Some needs unmet in secondary CVD prevention despite aspirin use; new agent may have role

Aspirin is the foundational treatment for secondary prevention of cardiac events and the standard therapy I have used for my patients for decades, but it can expose some patients to bleeding risk.

For each patient, I balance the benefit-risk ratio and tailor the aspirin (acetylsalicylic acid) therapy to the greatest response and adherence with the lowest risk for bleeding. A recent review article in Clinical Pharmacokinetics on a new formulation of aspirin caught my attention, “Pharmacokinetic and Pharmacodynamic Profile of a Novel Phospholipid Aspirin Formulation.” The paper reviews an innovative approach to aspirin delivery that offers optimal absorption while protecting against local gastrointestinal (GI) injury.

Graphical depiction of source quote presented in the article — **C. Michael Gibson, MS, MD**, is with the Boston Clinical Research Institute.

We know that aspirin is the only drug that targets the thromboxane A2 activation pathway of platelets by irreversibly blocking the cyclooxygenase (COX-1) enzyme. Aspirin has been the antiplatelet agent that all other antithrombotic therapies have stacked upon in clinical trials to improve CV events. It is a class IA guideline foundational therapy for secondary prevention.

With the benefit of aspirin, there is also a potential side effect of upper GI adverse events. These range from gastroesophageal reflux and dyspepsia to ulceration/erosion. There are two pathways that lead to GI ulceration and erosion with aspirin, a systemic and a “local” or direct effect.

The systemic effect is related to inhibition of prostaglandin synthesis (the same pathway that leads to thromboxane formation) by inhibiting the COX-1 enzyme. In addition to the systemic effect on prostaglandins, there is an element of local GI injury that takes place where aspirin binds to the protective phospholipids lining the GI tract and in doing so allows stomach acid to damage the stomach lining. Because aspirin limits platelet aggregation, when gastric ulceration/erosion occurs, this can become a serious event.

The limitations of low-dose enteric-coated aspirin

To reduce the risks for GI damage, the use of daily low-dose enteric-coated aspirin is currently the most widely used formulation of aspirin in secondary prevention. Unfortunately, it may not be the optimal solution we would hope for our patients.

Enteric-coated aspirin was developed specifically to protect against the GI effects of immediate-release aspirin. Enteric-coated formulations are delayed-release. By definition, this requires the pill to stay intact in acid pH for at least 2 hours, simulating residence time in the stomach with the goal of avoiding the stomach and delivering aspirin for release in the less acidic upper part of the small intestine. There are many different types of enteric-coated aspirin, with varying dissolution or absorption profiles. In addition, the delay in absorption of enteric-coated formulations may result in degradation of aspirin and affects how much aspirin is available to be absorbed.

The potential for erratic absorption with enteric-coated aspirin is described in the FDA label. FDA labeling also states: “In general, immediate-release aspirin is well and completely absorbed from the GI tract.” We are taught to use immediate-release aspirin for new onset of ACS and pre-PCI procedure, but most patients in the U.S. end up on enteric-coated aspirin.

What does erratic absorption mean?

Much has been written on aspirin resistance or nonresponse. Reasons for failure to respond to aspirin may be pharmacokinetic (failure to achieve an adequate level of drug) or pharmacodynamic (failure to inhibit platelet function). Early studies have largely overlooked this distinction because it is assumed that all preparations deliver an adequate aspirin dose. In addition, when contemplating causes of resistance to any drug, poor patient compliance, inadequate dosing and drug interaction must also be considered at the outset.

Studies have yielded enteric-coated aspirin’s variable response, sometimes no response or incomplete response. This is actually a treatment failure, which might especially be of concern in high-risk patients with early ACS, diabetes and/or heavier weight.

Adequate antiplatelet therapy is important for all patients and especially those at higher risk with diabetes or experiencing ACS. An overlooked problem with enteric-coated aspirin is that unpredictable bioavailability and erratic absorption may lead to inadequate treatment effect or breakthrough events when a drug is not adequately absorbed, making it less effective managing new or angry/activated platelets that are introduced into the system each day and left uncovered. Platelet turnover is even more frequent in higher-risk patients. Patients with diabetes may also be overweight and may not be getting enough drug to provide adequate antiplatelet effects.

Enteric-coated aspirin and GI issues

A number of studies have raised doubts about the protective effects of enteric-coated aspirin against GI injury. Multiple reports have reported that there is little difference in GI damage among patients taking enteric-coated and immediate-release aspirin. In fact, there is concern that sustained-release formulations may raise the risk for adverse events due to increased exposure to the drug.

Additionally, a strategy health care providers commonly recommend helping to minimize dyspepsia is to advise taking the medication with food. This is also problematic. There is evidence that ingesting enteric-coated aspirin with food could further lower bioavailability of the drug and reduce its effectiveness.

A novel aspirin option

There is obviously a need for innovation with aspirin that provides reliable bioavailability and prevents local GI injury. Research reviewed by Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiology programs and Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, and colleagues in a Clinical Pharmacokinetics article offers evidence that the first FDA-approved liquid-filled aspirin capsule with a novel delivery mechanism could provide a promising alternative to current options.

Phospholipid-aspirin complex (PL-ASA; Vazalore, PLx Pharma) is a liquid complex formed by the pre-association of aspirin and lipidic excipients. When pH is low in the GI tract, the lipidic excipients and the aspirin remain as a complex, but dissociate when pH rises. The chemical properties of PL-ASA ensures that free aspirin does not become available and interact with the phospholipids of the upper GI mucosa, thereby protecting the gastroduodenal lining while maintaining the drug’s bioavailability and providing fast and predictable absorption like immediate-release or plain aspirin.

The research reviewed in the article evaluated PL-ASA’s platelet effects, aspirin bioequivalence, bioavailability and absorption, and GI effects. Following is a summary of those findings:

A pharmacokinetics/pharmacodynamics study by Dominick J. Angiolillo, MD, PhD, professor of medicine and chief of cardiology at University of Florida Health in Jacksonville, and colleagues confirmed bioequivalence to immediate-release/plain aspirin. An additional study confirmed that the PL-ASA complex did not affect the aspirin component’s ability to prevent platelet aggregation, and several clinical studies have shown complete and reliable aspirin absorption with PL-ASA and established bioequivalence from both a pharmacodynamic and pharmacokinetic perspective to immediate-release aspirin at 325 mg and 650 mg doses.
The food effects on PL-ASA bioavailability were assessed in an open-label, randomized, two-way crossover, single-center study of 20 healthy individuals taking a single 650 mg dose of PL-ASA in a fed or fasted state. Those administered PL-ASA with a high fat meal showed a small decrease in salicylic acid levels and a later peak in concentration, but no significant effect of systemic exposure (area under the curve) was seen. These findings are consistent with the known effects of food on aspirin bioavailability, which is that food decreases the rate but not the extent of absorption.
A pharmacokinetics/pharmacodynamics study evaluated absorption of immediate release PL-ASA and enteric-coated aspirin in 40 patients with obesity and type 2 diabetes receiving 325 mg of one formulation for a 3-day treatment period. The study found enteric-coated aspirin had lower peak plasma concentrations (C_max) and AUCvalues and took a longer time to reach C_maxcompared with plain aspirin or PL-ASA formulations. PL-ASA values were equivalent to aspirin but 2.3 and 4.5 times higher than those of enteric-coated aspirin. Patients never achieving a complete response was also higher among those taking enteric-coated aspirin compared with both PL-ASA and immediate-release aspirin.
An additional analysis was conducted from two randomized crossover studies in patients with obesity and diabetes comparing pharmacodynamic parameters after three doses of 325 mg enteric-coated aspirin or PL-ASA were pooled at the patient level. Regression analysis was performed to detect the impact of weight on thromboxane B2 (TXB2) inhibition. Weight was inversely associated with TXB2 inhibition in the overall analysis, with the trend line crossing below the 99% TXB2 inhibition threshold (complete aspirin response) at 117 kg. Similar relationships were seen individually for PL-ASA and enteric-coated aspirin; however, there was significantly earlier drop below the threshold with enteric-coated aspirin than PL-ASA (95 kg vs. 131 kg, respectively; P < .001). The authors concluded that an inverse relationship exists between weight and aspirin response in patients with diabetes. The choice of aspirin formulation can modulate the weight threshold associated with an incomplete response. PL-ASA may be an attractive alternative over enteric-coated aspirin in this population.
A randomized, blinded control study endoscopically assessed upper GI injury among 204 healthy adults aged 50 to 74 years given 325 mg once-daily dosage of noncoated aspirin or PL-ASA for 7 days. Among the aspirin-treated adults, 42.2% developed multiple erosions and/or ulcers, and gastroduodenal ulcers were detected in 17.6% of those adults compared with 22.2% and 5.1%, respectively, of those treated with PL-ASA. The study found that PL-ASA use was associated with significantly lower rates of acute upper GI injury and aspirin-induced gastric mucosal damage. While erosions and ulcers may be considered the biomarkers for GI bleeding, this study did not evaluate if reduced acute GI injury would translate to less GI bleeding, nor did it assess how PL-ASA would compare with enteric-coated aspirin.

Since the publication by the authors, a pharmacokinetics/pharmacodynamics study was presented on the 81 mg dose of PL-ASA compared with 81 mg enteric-coated aspirin at TCT 2021. This was a randomized, open-label, crossover study demonstrating PL-ASA 81 mg provided fast and reliable absorption after a single dose compared with enteric-coated aspirin at an 81 mg dose. While the authors of the review paper acknowledge some limitations to the studies reviewed, including the lack of data specific to PL-ASA 81 mg dosing, which is commonly used for secondary prevention of CV events, and the long-term GI effects, the evidence provided thus far is strong and exciting.

There remains an unmet need for a potent but protective formulation of aspirin that yields predictable inhibition. Uncoated aspirin is potent but not protective of the gastrointestinal tract. Enteric-coated aspirin is not promptly absorbed and may not be as protective of the gastrointestinal tract as commonly believed. The response to enteric-coated aspirin is not predictable, with some patients being nonresponsive. The new drug delivery system of PL-ASA is potent, prompt, predictable and protective and may offer a novel solution to this unmet need.

References:

For more information:

C. Michael Gibson, MS, MD, is with the Boston Clinical Research Institute. He can be reached at Boston Clinical Research Institute, 1340 Centre St., Suite 203, Newton Center, MA 02459; email: info@bostonclinicalresearchinstitute.com; Twitter: @cmichaelgibson.

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Sources/Disclosures

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Disclosures: Gibson reports receiving consultant fees from PLx Pharma.

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