short-term dual antiplatelet therapy with aspirin and clopidogrel is superior to antiplatelet monotherapy in secondary stroke prevention when used in patients with mild noncardioembolic stroke or high-risk transient ischemic attack. Dual therapy, however, is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30days. Similarly, aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. In patients with symptomatic intracranial stenosis, aggressive medical management in addition to dual antiplatelet therapy up to 90days is recommended. Antiplatelet therapy has an essential role in the management of ischemic stroke. The specific antiplatelet regimen should be individualized based on the stroke characteristics, time from symptom onset, and patient-specific predisposition to develop hemorrhagic complications.

Selecting an Optimal Antiplatelet Agent for Secondary Stroke Prevention.

Four seminal randomized controlled trials (RCTs) have investigated aspirin, aspirin plus extended-release dipyridamole, and clopidogrel for the prevention of recurrent vascular events. Despite studying over 32,000 patients with stroke in these trials, the decision on which antiplatelet agent to select for secondary stroke prevention remains controversial. Attempts to translate the results of these RCTs into clinical practice are complicated by each trial's selection of participants and choice of primary outcome. Herein, we argue that by examining RCT results with participant selection limited to patients with ischemic stroke or TIA and by focusing on recurrent stroke as our outcome, we can use the standard epidemiology 2 × 2 table to assist in selecting an antiplatelet agent for secondary stroke prevention.

InstaSpheres TA (Tartaric acid) as functional starter core for extended release formulations

The modulation of pH is used to develop products which have pH dependent solubility. The mechanism is still not clear on the extent and the duration of the pH-modifying effect. This requires that pH modifier should not leach out quickly from the dosage form instead it must be present in sufficient quantity until the complete drug release. The aim of the study is to demonstrate InstaSpheres TA (seal coated tartaric acid spheres) as pH modifier starter core for extended drug delivery of weakly basic drug and to confirm the effect of resultant acidic microenvironment on drug release at higher pH. We hypothesized that InstaSpheres TA can prevent direct contact between tartaric acid and the drug and control the release of tartaric acid to modulate the pH in the vicinity of the drug. We developed multilayered extended release (ER) pellets of dipyridamole using InstaSpheres TA as the starter core by fluid bed coating. The drug layered InstaSphere TA pellets were coated with protective coat followed by enteric coating to formulate stable ER dipyridamole pellets. The controlled release profile of dipyridamole and tartaric acid was observed as a result of low micro-environmental pH within the pellet throughout entire dissolution period. The formulation avoids direct contact of tartaric acid with drug, prevents premature release of dipyridamole and tartaric acid and increases drug release at higher pH. It shows similarity in dissolution with reference product and also stability over entire duration of accelerated stability studies. InstaSpheres TA is therefore a viable pH modifying functional starter core for weakly basic drugs.

Case Series about the Changed Antiplatelet Protocol for Carotid Endarterectomy in a Teaching Hospital: More Patients with Complications?

Introduction In the Netherlands, clopidogrel monotherapy increasingly replaces acetylsalicylic acid and extended release dipyridamole as the first-choice antiplatelet therapy after ischemic stroke. It is unknown whether the risk of peri- and postoperative hemorrhage in carotid artery surgery is higher in patients using clopidogrel monotherapy compared with acetylsalicylic acid and extended release dipyridamole. We therefore retrospectively compared occurrence of perioperative major and (clinical relevant) minor bleedings during and after carotid endarterectomy of two groups using different types of platelet aggregation inhibition after changing our daily practice protocol in our center. Material and Methods A consecutive series of the most recent 80 carotid endarterectomy patients (November 2015–August 2017) treated with the new regime (clopidogrel monotherapy) were compared with the last 80 (January 2012–November 2015) consecutive patients treated according to the old protocol (acetylsalicylic acid and dipyridamole). The primary endpoint was any major bleeding during surgery or in the first 24 to 72 hours postoperatively. Secondary outcomes within 30 days after surgery included minor (re)bleeding postoperative stroke with persistent or transient neurological deficit, persisting or transient neuropraxia, asymptomatic restenosis or occlusion, (transient) headache. Reporting of this study is in line with the ‘Strengthening the Reporting of Observational Studies in Epidemiology’ statement. Results Although statistical differences were observed, from a clinical perspective both patients groups were comparable. Postoperative hemorrhage requiring reexploration for hemostasis occurred in none of the 80 patients in the group of the clopidogrel monotherapy (new protocol) and it occurred in one of the 80 patients (1%) who was using acetylsalicylic acid and dipyridamole (old protocol). In three patients (4%) in the clopidogrel monotherapy and one patient (1%) in the acetylsalicylic acid and extended release dipyridamole protocol an ipsilateral stroke was diagnosed. Conclusion In this retrospective consecutive series the incidence of postoperative ischemic complications and perioperative hemorrhage after carotid endarterectomy (CEA) seemed to be comparable in patients using clopidogrel monotherapy versus acetylsalicylic acid and extended release dipyridamole for secondary prevention after a cerebrovascular event. This study fuels the hypothesis that short- and midterm complications of clopidogrel and the combination acetylsalicylic acid and extended release dipyridamole are comparable.

Oral Dipyridamole-Associated Circulatory Collapse

Extended-release dipyridamole plus aspirin is widely used for secondary prevention of ischemic stroke, although the molecular pharmacodynamics of dipyridamole are not completely determined. Adverse effects of fixed-dose combination of aspirin and dipyridamole include headache, bleeding, and gastrointestinal events. Previously, intravenous infusion of dipyridamole in cardiac stress testing has been associated with cardiogenic shock and pulmonary edema. Herein, we report a case study of a 72-year-old man, presented with a transient ischemic attack who suffered a circulatory collapse after an oral dose of 200 mg extended-release dipyridamole. The possible molecular mechanisms of dipyridamole on the cardiovascular system are reviewed. This is the first case report of a circulatory collapse induced by an oral intake of dipyridamole.

Development of pH Independent Drug Release System for Dipyridamole

Abstract: Introduction: Dipyridamole is an Anti-platelet agent exhibits release problems at higher pH of small intestine due to its pH dependent solubility and precipitation followed by interruption of drug release from dosage form. To overcome this extended release formulation was developed by using pH modulating agent (tartaric acid). Objective: Present study was undertaken with a view of the formulations evaluated by performing dissolution testing on developed extended released tablets. Method: development of dissolution method at different time points and USP Apparatus 1 (basket) and 2 (paddle) at rotating speeds of 50 or 100 rpm used to evaluate the release characteristics of the formulations. Furthermore, solubility and in vitro dissolution studies of formulated tablets were performed at pH values of 1.2 and 5.5. Results: In this study we found increasing volume of dissolution medium pH 5.5 phosphate buffers drug precipitation is increased. The developed dissolution method was validated according to ICH guidelines for various parameters such as specificity, accuracy, precision, and stability. The dissolution method was confirmed by determining the dissolution rate of extended released Dipyridamole tablets containing pH modulating agent. The best in vitro dissolution profile was obtained using pH 5.5 phosphate buffer as the dissolution medium (500 ml) stirred at 100 rpm. A comparison of the dissolution profiles in official and developed media showed significant differences based on f1 and f2 values. Conclusoni: The developed dissolution test exhibited a higher capacity than the compendia methods in differentiating the release profiles of pH independent extended release tablets. It can be applied during formulation development and quality control analysis of pH independent extended release tablets for evaluation of the effects of pH modifier in dissolution medium and processing parameters. Key words: Tartaric acid, Dissolution media, Extended release Dipyridamole Tablets.

Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke

BackgroundWhether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown.MethodsIn a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory.ResultsWe enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group.ConclusionsAmong adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.)

Antiplatelet and Anticoagulant Therapies for Prevention of Ischemic Stroke.

Ischemic stroke represents one of the leading causes of death and disability in both the United States and abroad, particularly for patients with prior ischemic stroke or transient ischemic attack (TIA). A quintessential aspect of secondary stroke prevention is the use of different pharmacological agents, mainly antiplatelets and anticoagulants. Antiplatelets and anticoagulants exhibit their effect by blocking the activation pathways of platelets and the coagulation cascade, respectively. Clinical trials have demonstrated the safety and efficacy of antiplatelets for noncardioembolic stroke prevention, while anticoagulants are more often used for cardioembolic stroke prevention. Commonly used antiplatelets include aspirin, clopidogrel, and aggrenox (aspirin plus extended-release dipyridamole). Furthermore, commonly used anticoagulants include warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. Each of these drugs has a unique mechanism of action, and they share some common adverse events such as gastrointestinal bleeding and intracranial hemorrhage in more serious cases. Consequently, physicians should carefully assess the benefits and risks of using different antiplatelet or anticoagulant therapies when managing patients with previous ischemic stroke or TIA. This review discuses the published literature on major clinical trials assessing the efficacy of different antiplatelet and anticoagulant drugs under varying circumstances and the subsequent guidelines that have been developed by the American Heart Association/American Stroke Association. Additionally, the role of imaging in stroke prevention is discussed.

Differences in Ischemic and Hemorrhagic Recurrence Rates among Race-Ethnic Groups in the PRoFESS Secondary Stroke Prevention Trial

Epidemiological studies show that vascular risk factors are the same across the world but their effect vary between different race-ethnic groups. However, few studies have evaluated differences in recurrent stroke rates in various race-ethnicities. In >20 000 patients spanning 35 countries encompassing most race-ethnicities, we evaluated the incidence of ischemic and hemorrhagic strokes and myocardial infarction in patients within the context of the largest secondary stroke prevention trial (Prevention Regimen for Effectively Avoiding Secondary Strokes) to identify any significant differences. There were 20 332 patients with a recent ischemic stroke randomized in a factorial design to receive the antiplatelet agent clopidogrel vs. aspirin plus extended-release dipyridamole, and 80 mg of the anthypertensive telmisartan vs. placebo. The primary outcome for the trial was the time to any recurrent stroke. Statistical analysis was used to detect race-ethnic differences in recurrent vascular events. Mean patient age was 66 (±8·6) years and 36% were women. The study included 58% European/Caucasian, 33% Asians, 5% Latin/Hispanic, and 4% Black African. There were 74% of patients that were hypertensive, and average systolic and diastolic blood pressure was 144·1/83·8 mmHg. There was at least one significant difference in the overall test of all race-ethnic groups in myocardial infarction and symptomatic intracerebral hemorrhage occurrence. In the Kaplan-Meier hemorrhage and stroke-free survival curves, Asians showed a significantly higher recurrence of ischemic stroke risk in the 135-150 mmHg and greater than 150 mm Hg blood pressure groups, and a greater risk of hemorrhage recurrence in the greater than 150 mmHg blood pressure group. We found a significant difference in myocardial infarction and symptomatic intracerebral hemorrhage recurrence among different race-ethnic groups. The risk of recurrent ischemic and hemorrhagic stroke was greater in Asians with high blood pressure.

Antiplatelet strategies for secondary prevention of stroke and TIA.

Stroke is a major public health issue, and stroke recurrence accounts for a quarter of all events. Antiplatelet therapy has been extensively studied for secondary stroke prevention and is established as effective in this high-risk population. Several agents have been evaluated in this setting, both in isolation and combination. The most widely used antiplatelet medications are aspirin, clopidogrel, and aspirin plus extended-release dipyridamole. However, new agents and combinations continue to be evaluated. A detailed review of the evidence supporting various antiplatelet regimens for secondary stroke prevention is outlined with special focus on recent developments that may impact clinical management of patients with stroke or TIA.

Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: a post hoc analysis.

Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP). This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20,332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function.

What is the best management of patients who experience a transient ischemic attack (TIA) while taking aspirin?

Evidence-Based Answer Aspirin plus extended-release dipyridamole is superior to aspirin monotherapy in preventing recurrent strokes in patients with a TIA or minor stroke, whereas no difference was noted between aspirin plus dipyridamole and clopidogrel in this risk group. No difference was apparent in stroke rates between aspirin plus clopidogrel and aspirin alone in patients with cardiovascular disease or risk factors alone (SOR B, consistent highquality RCTs).

Abstract W P155: Antiplatelet Therapy Benefit in Secondary Stroke Prevention in Patients With Suboptimally Controlled Treatable Cerebrovascular Risk Factors

Objective: To assess the impact of antiplatelet therapy for secondary stroke prevention in patients with suboptimally controlled treatable cerebrovascular risk factors per guidelines. Results: Of the 1755 patients, 219 (12.47%) patients had a second stroke event between November 2006-December 2012. Mean age of this group of patients was 66.4 years old with male predominance (M:F=1.5:1). 192 (88%) patients were on antiplatelet therapy at the time of the second stroke. 27 (12 %) were not on antiplatelet therapy. Of the total cohort, treatable risk factors were poorly controlled in 130 (59%) patients: 121 (55%) hypertension; 78 (36%) hyperlipidemia, 44 (20%) diabetes. Antiplatelet agents included aspirin, clopidogrel alone or in combination with aspirin, and extended-release dipyridamole. The data showed no significant difference among antiplatelet agents for secondary stroke prevention (p&lt;0.05). Stroke classification was as follows: 162 (74%) ischemic and 57 (26%) hemorrhagic. Categories of ischemic stroke were as follows: large-artery atherosclerosis 40 (18%), small vessel disease 45 (21%), cardioembolic 42 (19%), 35 (16%) cryptogenic / stroke of undetermined etiology. Of the 192 patients on antiplatelet therapy with stroke, 116 (60%) had poorly controlled risk factors. Conclusions: This study suggests that the use of antiplatelet therapy, regardless of which agent, for secondary stroke prevention may not be important or beneficial in the absence of optimal treatable cerebrovascular risk factor control. Further studies are needed to support this finding including further analysis of our data to assess risk factor control in those patients on antiplatelet therapy who did not suffer a second stroke during the period of surveillance

Stroke Subtypes and their Possible Implication in Stroke Prevention Drug Strategies

Thrombotic strokes can affect large or small arteries in the brain. Drugs to prevent atherosclerosis complication such as thrombotic strokes, should be drugs able to prevent the accumulation of intravascular fat, reduce vascular proliferation, decrease blood pressure levels with the resulting shear stress, reduce platelet aggregation, and possibly partially or totally reverse carotid plaques. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental and clinical data suggest that reducing the activity of the renin-angiotensin aldosterone system (RAAS) may have beneficial effects beyond the lowering of blood pressure to reduce stroke incidence. In clinical trials, statins consistently reduced the risk of ischemic stroke in patients with or without CHD whereas the data on the effects of other lipid modifying drugs on stroke risk are limited. Approximately 25% of strokes are recurrent. Antiplatelet therapy is indicated for the prevention of recurrent stroke in patients with a history of noncardioembolic minor stroke or transient ischemic attack (TIA). Although clinicians may choose acetylsalicylic acid (ASA) as first-line therapy for secondary prevention, clinical guidelines and evidence from trials suggest that ASA may not be the most effective strategy. A recent review discussed results from clinical trials that have compared the efficacy of ASA monotherapy versus ASA + extended release dipyridamole in secondary stroke prevention. Therefore it is difficult to extrapolate the real benefit of pharmacological prevention strategies against atherothrombotic subtype for excellence in the TOAST classification subtype that is represented by the LAAS and also with regard to lacunar subtype as an expression of lipohyalinosis process which is a further aspect of atherosclerosis.

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

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. 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. 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. 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.

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

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

Types of Stroke Recurrence in Patients with Ischemic Stroke: A Substudy from the PRoFESS Trial

Risk profiles for stroke recurrence are poorly characterized. We determined the variation in the risk and type of recurrent stroke among index ischemic stroke subtypes, and whether index stroke subtype and conventional stroke risk factors were predictors of stroke recurrence. Patients enrolled in the Prevention Regimen for Effectively Avoiding Second Strokes trial were included in this study. In 1794 patients' recurrent stroke subtypes were the same as the index stroke in: 48·3% of patients with large artery atherothrombosis stroke; 50% of patients with cardioembolic stroke; 48·7% of patients with small artery occlusion stroke; 8·1% of patients with stroke of other etiology, and 45·3% of patients with undetermined etiology stroke. Patients with cardioembolic stroke, who were unwilling or unable to take oral anticoagulants, had the greatest risk of stroke recurrence. Predictors of stroke recurrence in multivariable analysis were: older age and previous stroke among large artery atherothrombosis strokes; older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use among small artery occlusion strokes; older age among cardioembolic strokes; atrial fibrillation and anti-diabetic medications among other etiology strokes; older age, previous stroke and atrial fibrillation among undetermined etiology strokes. Predictors of brain hemorrhage as recurrent stroke were index small artery occlusion stroke, older age, previous stroke, and antiplatelet treatment with aspirin plus extended-release dipyridamole. Risk predictors for stroke recurrence and for brain hemorrhage differ by index ischemic stroke subtype, information that is important when initiating secondary prevention therapy.

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

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. 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 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®). 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.

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.