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The Patient’s Benefit With Low Dose Acetylsalicylic Acid Treatment


Background

Cerebrovascular disease (CVD) contributes considerably to the escalating costs of healthcare in Europe and the USA and accounts for 15% of the total healthcare costs. CVD results in substantial disability, lost of productivity, a marked reduction in quality of life, and is the main cause of morbidity and mortality in the adult Western population.1 The World Health Organization estimates that, by 2020, a further 25% of healthy life-years will be lost to CVD, making it largest single cause of disease burden. Approximately 50% of first CVD events are fatal, and estimates suggest that 30-40% of acute coronary events occur without prior warning in people who are unaware that they have CVD. There is no doubt that effective preventive strategies are essential to reduce the global burden of CVD. According to the recent information, approximately 25% of the reduction rate of death from coronary heart disease that has occurred during the past 30 years can be explained by the practice of primary prevention.2
At the core of primary prevention lies the concept of risk reduction. The five major risk factors associated with an increase in the incidence of CVD are diabetes mellitus, hypertension, hypercholesterolaemia, cigarette smoking, and family history. Atherosclerosis and vascular thrombosis are major contributors to CVD, and it is generally accepted that platelets also have an essential role to play. Individual with diabetes are 2-4 times more likely to develop CVD than individuals without diabetes. A major mechanism is increased synthesis of platelet thromboxane (TXA2) – a potent vasoconstrictor and platelet aggregant. Investigators have found evidence in vivo of excess TXA2, release in type 2 diabetic patients with CVD. Hypertension has been shown to increase the risk of stroke, coronary heart disease, death or nonfatal myocardial infarction. The World Health Organization has shown that hypertension causes approximately 50% of all cases of coronary heart disease worldwide. CVD is multifactorial origin and, when estimating the CVD risk for an individual, it is important to consider all risk factors simultaneously 2

Thromboembolic Disease, Why is ASA so Important?

Risk factors can cause damage to the innermost layer of an artery. This results in atherosclerosis, a complex and progressive disease that begin early in life and ultimately leads to cardiovascular disease. Atherosclerosis results in the formation of fatty streaks consisting of foam cells, which can be lipid-laden macrophages or smooth muscle cells in the inner lining of an artery. This build-up is called a plaque. Plaques lead to a spectrum of clinical disorders ranging from asymptomatic atherosclerosis, angina pectoris, myocardial infarction and stroke, to vascular forms of renal failure. With time, the plaques may become brittle and rupture, leading to a cascade of events that includes platelet adhesion, activation, aggregation, and a subsequent thrombus (blood clot) formation. The clot may further narrow and even occlude the artery. A portion or all of a thrombus may break loose and travel through the bloodstream until it lodges in another vessel. It is then known as an embolus and cause a blockage or occlusion in the end vessel.3
A key factor in thrombus development is platelet aggregation, and because Acetylsalicylic Acid (ASA) is a safe and effective antiplatelet and anti-inflammatory agent, there is a strong rationale and strong clinical evidence for its use in primary prevention. Platelet aggregation plays a pivotal role in the development of thrombosis. A key factor is the interaction between platelets and the vessel wall following arterial injury. This is regulated by the dynamic between the prostaglandin thromboxane A2 (TXA2) and prostacyclin (PGI2). ASA exerts its effect primarily by interfering with the biosynthesis of TXA2, PGI2, and other prostaglandins. These are generated through the enzimatically catalysed oxidation of arachidonic acid - a fatty acid derived from membrane phospholipids – by cyclo-oxygenase (COX). COX has two isoforms, COX-1 and COX-2. ASA inhibits COX and provides an antiplatelet effect by irreversibly binding its acetyl residue to the active centre of COX-1 in platelets. In doing this, ASA blocks the mechanism required to generate TXA2, which has strong aggregating and vasoconstricting effects.3
The defect induced by ASA cannot be repaired during their life span (7-10 days), because platelets are anucleated and unable to synthesis new COX. After treatment with ASA is stopped, COX activity recovers slowly, as a function of platelet turnover. This explains how a drug with a 20-minute half life in the systemic circulation can be fully effective as an antiplatelet agent when administered once daily.3
ASA improves endothelial function. Treatment with low-dose ASA can restore endothelial-dependent vasodilatation in hypertensive patients, possibly via increased nitric oxide (NO) production. ASA facilitates the inhibition of platelet activation by neutrophils. In the presence of ASA, neutrophils significantly inhibit thrombin-induced platelet activation, possibly by means of an NO/cyclic guanosine monophosphate (cGMP)-related pathway.4
ASA is a potent scavenger of hydroxyl radicals and protects the endothelial cells of the vascular wall from damage by free radicals. It produces a 5-fold increase in ferritin generation, which protects cell from the damaging oxidative and inflammatory influences of the free iron in cellular plasma. This observation also explains the fact that ASA increases the resistance of inner vascular walls to damage caused by oxidation, protecting against the development of atherosclerosis and CVD.5
Inflammation may increase the risk of a first thrombotic event, and ASA can provide an anti-inflammatory protective effect to the vasculature. High level of C-reactive protein (CRP) are associated with an increased risk of myocardial infarction (MI) or stroke. A 56% reduction in the risk of a first MI among men with high CRP levels was observer following treatment with ASA compared with a 14% reduction among those with low CRP levels.6 This suggests that inflammation may increase the risk of a cardiovascular event and demonstrates that ASA has clinical benefits in preventing CVD.

ASA in the Primary Prevention of CVD – The Clinical Evidence

ASA in Healthy Individual
A randomized, placebo-controlled, double-blind trial was designed to evaluate whether low-dose ASA reduced the mortality caused by CVD. The trial involved 22,071 apparently healthy male physicians: 11,037 participants received ASA (325 mg every other day) and 11,034 participants received placebo. The participants were assessed by their response to questionnaires asking about the occurrence of any relevant cardiovascular events.
Total MI was significantly reduce by 44% in the group receiving low-dose ASA compared with those receiving placebo; non fatal MI was reduced by 41% in the ASA-treated group.7 Treatment with ASA resulted in significant reduction (18%) in the total number of severe vascular incidents (nonfatal MI, nonfatal stroke, vascular death) compared with placebo. In a subgroup analysis of 333 patients who had chronic stable angina but no history of MI, low-dose ASA was effective in reducing the risk of a first-time by 87%.8 A meta-analysis of five trials conducted in 53,000 patients with no previous CVD showed that treatment with ASA reduced the risk of a nonfatal MI and fatal coronary heart disease by 28%.9

ASA in the Primary Prevention of Ischaemic Heart Disease
A randomized trial of 5,499 men aged 49-69 years was conducted to evaluate the effectiveness of warfarin and low-dose ASA in the primary prevention of ischaemic heart disease (IHD). Initially 1,427 men were randomized to receive warfarin or placebo for a median of 1.1 years. Subsequently, 1.013 of these men entered the second phase of the trial, along with additional 4,072 men. In the second phase, participants received warfarin (4.1 mg/day) and ASA (75 mg/day), warfarin and placebo, ASA and placebo, or double placebo for a median of 6.8 years.
In individuals receiving low-dose ASA only, IHD was reduced by 20% compared with placebo; this was almost entirely owing to a 32% reduction in nonfatal events. Combined treatment with low-dose ASA and warfarin was more effective at reducing the incidence of IHD (34% reduction compared wit placebo) than either agent alone. Noncerebral bleed were almost frequent in the groups receiving warfarin only or warfarin and ASA than in group receiving ASA only (80 versus 53 versus 48 bleeds, respectively).10

ASA in Patients with Hypertension
A prospective study was conducted in 18,790 patients to assess the optimum target diastolic blood pressure and the potential benefit of low-dose ASA in the treatment of hypertension. Patients with diastolic blood pressure between 100-115 mmHg were assigned a target blood pressure: ≤ 90 mmHg, ≤ 85 mmHg, or ≤ 80 mmHg. Felodipine (5mg) was given as a baseline therapy with the additional of angiotensin-converting enzyme inhibitors or β-blockers in accordance with five-step regimen. Half of the patients received ASA (75 mg/day) and half received placebo.
ASA treatment significantly reduced major cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death) by 15 and the risk of all MI by 36% compared with placebo. Treatment with low-dose ASA (75 mg/day) significantly reduced the risk of an acute MI (by 36%) compared with placebo in hypertensive patients, resulting in the prevention of 1.5 MIs per 1,000 patients treated for 1 year. No increase in the incidence of cerebral haemorrhage was observed in patients treated with ASA compared with those receiving placebo (12 events in each group), confirming that ASA therapy does not enhance the risk of haemorrhagic stroke in hypertensive patients.11

ASA in Patients with Diabetes Mellitus
A double-blind, randomized, placebo-controlled trial was designed to assess the effects of ASA on mortality and the incidence of cardiovascular events in 3,711 patients with diabetes. Patients were randomly allocated to receive ASA (650 mg/day) or placebo.
The 5-year risk of fatal and nonfatal MI was significantly reduced by 27% in patients receiving ASA compared with those receiving placebo.12 In support of this, data from a study of 19,000 hypertensive patients showed that, in a subgroup of 1,501 patients with hypertension and diabetes, ASA (75 mg/day) could prevent 2.5 MIs per 1,000 patients treated for 1 year.11 Furthermore, in 22,071 apparently healthy male physicians, ASA (325 mg every other day) reduced the risk of fatal and nonfatal MI by 60% in individuals with diabetes compared with 44% in nondiabetic participants.7

ASA in Patients with Hyperlipidaemia and Elderly Patients
In a study of US male physicians with no history of MI, an analysis of individuals with hyperlipidaemia (defined as serum cholesterol >6.5 mmol/L) showed that ASA (325 mg, every other day) reduced the risk of a nonfatal MI by 41%. This study also showed that treatment with ASA, resulted in a 44% reduction in the risk of an MI, only effective in those aged >50 years.7
A prospective study of US nurse aged 34-65 years without a history of diagnosed coronary artery disease showed a 32% decrease in CVD in those who took one to six ASA tablet per week. This effect was seen only in those aged >50 years.13

ASA and the Risk of Intracerebral Haemorrhage
A meta-analysis was conducted of trials that involved participants who were randomized to ASA or a control treatment for at least 1 months, and in which the incidence of stroke subtype was reported. Data from 16 trials with 55,462 participants and 108 haemorrhagic stroke cases were analysed. The mean dosage of ASA was 273 mg/day and the mean duration of treatment was 37 months.
Treatment with ASA significantly reduced the risk of MI by 32% corresponding to an absolute reduction in the risk of an MI of 13.7 events per 1,000 patients treated. ASA therapy was associated with a significant reduction in the absolute risk of ischaemic stroke (3.9 events per 1,000 patients treated) and a small increase in the risk of a haemorrhagic stroke (1.2 events per 1,000 patients treated).14 In the HOT Study and the Primary Prevention Project, the incidence of haemorrhagic stroke was very low and almost as frequent in the control group as in the ASA group (15 versus 14 and 3 versus 2, respectively).11,15 These data show that the benefits of ASA use in preventing MI and ischaemic stroke clearly outweigh the possible risk of haemorrhagic stroke.

Benefit vs Harm of ASA Therapy
A meta-analysis of 5 primary prevention studies provides convincing evidence of the benefits of the long-term use of low-dose ASA in reducing the risk of a first MI. The meta-analysis provides the rationale behind the recent US Preventive Services Task Force (USPSTF) recommendation that supports the use of ASA for the primary prevention of cardiovascular events in high risk patients.
ASA reduced the risk of a nonfatal MI or fatal coronary heart disease (CHD) by 28% and the risk of fatal CHD by 13% in patients with no previous cardiovascular disease. This substantial benefit of ASA outweighs the possible harmful effects in patients at high risk of cardiovascular events. For example, for every 1,000 patients with a 5% risk of CHD events over 5 years, ASA will prevent 6-20 MIs, but might cause 0-2 haemorrhagic strokes and 2-4 episodes of gastrointestinal bleeding. The USPSTF concluded that the balance of benefit and harmful effects is most favorable in patients at high risk of CHD (those with a 5-year risk of 3% or 1-year risk of ≥ 0.6%).9
ASA for the Primary Prevention of CVD

ASA is the most studied and most widely used drug in the world. Based on key clinical trials, major international organizations have recommended the use of ASA for prevention of CVD in a variety of patient populations and its use has been established in various treatment guidelines.
For the primary prevention of CV, the US Preventive Services Task Force recommends ASA treatment for patients at increased risk for coronary heart disease.16 The British Hypertension Society recommends ASA treatment for patients aged ≥ 50 years who have hypertension but whose but whose blood pressure is satisfactorily controlled (<150/90 mmHg), and who have either target-organ damage, diabetes or a 10-year CVD risk of ≥ 5%.18 The American Diabetes Association,17 American Heart Association,18 and the Third National Health and Nutrition Examination Survey19 have also produced specific guidelines for ASA use in primary prevention.