Drug Delivery and Therapeutic Impact of extended-release Acetylsalicylic Acid

Abstract

Current treatment guidelines recommend once-daily, low-dose acetylsalicylic acid (ASA; aspirin) for secondary prevention of cardiovascular events. However, the anti-thrombotic benefits of traditional ASA formulations may not extend over a 24-h period, especially in patients at high risk for a recurrent cardiovascular event. A next-generation, extended-release ASA formulation (ER-ASA) has been developed to provide 24-h anti-thrombotic coverage with once-daily dosing. The pharmacokinetics of ER-ASA indicates slower absorption and prolonged ASA release versus immediate-release ASA, with a favorable safety profile. ER-ASA minimizes systemic ASA absorption and provides sustained antiplatelet effects over a 24-h period.

KEYWORDS :

• acetylsalicylic acid
• antiplatelet
• cardiovascular disease
• diabetes
• Durlaza
• extended-release
• microcapsule
• secondary prevention
• thrombosis

Cardiovascular disease (CVD), including heart disease and stroke, is one of the leading causes of death and disability in the USA [1,2]. Coronary heart disease (48%) and stroke (16%) are the most common causes of CVD-related mortality [1]. In 2011, approximately 85.6 million adults (more than one in three) in the USA were reported to have CVD, and the incidence is anticipated to increase through 2030 [1]. CVD is among the leading medical conditions resulting in functional disability, and causes approximately $125 billion annually in lost worker productivity [1]. Annual direct cost of CVD (e.g., healthcare provider visits, hospital services, medication) in 2011 was approximately $196 billion. Total direct medical costs of CVD are estimated to increase to $918 billion by 2030 [1].

Patients with CVD are at increased risk of secondary cardiovascular (CV) event occurrences. Approximately 15% of patients with CVD and up to 45% of patients with CVD and comorbid diabetes experience a secondary CV event [3–5], and these higher-risk patient cohorts have an increased risk of CVD-related mortality versus individuals without these conditions [6]. The American College of Cardiology Foundation, in collaboration with the American Heart Association and the American Diabetes Association, has recommended long-term, uninterrupted therapy with low-dose (75–162 mg) acetylsalicylic acid (ASA; aspirin) for the secondary prevention of CV events [7,8]. Unfortunately, the recommended once-daily, low-dose ASA may not provide adequate prevention in a substantial percentage of patients [9]. Therefore, additional therapeutic options are needed to maximize risk reduction. In the current article, we review the role of traditional oral ASA formulations in prevention of secondary CV events, and discuss the potential advantages of a new extended-release (ER)-ASA formulation that is currently undergoing US regulatory review for secondary prevention of CV events.

Overview of traditional immediate-release ASA

• ASA pharmacology

The antipyretic and analgesic effects of salicin, the compound in willow bark that provides a therapeutic benefit, have been known since antiquity [10]. In 1897, the acetylated form of salicylic acid (SA) was synthesized [10], and during the 1950s, it was discovered that ASA had anti-thrombotic effects [10]. In 1971, the mechanism underlying the cardioprotective effects of ASA (i.e., inhibition of prostaglandin [PG] synthesis) was elucidated [11].

Platelets may be activated by a variety of stimuli including shear, epinephrine, ADP, thrombin and adhesion to exposed collagen and von Willebrand factor at the site of the injured vessel wall [12]. Upon activation, platelets release positive feedback mediators that facilitate platelet activation, as well as transmitters that impact the vessel wall and other cells and contribute to vasoconstriction, increased capillary permeability and coagulation [13].

Platelet activation and aggregation are the most critical factors in the generation of ischemic event occurrences [12–14]. ASA selectively, rapidly and irreversibly acetylates a serine residue in the cyclooxygenase (COX)-1, and thereby prevents binding of arachidonic acid to the catalytic site and reduces production of PGH₂ [15]. Under ‘normal’ conditions, PGH₂ is converted to a variety of PGs (e.g., PGI₂ [prostacyclin]) and thromboxane A₂ (TxA₂) through the actions of tissue-specific synthases [15]. Reduced production of PGH₂, attributable to ASA inhibition of the COX-1 enzyme, results in lower levels of prothrombotic TxA₂ and subsequent TxA₂-induced platelet aggregation [15]. Although ASA inhibits both COX-1 and COX-2, the affinity of ASA for COX-1 is 166 times greater than for COX-2; thus COX-1 inhibition is primarily responsible for ASA-induced reductions in TxA₂ [15].

Multiple formulations of ASA (single entity and combination products) have been developed, including immediate-release (IR) ASA, which disintegrates in and is rapidly absorbed by the stomach and upper small intestines, and enteric-coated ASA, which breaks down and is absorbed primarily within the duodenum. In humans, a single dose of IR-ASA provides a peak plasma concentration within 40 min and inhibition of platelets within 1 h postdose [15]. Enteric-coated ASA has a slower dissolution profile than IR-ASA, which extends the time to absorption up to 5 h [16]. The overall bioavailability of ASA also differs between the two formulations: the bioavailability with IR-ASA (50%) is greater than that of enteric-coated ASA [17–19]. Once absorbed, ASA is rapidly deacetylated to salicylic acid by carboxylesterases within the liver and the GI tract (i.e., within the portal circulation) [20]; thus, ASA in plasma has a short half-life of approximately 15–20 min, regardless of delivery formulation [17]. Inhibition of platelet activity was observed before systemic levels of ASA were detected, suggesting that inhibition of the COX-1 enzyme of platelets occurs in the prehepatic circulation [12].

The antiplatelet effect of ASA is critically dependent on the concentration of unmetabolized ASA in circulation and platelet generation and turnover [21]. Platelets are continuously generated throughout the day [22] (∼10% of the total platelet population is regenerated during a 24-h period [23]) and have a typical life span of 8–10 days [23,24]. The irreversible acetylation of COX-1 ensures enzyme inhibition for the entirety of a platelet’s lifespan; however, this anti-thrombotic effect is negatively impacted over time as new platelets with uninhibited COX enzymes are continually released into systemic circulation [25].

The pharmacodynamic effects of ASA occur quickly (within hours) after administration [19], as might be expected from its original development as an analgesic aimed at providing immediate pain relief [10]. Serum thromboxane B₂ (TxB₂; a stable metabolite of TxA₂) levels in healthy volunteers decline within the first 20 min of ASA administration and remain low (∼100 ng/ml), despite reductions in plasma ASA concentrations [19]. The significantly lower level of TxB₂ correlates with the inhibition of arachidonic acid-induced platelet aggregation as measured by ex vivo assays [12]. Repeated administration of low-dose ASA in healthy individuals results in cumulative and selective inactivation of platelet COX-1 activity [26]. Upon ASA withdrawal, COX-1 activity recovers within approximately 9 days, in accordance with platelet lifespan [26]. However, reemergence of functional platelet COX-1 in circulation may occur as quickly as within 24 h in patients with a higher rate of platelet turnover, such as those with CVD [27], metabolic syndrome [28], or diabetes [29], or after cardiac surgery [12,30].

Figure 1. Recovery of platelet aggregation and thromboxane A₂ production after immediate-release acetylsalicylic acid administration.

(A) Arachidonic acid-induced platelet aggregation and (B) TxB₂ production in healthy volunteers and patients with cardiovascular disease after a single dose of IR-ASA 75 mg. Platelet aggregation was measured using the Multiplate^® Analyzer (Roche Diagnostics International LDT, Rotkreuz, Switzerland), which detects differences in electric resistance between two electrodes in aggregated whole blood. Platelet aggregation was stimulated by arachidonic acid 1.0 mM and collagen 3.2 µg/ml. Serum TxB₂ concentrations were measured using an ELISA (Cayman Chemical, Ann Arbor, MI, USA). Platelet aggregation and TxB₂ production were significantly greater 24 h after ASA dosing compared with 1 h post-treatment.

ASA: Acetylsalicylic acid; CAD: Coronary artery disease; ST: Stent thrombosis; TxB₂: Thromboxane B₂.

Reproduced with permission from [61].

Figure 2. Micropump^® (Flamel Technologies SA, Pessac, France) delivery platform for extended-release acetylsalicylic acid.

Each extended-release capsule contains a core of release rate-limiting, film-coated microcapsules containing 162.5 mg of ASA.

ASA: Acetylsalicylic acid.

Figure 3. Characteristic diffusion-based dissolution profile based on Fick’s second law.

Figure 4. Pharmacokinetics of extended-release acetylsalicylic acid.

(A) Mean concentration time profiles of single-dose ASA for ER-ASA and IR-ASA; and (B) single-dose mean concentration time profiles of SA for ER-ASA and IR-ASA.

ASA: Acetylsalicylic acid; ER: Extended release; IR: Immediate release; SA: Salicylic acid.

Data taken from [75].

Figure 5. Antiplatelet effects of a single dose of extended-release acetylsalicylic acid.

(A) Mean percent inhibition of TxB₂ production and (B) 11-dehydro-TxB₂ after single-dose exposure to ER-ASA 162 mg and IR-ASA 81 mg in healthy volunteers. ER-ASA provides 24-h reduction of TxB₂ production.

ASA: Acetylsalicylic acid; ER: Extended release; IR: Immediate release; TxB₂: Thromboxane B₂.

Data taken from [75].

Figure 6. Inhibition of prostacyclin levels^† in healthy volunteers with extended-release acetylsalicylic acid 162.5 mg/day for 10 days.

Mean vascular prostacyclin levels were not reduced after multiple extended-release acetylsalicylic acid administrations.

^†Mean urine excretion level of 6-keto prostaglandin F1α is a surrogate marker for vascular prostacyclin level

• ASA reduces risk of CV events in high-risk patients

A large body of data has demonstrated that ASA reduces the risk of secondary CV events and mortality. A meta-analysis of 17,000 high-risk patients (i.e., patients with a previous CV event) from 16 clinical trials indicated a significant reduction in the risk of CV events in patients who received antiplatelet therapy versus those who did not [31]. This risk reduction occurred regardless of predisposing medical conditions, including carotid disease and diabetes [32]. In a meta-analysis of 13 studies that examined the efficacy of ASA for the prevention of secondary CV events in patients with diabetes, ASA significantly reduced the risk of all-cause mortality compared with no ASA treatment (relative risk: 0.82; 95% CI: 0.69–0.98; p = 0.03) [33]. The extent of risk reduction for CV-related mortality and for occurrence of a secondary CV event was not related to ASA dose; higher ASA doses (up to 1300 mg/day) did not appear to confer additional risk reduction [32,33]. Moreover, high-dose (150–325 mg/day) ASA has been associated with increased risk of bleeding compared with low-dose (75–149 mg/day) ASA in at least one high-risk population (i.e., patients receiving medical treatment for acute coronary artery syndrome) [34].

• ASA resistance

Current treatment guidelines for secondary prevention of CV events recommend once-daily, low-dose (75–325 mg/day) ASA in high-risk patients [7–8,35]. It has been widely reported that a substantial percentage of patients treated with low-dose ASA exhibit laboratory ASA resistance [36], but the relationship of this phenomenon to clinical outcomes is controversial. A reliable and specific laboratory method to identify ASA resistance has not yet been uniformly defined. Laboratory point-of-care methods, including assays that use platelet agonists such as ADP, collagen, shear and epinephrine (i.e., ‘COX-1 nonspecific’ methods) to stimulate platelets, reflect multiple signaling pathways, not solely COX-1 activity [36,37]. The best definition of ASA resistance or ASA nonresponse is one based on the specific observation of residual COX-1 activity [36]. Assays that measure serum TxB₂ and arachidonic acid-induced platelet aggregation are the most specific methods for assessing COX-1 activity [38]; however, other assays that employ arachidonic acid in evaluation of ASA responsiveness are also commonly reported in the literature [38]. With adequate doses of ASA, ASA nonresponse based on COX-1 activity alone occurs in <5% of patients [38]. However, up to 37% of patients with a history of CVD and up to 42% of patients with diabetes, many of whom also have metabolic syndrome [39], show a reduced response to ASA [40–42]. The higher prevalence of ASA resistance, as reported in the latter studies, is due to use of ‘COX-1 nonspecific’ methods (i.e., ADP-, and collagen-induced platelet aggregation). Other nonmethodologic factors (e.g., BMI, aging, ASA formulation, ASA dose, ASA drug–drug interactions, patient adherence and alterations in platelet characteristics [e.g., reactivity and turnover]) may also contribute to ASA nonresponse [43].

• Platelet turnover & reactivity impact ASA response

Patients at high risk for CV events (e.g., patients with coronary artery disease [CAD], diabetes, or metabolic syndrome, smokers and patients undergoing cardiac surgery) tend to have increased platelet turnover [28–30,44–46] and reduced ASA responsiveness [28,40,42,47–54]. Markers of increased platelet turnover (e.g., increased mean platelet volume [MPV], immature platelet fraction) are present in high-risk patients [27,55–56] and have been shown to be predictive of worse adverse cardiac outcomes [57] and CV-related death [58,59].

Studies in patients with disease states associated with high platelet turnover have observed substantial recovery of TxA₂ production and platelet aggregation (i.e., nonresponse to ASA) in the presence of low-dose ASA [60,61]. Overall TxA₂ synthesis must be inhibited by ≥95% before any clinical effects of ASA are observed [12]. Adequate inhibition of TxA₂ may require inhibition of alternative TxA₂ production pathways, such as production by thromboxane synthase, which is unaffected by ASA [12]. In addition, uninhibited COX-2 may be rapidly resynthesized by endothelial cells and monocytes/macrophages and may feed TxA₂ intermediates (e.g., PGH₂) into the thromboxane synthase pathway [12]. This alternate mechanism of TxA₂ production may be particularly important at sites where monocytes and macrophages accumulate with platelets (e.g., sites of plaque rupture) [12]. Under normal conditions, COX-2 expression is generally low; however, in patients with high platelet turnover, such as patients who have undergone coronary artery bypass surgery, COX-2 expression may increase to as much as 60% and contribute to high TxA₂ concentrations despite COX-1 inhibition by low-dose (81 mg/day) ASA [12]. Würtz et al. [61] demonstrated significant recovery of platelet aggregation (Figure 1A) and increased TxA₂ production (Figure 1B) within 24 h of administration of ASA 75 mg/day, not only in high-risk patients (i.e., those with previous stent thrombosis or stable CAD) but also in healthy individuals. Although once-daily ASA doses of 162 and 325 mg have been shown to reduce COX-dependent platelet aggregation and TxA₂ production in high-risk patients (e.g., patients with diabetes and CAD) [62], a more substantial reduction in these parameters has been observed with twice-daily dosing [63]. Twice-daily dosing of ASA provides a second opportunity or window of time during which COX-1 enzymes within newly generated platelets become inhibited. This additional inactivation period may be particularly relevant for patients with higher rates of platelet turnover.

Accelerated platelet turnover results in an increase in the proportion of immature platelets with COX-2 in systemic circulation [10,64] and increases the rate at which platelets with ASA-inhibited COX-1 are replaced by new, uninhibited platelets [10]. Immature platelets have a larger overall volume [10,65], are more adherent to endothelial surfaces and fibrin meshwork [10], and can synthesize prothrombotic factors (e.g., fibrinogen and adhesion factors) [66]. Immature platelets are also highly reactive, with augmented production of TxA₂ and platelet aggregation compared with mature platelets [67,68]. Indices of immature platelets have been associated with nonresponse to ASA [25,67,69]. A significant association between ASA nonresponse and platelet turnover was observed when nonresponse was stratified by platelet volume in healthy volunteers [67]. In patients with stable CAD, a reduced response to ASA 75 mg/day was associated with increased platelet turnover (as assessed by larger MPV and higher IPC) [25]. Data also have shown a trend toward increased platelet turnover and IPC in patients with previous stent thrombosis who were receiving ASA 75 mg/day, although this did not reach statistical significance [69].

• Unmet need for ER-ASA

The COX-1 enzyme in platelets is irreversibly inhibited by ASA, and is not replaced in mature, anucleate platelets [10]. Because of this, the anti-thrombotic effects of ASA extend beyond its short half-life and are assumed to be maintained throughout a 24-h period, supporting the recommendation of once-daily dosing for prevention of secondary CV events [7–8,35]. However, the effects of ASA decline over time as newly generated platelets with uninhibited COX-1 enzymes enter circulation [10,60–61,70]. For patients who take their ASA dose in the morning, ASA concentrations are higher at the time of day during which CV events are most common (i.e., upon awakening) [71,72]. Unfortunately, this protective antiplatelet effect likely declines during the evening hours as inhibited platelets are replaced; therefore, a continuous concentration of ASA is needed to ensure adequate anti-thrombotic protection over a 24-h dosing period. Twice-daily dosing of ASA provides an additional window of time for inhibition of platelet activation in patients with high platelet turnover, which may improve response [63]. Unfortunately, only 65% of patients report adherence to their current secondary preventive ASA regimen [73]; a more complicated dosing regimen may further reduce adherence, potentially affecting overall efficacy of preventative measures [74].

Extended-release ASA

• Extended-release technology

An ER-ASA was initially developed by Flamel Technologies (Flamel of Pessac, France) using ER microcapsule technology. This technology has been successfully applied to other CVD drugs (e.g., carvedilol [Coreg CR^®; GlaxoSmithKline, Research Triangle Park, NC]) to provide 24-h exposure with once-daily dosing. In contrast to conventional IR-ASA formulations, ER-ASA (NHP-554C) was designed to release ASA over the entire 24-h period with once-daily dosing. In addition, this formulation delivers ASA into the hepatic circulation in a manner that allows metabolism of ASA and reduces circulating ASA levels, thereby sparing peripheral endothelial prostacyclin levels.

Each soft gelatin ER capsule contains a core of individually film-coated, 300–500 µm, ASA microcapsules (Figure 2). The proprietary, release rate-limiting film coating of the microcapsules acts as a semipermeable membrane to allow diffusion of ASA throughout the GI tract, thereby slowing absorption and extending the availability of ASA for a prolonged antiplatelet effect. This diffusion-based drug delivery formulation displays a characteristic diffusion profile (Figure 3) in which approximately 30% of the total ASA dose is delivered within the first 3 h after administration, followed by sustained release for the remainder of the 24-h period.

• ER-ASA clinical development program

The overall clinical development program of ER-ASA focused on creating an ASA formulation that inhibited >90% of circulating TxA₂ during a 24-h period. Multiple studies (∼15 clinical studies in addition to investigator-initiated studies) have been conducted in healthy individuals and patients with CVD to establish the pharmacokinetics, pharmacodynamics and safety of ER-ASA. As the efficacy of ASA for secondary prevention is well established, only two clinical pharmacology studies (a dose–response study [75] and a food effect study [flamel technologies, venissieux, france, data on file]) were required for US FDA approval, and ER-ASA is currently undergoing regulatory review.

• Pharmacokinetics of ER-ASA

A single-dose study of the pharmacokinetics of ER-ASA 20–325 mg versus IR-ASA 5–81 mg was undertaken in healthy volunteers in a Phase I, open-label, US registration trial [75]. As anticipated, the pharmacokinetic profile of ER-ASA differed from that of IR-ASA. Dose-normalized mean maximum plasma concentrations of ASA and SA, a stable metabolite of ASA, were approximately sixfold and approximately two- to three-fold higher, respectively, with IR-ASA versus ER-ASA [75]. However, the dose-normalized area under the time-concentration curve from time 0 to the time of the last quantifiable concentration for SA was similar with both ASA formulations [75], suggesting that an overall comparable amount of active drug was delivered. Consistent with its ER pharmacokinetic profile, time to maximal plasma ASA concentration occurred later with ER-ASA (2–4 h postadministration) than with IR-ASA (1–2 h postadministration) (Figure 4A) [75]. In addition, peak serum concentrations of SA were delayed with ER-ASA compared with IR-ASA and remained detectable during a 24-h period (Figure 4B) [75]. The prolonged release of ASA from the ER-ASA formulation provides a greater time frame during which platelets may be exposed to intact ASA, thereby extending the window of time for platelet inactivation. Plasma concentrations of ASA with ER-ASA administration were quantifiable throughout an 8-h observation period, whereas ASA was undetectable 6 h after administration of IR-ASA. In a separate food effects study, the overall exposure of ER-ASA did not vary when administered with food; however, absorption was delayed fivefold [flamel technologies, venissieux, france, data on file].

• Anti-thrombotic activity

Pharmacodynamic properties of ER- versus IR-ASA were examined in the same Phase I, single-dose study of healthy volunteers [75]. Maximal inhibition of TxB₂ production with a single dose (mean percentage reduction ±SD: 90.5% ± 9.8% and 96.5% ± 4.1% with ER-ASA 162.5 mg and IR-ASA 81 mg, respectively) occurred within 8 h after drug administration for both formulations [75]. Marked inhibition of TxB₂ production (Figure 5A) and mean inhibition of urinary 11-dehydro-TxB₂ excretion (Figure 5B) were maintained during a 24-h period after administration of single-dose ER-ASA 162.5 mg and single-dose IR-ASA 81 mg [75]. In addition, arachidonic acid-induced platelet aggregation 24 h postdose was reduced by 28% with single-dose ER-ASA 162.5 mg and 60% with single-dose IR-ASA 81 mg [75]. It should be noted that this study did not assess steady-state pharmacodynamic effects, and time to reach maximum PD effects was not evaluated. In a comprehensive pharmacodynamic study in 40 patients with Type II diabetes and multiple CVD risk factors (NCT02370680), 162.5 mg ER-ASA (NHP-554C) provided sustained antiplatelet effects over 24 h following 10–14 days of maintenance treatment [data on file].

• Safety & tolerability of ER-ASA

Published data on the long-term safety and tolerability of ER-ASA is relatively limited. However, there is extensive long-term safety and tolerability data available for IR-ASA [76], and no additional safety concerns are anticipated with ER-ASA. Systemic exposure to ASA is limited with ER-ASA; therefore, prostacyclin production is spared (Figure 6) [flamel technologies, venissieux, france, data on file]. Based on data from two clinical studies (one in high-risk patients with a history of atherosclerotic disease and one in healthy volunteers), ER-ASA and IR-ASA appear to have similar safety profiles [77,78]. No tolerability issues or safety concerns were noted in patients with atherosclerosis who were switched from a previous low-dose ASA regimen to 162.5 mg ER-ASA or 150 mg or 75 mg IR-ASA for 28 days [77]. Two of 104 patients (2%) who were enrolled and completed the run-in period of the study were discontinued from the study: one patient in the ER-ASA 162.5 mg group because of nausea and one patient in the IR-ASA 75 mg group because of loin pain [77]. In a randomized, double-blind, crossover study in healthy volunteers, endoscopically assessed erosions and petechiae were significantly lower with single-dose ER-ASA versus enteric-coated ASA 75 mg in healthy volunteers (p < 0.001 for both) [78].

• Current status

A new drug application for ER-ASA was submitted to the FDA following completion of the clinical development program. The indications proposed for ER-ASA include:

• Reduction of the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli.

• Reduction of the combined risk of death and nonfatal myocardial infarction (MI) in patients with a previous MI or unstable angina pectoris.

• Reduction of the combined risk of MI and sudden death in patients with chronic stable angina pectoris.

• For use in patients who have undergone revascularization procedures (i.e., coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or carotid endarterectomy) when there is a preexisting condition for which ASA is already indicated.

Because of the altered pharmacokinetics of ER-ASA, it should not be given in situations where a rapid onset of action is necessary (e.g., acute treatment of MI).

Conclusion

CVD is a serious health concern faced by millions of patients. ASA is a mainstay therapy for secondary prevention of CV events, yet up to 60% of patients experience inadequate preventative coverage (i.e., display laboratory testing resistance to ASA and remain at increased risk of a CV event), especially those at high risk for experiencing a second CV event [9,40–42]. This inadequate coverage is at least partially related to biologic factors (e.g., increased platelet turnover), which may attenuate the anti-thrombotic efficacy of low-dose ASA over a 24-h time period [60–61,70]. The pharmacokinetic profile of ER-ASA indicates a longer window of time during which platelet inhibition may occur. Antiplatelet effects (e.g., reduction of TxA₂ production) are consistent with the extended pharmacokinetics of ER-ASA, thus ER-ASA provides a unique formulation of ASA that may potentially overcome some of the limitations of IR-ASA by providing 24-h coverage. The potential benefit of the antiplatelet effects provided by ER-ASA has yet to be evaluated in a large-scale clinical outcomes trial.

Future perspective

IR-ASA is the bedrock of antiplatelet therapy for CV risk prevention and has been for the last four decades [12], but the optimal dose and duration of aspirin therapy in high-risk patients are still elusive. It is not surprising that clinicians have been somewhat less than diligent in recommending and/or monitoring IR-ASA for secondary prevention. Thus far, ASA has had a long history of use with little advancement in delivery formulation, and clinicians have had little ability to assess antiplatelet response to aspirin or monitor adherence with IR-ASA regimens. With increased prevalence of both diabetes and obesity [79], treating these patients with optimal doses is very challenging in the absence of any proven pharmacodynamic or clinical benefits. Patients with CVD have multiple risk factors that amplify CV risk, such as vasculopathy (e.g., endothelial dysfunction) [80], higher-than-normal platelet turnover [46] and high on-therapy platelet reactivity [60,61]. Until now, these phenomena were rarely taken into account when considering optimal treatment regimens. As our knowledge regarding the pathophysiology of CVD increases, the overall approach to management of CVD – and IR-ASA’s place within that scheme – is likely to change. The proposed strategies include increasing IR-ASA dose or use of twice-daily IR-ASA dosing in high-risk patients to achieve improved antiplatelet benefits. The position of an ER-ASA formulation in future CVD treatment regimens is under investigation. Recent demonstrations of ER-ASA prolonging plasma ASA concentrations and reports of the 24-h antiplatelet effects provided by this formulation [75] are promising. Treatment with ER-ASA based on assessment of antiplatelet responsiveness may facilitate ‘guided’ strategies in the near future.

EXECUTIVE SUMMARY

Mechanism of acetylsalicylic acid cardioprotection

• Acetylsalicylic acid (ASA) prevents cardiovascular thrombus formation by reducing platelet production of thromboxane A₂ (TxA₂), a vasoconstrictor and platelet activator.

• ASA irreversibly inactivates COX-1, the main enzyme responsible for TxA₂ production, in platelets as they travel through portal circulation.

Limitations of immediate-release ASA

• Immediate-release (IR) ASA has a short half-life of approximately 15–20 min, which provides a limited window of time during which platelet COX-1 inactivation can occur.

• Although ASA inactivates platelet COX-1 enzymes for the entire life span of the platelet, platelets are constantly regenerated (∼4 billion new platelets per hour); therefore, ASA levels throughout a 24-h period maintain consistent COX-1 inhibition, especially in patients with higher than normal platelet turnover (e.g., patients with diabetes).

Extended-release ASA formulation

• Extended-release (ER) ASA was formulated to provide 24-h ASA exposure with once-daily dosing.

• Each ER-ASA capsule contains an inner core of individually coated microcapsules containing 165.2 mg ASA.

• The proprietary release rate-limiting film coating of the microcapsules acts as a semipermeable membrane to allow 24-h distribution of ASA into the GI tract.

Pharmacokinetics & pharmacodynamics of ER-ASA

• Consistent with its ER design, ER-ASA provides ASA and salicylic acid over a longer time period than IR-ASA.

• Maximal plasma concentration of ASA after a single oral dose was lower with ER-ASA than IR-ASA, supporting reduced systemic exposure.

• Platelet aggregation and inhibition of COX-1 activity (as measured by thromboxane B₂ production) was maintained throughout a 24-h period after a single dose of ER-ASA.

ER-ASA safety

• The long-term safety of ASA is well established, and no additional safety concerns are anticipated with ER-ASA.

Conclusion

• ER-ASA is a unique formulation of ASA that was developed to deliver low-dose aspirin throughout the 24-h dosing interval for platelet inhibition.

Financial & competing interests disclosure

J Patrick and AT Pennell are supported by and are employees of New Haven Pharmaceuticals, Inc. PA Gurbel reports serving as a consultant for Daiichi Sankyo/Lilly, Bayer, AstraZeneca, New Haven Pharmaceuticals, Inc., Accumetrics, Merck, Medtronic, Janssen, CSL, and Haemonetics; receiving grants from the NIH, Daiichi Sankyo, Lilly, CSL, AstraZeneca, Haemonetics, Harvard Clinical Research Institute, and Duke Clinical Research Institute; receiving payment for lectures, including service on speakers’ bureaus, from Lilly, Daiichi Sankyo, and Merck; and receiving payment for development of educational presentations from Merck, the Discovery Channel, and Pri-Med. PA Gurbel also is holding stock or stock options in Merck, Medtronic, and Pfizer; and holding patents in the area of personalized antiplatelet therapy and interventional cardiology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was utilized in the production of this manuscript. Technical editorial and medical writing support, under direction of the authors, was provided by Mary Beth Moncrief, PhD, and Jillian Gee, PhD, Synchrony Medical Communications, LLC, West Chester, PA, with support from New Haven Pharmaceuticals, Inc.

Additional information

Funding

J Patrick and AT Pennell are supported by and are employees of New Haven Pharmaceuticals, Inc. PA Gurbel reports serving as a consultant for Daiichi Sankyo/Lilly, Bayer, AstraZeneca, New Haven Pharmaceuticals, Inc., Accumetrics, Merck, Medtronic, Janssen, CSL, and Haemonetics; receiving grants from the NIH, Daiichi Sankyo, Lilly, CSL, AstraZeneca, Haemonetics, Harvard Clinical Research Institute, and Duke Clinical Research Institute; receiving payment for lectures, including service on speakers’ bureaus, from Lilly, Daiichi Sankyo, and Merck; and receiving payment for development of educational presentations from Merck, the Discovery Channel, and Pri-Med. PA Gurbel also is holding stock or stock options in Merck, Medtronic, and Pfizer; and holding patents in the area of personalized antiplatelet therapy and interventional cardiology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript. Technical editorial and medical writing support, under direction of the authors, was provided by Mary Beth Moncrief, PhD, and Jillian Gee, PhD, Synchrony Medical Communications, LLC, West Chester, PA, with support from New Haven Pharmaceuticals, Inc.