Clopidogrel Dual Antiplatelet Therapy and Novel Treatments for Atherothrombosis

Written by Shaden Salimi Graduate Student at McGill University

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What is Atherothrombosis?

Atherothrombosis is a condition characterized by the formation of blood clots due to the accumulation of lipids and minerals (known as plaques) in the arterial walls (Viles-Gonzalez et al., 2004). Severe complications from atherothrombosis can lead to heart attack, stroke, peripheral artery disease (PAD), and other cardiovascular diseases or death. Until the early 2000s, a large gap existed regarding proper treatment plans for preventing atherothrombosis.

For example, aspirin is a widely successful drug for the prevention of a range of cardiovascular diseases. However, it is not as effective in treating atherothrombosis alone in patients, as the risk of recurrent vascular events remains relatively high—about 8% to 18% (Mason et al., 2005). This could be due to differences in how individuals metabolize aspirin, and that aspirin alone might not be enough to inhibit the accumulation of platelets (Mason et al., 2005). Although aspirin alone did not look like a promising therapeutic for atherothrombosis, the addition of clopidogrel was later identified as a potential treatment.    

Clopidogrel for treating atherothrombosis

The discovery of clopidogrel goes back to 1987 in rat platelets, when it was shown to inhibit the aggregation of platelets by inhibiting ADP receptors existing on the surface of the platelets (Féliste et al., 1987). Clopidogrel, like aspirin, is an antiplatelet medicine. These are essentially medications that prevent blood clots from forming. However, the two drugs have different mechanisms of action for preventing the formation of blood clots.

Aspirin inhibits the COX enzyme which synthesizes prostaglandins (Gosavi et al., 2023). Accumulation of prostaglandins leads to inflammation in the body, including the heart. On the other hand, clopidogrel works by blocking P2Y12, which is a receptor on the surface of the platelets that is essential for their activation (Al-Najjar et al., 2022).  

Figure 1: Aspirin vs. Clopidogrel’s pharmacological targets (Cattaneo, 2004)

Combination treatment with aspirin and clopidogrel

Since aspirin and clopidogrel have different mechanisms of action for the prevention of platelet aggregation, a combination therapy was explored as it was not previously studied in patients who were more likely to experience cardiovascular events related to atherothrombosis. In a pioneering study in 2006, Bhatt and colleagues investigated the safety and efficacy of using clopidogrel and low-dose aspirin compared to aspirin alone to prevent atherothrombosis.

The study investigated whether dual antiplatelet therapy could prevent atherothrombosis in high-risk patients for this disease and whether this drug regimen works better for patients with certain indications. The indications they specifically analyzed were patients who had a history of cardiovascular disease (symptomatic) and those who did not have cardiovascular disease but had atherothrombotic risk factors (asymptomatic) (Figure 2).

The advantage and disadvantage associated with clopidogrel

Advantage: The study revealed that even though there was no large-scale significant reduction in the first occurrence of heart attack, stroke, or death due to cardiovascular issues, this analysis revealed that the dual therapy was beneficial in symptomatic patients compared to placebo and aspirin alone.

Disadvantage: Unfortunately, the rate of moderate bleeding was greater in the clopidogrel and aspirin group compared to the placebo plus aspirin group, which shed light on the toxicity associated with combining aspirin and clopidogrel.

Figure 2: Schematic of patient categories and outcomes

Overall, this study provided valuable insights into the safety and efficacy of the combination of two antiplatelet medications for preventing atherothrombosis as compared to aspirin alone both at large scale and at subgroup levels. Importantly, it sheds light on various pharmacokinetic properties of drugs and how important these factors are for determining the long-term use of drugs on the body such as safety, efficacy, potency, and toxicity.

The idea behind the drug testing procedure is to ensure that the drug of interest is indeed safe and does not cause a multitude of symptoms in the patients and that the benefits of taking the drug outweigh the side effects. In addition, each drug’s pharmacokinetic parameters and patient performance should be compared to other interventions in the patients to ensure that the chosen drug has the most optimal properties for patient well-being.

How Clopidogrel paved the path for alternative treatments for atherothrombosis

The study on the dual combination therapy with clopidogrel shed light on other biological pathways that were not a major area of scientific concern as the majority of pathways that were previously targeted were those associated with aspirin. It also sparked the interest of researchers to investigate and target other pathways that lead to the activation of platelets to develop new treatments with higher efficacy and lower toxicity profiles. An example of one of these newer interventions is ticagrelor, which works in a similar fashion to clopidogrel in that it inhibits the P2Y12 receptor to halt platelet aggregation. Fortunately, the number of diseases and deaths caused by several heart problems are lower when patients use ticagrelor compared to clopidogrel (Wallentin et al., 2009).

Other interventions are also being investigated and this would give healthcare providers an opportunity to provide patients suffering from heart problems the best prevention as well as treatment options. These interventions include GPIIbIIIa receptor inhibitors on the surface of the platelets, which prevent platelet aggregation (Jourdi et al., 2022), as well as cilostazol, which is a phosphodiesterase inhibitor, inhibiting factors that can induce platelet aggregation, such as collagen, 5’-ADP, epinephrine, and arachidonic acid (Biondi-Zoccai, 2010). Furthermore, colchicine, an anti-inflammatory medication which has traditionally been used for gout and pericarditis, has recently been shown to be a promising agent for preventing atherothrombotic events, as it can diminish inflammatory white blood cell uptake and hence is able to reduce vascular inflammation (Cimmino et al., 2023; Meyer-Lindemann et al., 2022).  

In addition to the more recent therapies being explored, the dual antiplatelet therapy with clopidogrel shed light on the use of precision medicine approaches and targeting specific receptors as biomarkers of atherothrombosis treatment. Hence, clinicians are moving from a “population-based approach” to “patient-centered precision” medicinal approaches instead by raising awareness regarding inter-individual variability in response to the different anti-thrombotic treatment regimens. Finally, the ongoing research for treating atherothrombosis, starting from aspirin, then to clopidogrel dual therapy, and finally to the newer therapeutic agents, enhances our understanding of the complex and intricate nature of cardiovascular diseases and the need to cater the antiplatelet agents in a way that meets individual patient needs (Jourdi et al., 2022).

Proteintech offers a wide range of research use antibodies for the study of atherothrombosis:

Target	Cat No.
COX-1	84151-4-RR
COX-2	66351-1-Ig
P2Y1	67654-1-Ig
P2Y12	11976-1-AP
CRP	83711-1-RR
TF	83776-4-RR
WWF	83854-2-RR
CD68	83014-5-RR
LOX1	11837-1-AP
MMP9	10375-2-AP
TBXAS1	67371-1-Ig
ICAM-1	82827-1-RR
APOB	84047-1-RR
4-Hydroxynonenal	68538-1-Ig

References

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