Pharmacokinetics and safety of a new aspirin formulation for the acute treatment of primary headaches.

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Review

Pharmacokinetics and safety of a new aspirin formulation for the acute treatment of primary headaches

1.

Introduction

2.

Mechanism of action

3.

Pharmacokinetic profile

Marzia Lecchi, Lidia D’Alonzo, Andrea Negro & Paolo Martelletti†

4.

Safety

†

5.

Efficacy in primary headache

6.

Conclusion

7.

Expert opinion

Sapienza University, Department of Clinical and Molecular Medicine, Rome and Sant’ Andrea Hospital, Regional Referral Headache Center, Rome, Italy

Introduction: For more than a century, aspirin has been used for the acute treatment of primary headaches. However, the many formulations available are characterized by differences in the pharmacokinetic profile that could affect therapy effectiveness. Areas covered: The formulations of aspirin affect the speed of absorption of the drug. This feature, in turn, moduates the peak plasmatic concentration (the faster the absorption, the higher the peak plasmatic concentration of aspirin). Recently, a new formulation, consisting in a micronized tablet with an effervescent nucleus, has been shown to be comparable to the formulations associated to the faster absorption. The efficacy of aspirin in migraine is well characterized: the drug is able to rapidly reduce pain and restore functionality, acting also on associated symptoms, in a manner comparable to that of oral sumatriptan. In tension-type headache, aspirin acts in a dose-dependent fashion. The safety profile of the drug is favorable: gastrointestinal complaints are generally mild in intensity and with an incidence comparable to that of ibuprofen and paracetamol. Expert opinion: According to international guidelines, aspirin should be considered as first-line therapy in primary headaches. Formulations that allow fast absorption, like the new micronized tablets, and portability, are to be preferred. Keywords: aspirin, headache treatment, micronized aspirin, migraine, pharmacokinetics, safety, speed of action, tension-type headache Expert Opin. Drug Metab. Toxicol. (2014) 10(10):1381-1395

1.

Introduction

The employment of salicylates for the relieve of pain and fever management constitutes one of the oldest pharmacological treatment ever known: the first description to their use dates back to 3500 years ago in the Ebers papyrus, and reference is made in Hippocrates and Celsius works [1]. Extracts from plants belonging to the genera Salix and Spirea, abundant in salicylates, were used until the nineteenth century, when the chemical structure of salicylic acid and salicin (its glycosidic form) were finally characterized [1]. In the same period, attempts were made to improve the flavor and the tolerability of the molecule, which led to the chemical synthesis of aspirin (acetylsalicylic acid), first by Charles Gerhardt in 1853, and then, in a more stable form, by Felix Hoffmann in 1897 [1,2]. The therapeutic improvement brought by aspirin made it to rapidly replace salicylic acid in the management of rheumatic pain and fever; moreover, the industrial production of the drug and its subsequent worldwide marketing by Bayer since 1899 made it one of the drugs with the largest use in the world [3]. 10.1517/17425255.2014.952631 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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The formulation of aspirin affects the rate of absorption of the drug. The peak plasmatic concentration of aspirin inversely correlates to the time required to reach this peak, and thus, faster formulations are also those with the highest peak plasmatic concentrations and better efficacy in the first 1 -- 2 h. A new formulation of aspirin has been developed, consisting in tablets composed by smaller particles and an effervescent nucleus. This formulation greatly enhances the absorption of aspirin. In migraine, aspirin has an efficacy on pain and associated symptoms comparable to that of sumatriptan, whereas in tension-type headache the drug shows a dose-dependent effect. When used as an analgesic, the safety of aspirin is good and comparable to that of other drugs generally regarded as safe, such as ibuprofen and paracetamol. Furthermore, aspirin is the only NSAID that is not associated to a cardiovascular risk and whose effects on renal functionality are minimal. According to international guidelines, aspirin can be considered as a first-line therapy for the treatment of primary headaches. Formulations that allow fast absorption and a good portability have to be preferred over the others.

This box summarizes key points contained in the article.

The popularity of the drug began in the first decades of the twentieth century, during the Spanish flu pandemic, when aspirin was the only antipyretic widely accessible to the general population [4]. However, subsequent decades of research shed light on additional, relevant clinical applications of the drug. In 1967, Weiss and Aledort published their observations on impaired platelet aggregation following aspirin administration [5] and, in the last 40 years, daily low-dose (81 -- 325 mg) aspirin became a mainstay of the primary and secondary preventions of vascular events in patients at high cardiovascular (CV) risk [6,7]. More recently, daily aspirin has been shown to be effective in the long-term prevention of colorectal cancer [8,9] and a possible preventive effect was suggested also for other types of cancer [10,11] and for metastases [12,13]. Other therapeutic areas for which the role of aspirin is under investigation -- although not yet clearly established -- encompass preeclampsia prevention during pregnancy [14,15] and dementia prevention in the elderly [16,17]. Regardless to the many different therapeutic uses the molecule has, its employment as an analgesic never declined, and nowadays, it still remains one of the most widespread over-the-counter analgesics in the world. In the present review, we discuss the role of aspirin in the management of primary headaches, bringing the emphasis on how the different formulations might influence the efficacy of the intervention. 1382

Mechanism of action

The mechanism of action of aspirin was clarified only in 1971, when the two independent works of Vane [18] and Smith and Willis [19] showed that aspirin and indometacin were able to block the synthesis of prostaglandins, through the inhibition of COX enzymes. COX enzymes are present in the human body with two isoforms, COX-1 and COX-2 [3]. All the isoforms are dimers that bind to the membranes of the endoplasmic reticulum and of the nuclear envelope, with the catalytic side exposed to the lumen of the reticulum [20]. COXs catalyze the conversion of arachidonic acid, which is released from the cell membranes by phospholipase A2, into prostaglandin (PG) H2. Tissue-specific isomerases then convert the PGH2 into a series of prostanoids, namely PGD2, PGE2, PGI2, PGF2a and thromboxane A2 [21]. Prostanoids are involved in a series of homeostatic processes, such as fertility, integrity of the gastrointestinal (GI) mucosa, blood pressure, kidney function, as well as in many processes that take place starting from external stimuli, such as platelet aggregation, nociceptive pain and inflammation [21,22]. COX-1 isoform is constitutively expressed, whereas COX-2 is an inducible isoform, whose expression is strongly upregulated during inflammation. However, the conditions in which the two isoforms are involved cannot be completely separated, because a role for COX-2 in normal homeostatic processes seems likely [22]. The blockade of COX enzymes is able to: stop acute inflammation, which is largely mediated by PGE2 and PGI2 [23]; reduce sensitization in nociceptive pain induced by PGE2 [24]; restore the physiological set-point for body temperature, which is altered by the central production of PGE2 (this PG is considered the ultimate endogenous pyrogen) [4]; inhibit platelet aggregation, which requires thromboxane A2 synthesis [1,2]. Aspirin irreversibly blocks COX activity by acetylating the serine 530, present in the active site of the enzyme [20]. In the case of COX-1, the covalent modification of the enzyme prevents arachidonic acid from reaching the active site. With COX-2, instead, the acetylation still allows arachidonic acid to enter the active site but the molecule is no longer converted into PGH2. Instead, the acetylation of COX-2 leads to the conversion of arachidonic acid in 11R- and 15-hydroxyeicosatetraenoic acid [25]. Aspirin is more selective for the COX-1 isoform, with a ratio COX-1/COX-2 comparable to those observed with naproxen and ibuprofen [26], although with a lower absolute affinity for COX-2 [27]. Following acetylation, salicylic acid is released from the active site of the enzyme. This metabolite still retains the ability to reversibly block COX enzymes, albeit with a potency lower than that of the aspirin [27]. This mechanism of action can explain the anti-inflammatory, analgesic, antipyretic effects of aspirin, as well as its protective action from adverse CV events [2,3]. Even the

Expert Opin. Drug Metab. Toxicol. (2014) 10(10)



chemopreventive effect of aspirin is now considered as a consequence of the reduction of platelet aggregation [28]. Interestingly, a second mechanism has been proposed, in addition to the above-mentioned one, to explain the antiinflammatory action of aspirin: the alternative metabolites of arachidonic acid produced when the COX-2 active site is acetylated [25] can become the substrate for leukocyte 5-lipoxygenase, leading to the production of aspirin-triggered 15-epilipoxin A4, a prostanoid with anti-inflammatory properties [29,30]. However, it is still not clear whether or not this second action effectively contributes to the anti-inflammatory action of aspirin, also because the presence of aspirin-triggered 15-epi-lipoxin A4 in humans following aspirin intake has not been definitely characterized, yet. 3.

Pharmacokinetic profile

Given the purpose of this review, only the pharmacokinetics of aspirin as an analgesic drug will be considered (i.e., intake for a short period, at dosages of 325 mg or higher). Table 1 summarizes the results of the main pharmacokinetic studies performed on aspirin in the last 30 years. Absorption The absorption of aspirin is quite fast, with most of the studies showing that the Cmax is achieved within an hour from ingestion. The formulation greatly affects the rate of absorption of the drug: the soluble (effervescent) tablets, orodispersible granules and tablets are associated to faster absorption rates, with significant levels of aspirin already detectable in the bloodstream after 5 min [31] and the time to peak plasmatic concentration (ttp) ranging from 15 to 25 min [31-37]. Chewable tablets have a somewhat slower absorption [32,34], followed by plain tablets, whose ttp can be up to 60 min [32]. The primary site of absorption of aspirin is the stomach [32,34], where the drug seems to be absorbed with a passive mechanism [38]. This explains why drug absorption can be so fast compared with other analgesics, such as paracetamol, that require stomach emptying for absorption to begin [31,33]. A confirmation comes from studies that evaluated the absorption of enteric-coated tablets, formulated in order to start releasing the drug only once the stomach has emptied. Indeed, with this formulation, the Cmax was achieved with longer times (4 h or more), whereas both the Cmax and the AUC were at least halved when compared to those observed with different formulations [32,34]. Also, the buccal absorption of aspirin is scarce [35], suggesting that the faster kinetics observed with soluble tablets and orodispersible granules are due to the fact that the drug is ready to be absorbed in the stomach once ingested, whereas plain tablets have to disgregate in the stomach before the drug can pass the gastric mucosa. The speed of absorption greatly influences the pharmacokinetic profile of aspirin. In Table 2, a series of correlations based on data reported in Table 1 is listed. Interestingly, 3.1

although the AUC positively correlates with the dose (Spearman’s Rho 0.69, p = 0.0002), this is not the case for Cmax (Spearman’s Rho 0.17, p = 0.3569). Instead, the Cmax of aspirin inversely correlates with the ttp, suggesting that the formulation is the primary determinant for the peak plasma concentration of aspirin: the faster the absorption allowed by the formulation, the higher the Cmax achieved. Indeed, as the half-life (t1/2) of aspirin is very short (0.5 -- 1 h), a fast absorption initially counteracts the rapid biotransformation of the drug, thus allowing the concentration in the bloodstream to reach higher levels. Conversely, a slower rate of absorption leads to a peak plasma concentration that is ‘blunted’ by the fast conversion of the drug into salicylic acid. Nevertheless, a negative correlation is observed also for the Cmax of aspirin and its t1/2 (Spearman’s Rho -0.56, p = 0.0014). This finding can be explained considering that the plasmatic levels of aspirin are the result of two opposite processes: the absorption of the drug, which tends to raise aspirin concentration in the bloodstream and the biotransformation of the molecule operated by tissue and plasma esterases and by hepatic metabolism, which lower the plasmatic concentration. When the absorption of aspirin is slow (which, as we have seen, is in turn associated to a lower Cmax), the observed plasma half-life of the drug is longer because its degradation is partly masked by the fact that for a relatively long time new drug is entering the bloodstream. With a fast absorption, instead, the drug enters the blood in a shorter timeframe (leading to a higher Cmax), meaning that the biotransformation of aspirin soon becomes the main determinant of its plasmatic level, thereby accounting for the shorter half-life observed. After a single dose, the Cmax ranges from a 3 -- 7 µg/ml with plain tablets [32,34,36,37,39-42] to 10 -- 16 µg/ml with soluble and micronized tablets [31-34,37]. Interestingly, orodispersible granules showed a Cmax lower than that observed, on average, with formulations with a similar rate of absorption [36,37]. At the moment, no explanation to this observation has been proposed. Maybe, when the granules are placed on the tongue, part of them are ingested within a few seconds, thereby accounting for the rapid absorption, while part stay in the oropharyngeal tract for longer times, where the absorption of aspirin is delayed. However, this hypothesis still requires an experimental confirmation. Multiple dosing regimens did not show significant accumulation of the drug. In fact, a true steady state cannot be achieved, due to the short half-life of aspirin [39,43]. The effect of food on absorption seems to be negligible: a food effect has not always been observed, and in any case it seems to minimally affect the therapeutic efficacy of the compound [33,38]. Caffeine promotes aspirin absorption [44]. On the other hand, interventions that raise the stomach pH slow the rate of absorption [39,41], because a higher pH induces the dissociation of the acidic moiety of aspirin, making it less permeable to the gastric mucosa [37].


1383

1384


500 500 500 500

Soluble tablets

Soluble tablets

Soluble tablets

Plain tablets

Gatti et al. (1989) [47]

7.12 10.04 9.48

600

6.5 (1.5)

4.3 (1.6) 7.7 (5.7)

2.91 3.56 6.49 3.35 6.85 7.54 7.6 (1.7) 0.2 (0.3) 6.9 (2.1)

Cmax (mg/ml)

3900 600

Data are reported as mean. Where published, standard deviation was reported in brackets. ttp: Time to peak plasmatic concentration.

Plain tablets Fast dissolving tablets (fasted) Fast dissolving tablets (fed)

975

Plain tablets

Hsyu et al. (1989) [39] Mustapha et al. (1996) [38]

1000

Corrocher et al. (1987) [41] Kershaw et al. (1987) [40]

600

600

Tablet (in patient with migraine) Soluble tablets (in patient with migraine) Plain tablets

600

600

320 300 325 800 600 650 600

Effervescent tablets Plain tablets Plain tablets Plain tablets Plain tablets Plain tablets Tablet (swallowed with water) Tablet (retained sublingually for 4 min) Tablet (dissolved on the tongue)

Brandon et al. (1986) [35]

650

Capsules

Yoovathaworn et al. (1986) [44] Latini et al. (1986) [42]

3000

Dose (mg)

Soluble tablets

Formulation

Helliwell et al. (1984) [43]

Study

5.78

8.1 (0.7)

3.1 3.1 6.4 5.5 7.1 7.4 8.53 (1.17) 0.31 (0.47) 7.92 (2.42)

AUC (mg/h/ml)

Aspirin

30

42 30

26 (8)

68.4 (30) 43.8 (30)

33.3 33.3 34.2 82.5 43.3 36.6 35.4 (15.6) 22.8 (31.2) 33 (18.6)

ttp (min)

1.03

0.34 1.04

0.53

0.61 0.41 0.45 0.66 0.72 0.59 0.28 (0.08) 0.20 (0.23) 0.45 (0.21)

t1/2 (h)

44.46

36.2 (11.4) 46 (8.2) 61.7 (8.3) 49 (8) 52.3 (6.6) 45.1 (8.2) 48.7 (6.1) 40.9 (5.6) 153 43.84

21.73 79.3 19.57 52.37 40.04 39.95 40.2 (4.3) 1.0 (1.4) 36.9 (5.7)

50.2

112

Cmax (mg/ml)

805

192.1

191.2

179.1

426.5 (81.1) 357 (47) 200.1

94.8 79.3 93.5 359.6 209.6 253.4 293.76 (104.87) 4.22 (5.94) 260.86 (112.37)

749 (129) 427

AUC (mg/h/ml)

120

150 (18) 28 (11) 32 (6) 32 (6) 75 (16) 101.4 120

(37.8) 97.2 (36) 84 (27.6) 2

95.0 81.7 7.67 160.0 120.0 86.3 105 (45) 55.2 (71.4) 112.8-

1.9

ttp (min)

Salicylic acid

Table 1. Pharmacokinetic parameters of aspirin and of salicylic acid, its main metabolite, reported in the main studies published.


0.371

0.28

2.8 (0.25) 2.77 (0.32) 2.52 (0.38) 2.47 (0.18)

5.58 (2.03) 2.6

2.15 2.26 2.85 2.78 2.53 3.26 3.79 (1.10) 0.17 (0.24) 3.57 (1.66)

4.31 (0.94)

t1/2 (h)

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600 600 600 600 600 500 650 500 650 600 900 900 500 500 500 500 500 500 500 500 500

Soluble tablets (fed) Orodispersible granules Plain tablets Micronized tablets Micronized tablets Plain tablets Orodispersible granules Effervescent tablets Effervescent tablets Effervescent tablets

Dose (mg)

Soluble tablets Plain tablets Soluble tablets Chewable tablets Plain tablets Enteric-coated tablets Plain tablets Enteric-coated tablets Effervescent tablets Chewable tablets Soluble tablets (fasted)

Formulation

Data are reported as mean. Where published, standard deviation was reported in brackets. ttp: Time to peak plasmatic concentration.

Voelker and Hammer (2012) [37]

Farinelli and Martelletti (2007) [36]

Stillings et al. (2000) [33]

Sagar and Smyth (1999) [34]

Muir et al. (1997) [32]

Muir et al. (1997) [31]

Study

10.79 5.23 13.82 5.66 5.51 1.44 3.75 0.875 11.25 5.37 16.8 (1.19) 13.7 (1.15) 5.34 (1.27) 3.63 (1.94) 13.8 (2.88) 13.1 (3.09) 4.4 (1.54) 6 (1.64) 11.7 (3.27) 9.4 (2.45) 11.5 (3.01)

Cmax (mg/ml)

6.46 3.62 7.12 5.79 7.99 (1.37) 8.47 (1.23) 4.97 (1.19) 4.25 (1.53) 6.2 (1.12) 6.7 (1.42) 6.5 (1.55) 7.0 (1.33) 5.5 (1.37) 4.9 (1.30) 5.9 (1.28)

6.83 6.49

AUC (mg/h/ml)

Aspirin

19.8

19.8

17.4

25

45

19.8

17.5

30

20

30

15.6 40.8 20.5 28.3 60.4 288 45.5 240 20.1 30.5 20

ttp (min) 0.33 0.58 0.27 0.61 0.53 0.47 0.66 0.45 0.32 0.6 0.38 (1.54) 0.30 (1.67) 0.35 (1.16) 0.51 (1.72) 0.35 (0.06) 0.36 (0.06) 0.54 (0.17) 0.46 (0.19) 0.32 (0.05) 0.31 (0.06) 0.33 (0.07)

t1/2 (h)

35.1 (6.68) 31.9 (6.51) 27 (4.86) 29.8 (6.57) 29.2 (4.95) 27 (5.27) 27.8 (5.47)

103.8 (1.11) 89 (1.05)

Cmax (mg/ml)

198.4 (54.12) 183.9 (53.99) 189.4 (50.59) 205.2 (54.29) 148.9 (36.94) 133.5 (40.73) 147.8 (44.22)

579.5 (1.26) 888.2 (1.2)

AUC (mg/h/ml)

49.8

45

45

120

180

49.8

45

120

90

ttp (min)

Salicylic acid

Table 1. Pharmacokinetic parameters of aspirin and of salicylic acid, its main metabolite, reported in the main studies published (continued).


2.55 (0.59) 2.68 (0.65) 2.79 (0.55) 2.70 (0.55) 2.50 (0.59) 2.46 (0.64) 2.49 (0.55)

4.72 (1.26) 6.86 (1.35)

2.3 2.4

t1/2 (h)


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Table 2. Spearman’s Rho coefficients obtained for correlations between different pharmacokinetic parameters of aspirin. Correlation

Number of points

Cmax versus dose AUC versus dose AUC versus Cmax Cmax versus ttp t1/2 versus Cmax

32 25 25 32 30

Spearman’s Rho (95% CI)

p (twosided)

0.17 (-0.19, 0.49) 0.69 (0.40, 0.85) 0.50 (0.13, 0.75) -0.67 (-0.83, -0.43) -0.56 (-0.77, -0.26)

0.3569 0.0002 0.0111 < 0.0001 0.0014

Correlations were based on data reported in Table 1. Data from enteric-coated tablets and from tablets retained sublingually were excluded from the analysis, because they would have strongly biased the results. Data from multiple dosing were excluded for the same reason. Data from fed conditions were retained in the analysis, because the food effect for aspirin absorption is considered minimal. ttp: Time to peak plasmatic concentration.

Distribution, metabolism and elimination The volume of distribution of aspirin is about 10 l [44]. As anticipated, the plasma half-life of the molecule is very short compared to those of other NSAIDs, generally ranging from 0.5 to 1 h. Aspirin undergoes extensive metabolization in the liver [45], mainly by the CYP 2C9 and UDPglucuronosyltransferase 1A6 isoforms [46], to the point that free, unaltered acetylsalicylic acid cannot be found in the urines [45]. Instead, the salicylic acid and salicyluric acid metabolites are excreted by the organism [45]. Salicylic acid contributes to the anti-inflammatory, analgesic and antipyretic effects of aspirin, because it can still reversibly block COX enzymes [27]. However, this additional activity depends on the starting dose of aspirin, because only for doses of 1000 mg or more plasmatic levels of salicylic acid able to block COX enzymes are obtained. Most of the pharmacokinetic studies on aspirin also dosed salicylic acid; the results are reported in Table 1. Salicylic acid is associated to a longer ttp, as it requires the biotransformation of aspirin to happen first. However, it presents a considerably higher Cmax, AUC and t1/2 [33,35,37-41,43,44,47]. In terms of analgesic and antipyretic efficacy, these features compensate for the reduced affinity of the metabolite to COX-1 and COX-2 [27]. 3.2

A new formulation of aspirin Recently, a new formulation of aspirin has been developed, consisting in tablets with an effervescent core and composed by granules of aspirin that are considerably smaller than those contained in plain tablets [37]. Once ingested, the sodium carbonate contained in these tablets boosts their disgregation, leading to an almost complete disgregation within 3 min from intake. Moreover, the granules released by the disgregation of the tablet have a size that is, on average, > 10-fold smaller than the granules of a plain tablet [37]. According to the Nernst-Brunner/Noyes Whitney equation, the increase in the surface obtained with smaller granules translates into a 3.3

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faster dissolution rate of the drug, thereby prompting its uptake in the stomach [37]. Pharmacokinetic studies with these micronized tablets showed that they are associated with a fast absorption (ttp of 17 -- 19 min), comparable to that of effervescent tablets and dry granules, and a Cmax among the highest attained with a single administration of aspirin [37]. 4.

Safety

The principal adverse reactions associated to aspirin are directly related to its pharmacological action: COXs are present in many tissues and normally contribute to their homeostasis; as a consequence, their inhibition can produce adverse reactions that result from alterations of the homeostasis and that are generally shared by all the other NSAIDs. Interestingly, marked differences among molecules in their selectivity for COX-1 and COX-2 have been associated to different patterns of toxicity [48]. GI safety GI disorders -- mainly dyspepsia -- were known to be associated to aspirin and other analgesic treatments well before the understanding of the mechanisms underlying them. In fact, aspirin was originally developed as a less irritant analgesic compared to salicylates present in plant extracts [1,3]. However, it was only several decades after its marketing that aspirin use was associated to more severe adverse reactions like gastric ulcers [49,50]. PGE2 and PGI2 reduce the acid secretion of parietal cells in the stomach, increase blood perfusion of the gastric epithelium and, in addition, PGE2 stimulates the secretion of mucus that acts as a barrier against the acidic environment of the stomach and retains the bicarbonate secreted by the epithelium [20]. Therefore, the suppression of PG synthesis in the stomach makes the gastric epithelium more susceptible to the acidic pH, increasing the occurrence of local damage, although most of the ulcers that form are asymptomatic and resolve spontaneously [51]. Moreover, the antiplatelet effect of aspirin may favor gastric bleeding of pre-existing ulcers [52]. Nevertheless, the evidence of the GI toxicity induced by aspirin comes mainly from studies on CV prevention, where the drug is administered at low doses, on a daily bases, and for periods that last for years [52-54]. However, this pattern of dosing does not mirror the one typical of the management of acute pain or fever, which is instead characterized by higher dosages for a very short period (often a single dose is sufficient for a complete resolution of symptoms) [52]. Interestingly, two meta-analyses recently took into account the adverse reactions coming from this latter modality of intake of aspirin, with a particular focus on the reactions occurring in the GI tract. The first is a meta-analysis of published results that collected data from 78 studies, for a total of 19,829 patients, 6712 of whom allocated to aspirin [55]. The meta-analysis showed that the short-term use of aspirin was not significantly associated to serious GI events, such as stomach perforation or bleeding. Drug use was significantly associated to an increase 4.1




of minor GI complaints, like dyspepsia and abdominal pain, with an overall odds ratio versus placebo (OR) of 1.46 (95% confidence interval [CI] 1.15, 1.86). When compared to other NSAIDs/analgesics, aspirin was still associated to a higher incidence of minor GI events, with an OR of 1.81 (95% CI 1.61, 2.04), confirmed by the head-to-head analysis with the two compounds more frequently used as comparators in the selected studies: paracetamol (OR 1.68, 95% CI 1.44, 1.96) and ibuprofen (OR 2.02, 95% CI 1.73, 2.37). However, as the authors noted, 90% of the events used for the head-to-head analysis were derived from a single study [56]. Therefore, the generalizability of the results is uncertain. For instance, when the results from this single study were removed from the analysis, the differences with paracetamol were no longer present [55]. The second meta-analysis was based on individual safety data from 67 studies performed by a single sponsor (Bayer), pooled together for a total of 13,222 patients, 6181 of whom allocated to aspirin [57]. Also, this analysis confirmed that serious GI events were rare and that only minor GI events were significantly associated to aspirin use versus placebo (OR 1.2, 95% CI 1.0, 1.5). However, head-to-head analysis failed to show any difference versus either paracetamol (OR 0.9, 95% CI 0.7, 1.3) or ibuprofen (OR 1.7, 95% CI 0.9, 3.3), suggesting that the risk of developing abdominal pain or dyspepsia with aspirin was comparable to that of these two molecules. A similar analysis performed on pooled results of nine studies conducted to test the efficacy of a single dose of 1000 mg of aspirin in different pain models (primary headache in 8 cases) substantially confirmed the previous observations [58]. This analysis was conducted on 2852 patients, 1581 treated with aspirin and 1271 with placebo, and showed an increase of GI adverse events in the aspirin group, with a number needed to harm of 42 (95% CI 25, 111). However, when only adverse reactions were considered (i.e., adverse events with at least a possible causation due to the intervention, according to the investigators’ judgment), the difference with placebo was no longer significant. Safety in other tissues Most NSAIDs show, to some extent, CV toxicity. This kind of toxicity was first characterized for COX-2 selective inhibitors, which were developed as NSAIDs with lower GI toxicity and that were thus supposed to be safer for long-term treatments [48,59,60]. However, subsequent analyses revealed that the use of each NSAID was associated to an increased risk of developing CV events [61,62] and that aspirin is therefore the only NSAID devoid of this effect. Similarly, aspirin is the NSAID associated to the lowest risk of developing hypertension when compared to other NSAIDs and paracetamol [63,64] and, probably for this reason, it is the only NSAID not associated to the development of kidney disease [65,66]. Aspirin is a dose-related hepatotoxin [67], although in fact its hepatic toxicity is largely caused by its main metabolite, 4.2

salicylic acid, and the compounds arising from the metabolic transformations on the latter operated in the liver by CYP2E1 and CYP3A4 enzymes [68]. An integrated analysis of liver toxicity induced by analgesics, realized by merging data from registries present in the US, Sweden and Spain, showed that aspirin accounted for almost 7% of the total liver injuries induced by NSAIDs, a frequency comparable of those observed with diclofenac, sulindac, naproxen, piroxicam, ibuprofen and nimesulide, but much lower than that observed with paracetamol (42%) [68]. However, when the percentages were adjusted for the defined daily dose and the number of years in the market, aspirin and nimesulide presented the highest incidence of acute liver failure among NSAIDs, although the adjusted incidence for paracetamol, the molecule associated to the highest crude incidence of liver toxicity, was not calculated. Still, it is not clear whether low-dose aspirin use was included or not in this analysis, and thus which is the actual incidence of acute liver failure associated to a single dose of aspirin or to an intake for a very short timeframe, typical of over-the-counter indications of aspirin. Furthermore, the hepatic toxicity of aspirin is lower than that of paracetamol [69], a drug that is generally considered safe when taken at therapeutic doses [70,71], although its hepatic toxicity is well recognized and has been extensively characterized [72,73]. Additionally, meta-analyses conducted to test aspirin safety did not show an increase of hepatic adverse events in patients treated with aspirin compared with the placebo group [55,57,58]. A severe, potentially fatal hepatic adverse reaction associated to aspirin is the Reye syndrome. This syndrome is very rare and consists in acute encephalopathy and selective hepatic dysfunction following a marked mitochondrial insult, accompanied by fatty infiltration of the viscera [74,75]. Reye syndrome develops usually in children aged 16 or less, following a viral infection -- mainly in cases of chickenpox or flu [75]. Exposure to salicylates during viral infections was associated to an increased risk of developing Reye syndrome in children [76,77], although the mechanism by which salicylates could induce Reye syndrome in subjects with an ongoing viral infection is not clear, and might involve some second-level metabolites [74]. Nevertheless, the restriction of aspirin and salicylates use to people aged > 16 years showed a marked decrease in the reporting of new cases of Reye syndrome [76], suggesting that the use of salicylates in older individuals can be considered safe. Allergic reactions Allergic reactions to aspirin can be divided in three types: the exacerbation of pre-existing respiratory diseases, dermatological reactions (erythema and urticaria) and anaphylactic reactions, the latter type being very rare [78]. Aspirin-exacerbated respiratory disease (AERD) can present in subjects suffering from chronic rhinosinusitis (an inflammation of the mucosa of the nasal cavity and paranasal sinuses lasting 12 weeks or more, associated to nasal obstruction, nasal discharge, postnasal drip and facial pressure) or with an history of asthma. 4.3


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The incidence varies according to the population considered, and can range from 24% in patients with severe asthma to 40% in patients with both asthma and chronic rhinosinusitis, and can lead to the development of nasal polyps [79]. AERD can develop following exposure to NSAIDs with a preferential selectivity to COX-1 isoform [80], because this can increase the production of leukotrienes through the lipoxygenase pathway [79], even if also, the reduction of PGE2 synthesis following COX-2 inhibition has been proposed as a mechanism that contributes to AERD, because PGE2 negatively regulates the production of leukotrienes [81,82]. A similar mechanism has been proposed also in patients with chronic urticaria, where the exposure to aspirin or other NSAIDs is thought to exacerbate symptoms through the reduction of PGE2 levels and the subsequent increase in leukotrienes synthesis [83]. Although one-third of patients suffering from chronic urticaria are likely to present exacerbations following aspirin or non-aspirin NSAIDs exposure [84], the incidence of skin reactions induced by aspirin is very low in the general population (0.07 -- 0.2%) [78]. Furthermore, a study with patients who had a cutaneous reaction attributed to an oral dose of aspirin or another NSAID showed that in only a minority of subjects (10%) the reaction appeared after a second challenge with the culprit substance [85]. Taken together, these results suggest that allergic reactions associated to aspirin exposure are relatively rare and that special attention should be paid only to patients with asthma or with a diagnosis of chronic rhinosinusitis. Importantly, respiratory and cutaneous reactions to aspirin are the consequence of the inhibition of COX enzymes, so in patients presenting these symptoms the use of every NSAID should be avoided or prescribed after careful examination of the possible risks and the expected benefits. 5.

Efficacy in primary headache

Despite aspirin has been used for headache management since its launch on the market at the end of the nineteenth century, an extensive characterization of its efficacy in this pain state began only a couple of decades ago [36,86-88]. Efficacy in migraine Aspirin, at dosages of 900 -- 1000 mg, is able to effectively reduce pain in migraine patients. A randomized clinical trial involving > 300 migraine patients enrolled in 36 centers in Germany showed that aspirin 1000 mg delivered with effervescent tablets was significantly better than placebo in producing an improvement of pain associated to migraine in the first 2 h after the assumption, with a percentage of painfree patients at 2 h higher (29.0%) in the aspirin group than that of the placebo group (16.7%, p < 0.007) [89]. A study employing mouth-dispersible aspirin tablets showed that the medication was able to induce significant relief versus placebo already 30 min after intake, with 26% of the patients in the aspirin group presenting a significant pain reduction 5.1

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compared to only 12% (p < 0.05) of the patients in the placebo group. The difference increased in the following time points (at 2 h 48 vs 19%, aspirin vs placebo, p = 0.0005) [90]. Aspirin is also more effective than placebo in reducing disability induced by migraine, [90,91], and the relief from pain lasts for at least 6 h [91]. An extensive characterization was conducted for a formulation of aspirin consisting in the lysine salt of the molecule, combined with 10 mg of metoclopramide in order to specifically target the associated symptoms of migraine, in particular, nausea and vomiting. Many clinical trials showed that such combination is superior to placebo in providing pain relief. For instance, a study showed that, within 2 h from the start of the treatment, the combination of aspirin 900 mg and metoclopramide 10 mg increased the percentage of patients with a significant relief of pain compared with placebo (54.3 % in the aspirin with metoclopramide group versus 25.9% in the placebo group, p < 0.001). The combination was also superior to placebo for the percentage of patients presenting a complete remission of symptoms; the reduction of patients requiring rescue medication; and the percentage of patients able to resume their everyday activities (44.1% in the aspirin with metoclopramide group versus 22.1% in the placebo group, p = 0.003) [92]. This observation was confirmed in other studies [93-95]. However, a study comparing aspirin 650 mg in combination with metoclopramide 10 mg to aspirin 650 mg found no difference between the two medications in the reduction of pain and nausea, questioning the role of an antiemetic in combination with aspirin for the management of migraine-associated symptoms [96]. Indeed, subsequent trials confirmed that aspirin alone is able to reduce migraine-associated symptoms: nausea, photophobia and phonophobia [91,97,98]. Interestingly, an individual patient data meta-analysis showed that baseline pain intensity in migraine does not influence the efficacy of aspirin: the therapeutic gains for patients with moderate or severe pain before treatment (the therapeutic gain was defined as the difference in the percentage of patients with headache relief at 2 h between the aspirin and placebo groups) were comparable: 18.5% (95% CI 12.8, 24.4) for moderate baseline pain and 13.8% (95% CI 7.7, 19.9) for severe baseline pain, p = 0.275 [99]. The efficacy of aspirin on migraine was compared also to that of other analgesics. In a cross-over study on 198 patients with recurrent migraine attacks aspirin 1000 mg almost or completely reduced pain in 52.3% of patients, versus 49.7% of the patients treated with a combination of paracetamol 400 mg and codeine 25 mg, showing substantial comparability of the two medications [100]. Instead, aspirin lysinate plus metoclopramide showed superiority to the combination of ergotamine and caffeine in two separate clinical trials that evaluated the effects of the two oral preparations [101,102]. Moreover, aspirin lysinate with metoclopramide, administered intravenously, had the same efficacy, but faster onset of action and fewer side effects, than subcutaneous ergotamine [103].



Table 3. Relative benefit resulting from the meta-analyses of the Cochrane collaboration, for the outcome: complete resolution of pain after 2 h from intake, with the corresponding NNT. Meta-analysis

Intervention

Number of studies included in the analysis

Relative benefit versus placebo (95% CI) for pain-free patients at 2 h

NNT (95% CI) for pain-free patients at 2 h

Kirthi et al. (2013) [107]

Aspirin 900 or 1000 mg Aspirin 900 mg + metoclopramide 10 mg Ibuprofen 200 mg Ibuprofen 400 mg Diclofenac 50 mg Paracetamol 1000 mg Sumatriptan 25 mg Sumatriptan 50 mg Sumatriptan 100 mg

6 2

2.1 (1.7, 2.6) 2.7 (1.6, 4.6)

8.1 (6.4, 11) 8.8 (5.9, 17)

2 6 2 3 3 13 16

2.0 1.9 2.0 1.8 2.7 2.7 3.2

9.7 (6.5, 18) 7.2 (5.9, 9.2) 8.9 (6.7, 13) 12 (7.5, 32) 6.2 (4.9, 8.5) 6.1 (5.5, 6.9) 4.7 (4.3, 5.1)


Rabbie et al. (2013) [111] Derry et al. (2013) [109] Derry and Moore (2013) [110] Derry et al. (2012) [108]

(1.4, (1.6, (1.6, (1.2, (1.8, (2.4, (2.8,

2.8) 2.3) 2.6) 2.6) 4.0) 3.1) 3.6)

The results are based on comparisons versus placebo. NNT: Number needed to treat.

Many clinical trials compared aspirin to triptans, mainly sumatriptan. The combination of aspirin lysinate 900 mg and metoclopramide 10 mg was comparable to sumatriptan 100 mg in the reduction of pain at 2 h [95,104] but superior in the reduction of nausea and with a lower incidence of side effects [104]. A third study that took into account more attacks for the same patient essentially confirmed the comparable efficacy between sumatriptan and the combination of aspirin and metoclopramide at the first attack, but pointed out that in subsequent attacks sumatriptan was associated to more pain relief and to a lower use of the rescue medication [105]. Geraud et al. [94] found comparable efficacy of the combination of aspirin 900 mg and metoclopramide 10 mg to zolmitriptan 2.5 mg in pain relief at 2 h (OR 1.06, 95% CI 0.77, 1.47), but an higher percentage of patients in the zolmitriptan group were pain-free at 2 h (OR 1.40, 95% CI 1.09, 1.78). Two studies compared aspirin 1000 mg to sumatriptan 50 mg. The first confirmed that the percentage of patients with a reduction of pain within the first 2 h was comparable between the two interventions, although an higher percentage of patients were pain-free in the sumatriptan group (p = 0.025) [97]. The second showed substantial equivalence between the two interventions in reducing migraine-associated symptoms [98]. Moreover, this study found no difference between aspirin 1000 mg and sumatriptan 50 mg in their ability to reduce pain [98]. Finally, two studies compared aspirin to ibuprofen. The first study showed a superior efficacy of ibuprofen 200 mg over aspirin 500 mg in pain relief [106]. However, this study considered a mixed population of patients suffering from migraine and tension-type headache (TTH), and with lower dosages of aspirin, thereby limiting the validity of the conclusions drawn. On the other hand, a study considering the efficacy of aspirin 1000 mg and ibuprofen 400 mg in migraine reported comparable efficacy of the two interventions (34.5 vs 31.3% of patients with pain reduction at 1 h, aspirin versus ibuprofen, difference not significant) [97].

In conclusion, aspirin at the dosage of 900 -- 1000 mg is a safe and effective treatment for migraine: a meta-analysis of the Cochrane collaboration estimated a risk ratio for the complete relief of pain versus placebo at 2 h of 2.08 (95% CI 1.70, 2.55) and a number needed to treat (NNT) of 8.1 (95% CI 6.4, 11) [107]. These results were comparable to those published, in similar meta-analyses, for the other analgesics commonly used for the management of migraine [108-111], suggesting that aspirin constitutes a valid alternative for the treatment of migraine and its associated symptoms. Table 3 reports a comparison among aspirin and other analgesics used in migraine treatment, according to the results published by the working groups of the Cochrane collaboration. Efficacy in TTH The efficacy of aspirin in TTH was shown in a clinical trial that compared effervescent tablets and plain tablets of aspirin, both at the 648 mg dosage. Both the formulations were able to induce significant pain relief versus placebo, but no difference was observed between the two active treatments [112]. The confirmation that even smaller doses of aspirin are associated with a good efficacy in TTH came from a multicentre study conducted in UK, which showed that a dose of 500 mg was able to induce significant pain relief within the first 2 h in 70.3% of patients, versus 54.5% of patients in the placebo group (p = 0.011), whereas the 1000 mg dose showed improvement in symptoms in 75.7% of patients (p = 0.0009 vs placebo). However, the superiority over placebo was obtained starting from 30 min with the 1000 mg dosage, but only after 2 h with the 500 mg dose, suggesting that the effect of aspirin on TTH is dose-dependent [113]. As for migraine, also for TTH, the efficacy of aspirin is not influenced by the initial severity of pain, with therapeutic gains comparable regardless to the severity of pretreatment headache with both the 500 and 1000 mg dosages [99]. 5.2


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Several studies compared aspirin to paracetamol in TTH, substantially showing similar efficacy in this type of headache [113-115]. However, some considerations point towards a slightly better efficacy of aspirin versus paracetamol. First, although a trial observed comparable pain relief at the same dosages (i.e., no difference was observed for pain relief with aspirin 500 mg and paracetamol 500 mg, or with aspirin 1000 mg and paracetamol 1000 mg) [113], a second study showed that similar efficacy between aspirin 650 mg and paracetamol 1000 mg [114]. Moreover, in the study of Steiner et al. [113], aspirin 500 mg and paracetamol 500 mg were associated with comparable pain relief, but only the latter was significantly better than placebo (p = 0.011), whereas the pain relief observed with paracetamol was not (p = 0.104). Aspirin 1000 mg had also comparable efficacy to a combination of paracetamol 300 mg and codeine phosphate 30 mg; the cumulative percentage of patients taking rescue medication in the aspirin group was significantly different starting from 2 h until the end of the study, whereas the cumulative percentage in the paracetamol with codeine group was significant only after 3 h [115]. Finally, a clinical trial involving 31 centers compared aspirin 1000 mg to metamizol 500 and 1000 mg. The three interventions were superior to placebo in reducing pain from TTH. Metamizol seemed to induce faster relief in the first hour from treatment start, although the differences at later time points were no longer apparent [116]. The available data thus suggest that aspirin, at the dosage of either 500 mg or 1000 mg, is an effective treatment for TTH. 6.

Conclusion

Since its marketing at the beginning of the nineteenth century, aspirin has been used for the treatment of primary headaches. Its efficacy was confirmed by more recent clinical trials, which showed that aspirin 900 or 1000 mg can rapidly bring pain relief in migraine patients, reducing also the associated symptomatology. The efficacy of aspirin can be considered comparable to that of other analgesics commonly employed for the attack therapy of migraine, including sumatriptan [117]. Nonetheless, several guidelines recommend aspirin as firstline therapy for the management of primary headache [118-123]. The intervention can also be considered safe: the use of aspirin for the attack therapy in primary headaches is often limited to a single administration, which is generally sufficient for a complete remission of symptoms. With this pattern of use, the incidence of adverse reactions (pertaining to the GI tract or to other tissues) is low and comparable to that of other commonly employed analgesics, such as paracetamol and ibuprofen [57]. 7.

Expert opinion

According to the directives of the American Academy of Neurology and the US Headache Consortium, the ideal 1390

management of acute migraine and TTH should adopt strategies that: act rapidly, restore patient’s functionality, minimize the use of rescue medications, favor and optimize self-care, ensure cost-effectiveness and have minimal or no adverse events [119,120]. Moreover, a rapid relief from pain (and associated symptoms in migraine) and a quick restore of functionality are the main determinants for patient’s satisfaction to the treatment [124]. In this perspective, aspirin constitutes a valuable tool for the attack therapy of primary headaches. Many formulations allow the rapid absorption of aspirin, mainly soluble (effervescent) and micronized tablets. Moreover, as we have pointed out, fast absorption kinetics are associated to the highest plasmatic levels. This aspect is especially important, because in migraine patients, the rate of absorption of an analgesic correlates to the onset of the effect [125]. Therefore, formulations of aspirin that ensure a prompt absorption of the drug should be preferred for the management of primary headaches. When dealing with a migraine attack, there is a general consensus that, in the absence of premonitory symptoms or aura, the medication has to be taken as soon as the first symptoms appear. However, modern lifestyles generally require patients to stay out of their homes for most of the day, where the occasions to dissolve soluble tablets in a glass of water might be scarce. Consequently, formulations that do not require to be dissolved in water prior to their intake help reduce the lag between symptoms appearance and medication intake. Taken together, two formulations of aspirin reveal themselves as particularly suitable for the management of headache: dry granules, which can be dissolved on the tongue without the need of water, thus minimizing the lag between symptom onset and treatment start, and micronized tablets, which can be swallowed and are associated to a very rapid absorption and a peak plasmatic concentration comparable to that of soluble tablets [37]. In a pain model, micronized tablets have also shown that can quickly provide sustained pain relief [126], although their efficacy in migraine and TTH has to be specifically addressed with randomized clinical trials in these pain states. The features of these two formulations improve the already favorable profile of aspirin in headache management: a very good efficacy profile, as confirmed by many clinical trials and subsequent meta-analyses [107], comparable to that of the other medications employed for headache management, as reported in Table 3; the ability to rapidly restore patient functionality [90,91]; the lower use of rescue medications if compared to other type of interventions [115]; the lower cost associated to the medication [117] and, finally, the favorable safety profile observed with patterns of assumption similar to those typical of headache management [55,57] and specifically confirmed by studies in migraine and TTH [58]. To sum up, our recommendation is that, according to the many guidelines published for the management of primary headaches, aspirin should be considered as first-line therapy for both migraine and TTH [118-120]. Particular attention should be paid to the choice of the formulation, which should also take into account patient preference. Dry



granules and micronized tablets, for their portability and quick action, should be considered the preferred option when aspirin is considered for the attack therapy of primary headaches.


Acknowledgements PM and ML conceived the study; ML drafted the manuscript; PM, LDA and AN revised the manuscript. All the authors approved the final version of the manuscript. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest P Martelletti received honoraria, research grants and educational funds from Allergan, ACRAF, Bayer, Nevro Corporation, St Jude, Pfizer. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. J Perinat Med 2014. [Epub ahead of print]

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Affiliation Marzia Lecchi1, Lidia D’Alonzo2, Andrea Negro3 & Paolo Martelletti†2,3 † Author for correspondence 1 University of Milan, Department of Biotechnology and Biosciences, Bicocca, Milan, Italy 2 Sant’Andrea Hospital, Regional Referral Headache Center, Via di Grottarossa 1035, 00189 Roma, Italy Tel: +39 06 33775111; Fax: +39 06 33775110; E-mail: [email protected] 3 Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy

Cooper SA, Voelker M. Evaluation of onset of pain relief from micronized


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Safety, tolerability and pharmacokinetics of MCI-186 in patients with acute ischemic stroke: new formulation and dosing regimen.

New formulation of old aspirin for better delivery.

[New formulation with improved pharmacokinetics].

Neurostimulation in the treatment of primary headaches.

Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy.

Pharmacokinetics of nifedipine derived from a new retard tablet formulation.

A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extended-release aspirin formulation.

Pharmacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans.

Pharmacokinetics of sodium fusidate after single and repeated infusions and oral administration of a new formulation.

The iontophoretic transdermal system formulation of sumatriptan as a new option in the acute treatment of migraine: a perspective.

Treatment of cluster headaches.

A systematic review of aspirin in primary prevention: is it time for a new approach?

Physicochemical stability of a new topical timolol 0.5% gel formulation for the treatment of infant hemangioma.

Zolmitriptan for acute migraine headaches in adults.

Eletriptan for acute migraine headaches in adults.

Combination of a new oral anticoagulant, aspirin and clopidogrel after acute coronary syndrome: new therapeutic standard?

Safety of IPX066 , an extended release carbidopa-levodopa formulation, for the treatment of Parkinson's disease.

Aspirin as Primary Prevention of Acute Coronary Heart Disease Events.

Intravenous magnesium as acute treatment for headaches: a pediatric case series.

Aspirin for the treatment of recurrent toxaemia.

The multimodal treatment in headaches.

Neurophysiologic peculiarities of pediatric primary headaches.

Loxapine inhalation powder (adasuve): a new and innovative formulation of an antipsychotic treatment for agitation.

Aspirin for primary prevention of cardiovascular disease.