Open access peer-reviewed chapter

Risk-Benefit Events Associated with the Use of Aspirin for Primary Prevention of Cardiovascular Disorders

By Deepak Kumar Dash, Vishal Jain, Anil Kumar Sahu, Rajnikant Panik and Vaibhav Tripathi

Submitted: December 11th 2019Reviewed: June 29th 2020Published: December 2nd 2020

DOI: 10.5772/intechopen.93286

Downloaded: 73


Aspirin had been introduced as a nonsteroidal anti-inflammatory molecule. As further research on aspirin started, other therapeutic effects have been revealed. Now, this molecule has become the polychrest in medical science. Aspirin has served as a drug of choice for the primary prevention of cardiovascular disease (CVD) for the last few decades. However, recent trials have raised questions on the use of aspirin for CVD prevention due to some life-threatening adverse drug events. In spite of that, outcomes of trials will surely assist to frame a guideline for anoxic administration regimen of aspirin in order to prevent CVD.


  • aspirin
  • CVD
  • clinical trial
  • adverse drug events

1. Introduction

In 1859, Hermann Kolbe was paved the foundation for the development of Aspirin moiety for clinical practice. Whilst, there were no scientific resemblance established for aspirin as medicine [1]. After a long laboratory modification Felix Hoffman had succeeded to evolve the finest, clinical molecule by means of acetylation. Clinical investigation had passed the salicylate compound with intended therapeutic effects with no or minimum side effect. Clinicians had accepted this molecule open handedly. On February 1, 1899 Aspirin is registered as an authentic molecule (Figure 1) [2]. Currently, aspirin has become renowned and huge blockbuster molecule as NSAIDs followed by primary prevention of CVD [3].

Figure 1.

First container of aspirin.

2. Chemistry of aspirin

Production of aspirin is completed as single chain reaction. Acidic and alkaline both medium are suitable for synthesis. In chemistry language, aspirin is produced by the mixing of salicylic acid and acetic anhydride with the aid of phosphoric acid. Acetylsalicylic acid possesses three functional groups, namely hydroxyl, acetyl and ester. It is due to the presence of hydroxyl group polarity index of salicylic acid is high than that of aspirin. The reaction equation is displayed (Figure 2) [4].

Figure 2.

Production reaction.

Aspirin is an O-acetyl derivative of salicylic acid (ASA—acetylsalicylic acid) and its dominant mechanism of action is believed to be through the transfer of this acetyl group to (▬OH) and amino (▬NH2) functionalities present in biological macromolecules as depicted in Figure 3. The acyl ester group is also unstable under basic conditions, and its hydrolysis to acetate is believed to proceed by a general base-assisted mechanism as described previously [5, 6]. More recent computational studies have suggested an n→π* interaction between the aromatic carboxylic acid and the carbonyl carbon of the acetate group [7]. This is consistent with a nuclear magnetic resonance spectroscopy (NMR) study [8], which posits the formation of a cyclic hemi-orthoester under basic conditions which can rearrange to give either the parent aspirin anion or a mixed anhydride.

Figure 3.

Chemical reaction at molecular level.

Although the prevalence and role of the mixed anhydride in the biochemistry of aspirin has yet to be determined, the broad scope of anhydride reactivity may help to explain promiscuous acetylation activity of aspirin in biological systems [9, 10]. Interestingly, it has also been shown that the mixed anhydride can react with the primary amino group of glycine in organic solvents to form N-salicyloylglycine, suggesting a second class of aspirin-mediated protein modifications [11]. The nonselectivity of aspirin-mediated acetylation was demonstrated by Richard Farr and co-workers in 1968 [12]. In these experiments, aspirin labeled with 14C at the acetyl carbonyl carbon was incubated with a series of blood proteins as well as common enzymes and nucleic acids. Following dialysis, substantial radiolabeling of albumin, immunoglobulins, α-macroglobulin, and other enzymes was observed. More recent mass spectrometry-based studies have validated this initial finding and the list of proteins acetylated by aspirin has grown to include histones, IKKβ (I-kappa-β-kinase beta), and many others [13]. At high concentrations (micromolar to millimolar), aspirin has been shown to react with nucleophilic groups on proteins resulting in irreversible acetylation. These include the functional groups of the residues lysine (▬NH2), arginine (▬NH2), serine (▬OH), threonine (▬OH), tyrosine (▬OH), and cysteine (▬SH) [31, 32]. Synthesis of 13C- or 14C-labeled aspirin has also facilitated the real-time analysis of acetylation of ubiquitin, hemoglobin, and human serum albumin [14].

3. Pharmacokinetics of aspirin

After absorption, as acetylsalicylic acid is rapidly converted to salicylic acid by hydrolysis and first-pass metabolism, peak plasma concentrations of acetylsalicylic acid are extremely sensitive to minor variations in solid dosage form dissolution and disintegration. In contrast, plasma concentrations of salicylic acid are predictable and relatively stable [15].

3.1 Absorption

Absorption of salicylate occurs rapidly by passive diffusion of un-ionized lipophilic molecules from the stomach at the low pH of the milieu. Aspirin (pKa 3.5) and salicylic acid (pKa 3.0) are weak acids, being 99% un-ionized at pH 1 and able to diffuse through lipid membranes. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration; this latter factor being maximal in alkaline pH. Although aspirin can spontaneously hydrolyze, this is slow so that there is little or no free salicylate in the intestine and it is absorbed as aspirin rather than salicylic acid. A complete picture of absorption track of aspirin is represented in Figure 4 [16]. Approximately 70% of aspirin reaches the peripheral circulation intact with maximum serum concentrations observed at 25 min after administration. After entering the bloodstream, aspirin undergoes enzymatic hydrolysis to yield acetate and salicylic acid. The major enzymes hydrolyzing aspirin in plasma are believed to be cholinesterases [17]. Acetylhydrolase-I, an intracellular erythrocyte platelet-activating factor, has been characterized as the major aspirin hydrolase of human blood [18].

Figure 4.

In vivo reaction of aspirin.

Intravenous aspirin has a distribution half-life of about 3 min and inhibits prostaglandin biosynthesis within 5 min of administration, reflecting the rapid onset of inhibition compared to oral dosing [19].

Recent studies by Lichtenberger et al. demonstrated that aspirin could enter the lymph fluid directly when administered intragastrically or intraduodenally, potentially increasing its pharmacologic activity as a chemopreventive agent for colorectal cancer [20].

Rectal absorption of salicylate is also possible and cutaneous absorption may occur from salicylate containing rubefacients. Following oral administration of an aqueous solution, the absorption kinetics of aspirin is found to follow a first-order process [21].

The factors affecting absorption of salicylate are Rate of gastric emptying volume of food, pH of stomach contents, nervous state, concurrent drugs, exercise, posture, formulation and Disease states associated with altered gastrointestinal transit time.

3.2 Distribution

Once absorbed, salicylates are distributed extensively through body fluids. Reported values for the apparent volume of distribution (Vd) of salicylate range from 9.6 to 12.7 L in adults with similar values (0.12–0.14 L/kg) in children [22].

Both aspirin and salicylic acid are partially bound to serum proteins. The distribution of aspirin is further enhanced by binding to human serum albumin [23, 24]. Human serum albumin is the most abundant protein found in blood and is often used as a plasma shuttle for steroids, hormones, and other small molecules. Binding studies suggest a conformational change in albumin upon acetylation that can influence transport and metabolism of other critical metabolites and drugs. For example, aspirin-induced acetylation of albumin can inhibit glucose binding [25], while increasing the binding of other molecules, as observed with the increased affinity of acetylated albumin for the marker anion acetrizoate [26]. Aspirin’s pharmacodynamic is also influenced by the interaction of other metabolites and serum albumin [24]. However, aspirin acetylation of serum albumin likely inhibits the binding of other metabolites commonly transported by albumin. In vitro studies have shown serum albumin binding and acetylation is dependent upon fatty acid binding, pH and temperature [27].

Both salicylic acid and aspirin have been found to diffuse slowly into the cerebrospinal fluid (CSF) due to the high degree of ionization of salicylic acid at the pH (7.4) of plasma. Salicylic acid readily crosses the placenta, fetal plasma concentrations being higher at birth than concurrent maternal concentrations [28].

3.3 Metabolism and excretion

Aspirin is rapidly converted to salicylic acid with a half-life of only 15–20 minutes [19]. This hydrolysis is due to nonspecific esterases found in many body. The acetyl component of aspirin after oral and intravenous dosing is found in gastric mucosal cells or is excreted as carbon dioxide after passing through the Krebs cycle [29]. During absorption, aspirin esterase activity in the gastrointestinal mucosal membranes contributes 28–35% of the hydrolysis of aspirin; though the activity of esterase enzyme may vary in relation to age and gender. Aspirin esterase activity is reduced in patients with alcoholic liver disease [17].

The major route of elimination of aspirin is through its hydrolyzed product salicylic acid. Salicylic acid is cleared from circulation via the kidneys with a serum half-life of approximately 2 h. A summary of the most common reactions of aspirin in biological systems are summarized in Figure 5.

Figure 5.

Reactivity of aspirin in different biological environments of proteins.

Salicylic acid is partly excreted unchanged and partly metabolized. Free salicylic acid diffuses readily across the glomerulus and is also actively secreted by the proximal tubule. The conjugates of salicylic acid are also excreted via kidney, being dependent on glomerular filtration and tubular secretion. The hydroxylated metabolite gentisic acid is excreted in the same way as free salicylic acid [30].

4. Pharmacodynamics of aspirin

The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti-inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process; aspirin might be used based on the induction of ATL [31].

The COX-inhibitory activity of aspirin is contingent on the administered dose. Low doses, those ranging from 75 to 300 mg, result in selective inhibition in platelet TXA2 production without suppressing prostacyclin (PGI2), a common platelet antagonist and vasodilator. PGI2 is expected to be derived mainly from vascular COX-2 suggesting that COX- 2 inhibition is minimal in the low-dose regime. Increased doses (>1200 mg) have analgesic and anti-inflammatory properties, properties associated with the pathophysiological inhibition of COX-1 and COX-2. It is important to note that COX- 2 can also utilize arachidonic acid for synthesis of lipoxins, particularly 15-hydroxyeicosatetraenoic acid [32, 33]. It is unlikely that the COX-2 is more than 5% acetylated while platelet-derived COX-1 is likely to be >70% acetylated. This suggests that regular low-dose aspirin will invariably maintain COX-1 inhibition in circulating platelets, with minimal effect in the inhibition of peripheral COX-2 [34].

A summary of the pharmacodynamic action of aspirin is summarized in Figure 6 [35, 36].

Figure 6.

Pharmacodynamics of aspirin.

5. Pharmacological action of aspirin

5.1 Therapeutic effects

Beneficial clinical impaction of aspirin is mainly anti-inflammatory and anti-pyretic action. Evidence suggests that aspirin is a better analgesic than salicylic acid [37, 38]. The analgesia produced by aspirin is dose-dependent, although the response does not parallel serum aspirin concentrations [39]. The dose of aspirin required for its antipyretic action is less than that required for analgesia [40].

The generally accepted therapeutic plasma concentration range of salicylate for the treatment of chronic inflammatory disease is 15–30 mg/100 ml (150–300 mg/L or 1–2 mmol/L), requiring daily doses in excess of 3 g [41].

Other indications for aspirin use are angina pectoris, angina pectoris prophylaxis, ankylosing spondylitis, cardiovascular risk reduction, colorectal cancer, ischemic stroke, ischemic stroke (prophylaxis), myocardial infarction, myocardial infarction (prophylaxis), osteoarthritis, revascularization procedures (prophylaxis), rheumatoid arthritis and systemic lupus erythematosus [42].

5.2 Adverse effects

The most common side effect of aspirin is gastrointestinal upset ranging from gastritis to gastrointestinal bleed. Other adverse effects are as followed:

5.2.1 Hypersensitivity

Excessive sensitivity to NSAIDs is normal among everyone. The rate is about 1–2%. Unwanted effects could be as gentle as a simple rash to angioedema and hypersensitivity. In case of asthmatic or interminable rhino-sinusitis patients, the predominance of these allergic susceptible indications could be as high as 26%. In the event that this is joined by nasal polyps and inflammation of the respiratory tract with eosinophils, it is known as aspirin triad. NSAID-exacerbated respiratory malady (NERD) is new term related with this disorder because of upper just as lower respiratory mucosal inflammation [43].

5.2.2 Reye syndrome

Reye condition, named after the Australian pathologist, Dr. R.D. Reye was first portrayed in 1963. It is an uncommon yet deadly condition with an expected death pace of somewhere in the range of 30% and 45%. It is a type of encephalopathy auxiliary to fatty changes in an otherwise healthy liver. The clinical vignette of Reye disorder comprises a viral infection of upper respiratory tract disease in kids and corresponding ingestion of aspirin for the treatment of fever. It is imagined that mitochondrial injury is optional to the previous viral disease which is the main hit to both the liver and the cerebrum. Aspirin or similar medicine gives the subsequent hit finishing the disorder. The occurrence has significantly diminished because of better mindfulness and utilization of acetaminophen for the treatment of fever in kids rather than aspirin. Despite the fact that the relationship between aspirin and Reye condition exists, a few authors contend that during diagnosis, salicylate levels were not routinely checked, biopsies were not acquired, and hereditary/intrinsic blunders of metabolism were not precluded [44, 45].

5.2.3 Intracerebral hemorrhage

Aspirin increases the risk of intracranial bleeding versus placebo [46].

5.2.4 Nephrotoxicity

Previous studies have shown conflicting results about the use of aspirin and the risk of chronic kidney diseases. Some earlier studies have shown that the use of aspirin is associated with chronic kidney disease [47].

5.2.5 Bleeding

Aspirin makes 2 3-crease increment in the danger of dose related peptic ulcer bleeding, a hazard that does not appear to be diminished by the utilization of enteric-covered aspirin. Sung et al. demonstrated that among people who had peptic ulcer blood loss, constant low-dose aspirin utilize expanded the danger of repetitive bleeding yet brought about lower overall cardiovascular and cerebrovascular mortality rates [48].

5.3 Contraindication

Aspirin is contraindicated in patients who salicylate sensitive, hemophilic, in peptic/bleeding ulcers, in children suffering from chicken pox or influenza. Cautious use is desirable in patients with anemia, impaired hepatic or renal functions, and asthma and in pregnant or nursing mothers. It should be avoided in diabetics with low cardiac reserve or frank CHF and in juvenile rheumatoid arthritis [49].

5.4 Drug interactions

Aspirin displaces warfarin, naproxen, sulfonylurea, phenytoin and methotrexate from binding sites. It antagonizes uricosuric action of probenacid. It blunts diuretic action of furosemide and thiazides and reduces the action of spironolactone. Aspirin reduces protein bound iodine levels by displacement of thyroxine; but hypothyroidism does not occur [50].

6. Role of aspirin in CVD

Efforts were being done for decades to prevent and treat cardiovascular disease (CVD). By the twentieth century, CVD had become a major cause of mortality and morbidity, and many efforts were being made to prevent it worldwide [51, 52, 53].

Given the prevalence of CVD, several strategies are being considered for its prevention, including lifestyle changes as well as strict management of cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia, and metabolic syndrome. In addition to traditional methods, other alternative methods have also been studied for its prevention. Along with this, some exploiters have used aspirin for the prevention of CVD, and with some controversy, it is believed that aspirin is beneficial in the primary prevention of CVD [54, 55].

Today aspirin is widely used for the primary prevention of CVD. In the United States alone, 40% of adults over the age of 50 are using aspirin for the prevention of CVD [56]. Aspirin is an irreversible and nonselective cyclo-oxygenase (COX) inhibitor class of drug, whose work is to reduce thromboxane A2 production and inhibit platelet aggregation and vasoconstriction. The ability to prevent platelet aggregation provides the potential to reduce arterial thrombosis, and when used at low doses, it is beneficial in preventing myocardial infarction (MI) and stroke. On the other hand, aspirin also inhibits the production of prostaglandin as well as reducing the side effects of GI bleeding by inhibiting COX 1 and protecting the gastrointestinal (GI) mucosa [57]. It has been assessed through successive clinical trials that aspirin is effective in the prevention of CVD. A number of tests have been performed to demonstrate its efficacy and it has been found that it is beneficial in secondary prevention of CVD even in patients with previous MI or ischemic stroke and at high risk [58].

7. Risk factors

Recently, the publication of a number of studies has raised doubts about the benefits of using aspirin as a primary prevention for patients with moderate cardiovascular risk. Three of the trials were published in 2018, A Study of Cardiovascular Events in Diabetes (ASCEND), Aspirin in Reducing Events in the Elderly (ASPREE), and ARRIVE.

The ASCEND study assessed the effectiveness and safety of aspirin use by arbitrarily assigning 14,480 diabetic patients into 100 mg aspirin or placebo teams and observing them for a median of 7.4 years. Internal hemorrhage has emerged as a haul within the safety assessment. All major bleeding during this study was 29% higher with the aspirin administration cluster and a high risk of bleeding was seen in patients with a high risk of vascular events. This study has concluded that aspirin use prevented serious vascular events in patients who had diabetes and no previous CVD, however this absolute profit was for the most part balanced by the same rate of bleeding hazard [59].

In the ASPREE trial, old patients aged 70 or above who did not have CVD, dementia or disability were randomized and given 100 mg aspirin or placebo at a median of 4.7 years of follow-up. Contrary to other studies that established the incidence of CVD as the primary endpoint, ASPREE evaluated all causes of death, dementia, and chronic physical incapacity as primary endpoints. Moreover, apart from other studies, the ASPREE study evaluated the cause of mortality. Death from any cause was 12.7 per 1000 person within the aspirin group and 11.1 per 1000 people within the placebo group with a considerably accrued risk in the aspirin cluster. However, the incidence of CVD was 10.7 within the aspirin and 11.3 within the placebo teams per 1000 person-years, which indicated there was no distinction between trial groups. They completed that once aspirin was taken for the first purpose of preventing CVD in healthy old subjects without CVD, there was no profit, but the risk of bleeding was larger and also the death rate was higher. Thus, the study has proposed that aspirin is not a significant prescribing agent as a practice in order to prevent CVD for healthy old individuals. The fascinating purpose of this study is that they enclosed insanity as a primary and secondary outcome as a result of there have been some previous suggestions that aspirin will scale back vascular insanity or physical inactivity by decreasing cerebral events [60, 61].

The ARRIVE was a randomized sort of trial, conducted with 12,545 patients of 55 years (men) or 60 years (women) and older people (mean age 63.9); who had a median cardiac risk to receive 100 mg aspirin or placebo for 60 months of follow-up. They restricted the patients who were at high risk of bleeding and diabetes. The first terminus (MI, stroke, cardiovascular death, unstable angina or TIA) occurred in 4.29% of patients within the aspirin cluster versus 4.48% of patients within the placebo teams. One of the significant the protocols to note within the ARRIVE trial is that the genuine cardiovascular event rate was less than the anticipated cardiovascular rate. This implies that the cluster concerned within the ARRIVE trials managed the CVD risk issue higher than within the former trials [62].

Thirteen randomized controlled trials comprising 164,225 patients were observed. The danger of all-cause and cardiovascular mortality was similar for both aspirin and control teams. Aspirin reduced the relative risk (RRR) of major adverse cardiovascular events (MACE) by 9%, myocardial infraction by 14%, and cerebrovascular accident by 10 percent, however was related to a 46% relative risk increase of major bleeding events as compared with controls. Aspirin use did not transform into a net clinical profit adjusted for event connected with mortality risk. There was associate degree interaction for aspirin impact in 3 patient subgroups: (i) in patients with statin drug treatment, aspirin was related to a 12% RRR of MACE and this impact was lacking within the no-statin group; (ii) in nonsmokers, aspirin was related to a 10% RRR of MACE and this impact was not observed in smokers; and (iii) in males, aspirin resulted in a 11% RRR of MACE with a nonsignificant impact in females. Aspirin use does not scale back all-cause of cardio vascular mortality associated with insufficient profit risk quantitative relation for CVD prevention. Nonsmokers, patients treated with statins, and males had the best risk reduction of MACE across subgroups. Systematic review registration: PROSPERO CRD42019118474 [63].

A systematic search of PubMed and Embase was conducted with the assistance of Antithrombotic Trialists’ (ATT). A set of thirteen trials randomizing 164,225 participants with 1,050,511 participant-years of follow-up were enclosed. The median age of trial participants was 62 years, 19 had diabetes along with the median baseline risk of the primary cardiovascular outcome was 9.2%. Aspirin use was related to important reductions within the composite cardiac outcome compared with no aspirin (57.1 per 10,000 participant-years with aspirin and 61.4 per 10,000 participant-years with no aspirin). Aspirin use was related to elevated degree accrued risk of major bleeding events compared with no aspirin (23.1 per 10,000 participant-years with aspirin and 16.4 per 10,000 participant-years with no aspirin). The administration of aspirin in without cardiovascular disease was related to a lower risk of cardiovascular events associated with an accrued risk of major bleeding. This data may be helpful to aware the patients concerning aspirin use for primary prevention of cardiovascular events and bleeding [64].

Another meta-analysis was performed in concurrence with the well-liked coverage things for Systematic Reviews and Meta-Analyses (PRISMA) tips. Electronic databases were explored for randomized trials that compared aspirin vs. placebo (or control) in subjects while not established atherosclerotic disease. The first efficaciousness outcome was all-cause mortality, whereas the first safety outcome was major bleeding. Outline estimates were reported employing a Der Simonian and Laird random effects model. A set of 11 trials with 157,248 volunteers were enclosed. At a mean follow-up of 6.6 years, aspirin was not related to a lower incidence of all-cause mortality. However, aspirin was related to high degree accrued incidence of major bleeding and intracranial bleeding. The same impact on all-cause mortality and major hemorrhage was incontestable in diabetic and high cardiovascular risk patients (i.e. 10-year risk >7.5%). Aspirin was related to a lower incidence of cardiac muscle infarction; but, this outcome was characterized by extensive heterogeneousness, and this impact was not evident upon limiting the analysis to the more modern trials. Trial ordered analysis confirmed the shortage of good thing about aspirin for all-cause mortality up to a relative risk reduction of 5%. Aspirin use among healthy people while known arterial sclerosis seems to be related to accrued damage and lack of mortality benefit. During this setting, aspirin is probably related to a considerable reduction in MI risk; but, this comes at a value of accrued major bleeding and together with intracranial hemorrhage. The routine use of aspirin for primary prevention has to be reconsidered [65].

8. Guideline for prevention of CVD

The most significant approach to forestall atherosclerotic vascular malady, cardiovascular breakdown, and atrial fibrillation is to advance healthy routine all through life. A group based consideration approach is a compelling technique for the avoidance of cardiovascular malady. Clinicians ought to assess the social determinants of wellbeing that influence people to advise treatment choices. Grown-ups who are 40–75 years old and are being assessed for cardiovascular illness prevention ought to experience 10-year atherosclerotic cardiovascular disease (ASCVD) hazard estimation and have a clinician–patient risk conversation before beginning on pharmacological treatment, for example, antihypertensive treatment, a statin, or aspirin [66].

To adjust the advantages and dangers, earlier US guidelines have suggested prophylactic aspirin medicine just in the setting of raised ASCVD risk (eg, as determined estimators like the PCE (Personal Care Evaluation) or dependent on the nearness of explicit ASCVD risk elements). Meta-relapse investigations of recorded trials show that watched ASCVD chance tracks sensibly well with standard assessed ASCVD hazard. Interestingly, noticed bleeding risk on aspirin medicine is less very much related with baseline evaluated ASCVD risk. (A nonthorough rundown of situations related with expanded danger of bleeding incorporates: a history with past gastrointestinal bleeding or peptic ulcer malady or seeping from different parts of body, age > 70 years, thrombocytopenia, coagulopathy, and simultaneous utilization of different prescriptions that provoke bleeding danger, for example, nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin.) In this unique circumstance, post hoc investigation of more established trials recommends that the benefit–risk proportion for prophylactic; aspirin medicine commonly turns out to be progressively great at >10% evaluated 10-year ASCVD risk [67].

Notwithstanding, the overall advantages of aspirin, explicitly in preventing nonmorbid MI and maybe stroke (with a pattern to bring down mortality) have been less apparent in later trials. Thus, in these ongoing preliminaries, the assessed ASCVD chance has for the most part surpassed the real hazard saw during development. This ongoing information are the justification for the lower COR for prophylactic aspirin in the current protocol (Class IIb) and the evacuation of a particular PCE risk threshold as an incorporation basis for aspirin. These progressions mirror the need to rather consider the totality of accessible proof for ASCVD chance [inclusive, where proper, of hazard improving components, for example, solid family ancestry of untimely MI, failure to accomplish lipid or BP or glucose targets, or huge rise in coronary artery calcium score [68]].

Recent, US guideline has recommended the use of prophylactic aspirin only in the clinically assessed parameters of elevated ASCVD risk as shown in Figure 7.

Figure 7.

Recommendations as per guideline [69].

9. Future prospects

The totality of randomized proof since 2008, and 3 trials specifically revealed in 2018, no longer exhibits a decrease in cardiovascular mortality or all-cause death among primary prevention grown-ups with low-dose aspirin. The entirety of the examinations for aspirin medicine in primary avoidance, regardless of whether previously or after 2008, likewise exhibit overabundance draining risk. In this specific situation, it seems to be very conspicuous that daily dose of aspirin is not warranted for primary prevention of CVD [70].

This is with regards to current European guidelines recommendations but negates current US rules, where aspirin is still suggested if 10-year CVD chance is assessed to be >10%. Refreshed American Heart Association/American College of Cardiology guidelines for the primary avoidance of CVD, announced in March 2019, have brought down the help for primary prevention with aspirin medicine from a Class 1 sign among those at raised CVD hazard to a class 2b proposal among high risk grown-ups matured 40–70 years (aspirin is no longer suggested for primary prevention among those >70 years). The rule additionally underscores the need to initially treat other CVD hazard variables to target and afterward just that aspirin may be considered with regards to bring down nondeadly MI risk [71].

On the other hand, the consequences of ASPREE, ASCEND, and ARRIVE all repudiate the proposal that weight-based dosing parameter may have utility in primary prevention, since none of these trials discovered advantage for low-dose aspirin among people at low weight. Regardless of whether high-dose aspirin may have a role in some primary prevention grown-ups (eg, overweight) stays theoretical and difficult to legitimize dependent on current proof. A progressing trial utilizing a novel plan is the aspirin dosing: A Patient-Centric Trial Assessing Benefits and Long-term (ADAPTABLE) trial, which will analyze high against low dose aspirin in 15,000 secondary prevention patients. In the event that ADAPTABLE finds no advantage for high-dose aspirin medicine in auxiliary prevention, at that point the weight-based dosing of aspirin for primary prevention (regardless of whether it is low-or high-dose) will turn out to be significantly tougher to legitimize [72].

10. Conclusion

The advantage of aspirin for auxiliary avoidance of CVD is entrenched, with meta-examination results preferring low-dose (75–150 mg/d) over high-dose (>150 mg/d) aspirin administered comparative viability yet lower bleeding danger. Conversely, the role of aspirin medicine in primary CVD counteraction is progressively questionable; though chronicled clinical evaluation discovered aspirin as a best alternative for PCVD (Primary Cardio Vascular Disease) anticipation [73].

The need to alter aspirin dose as indicated by weight has physiological credibility. For instance, aspirin requires de-acetylation to get dynamic, and pharmacokinetic contemplates have discovered that pudginess is related with improper treatment regimen response to aspirin medicine, as surveyed by thromboxane hindrance.

A 2018 meta-examination by Rothwell et all, which incorporated 9 clinical examination of aspirin for primary prevention (counting 103,000 volunteers) and 4 trials of secondary prevention of stroke (17,000 volunteers), detailed that the viability of aspirin at a dose of ≤100 mg in lessening cardiovascular occasions diminished with expanding weight, with advantage found in patients weighing 50–69 kg yet not in those weighing 70 kg or more. Reliable with this, low-dose of aspirin medicine possibly expanded danger of bleeding when bodyweight was <90 kg. On the other hand, aspirin (≥325 mg) had the contrary interaction with body weight, diminishing cardiovascular occasions exclusively among those >70 kg [62, 74].

In spite of the debate over the security and efficacity of aspirin, low-dose of the medicine has been broadly utilized for the primary prevention of CVD. As indicated by the investigation of National Health and Nutrition Examination study information, 22.5% of patients without a mitigated CVD were delegated as high risk, and 40.9% of them were advised to take aspirin by their health care professional. Likewise, 26.0% of individuals at low risk were advised to take the medicine paying little mind to their risk category [75].

Recently, questions have been raised about the administration of aspirin medicine for primary avoidance of CVD. Specifically, there are worries that GI bloodletting and hemorrhagic stroke, side-effects that can appear in adults utilizing aspirin, are expanded [76]. Whether the advantages of aspirin in the avoidance of CVD exceed the dangers related with side-effects is at the core of the discussion. One of the significant explanations behind the change in perspective about aspirin use is a decrease in the overall frequency of CVD.

As per European CVD measurements in 2017 distributed by the European Heart Network, CVD mortality and the age-standardized pervasiveness pace of CVD are currently falling in most European nations. Besides, from 1975 through to 2019, mortality rate from CVD have fallen in US men and women [77]. Globally, the age-standardized disability adjusted life-years (DALY) rates (per 100,000) in 2005–2015 for CVD diminished from 6231.9 to 5179.7 [78].

The considerable decrease of CVD death and frequency is because of improved prevention treatments, which deal with the principle risk components of CVD, for example, smoking, physical idleness, dyslipidemia, and hypertension. Moreover, the adjustment of overall routine of life, for example, weight reduction or regular physical exercise, has become popular [79].

Moreover, current prescription use, for example, statins, new anticoagulation agents, and hypertensive medications, has added to lessening the CVD chance for the whole populace [80]. The extent of the risk decrease by aspirin in CVD primary prevention relies upon the level of profound risk in the people [81].

A few examinations have demonstrated that if a patient’s danger of CVD increments (above 1% every year), the advantage of administering aspirin medicine as primary prevention is additionally expanded. Hence, the overall CVD risk decrease brought about by another preventive methodology appears to lessen the primary prevention of aspirin for CVD contrasted with previously. The way that the cardiovascular occasion rates for all patients who took an interest in the recent published Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) clinical investigation was lower than anticipated additionally underpins this hypothesis [62]. Rather than the ongoing diminishing in the effectiveness of aspirin for the primary counteraction of CVD, the bleeding danger related with aspirin medicine still exists [82].

In numerous investigations, it is notable that the application of low-dose aspirin was related with an essentially expanded risk of significant bleeding occasions. It is flawed whether the utilization of aspirin medicine for CVD primary prevention will have a critical impact when contrasted with the danger of aspirin in the current time. Ongoing patterns have seen that the utilization of aspirin for primary prevention of CVD is reducing in the United States. In this way, it is important to consider whether it is suitable to proceed with aspirin for the primary avoidance of CVD in every patient [83].

Numerous hypotheses have been taken into account regarding why low-dose aspirin no longer seems effective in primary prevention. These encompass a reducing return for efficacy with regards to contemporary consideration (e.g., smoking suspension, statins) and the likelihood that one aspirin medicine dose may not “fit for all” patients.

In this chapter, we sum up proof for and against aspirin dosing in primary prevention, place this proof with regards to current published aspirin clinical trials, and provide refreshed clinical guidance for aspirin use in the primary prevention of CVD in the year 2020 and beyond.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Deepak Kumar Dash, Vishal Jain, Anil Kumar Sahu, Rajnikant Panik and Vaibhav Tripathi (December 2nd 2020). Risk-Benefit Events Associated with the Use of Aspirin for Primary Prevention of Cardiovascular Disorders, Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications, Farid A. Badria, IntechOpen, DOI: 10.5772/intechopen.93286. Available from:

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