Will the new pharmaceutical lipid-aspirin complex formulation restore the once lost trust of aspirin on cardiovascular protection?

KEYWORDS:

• Aspirin
• cardiovascular disease
• myocardial infarction
• GI bleeding
• gastric ulceration

A recent Food and Drug Administration (FDA) approval has launched supplemental New Drug Applications (sNDAs) for Vazalore, the first liquid formulation of a pharmaceutical lipid-aspirin complex (PL-ASA) on the market [1]. The major claim of PL-ASA is its proprietary drug delivery platform that will deliver therapeutic levels of aspirin (ASA) while reducing the risk of gastrointestinal (GI) injury [2]. GI adverse effects such as bleeding and perforation are common side effects associated with ASA use [3]. Many ASA formulations, such as enteric-coated ASA and buffered ASA, have been developed over the years with the expectation that they would be less likely to cause GI bleeding compared to plain immediate-release aspirin. These formulations, however, have not been found to curtail ASA-related GI injury [3]. Additionally, these ASA formulations do not measure up pharmacokinetically or pharmacodynamically as they have been shown to have incomplete absorption, reduced bioavailability, and an impaired platelet inhibitory effect [4]. The novel PL-ASA formulation uses ASA that is noncovalently bound to a pharmaceutical lipid (phosphatidylcholine), which makes it more lipophilic. The increased lipophilicity may help facilitate ASA transit across the GI mucosal layer while reducing gastric surface injury and with no loss in functional bioavailability [5].

Pharmacokinetic and pharmacodynamic (PK/PD) studies have compared PL-ASA with enteric-coated ASA and plain immediate-release ASA. Compared to enteric-coated ASA, the PL-ASA formulation was found to produce more rapid and more extensive absorption in obese patients with type 2 diabetes [4]. The increased bioavailability was matched by a more robust and predictable pharmacodynamic response with the PL-ASA formulation versus enteric-coated ASA. Immediate-release ASA and PL-ASA were found to have PK/PD bioequivalence; however, an endoscopic study found that PL-ASA caused significantly fewer GI erosions and ulcers [5,6]. While these are encouraging data, it is important to keep in mind that none of these PK/PD studies went beyond 7 days, and thus, the effects of chronic administration, which can alter the ASA pharmacodynamic response, remain unknown. For instance, an initial poor pharmacodynamic response from enteric-coated ASA, due to delayed and reduced drug absorption, can be overcome with chronic administration [7]. One could argue that a 7-day study is not enough to address the safety and efficacy of a medication given for a lifetime. In addition, beyond GI adverse effects, ASA has other serious bleeding complications such as intracranial hemorrhage and hemorrhagic stroke that also require further study with the new formulation.

Although the assertions of this new ASA-PL formulation appear at first hand to be quite dramatic, as always, we must always exercise caution and allow the initial excitement to settle down before we rush into changing our clinical practices. The novel PL-ASA formulation will carry indications similar to other available ASA formations including use as a pain reliever, fever reducer, and for other ‘ASA therapy’ indications [8]. Obviously, the latter must be carefully reviewed. Specifically, we cautiously raise our concerns reminding healthcare providers that to date, no study has been published to specifically address the potential value of this new formulation with regard to cardiovascular disease (CVD) protection.

First, let us step back and be reminded of the recent data that initially challenged our old customary ways as we have supported for decades ASA use for primary prevention of CVD in those individuals at increased risk [9]. The ASCEND (A Study of Cardiovascular Events in Diabetes) study found the use of aspirin for primary prevention in adults who had diabetes, resulting in fewer serious vascular events, but the benefit was counterbalanced with an increased risk of major bleeding [10]. This was followed by the ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) study that showed that the use of aspirin for primary prevention in individuals considered at an average risk did not lessen the risk of CVD events [11]. Finally, the ASPREE (Aspirin in Reducing Events in the Elderly) study showed that older adults assigned to receive ASA had an increased overall mortality without any change in their CVD mortality [12].

Following these trial results, several key groups updated their guidelines. The primary prevention guidelines released by the American Heart Association and American College of Cardiology (AHA/ACC) recommended that the use of low-dose ASA (75 to 100 mg/d) might be considered for the primary prevention of atherosclerotic CVD but only among select adults ages 40 to 70 years at higher CVD risk but not at increased risk of bleeding. The new guidelines also categorically recommend against aspirin use in those over age 70 and in those at high risk for bleeding, such as patients with chronic renal disease or thrombocytopenia [13]. The American Diabetes Association made similar adjustments to their low-dose ASA in primary prevention guidance, but narrowed the recommended age range to those between 50 and 70 [14,15]. Likewise, the US Preventive Services Task Force (USPSTF) updated its recommendations as follows: (a) the decision to initiate low-dose ASA use for the primary prevention of CVD in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one, (b) recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults age 60 years or older, and (c) evidence is inadequate that low-dose ASA use reduces CVD incidence or mortality [16].

O’Brien et al. provided us with data from the Sample Adult component of the 2017 National Health Interview Survey (NHIS), a nationally representative in-person household survey of health and disability among US adults [17]. Their sample included 14,328 adults (the mean age was 57.5 years; 54% women and 33% nonwhite), and they reported a final response rate of 53.0% [17]. Most importantly, these investigators found some critical and disturbing findings despite several limitations found with this study including the fact that ASA use was self-reported data; ‘low-dose’ ASA was not clearly defined; adults younger than 40 years were not asked about their ASA use, and atherosclerotic CVD risk scores were not calculated [17]. However, these investigators found that a significant number of adults aged 40 years or older use ASA to prevent CVD. Nearly half of these older adults were without self-reported CVD, and a quarter of adults were without CVD but with a history of peptic ulcer disease. More importantly, investigators noted that a substantial portion of adults may be taking ASA without their physician’s advice and potentially without their knowledge [17]. These data from the study by O’Brien et al. can be roughly translated, as seen in the National Institutes of Health website, as 29 million people who do not have CVD disease use ASA daily for CVD prevention while approximately 6.6 million individuals nationwide do so without discussing this intervention with their healthcare provider nationwide [17].

So, these bring us to the crux of the problem with regard to the PL-ASA formulation and our current stance with ASA. First, we might not know the whole extent to which populations take ASA for primary prevention in the US. Second, however, of those we know to be ASA users, it can be deduced that ASA use in the US is certainly widespread among groups at risk for harm. Third, as healthcare practitioners, we now have a tremendous obligation to inquire, in light of recent trials and guidelines, about ongoing ASA use and to counsel patients about the balance of benefits and harms of use, especially among older adults and those with prior peptic ulcer disease. Fourth, significant concerns need to be raised in patients taking EC aspirin as these might patients might not be fully cardio protected. Finally, we eventually need to address how PL-ASA could change the same landscape of uncertainty. Most importantly, we ought to have robust data before ever considering PL-ASA in terms of CVD protection, despite available PK/PD data [17,18].

Certainly, we need to do our due diligence and be more proactive in talking to our patients not only about all medications, and including all over-the-counter preparations they are taking, but also about their ASA use and if they have considered using this new ASA formulation, as TV commercials have already started advertising this product. The latter is critically important, as this recent paradigm shift has placed millions of people nationwide and across the world at risk and questions would continue to pile up for healthcare providers to answer, particularly, when heart disease continues to be the leading cause of death in the United States, killing roughly 659,000 people each year [19], while 17.9 million die each year across the globe [20].

Disclosure of any financial/other conflicts of interest

The authors have no relevant conflicts of interest to disclose. Peer reviewers of this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None stated.

Additional information

Funding

The authors have no funding to report.