Purpose Results of a study to test the hypothesis that taking niacin simultaneously with different forms of aspirin would reduce the occurrence of niacin-induced flushing are reported.
Methods Traditionally, taking enteral absorbed aspirin 30 minutes before a niacin dose has been shown to reduce flushing by 30–50% relative to nonuse of aspirin. The objective of the study was to evaluate the efficacy of enteral absorbed and orally dissolved aspirin, taken at the same time as niacin, in reducing the frequency of moderate-to-severe flushing. In a prospective, double-blind, placebo-controlled crossover trial, healthy adult male and female volunteers were asked to take aspirin or a placebo (both agents were taken in both orally dissolved and swallowed formulations) immediately before niacin administration. Subjects then self-evaluated flushing symptoms on a validated scale.
Results Simultaneous administration of swallowed aspirin and niacin reduced moderate-to-severe flushing events by a mean of 36.1%, from 2.35 to 1.5 events per subject (p = 0.003), relative to event rates with use of niacin alone. In a subset of subjects who had experienced moderate-to-severe flushing symptoms despite taking swallowed aspirin, flushing in response to subsequent niacin use was decreased by 20.5% (p = 0.05) with coadministration of orally dissolved aspirin and by 18.0% with a regimen containing both orally dissolved and swallowed aspirin (p = 0.03).
Conclusion Novel regimens of niacin and aspirin, including orally dissolved aspirin, were effective in reducing niacin-induced flushing in a small sample of healthy adult volunteers.
High-dose niacin therapy has well-established cardiovascular benefits, but niacin-induced flushing has limited its popularity among patients and prescribers.
In a randomized crossover study, regimens containing simultaneously administered orally absorbed aspirin and swallowed niacin were superior to both placebo and swallowed aspirin alone in reducing flushing events.
A formulation containing both niacin and orally absorbed aspirin may prove more convenient and tolerable for patients.
High-dose niacin therapy, including daily use of niacin doses ranging from 500 mg to 3 g, has been shown to have significant cardiovascular benefits by increasing high-density lipoprotein cholesterol concentrations and decreasing levels of triglycerides and low-density lipoprotein (LDL) cholesterol.1,2 It has further been shown to decrease mortality and myocardial infarction in patients with cardiovascular disease.2 However, niacin-induced cutaneous flushing (also called niacin flush), a prickly flushing of the skin that happens after taking agonists of GPR109A, or niacin receptor 1, has been identified as the primary reason for poor compliance with high-dose niacin therapy among eligible patients.1,3
Prescribers have adopted 2 common approaches to niacin flush reduction: the use of slow-release niacin formulations and administration of cyclooxygenase (COX) inhibitors such as aspirin prior to niacin ingestion. Slow-release niacin formulations have been shown to decrease the flushing response considerably, but due to a second metabolic pathway of niacin favored by slow-release formulations, they pose an increased risk of hepatotoxicity.3 Aspirin, a commonly available irreversible COX inhibitor, has been shown to be more effective than other, reversible COX inhibitors in controlling niacin-induced flushing.4
The development of an “extended-release” formulation of niacin with a release profile that lies between those of immediate- and slow-release formulations allowed for modest decreases in flushing symptoms with a reduced risk of hepatotoxicity. Additionally, there are several newer approaches to lowering the risk of niacin flush through the use of new molecules as well as a combination of aspirin and niacin.5 A novel formulation includes niacin with orally dissolved aspirin (VTS-Aspirin, Vitalis LLC, New York, NY). This combination could potentially reduce niacin flush without the need for aspirin to be taken at a different time than niacin; that would allow for 2 widely used medications to be used in conjunction. Also, many patients who require niacin therapy already use aspirin daily for cardiovascular health.
We conducted a double-blind, randomized, controlled crossover study of healthy volunteers to evaluate the efficacy of orally dissolved aspirin, as compared with enteral absorbed aspirin, in reducing moderate-to-severe flushing induced by niacin. Two secondary analyses were also completed: (1) a subgroup analysis excluding subjects who received the niacin calibration dose and had no major flushing events, and (2) a subgroup analysis excluding subjects who received the calibration dose or the traditional (i.e., swallowed) aspirin dose and did not experience a flushing event.
Study design. Healthy adult subjects 18 years of age or older were recruited using e-mail lists and poster advertising, and 26 volunteer subjects were screened and enrolled after giving written informed consent. The study exclusion criteria included allergy to aspirin, allergy to niacin, renal disease, liver disease, pregnancy, breastfeeding, and use of aspirin in the previous 7 days. Subjects were instructed not to take nonsteroidal antiinflammatory drugs during the study. Subjects were compensated with a $50 debit card. The institutional review board (IRB) at Drexel University College of Medicine approved this human subjects research study (IRB ID# 1205001258).
Drug regimens. Each subject took a total of 4 regimens. The first regimen was the calibration dose of 1,000 mg of niacin only.a The other 3 regimens consisted of combinations of the following: (1) niacin 1,000 mg (2) non–enteric-coated, orally dissolvable aspirin 81 mg,b and (3) a placebo.c Each of the study regimens required that a subject take 5 pills in total, with 1 of them being 1,000 mg of niacin. The 3 study regimens were (1) swallowed niacin 1,000 mg, orally dissolved aspirin 162 mg, and swallowed placebo, (2) swallowed niacin 1,000 mg, orally dissolved placebo, and swallowed aspirin 162 mg, and (3) swallowed niacin 1,000 mg, orally dissolved aspirin 81 mg, swallowed aspirin 81 mg, and orally dissolved and swallowed placebo.
Study protocol. After consent and enrollment into the study, subjects received each of 3 different regimens of medications in a random order. The first dose taken by each subject was the calibration dose of swallowed high-dose niacin (1,000 mg) taken alone after eating a meal. Over the following 4 hours, the subject rated flush symptoms every 30 minutes on a scale of 0–10, with higher scores indicating worse flushing, using the previously validated Global Flushing Severity Score (GFSS) until their flushing became mild (a rating of <4).6,7
After the calibration dose, subjects waited at least 24 hours before continuing with the study protocol. This delay was intended to ensure that the niacin, which has a half-life of <1 hour, would be completely metabolized prior to the next dose. Based on data from previous studies of cutaneous flush symptoms and aspirin,8–10 for the remaining 3 dosing regimens the study subjects were instructed to allow for a 24- or 48-hour washout period between regimens.
Specifically, for each of the 3 remaining dosing regimens, subjects took niacin 1,000 mg followed immediately by ingestion of 4 pills: 2 pills to be swallowed and 2 orally dissolvable pills. With regard to the dissolvable pills, the subjects were instructed to first sip soda water and then chew the pill(s); next, they were to rub the chewed pills on the inner part of their mouth and gums, mimicking delivery of the novel orally dissolvable formulation. As soda water is acidic, it was used to improve absorption of aspirin through the oral mucosa.11 The subjects were instructed to spit out pill residual and not to swallow any of the residual dissolvable medication. The subjects then swallowed the other half of the pills with water. Subjects then rated their flush sensation every 30 minutes using the GFSS.
Blinding. The subjects, researchers, and statistician were blinded to the order of the regimens. The subjects and statistician were also blinded to the composition of the regimens received by each subject. The data were unblinded only after the completion of data analysis. In order to blind the regimens, each regimen beyond the calibration dosage was assigned a color (Figure 1).
Study outcomes. The primary outcome of the study was the difference in the mean number of moderate-to-severe flushing events, defined as a GFSS of ≥4. Two a priori subgroup analyses were performed in subjects who had a major flushing event. The first subgroup analysis excluded subjects who received the calibration dose and had no significant flushing events. The second subgroup excluded subjects who were administered the calibration dose or the yellow regimen (containing swallowed aspirin) without experiencing notable flushing events.
Statistical analysis. The differences in flushing scores at each time interval with each of the 3 active treatment regimens versus the calibration dose were analyzed using the Wilcoxon signed rank test. A 1-tailed alpha error of 0.05 or less was considered to be statistically significant. The a priori level of significance was 0.05. Data analysis was performed using STATA 13 (StataCorp, College Station, TX).
Study population. A total of 26 healthy subjects were included in the study; 12 were female, and the overall mean age was 24.8 years. All subjects completed the study and took all the doses. Of the 26 subjects enrolled, 18 were of Caucasian descent, 4 were of South Asian descent, 3 were of East Asian descent, and 1 was an African American.
Flushing events with aspirin regimens. A total of 61 moderate-to-severe flushing events were recorded. Twenty-four of the 26 subjects experienced moderate-to-severe flushing symptoms with niacin alone (i.e., the calibration dose). In these subjects, a reduction in moderate-to-severe flushing events (relative to events reported after the calibration dose) was achieved with each evaluated aspirin regimen. The regimen containing swallowed aspirin reduced the mean number of moderate-to-severe flushing events by 36.1%, from 2.35 to 1.5 events per subject (p = 0.003). Similarly, the regimens containing orally dissolved aspirin only or both orally dissolved and swallowed aspirin reduced flushing events by 32.9% (p = 0.003) and 32.9% (p = 0.003), respectively (Table 1). Rates of flushing events with the 2 regimens containing orally dissolved aspirin were not significantly different from the rate with swallowed aspirin only.
Flushing events in subjects with flushing after calibration dose. Of the 26 enrolled subjects, 2 did not experience flushing during the calibration dose. Among the remaining 24 subjects, the occurrence of moderate-to-severe flushing symptoms was reduced from the calibration baseline by a mean of 36.0%, from 2.54 to 1.63 flushing events per subject, with the use of swallowed aspirin only (p = 0.003). Similarly, with the use of the regimens containing orally dissolved aspirin only or both orally dissolved and swallowed aspirin, the rates of flushing were reduced from baseline levels by 34.4% (p = 0.009) and 35.8% (p < 0.001), respectively (Table 2). The 2 regimens with orally dissolved aspirin were not significantly different from the regimen with swallowed aspirin in terms of effectiveness.
Flushing events in subjects with flushing after both calibration and swallowed aspirin doses. Of the 26 enrolled subjects, 8 did not experience flushing after receiving the niacin calibration dose and the traditional swallowed aspirin dose. Of the remaining 18 subjects, the frequency of moderate-to-severe flushing symptoms was reduced from calibration-dose levels by a mean of 23.5%, from 2.83 to 2.12 events per subject, with the use of swallowed aspirin only (p = 0.04). Similarly, with use of the regimens containing orally dissolved aspirin only or both orally dissolved and swallowed aspirin, flushing events were reduced by 39.2% (p = 0.005) and 37.1% (p = 0.002), respectively (Table 3).
Furthermore, when the regimen of orally dissolved aspirin only was compared with the regimen of swallowed aspirin only, the former was associated with a 20.5% decrease in the mean number of flushing events, from 2.12 to 1.72 events per subject (p = 0.05). Similarly, there was a relative 18.0% decrease for the regimen containing both orally dissolved and swallowed aspirin (p = 0.03) (Table 3).
Adverse events. During the study, no subjects reported any adverse events, including gastritis, oral mucosal irritation, allergic reaction, bleeding, and abdominal pain.
Our study found that administration of swallowed aspirin and niacin simultaneously reduced moderate-to-severe flushing events by 36.1% from the calibration baseline and that the regimens containing orally dissolved aspirin only or both orally dissolved and swallowed aspirin equally reduced flushing events (by 32.9%, p = 0.003). In the subset of subjects who experienced moderate-to-severe niacin flush despite taking a swallowed aspirin dose, on subsequent niacin administration the occurrence of flushing was decreased by 20.5% (p = 0.05) with use of an orally dissolved aspirin formulation and by 18.0% with use of both orally dissolved and swallowed aspirin formulations (p = 0.03).
The doses of aspirin and niacin evaluated in our study were reflective of doses commonly employed in both clinical practice and prior research studies; however, those doses might not be optimal for reduction of flushing. Aspirin is given at a dosage of 81–325 mg once daily for prevention of cardiovascular events, with 162 mg being the most commonly used daily dose worldwide. As such, for our study we used the 162-mg dose of aspirin even though a higher dose could potentially produce a greater reduction of niacin-induced flushing than was observed. However, we also employed a relatively low dose of niacin (1,000 mg), as that dose was well tolerated in prior studies.12 Since we were studying healthy subjects, we decided to use a low dose of niacin to minimize the dropout rate. Future studies are needed to examine the ideal doses of aspirin and niacin for flush reduction.
Recent work attempted to show both the cardiovascular benefits of niacin in patients already receiving statin therapy and the tolerability of a new niacin formulation designed to reduce flushing. The HPS2-THRIVE study, a large randomized controlled outcomes trial, tested over 25,000 patients using a novel combination of niacin and a flush-reducing prostaglandin receptor inhibitor, laropiprant, with 60% of patients enrolled from Europe and 40% from China.13 The overall results of the study were negative, with a nonsignificant 4% reduction in major cardiac events in the treatment group and the occurrence of 2 adverse effects not previously correlated with niacin use: increased bleeding and infection rates. The HPS2-THRIVE study was criticized on 2 main grounds: (1) all patients enrolled were taking and were generally well controlled on statins, with an average LDL cholesterol concentration of <80 mg/dL (a lipid profile that would not typically prompt treatment with niacin), and (2) laropiprant likely contributed to increased rates of bleeding and infection, as a recent Bayesian analysis of HPS2-THRIVE data has suggested.14 However, subgroup analyses of HPS2-THRIVE patients showed statistically significant benefits in those with residual risk: those with high triglycerides, those with higher baseline LDL cholesterol levels, smokers, and those on β-blockers. The European subgroup as a whole showed a trend toward benefit (p = 0.06) relative to the Chinese subgroup even without further subdivisions (consistent with observational data that niacin is less effective in Asian populations).
Since many patients who require high-dose niacin are already taking aspirin for cardiovascular health, we speculate that concomitant aspirin and niacin administration or a combination product consisting of niacin and orally dissolved aspirin would make for a more tolerable regimen and ultimately improve compliance. Our data suggest that any simultaneous administration of aspirin (chewed, swallowed, or combination formulations) decreases flush response overall. In those subjects who continued to experience moderate-to-severe flushing despite the combination of swallowed aspirin and niacin, further flush reduction was achieved with regimens containing orally dissolved aspirin. In previous studies, it was estimated that approximately 25% of patients discontinue niacin because of flushing episodes.8 Another study, by McKenney et al.,12 found that 17% of patients withdrew from niacin treatment because of flushing, and 53% of treated patients described moderately bothersome flushing as an adverse effect even after taking a dose of aspirin 30 minutes before niacin administration. Our results show that concomitant administration of aspirin could potentially reduce flushing enough to minimize the chances of a patient withdrawing from niacin treatment because of flushing. However, further studies are needed to examine this hypothesis.
While our study was a placebo-controlled, double-blind crossover trial, it had a small number of subjects. The study group consisted of relatively young subjects, and ethnic diversity was limited. Despite the small sample size, the novel aspirin-containing regimens produced a significant reduction of flushing associated with niacin use relative to the use of niacin alone or the use of niacin and swallowed aspirin together.
Another study limitation was that the amount of flushing was self-reported by the subjects. Furthermore, the calibration dose was not blinded. The study was purposely designed this way so that subjects who had not experienced flushing (and thus had used the GFSS) would be able to “calibrate” their largest flush response (i.e., that experienced with niacin alone) against the 11-point scale and, therefore, would be able to properly record subsequent flushes within the scale.
Subjects were instructed to spit out the remainder of the dissolvable pills after rubbing them on the oral mucosa. This occurred after subjects ingested 162 mg of dissolvable aspirin in the blue regimen and 81 mg of dissolvable aspirin in the green regimen; therefore, the flush reduction associated with these 2 test regimens may have been underestimated. If niacin and orally dissolving aspirin were formulated as a single pill, patients would swallow all of the remaining aspirin. Therefore, it is reasonable to assume that this type of product might produce a larger flush reduction than was demonstrated in our study.
Last, since our study focused only on healthy volunteers, our results cannot be generalized to the patient population that typically takes niacin and aspirin.
Novel regimens of niacin and aspirin, including orally dissolved aspirin, were effective in reducing niacin-induced flushing in a small sample of healthy adult volunteers.
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