Platelet Activation in Ischemic Heart Disease: Role of Modulators and New Therapies (Pharmacotherapy of Ischemic Heart Disease) Part 2

Indications, dosage, and side effects

Aspirin is widely used for the primary prevention of ischemic events in patients at risk, as well as secondary prevention of cardiovascular events in patients with IHD and cerebrovascular and peripheral vascular disease. Aspirin is usually administered once a day at a dose between 75-325 mg, with 75-100 mg being recommended for most indications. When fast platelet inhibition is needed, a dose of at least 160 mg should be given orally. Higher doses of aspirin have not been shown to be more effective than lower doses, and in fact, reduced efficacy has been reported with higher doses. As discussed above, very high doses of aspirin (i.e., 1 g/ d) can have a paradoxical prothrombotic effect due to the inhibition of COX-2.

Long-term daily oral enteric-coated aspirin has been demonstrated to reduce (1) the incidence of anginal episodes in patients with chronic stable angina, as well as in survivors of unstable angina and myocardial infarction (MI), and (2) the risk of recurrent infarction, stroke, or cardiovascular mortality by 25% following an MI compared with placebo. It has also been established that low doses of aspirin may be given immediately after an MI to reduce the risk of another MI or of the death of the myocardium.

Aspirin is equally effective in men and women, although in men it mainly reduces the risk of MI, while in women it lowers the risk of stroke. Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds, these events are rare, and are by far outweighed by aspirin’s positive effects.

The most common side effects of aspirin use are gastrointestinal, ranging from simple stomach upset, to erosive gastritis, to peptic ulcers with bleeding and perforation, all of which are dose-dependent. For these reasons, aspirin should never be administered to individuals with a history of gastrointestinal bleeding or severe stomach upset. Although the use of enteric-coated or buffered aspirin may relieve some of these symptoms, they do not eliminate the risk of gastrointestinal complications due to the inhibition of gastroprotective prostaglandins as part of the actions of aspirin. The overall risk of major bleeding with aspirin is low, however, estimated at 1-3% per year, but is increased when aspirin is given in conjunction with anticoagulants (e.g., warfarin). In these situations, a lower dose of aspirin should be given (e.g., 75-100 mg/d). In patients with a documented history of peptic ulcer disease caused by Helicobacter pylori infection, treatment of the infection and administration of a proton pump inhibitor (PPI) may reduce the risk of aspirin-induced gastrointestinal bleeding. Aspirin should also never be given to individuals with a history of allergic responses to salicylates, particularly those associated with bronchospasm.

Thienopyridines

A second class of antiplatelet drugs commonly used in IHD is the thienopyridines. These structurally related drugs have similar benefits as aspirin in patients with stable chronic IHD and may be used instead of aspirin when aspirin is contraindicated. The thienopyridines include clopidogrel (Plavix®), ticlopidine (Ticlid®), and prasugrel (Effient®). A structurally unrelated but functionally similar drug is ticagrelor (Brilinta®).

Mechanism of action

The thienopyridines are prodrugs that must first be metabolized by the hepatic cytochrome P450 enzyme system before they can exert any biological activity, so their onset of action can be delayed for several days. They interfere with the aggregation of platelets by competitively and irreversibly inhibiting the adenosine diphosphate (ADP) chemoreceptor P2Y12 on the surface of platelets, which is crucial for the conformational change that activates GP IIb/IIIa and ultimately leads to platelet aggregation and cross-linking by fibrin.

Clopidogrel (Plavix®)

Clopidogrel is an oral thienopyridine marketed under the trade name Plavix by Bristol-Myers Squibb and Sanofi-Aventis as 75 mg oral tablets.

Indications, dosage, and side effects

Clopidogrel is indicated for the prevention of vascular ischemic events in patients with symptomatic atherosclerosis, acute coronary syndromes, and MI. When compared with aspirin in patients with recent ischemic stroke, MI, or peripheral arterial disease, clopidogrel further reduced the risk of cardiovascular death, MI, and stroke by nearly 10%. Thus, although clopidogrel is actually more effective than aspirin in reducing morbidity and mortality of IHD, it is also considerably more expensive and not as readily available. It is also used, together with aspirin, for the prevention of thrombotic events after placement of intracoronary stents, or as an alternative to aspirin in patients who have a contraindication for aspirin.

Combination therapy consisting of aspirin and clopidogrel has been shown to reduce morbidity and mortality in patients with angina and it also reduces the risk of thrombosis in patients who have undergone coronary artery stenting (the risk of gastrointestinal bleeding in these patients can be reduced by also prescribing a PPI while on this combination therapy). The combination therapy of clopidogrel and aspirin capitalizes on the capacity of these drugs to inhibit complementary pathways of platelet activation and is associated with a highly statistically significant 20% relative risk reduction when comparing each drug alone.

In patients with a history of acute coronary syndrome, it is standard medical practice to administer aspirin indefinitely, and it is recommended that combination therapy with clopidogrel be given for 1-3 months after the implantation of a bare metal stent. With the use of drug-eluting stents, which deliver antiproliferative drugs locally (e.g., rapamycin or paclitaxel), combination therapy should continue for at least one year because these drugs are associated with delayed endothelial healing that prolongs the window during which there is an increased risk for thrombosis around the area where the stent was placed. Although aspirin and clopidogrel may help prevent coronary thrombosis associated with stenting, there is no evidence that these drugs reduce the occurrence of re-stenosis. However, the use of drug-eluting stents can reduce re-stenosis to near zero within the stent itself and less than 10% at its edges.

There is little evidence of additional benefit of adding clopidogrel to the routine regimen of aspirin in patients with chronic stable IHD that have not undergone stenting. However, "aspirin resistance" has been noted in up to 10% of patients, more frequently in patients treated with lower doses of aspirin. In these cases, the use of higher doses of aspirin and/or combination therapy with clopidogrel should be considered. Although the routine management of patients with IHD is medical, many patients show greater improvement after undergoing interventional coronary revascularization. These invasive procedures should not take the place of the required ongoing modification of risk factors and medical therapy but rather should be performed in combination with them.

Combination therapy of aspirin and clopidogrel increases the risk of major bleeding to about 2% per year, a risk that will exist even if the daily dose of aspirin is reduced to 100 mg. Thus, the combination of clopidogrel and aspirin should only be used when there is a clear benefit. For example, combination therapy has not been shown to reduce the risk of acute ischemic stroke relative to clopidogrel alone or to reduce the risk of primary cardiovascular events when compared to aspirin alone.

As mentioned above, the onset of action of clopidogrel is slow, so even though platelet inhibition can be seen within a few hours after a single oral dose of the drug, a loading-dose between 300-600 mg is commonly given when prompt inhibition of the ADP receptors is desired, which is continued as a once daily oral dose of 75 mg for maintenance.

The documented adverse effects of clopidogrel include bleeding, severe neutropenia, and thrombotic thrombocytopenic purpura (TTP). Patients with a history of resolved aspirin-related peptic ulcers who received aspirin plus a PPI (e.g., esomeprazole) were shown to have a lower incidence of recurrence of peptic bleeding when compared to patients receiving clopidogrel instead. Another study suggested that prophylaxis with PPIs when undergoing treatment with clopidogrel following an acute coronary syndrome (ACS, i.e., unstable angina or MI) may increase the incidence of adverse cardiac events, perhaps as a result of the inhibition of the cytochrome P450 variant CYP2C19, which is required for the conversion of clopidogrel to its pharmacologically active form. However, even after some government health agencies issued a statement on a potential drug interaction between clopidogrel and PPIs, people within the cardiology community manifested concerns regarding the possible existence of flaws in the studies that served as the basis for these conclusions and subsequent warnings, putting into question the veracity of an adverse drug interaction between clopidogrel and PPIs.

Clopidogrel, was issued a black box warning from the FDA on March 12, 2010 because it is estimated that 2-14% of the US population have low levels of the CYP2C19 liver enzyme needed to activate clopidogrel and, therefore, may not get the full effect from the drug. However, there are tests available to predict if a patient will be susceptible to this reduced pharmacological effect.

Ticlopidine (Ticlid®)

Ticlopidine is an oral thienopyridine marketed under the trade name Ticlid by Roche Pharmaceuticals as 250 mg oral tablets.

Indications, dosage, and side effects

Ticlopidine is typically administered as an oral twice-daily dose of 250 mg. Like aspirin, ticlopidine is more effective than placebo at reducing the risk of cardiovascular death, MI, and stroke in patients with atherosclerotic disease, but due to its delayed onset of action, ticlopidine is not recommended for patients with acute MI. Ticlopidine has been routinely used in addition to aspirin after coronary artery stenting, and as a substitute for aspirin in patients with a contraindication to aspirin. However, because ticlopidine is less potent than clopidogrel and is associated with greater risk of hematologic disorders (e.g., neutropenia, TTP, thrombocytopenia, aplastic anemia), it has largely been replaced by clopidogrel. Due to the known hematologic side effects, which usually become manifest within the first few months of beginning therapy, frequent blood counts must be carefully performed when taking ticlopidine. As with clopidogrel, it is contraindicated in patients having hypersensitivity reactions to thienopyridines, as well as bleeding disorders, active bleeding, and liver disease.

Prasugrel (Effient®)

Prasugrel is an oral thienopyridine marketed under the trade names Effient, Efient, Apagrel, and Prasita. It was developed by Daiichi Sankyo Co. and is currently marketed in the United States in cooperation with Eli Lilly and Co. as 5 mg and 10 mg oral tablets.

Indications, dosage, and side effects

Prasugrel was approved for patients with acute coronary syndrome who will be undergoing a percutaneous coronary intervention (PCI) to reduce the occurrence of cardiovascular thrombotic events. Prasugrel is faster than clopidogrel at inhibiting ADP-induced platelet aggregation and does so to a greater extent than both normal and higher doses of clopidogrel in healthy individuals, as well as in patients with coronary artery disease, including those undergoing PCI. Unlike clopidogrel, prasugrel has not been shown to produce a lesser effect in patients who have a low level of hepatic CYP2C19 enzyme. Prasugrel should be administered as a single 60 mg oral loading dose and then continued at a dose of 10 mg orally once daily. Patients should also take aspirin (75-325 mg) per day.

A study published in the New England Journal of Medicine that compared prasugrel with clopidogrel in patients with acute coronary syndromes, both in combination with aspirin, found that prasugrel was a more potent anti-platelet agent, demonstrating a 1.2-fold reduction in the combined rate of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. However, prasugrel was associated with a 1.6-fold rate of serious bleedings and 4-fold rate of fatal bleedings, even though overall mortality did not differ between the two patient groups.

Ticagrelor (Brilinta®)

Ticagrelor is an oral cyclopentyltriazolopyrimidine (CPTP) agent marketed under the trade names Brilinta, Brilique, and Possia. The drug was approved for use in the European Union on December 3, 2010 and by the US Food and Drug Administration on July 20, 2011, being marketed in the United States by AstraZeneca as 90 mg oral tablets.

In contrast to the other antiplatelet drugs clopidogrel, ticlopidine, and prasugrel, ticagrelor is a reversible allosteric inhibitor that does not require hepatic activation, making it a better choice for patients with hepatic insufficiency or those carrying low levels or genetic variants of the CYP2C19. Due to its reversible mode of action, ticagrelor is both faster and shorter acting than clopirogrel, making it a easier to discontinue (e.g., surgery, hypersensitivity), but typically requiring more frequent dosing, which can present an issue with compliance.

In a study by AstraZeneca, ticagrelor was associated with ~2% lower mortality rate than clopidogrel in patients with ACS and it was found that taking ticagrelor displayed a lower mortality rate from vascular causes, heart attack, or stroke. However, patients taking ticagrelor was associated with 1.5% higher propensity of non-lethal bleeding.

Indications, dosage, and side effects

Treatment with ticagrelor should be initiated as an oral loading dose of 180 mg, and then continued at 90 mg orally twice daily. Patients should also take aspirin (75-100 mg) daily. Ticagrelor is indicated for the prevention of thrombotic events in patients with ACS or MI, in combination with aspirin unless the latter is contraindicated. Compared with clopidogrel, ticagrelor significantly reduces the mortality rate in patients with ACS. The drug is contraindicated in patients with hepatic insufficiency and a history of pathological bleeding. It also should not be given in combination with other drugs that affect the CYP3A4 liver enzyme, since the drug is metabolized by CYP3A4 and is mainly excreted via bile and feces.

The most common side effects of ticagrelor are dyspnea as well as bleeding (e.g., gastrointestinal, nasal, subcutaneous/dermal). To date, less than 1% of patients taking ticagrelor have reported allergic reactions.

Inhibitors of hepatic CYP3A4 enzyme (e.g., ketoconazole and (?) grapefruit juice), increase blood plasma levels of ticagrelor and can therefore cause bleeding and other adverse effects. Conversely, activators of hepatic CYP3A4 (e.g., rifampicin and (?) St. John’s wort), can reduce the effectiveness of ticagrelor. Furthermore, drugs that are also metabolized by CYP3A4 (e.g., simvastatin), will display higher plasma levels, which can result in an increase of the side effects of these drugs when combined with ticagrelor.

Thienopyridine resistance

There is variability among different individuals in the ability of the thienopyridines to inhibit ADP-induced platelet aggregation. To a certain extent this variability reflects genetic polymorphisms in the CYP isoenzymes associated with the metabolic activation of these drugs. For example, individuals carrying the CYP2C19*2 allele have been shown to display a lower responsiveness to clopidogrel, in a similar fashion as those having a lower activity of hepatic CYP3A4. These observations have resulted in the proposal that genetic testing may lead to the identification of individuals that may experience resistance to the effects of thienopyridines.

Phosphodiesterase inhibitors and adenosine reuptake inhibitors

As the name implies, phosphodiesterase inhibitors interfere with the function of the enzyme phosphodiesterase, which breaks down the intracellular second messenger cyclic adenosine monophosphate (cAMP). This results in increased levels of cAMP, ultimately leading to the inhibition of platelet activation and vasodilation.

Cilostazol (Pletal®)

Cilostazol is an oral phosphodiesterase inhibitor marketed under the trade name Pletal. The drug is marketed in the United States by Otsuka Pharmaceutical Co. as 50 and 100 mg oral tablets. Cilostazol is not used in the treatment of ischemic heart disease but rather in the relief of intermittent claudication in patients with peripheral vascular disease.

Dipyridamole (Persantine® and Aggrenox® (in combination with aspirin))

Dypyridamole is an oral phosphodiesterase inhibitor marketed as a single drug under the trade name Persantine, and as an extended-release combination with low-dose aspirin under the name Aggrenox. Persantine drug is marketed in the United States by Boehringer Ingelheim Pharmaceuticals, Inc. as 25, 50, and 75 mg oral tablets, while Aggrenox contains 200 mg of extended-release dipyridamole and 25 mg of aspirin.

Dypiridamole also inhibits the reuptake of adenosine by platelets, red blood cells, and vascular endothelial cells, as well as the enzyme adenosine deaminase, which metabolizes adenosine into inosine. Both of these effects increase the extracellular concentration of adenosine, which causes smooth muscle relaxation and is, at least in part, responsible for the vasodilatory effects of dipyridamole. Persantine causes vasodilation when given at high doses over a short time and it inhibits thrombosis when given long term by also acting as a thromboxane synthase inhibitor.