DURLAZAâ„¢ (aspirin): Extended-Release Aspirin for Prevention of Recurrent Cardiovascular Events

This article was sponsored by New Haven Pharmaceuticals, Inc.

Aspirin Reduces the Risk of Recurrent Cardiovascular Events

Patients who have previously experienced a cardiovascular (CV) event are 2 times more likely to experience a subsequent CV event than are individuals who only have risk factors for cardiovascular disease (CVD).¹ Aspirin reduces the risk of CV events by preventing clot formation associated with platelet activation. Platelets circulating in the blood become activated when they encounter endothelial damage and/or other activated platelets. Activated platelets elicit a variety of signals that prompt the formation of a vascular clot, including production of the platelet activator thromboxane A₂ (TXA₂). Aspirin exerts its antiplatelet effects by inhibiting cyclooxygenase (COX) enzymes that produce prostaglandin H₂, which is the substrate necessary for TXA₂ production. Because inhibition of COX enzymes by aspirin is irreversible, the antiplatelet effects of aspirin are maintained throughout the lifespan of the platelet (~10 days).² Current medical guidelines recommend once-daily, low-dose aspirin (75 to 162 mg) for patients who have an increased risk of experiencing a CV event. However, traditional aspirin formulations may not provide anticlotting effects throughout a full 24-hour period.^3-5

Limited 24-Hour Platelet Inhibition With Traditional Aspirin

Although traditional immediate-release and enteric-coated aspirin formulations provide peak plasma aspirin concentrations 40 minutes to 3 hours after administration, this peak is followed by a rapid decline of plasma aspirin concentrations in accordance with aspirin’s short half-life (20 minutes). This means that with once-daily aspirin dosing, new platelets that are being generated (~4 billion per hour) may not be exposed to aspirin and thus would not be inhibited during an entire 24-hour period. Therefore, the antiplatelet effects of aspirin may not provide adequate coverage in high-risk populations that exhibit rapid platelet turnover.⁶

In studies of patients with CVD with or without comorbid diabetes, the antiplatelet effects of aspirin were not maintained over an entire 24-hour period.^3-5 In addition, the incidence of CV events during a 3-year period increased in patients with symptomatic CVD compared with patients with CV-related risk factors alone, despite preventive treatments including aspirin.¹ Alternate aspirin regimens (eg, twice-daily dosing) may extend or provide an additional window of time for platelet inhibition during a 24-hour period but also increase the total dose of aspirin received and raise the risk of aspirin-associated bleeding events.⁷ In addition, twice-daily dosing may negatively affect an already low rate of patient adherence. Increasing aspirin administration from once to twice daily has been shown to significantly reduce adherence rates.⁸

DURLAZA^TM (aspirin): 24-Hour Aspirin Coverage With Once-Daily Administration

DURLAZA (New Haven Pharmaceuticals, Inc; North Haven, CT) is an extended-release aspirin formulation for the secondary prevention of CVD events and CVD-related mortality.⁹ DURLAZA employs the same 24-hour extended-release microcapsule technology that has been applied to other CVD drugs (eg, Coreg

CR^® [carvedilol]; GlaxoSmithKline; Research Triangle Park, NC). Each DURLAZA capsule contains a core of individually film-coated aspirin microcapsules. Each microcapsule is coated with a proprietary, release rate-limiting film that acts as a semipermeable membrane, allowing diffusion of aspirin throughout the gastrointestinal tract. This diffusion-based drug-delivery formulation slows systemic absorption and provides continuous aspirin release throughout a 24-hour period.

Because of the unique pharmacokinetic profile of DURLAZA, a higher aspirin dose (162.5 mg) is required to provide antiplatelet effects at steady state similar to those observed with a low dose (81 mg) of immediate-release aspirin.¹⁰ DURLAZA dose-normalized area under the plasma concentration-time curve from time 0 to the last measurable concentration of aspirin and salicylic acid was approximately 6 times and 2 to 3 times greater, respectively, compared with immediate-release aspirin. The time required to reach the maximal plasma concentration of aspirin with DURLAZA is delayed (2-4 hours postdose) compared with immediate-release aspirin (1-2 hours postdose). DURLAZA provided detectable plasma concentrations of aspirin (acetylsalicylic acid) throughout an 8-hour postdose observation period versus 6 hours with immediate-release aspirin (Figure 1A).¹⁰ This suggests that the window of time during which platelets may be inhibited is longer with DURLAZA than with immediate-release aspirin. In addition, the concentration of salicylic acid, a metabolite of aspirin, at 24 hours postdose was greater with DURLAZA than with immediate-release aspirin (Figure 1B).¹⁰

There have been no long-term studies on the safety and tolerability of DURLAZA; however, safety and tolerability are anticipated to be consistent with traditional aspirin formulations. Data from 2 clinical trials of microencapsulated aspirin^11,12 suggested that DURLAZA is at least as tolerable as traditional aspirin.

Role of the Pharmacist

Pharmacists play a pivotal role in educating patients about the importance of secondary CVD prevention and how prescription DURLAZA differs from traditional, OTC aspirin formulations. DURLAZA, similar to traditional low-dose aspirin, blocks the action of a key enzyme within the body’s natural clot-forming process, thereby reducing the risk of having a secondary CVD event. However, once-daily dosing of traditional OTC aspirin formulations provides inhibition of platelets for only part of the day due to the rapid metabolism of aspirin and continuous platelet generation throughout the day. In contrast, DURLAZA, administered once daily, slowly releases the drug throughout the day to help inactivate newly generated platelets, thus extending the period of time during which the body is protected from clot-forming activity. Because DURLAZA was designed to provide extended anticlotting effects instead of rapid pain relief, DURLAZA has different properties than traditional aspirin formulations. These unique properties of DURLAZA allow once-daily administration that may be beneficial for patients who might otherwise require twice-daily aspirin dosing for 24-hour anticlotting coverage, but limit the usefulness of DURLAZA for analgesia or situations that require rapid aspirin effects. Thus, DURLAZA should not be used in situ­ations in which rapid onset of action is required (eg, planned cardiac procedures). As well, important safety considerations with DURLAZA include: it should not be taken with alco­hol, and use of DURLAZA increases the risk of bleeding. Because DURLAZA is the first approved prescription aspirin product, pharmacists may be able to more easily encourage adherence to DURLAZA regimens than to OTC aspirin regimens, although studies have not been conducted to explore this. Overall, aspirin is a key therapy for the secondary prevention of CVD, and once-daily DURLAZA provides an important opportunity to potentially overcome some of the issues concerning 24-hour antiplatelet coverage with traditional OTC aspirin formulations in high-risk populations.

REFERENCES

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• Durlaza [package insert]. North Haven, CT: New Haven Pharmaceuticals, Inc; 2015.
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• Donnelly MT, Stack WA, Richardson P, et al. Microencapsulated aspirin, Asacard, reduces endoscopic damage in healthy volunteers compared to conventional encapsulated aspirin [abstract G0440]. Gastroenterology. 1998;114A107.
• Brown N, May JA, Wilcox RG, et al. Comparison of antiplatelet activity of microencapsulated aspirin 162.5 mg (Caspac XL), with enteric coated aspirin 75 mg and 150 mg in patients with atherosclerosis. Br J Clin Pharmacol. 1999;48(1):57-62.

For full prescribing information, please see the DURLAZA package insert (http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/200671s000lbl.pdf).