(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Antiplatelet Agents
Antiplatelet agents are used in virtually all patients with coronary heart disease (CHD). Aspirin, the pioneer hallmark agent, is of proven value for the management of:
Acute myocardial infarction (MI).
Post-MI prophylaxis.
Unstable angina.
Stable angina.
Following coronary artery bypass graft (CABG).
Coronary angioplasty and coronary stents when combined with clopidogrel.
Lone atrial fibrillation in individuals aged <65 years. Here apixaban or rivaroxaban may have a role.
Transient ischemic attacks (TIAs) or following nonhemorrhagic stroke.
Available antiplatelet agents include:
Aspirin
Clopidogrel
Dipyridamole + aspirin
Prasugrel
Ticagrelor
Platelet glycoprotein IIb/IIIa receptor blockers
The patient with CHD may have to face unstable angina, MI, and early cardiac death. There is now convincing evidence that antiplatelet agents and heparin (both unfractionated [UF] and low molecular weight [LMWH]), bivalirudin, and fondaparinux improve morbidity and mortality rates in patients with CHD.
Coronary thrombosis is known to be the major cause of coronary artery occlusion resulting in acute MI. In a hallmark study by DeWood et al. (1980), coronary thrombus was present in 87 % of 126 patients who had coronary arteriography performed within 4 h of the onset of symptoms and in 65 % of those studied 12 h or more after the onset of symptoms.
Davies and Thomas (1984) observed that, of patients with sudden cardiac ischemic death, 74 of 100 had coronary thrombi; 48 (65 %) of the 74 thrombi were found at sites of preexisting high-grade stenosis. In patients with thrombi, the most common finding is an underlying fissured plaque. The contents of the plaque and denuded endothelium are highly thrombogenic and initiate thrombosis, resulting in coronary occlusion. Thus, the prevention of the atherosclerotic process, plaque rupture, and thrombosis and dissolution of thrombi with dilation of the stenotic lesions are important therapeutic goals.
Antiplatelet agents (so called because they inhibit platelet aggregation) have a role in the prevention of coronary thrombosis, MI, and cardiac death. Platelets clump onto atherosclerotic plaques, causing occlusion of the artery, and/or embolize downstream, occluding coronary arterioles. This effect may induce fatal arrhythmias and precipitate death. Angioscopic studies (Sherman et al. 1986) have confirmed the presence of platelet clumps on eccentric atheromatous plaques in patients with unstable angina and no such platelet aggregation in patients with stable angina. It is not surprising, therefore, that aspirin, a potent antiplatelet agent, has proved effective in preventing acute MI in patients with unstable angina. A small, but timely, trial by Lewis et al. (1983) showed that aspirin 325 mg reduced nonfatal and fatal infarction rates by about 50 % in patients with unstable angina. In the second International Study of Infarct Survival (ISIS-2), patients with acute MI administered aspirin 160 mg achieved a 25 % reduction in the 35-day vascular mortality rate and a 50 % decrease in the incidence of reinfarction. The addition of aspirin to streptokinase enhanced thrombolytic efficacy, resulting in a 48 % decrease in the 35-day vascular mortality rate over the period (ISIS-2 1988a).
Antiplatelet agents are not expected to prevent all forms of thrombotic events.
Thrombi occurring in arteries are rich in platelets, so antiplatelet agents are effective.
In obstructed arteries, with low flow, the thrombus consists mainly of red cells within a fibrin mesh and very few platelets. This situation is similar to venous thrombosis, in which platelets are not predominant. The contents of a ruptured plaque are highly thrombogenic. Aspirin is only partially effective in preventing coronary thrombosis following plaque rupture, the usual cause of acute MI (Clarke et al. 1991, see Chap. 11). Thus, antiplatelet agents may not help sufficiently in this situation and direct thrombin inhibitors, such as bivalirudin, hirudin, hirulog, and fondaparinux, and newer types of oral anticoagulants specific for thrombin and derivatives of atheromatous plaque contents are receiving intensive study and clinical testing.
Drug name: | Aspirin (acetylsalicylic acid) |
Dosage: | 75–81 mg [non-enteric-coated] daily for ischemic heart disease (IHD) prophylaxis or for others with atherosclerotic disease |
240–324 mg [3–4 tabs, 75–81 mg] chewed and swallowed at onset of pain caused by a probable heart attack. UK advice: Aspirin 300 mg (chewed or dispersed in water) is recommended.
Aspirin [acetylsalicylic acid (ASA)] has rightly gained widespread use in the management of unstable angina (Lewis et al. 1983; Cairns et al. 1986) and acute MI and in the prevention of nonfatal and fatal MI during the years following infarction. Also, salutary effects have been demonstrated in patients with stable angina and TIAs and in the prevention of occlusion of CABGs (see indications, Table 19-1).
Table 19-1
Indications for aspirin
Cardiovascular | Comment | |
|---|---|---|
1. | Unstable angina | Proven |
2. | Stable angina | Proven |
3. | Acute-onset myocardial infarction | Proven, also enhances effect of thrombolytic agents |
4. | Post MI | Proven effective |
5. | Silent ischemia | Strongly advisable |
6. | Coronary artery bypass surgery | May prevent graft occlusion |
7. | Post-coronary angioplasty | Modest decrease in reocclusion |
8. | Lone atrial fibrillation | In selected patients |
9. | Bioprosthetic valves | In combination with dipyridamole |
10. | Transient cerebral ischemic attacks | Proven in both men and women |
11. | Post-nonhemorrhagic strokes | |
12. | Patients over age 45 years at high risk | Strong family history of MI and significant dyslipidemia |
13. | Diabetics at high risk for CHD | Advisable |
Historical Review
Although this text has not given historical reviews of pharmacologic agents, it would appear timely to document briefly a few of the historical details that led to the widespread acceptance of aspirin, a drug that can prolong life.
Hippocrates approximately (400 BC) treated his patients for pain with willow bark, which contains salicylic acid.
1763: Reverend Stone of Chipping Norton described the benefit of willow bark for ague.
1853: Von Gerhardt of Bayer developed aspirin.
1899: Felix Hoffman, a Bayer chemist, treated his father for rheumatism with aspirin.
1948–1953: Lawrence Craven treated ~1,500 relatively healthy, overweight, sedentary men aged 40–65 years to obviate coronary thrombosis and reported his findings in the Mississippi Valley Medical Journal “In Those with Risk Factors for Coronary Artery Disease” (Craven 1953). Craven apparently started treating his patients with high doses of aspirin and finally concluded that one aspirin a day was sufficient because none of his 1,500 or more patients given this low dose for ~5 years experienced a cardiac event (Craven 1953).
1971: John Vane discovered that aspirin blocks the production of prostaglandins.
1974: Elwood et al. (1974) reported negative results of a randomized trial of aspirin in the secondary prevention of mortality from MI. Aspirin was once more forgotten until it became clear that the clinical trial had studied patients who were given the drug 2, 3, and even 12 months after infarction.
1972–1977: The Stroke Trial of Fields and associates (Fields et al. 1977) showed a favorable trend.
1978: Barnet and colleagues reported that male patients with TIAs treated with aspirin showed a significant reduction in stroke rate. These investigators emphasized that aspirin did not have beneficial effects in women in their study, and this notion was perpetuated by others for several years. The trial had enrolled ~90 % men; there were not a sufficient number of women to test the hypothesis.
1983: The timely randomized trial of Lewis et al. showed conclusively that one Alka-Seltzer (ASA, 325 mg) produced a 49 % reduction in nonfatal MI. Cairns et al. (1986), in a larger study, confirmed the observation using 1,300 mg aspirin daily.
1988: ISIS-2 confirmed an increase in survival in patients given aspirin within 6 h of the onset of infarction. Aspirin enhanced the salutary effects of streptokinase and further improved survival rates (see Chap. 11).
1988: Primary prevention in 22,071 male physicians, aged 40–80 years, randomly assigned to 325 mg aspirin on alternate days, resulted in a 44 % reduction in fatal and nonfatal MI (p < 0.0001).
1989: The American College of Chest Physicians recommended (Resnekov et al. 1989) that aspirin, 325 mg daily, be considered for virtually all individuals with evidence of CHD and selected patients with risk factors for CHD.
The Swedish Angina Pectoris Aspirin Trial studied 2,035 patients with chronic stable angina without infarction. Aspirin 75 mg reduced the occurrence of infarction and sudden death by 34 % in the treated patients versus placebo (Juul-Moller et al. 1992).
Table 19-1 gives the clinical indications for aspirin, and Table 19-2 defines patients at risk in whom aspirin is advisable.
Table 19-2
Patients at risk, aspirin advisable
1. | Hyperlipidemia: total cholesterol level >240 mg/dL (5.2 mmol/L) especially if HDL-C <35 mg/dL (0.9 mmol/L) |
2. | Mild hypertensiona |
3. | Diabetes, except hemorrhagic retinopathy |
4. | Strong family history of vascular thrombosis: |
Myocardial infarction at age <60 years, stroke at <70 years | |
5. | Refractory smokers with any one of the above factors strengthens indication |
6. | Following hip or knee surgery for 3 weeks if oral anticoagulants not used |
Dosage: use aspirin noncoated 75–162 mg daily with food; or enteric coated, 81–325 mg daily | |
The results of five randomized trials in patients with atrial fibrillation led to the following conclusions:
Patients aged under 60 years with lone atrial fibrillation (no risk factors and no structural heart disease) can be treated with aspirin 60–162 mg daily. They usually do not require oral anticoagulants for stroke prevention because the risk of stroke is low (<0.5 % per year).
In patients aged 65–75 years with lone atrial fibrillation, the stroke rate is also low (<2 % per year) and aspirin therapy is recommended by some, but anticoagulant therapy should be individualized because there are no clear answers.
In patients over age 75 years, warfarin has proved more effective than aspirin, but most of this benefit was lost because of a high rate of intracranial hemorrhage caused by warfarin. In addition, the mean age of patients in these trials was 69 years, and only about 25 % were over age 75 years (Atrial Fibrillation Investigators 1994). Thus, until further trial results are available in patients older than 70 with lone atrial fibrillation, treatment should be individualized.
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Acetylsalicylic acid irreversibly acetylates the enzyme cyclooxygenase. This enzyme is necessary for the conversion of platelet arachidonic acid to thromboxane A2. The latter is a powerful platelet-aggregating agent and vasoconstrictor.
The conversion to thromboxane A2 and platelet aggregation can be initiated by several substances, especially those released following the interaction of catecholamine or platelets with subendothelial collagen. Endothelial and smooth muscle cells, when stimulated by physical or chemical injury, cause cyclooxygenase to convert membrane arachidonic acid to prostacyclin (prostaglandin I2 [PGI2]), which is then released. Prostacyclin is a powerful inhibitor of platelet aggregation as well as a potent vasodilator. Prostacyclin, therefore, may help keep the vessel wall clean.
Prostacyclin production is greatly reduced in diseased arteries. Aspirin further reduces the formation of prostacyclin in the vessel wall, and this is an undesirable effect. Low-dose aspirin inhibits thromboxane A2 synthesis and platelet aggregation and does not inhibit PGI2 production significantly.
Dosage: The author recommends soft chewable aspirin [noncoated] 80–81 mg daily after a meal, preferably the evening meal.
General recommendation is enteric-coated aspirin 75–325 mg daily. An 80- and 81-mg enteric-coated tablet is available in North America; 60–75 mg is often used in Europe. Chewable 80–81 mg is useful, for daily use, and if chest pain occurs, the chew tablet is readily available: take 160–240 mg at the onset of symptoms of chest pain suggestive of MI.
Aspirin, 20–60 mg daily, inhibits serum thromboxane A2 generation without affecting prostacyclin synthesis and completely suppresses platelet aggregation (Patrono and Wood 1994). It is advisable not to exceed 325 mg daily; 60–81 mg appears to be optimal. In the Aspirin Reinfarction Study, although infarction rates decreased, sudden deaths were increased (Aspirin Myocardial Infarction Study Research Group 1980). In addition, prostacyclin infusion has been shown to prevent ventricular fibrillation (VF) after circumflex artery occlusion in dogs. The importance of inhibition of prostacyclin by doses higher than 325 mg cannot be dismissed. The inhibition of prostacyclin synthesis by aspirin 1 g daily may increase the risk of sudden death during acute infarction.
The cardiovascular indications for aspirin are listed in Table 19-1.
Aspirin Resistance
The exact prevalence of aspirin resistance is unknown; estimates suggest that between 5.5 and 60 % of patients using this drug may exhibit a degree of “aspirin resistance,” depending upon the definition used and parameters measured; aspirin resistance may be related to the use of nonsteroidal anti-inflammatory agents and proton pump inhibitors (Gasparyan et al. 2008). These investigators failed to consider the effect of enteric coating; however Kapoor (2008), in a letter, stated that it is important to take note of recent reports of incomplete suppression of platelet aggregation with enteric-coated aspirin as shown by Cox et al. (2006) and Maree et al. (2005). In a randomized, open-label, crossover study of healthy volunteers, incomplete thromboxane (TX) B2 inhibition was found to occur in 8 % of the aspirin group and 54.3 % of the enteric-coated aspirin group (p = 0.0004) (Cox et al. 2006). In another study of 131 stable cardiovascular patients treated with enteric-coated aspirin (75 mg/day), 44 % of patients failed to attain optimal inhibition of serum TX, indicating a suboptimal inhibition of platelet COX-1 activity, and those with an incomplete aspirin response were more likely to demonstrate platelet aggregation to arachidonic acid (21 % vs. 3 %; p = 0.004) (Maree et al. 2005).
It is advisable to administer 75–81 mg soft chewable aspirin daily instead of enteric-coated aspirin for the prevention of CAD and stroke. Importantly, individuals who use soft chewable aspirin daily would have the product on hand and would be able to take 3–4 soft aspirins for chest pain that is unrelieved by nitroglycerin.
It is important for physicians to advise patients who have symptoms suggestive of a heart attack that the immediate use of 3–4 soft aspirins could prevent a fatal or nonfatal MI, and in this setting, aspirin intake is more important than the use of nitroglycerin which does not prevent heart attacks.
Sound advice on the use of aspirin therapy for cardiovascular disease prevention is given by the European Society of Cardiology (Halverson et al. 2014).
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Drug name: | Dipyridamole |
Trade names: | Persantine, Persantin, Persantin Retard |
Supplied: | 25, 50, and 75 mg; Retard 200 mg |
Dosage: | 50–75 mg three times; Retard 200 mg twice daily |
The drug is useful only when combined with aspirin. It inhibits platelet adhesion to vessel walls and surfaces but has a low effect on platelet aggregation.
Caution: The drug may increase ischemia and angina owing to coronary steal and is contraindicated in unstable angina and immediately after MI.
The combination of dipyridamole and aspirin for the management of stroke and TIA is not advisable in patients with CHD because angina or ischemia may be precipitated.
Interaction: The drug causes an accumulation of adenosine; thus, severe hypotension may occur if IV adenosine is given for supraventricular tachycardia; the dose of adenosine should be halved.
Indications
1.
Prosthetic heart valves. The combination of dipyridamole and warfarin has been shown to be more effective than oral anticoagulants alone in preventing embolization in patients at risk (i.e., those with previous embolism).
2.
Patients with tissue valves who show evidence of embolization.
3.
Dipyridamole combined with aspirin (Aggrenox) appears to provide beneficial effects for secondary prevention after stroke (EPS Group 1987). Dipyridamole should be added to aspirin if TIAs are recurrent.
A randomized controlled trial (RCT) indicated that dipyridamole (slow-release formulation, 200 mg plus aspirin 50 mg twice daily) resulted in a highly significant reduction in the occurrence of stroke (p < 0.001). The risk reduction for aspirin and dipyridamole for stroke was 37 % vs. 15 % for dipyridamole alone and 18 % for aspirin alone. At present, the combination of aspirin and dipyridamole or clopidogrel appears to be the most effective and safest therapy for secondary prevention of stroke, but see caution given above.
Drug name: | Clopidogrel |
Trade name: | Plavix |
Supplied: | 75 mg |
Dosage: | 75 mg daily with or without food |
This thienopyridine is established therapy prior to PCI for STEMI and NSTEMI. A loading dose of 600 mg is recommended prior to planned PCI. A 75 mg daily dose is continued for 1–2 years or longer in selected cases.
Studies have suggested that adverse cardiovascular outcomes with the combination of clopidogrel and a proton pump inhibitor [PPI] are explained by the individual PPI. The use of a PPI that inhibits CYP450 2C19, including lansoprazole, or rabeprazole and notably, omeprazole has been reported to significantly decrease the inhibitory effect of clopidogrel on platelet aggregation.
One study reported that the PPI pantoprazole was not associated with recurrent MI among patients receiving clopidogrel, possibly due to pantoprazole’s lack of inhibition of CYP450 2C19 (Juurlink et al. 2009).
Morphine has been shown to decrease clopidogrel absorption, decrease concentrations of clopidogrel active metabolite, and diminish its salutary effects. This can cause treatment failure in susceptible patients (Hobl et al. 2014).
In the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/-2 2005), patients with acute MI received aspirin and were randomized to receive clopidogrel 75 mg/day or placebo. Clopidogrel caused a significant reduction in death, reinfarction, or stroke (9.2 % vs. 10.1 %; relative risk reduction, 9 %; p = 0.002).
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial (Bhat et al. 2006) showed that clopidogrel plus aspirin administered to patients with stable CHD was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular causes.
Gebel points out that clinical studies provide little evidence that clopidogrel, with or without aspirin, is more efficacious for the prevention of strokes than aspirin alone (Gebel 2005). The increased risk of bleeding episodes with clopidogrel and aspirin in combination probably outweighs any small reductions in secondary event risk. In contrast, extended-release dipyridamole (ER-DP) plus aspirin reduces secondary stroke risk to a significantly greater extent (23 % relative risk reduction) than aspirin alone.< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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