Viewpoint: “Underutilisation of novel antiplatelet agents – myths, generics, and economics”

Abstract

Two oral antiplatelet agents have been recently introduced for acute coronary syndromes indication providing alternatives for dual therapy with aspirin and clopidogrel. In fact, worldwide prasugrel has been on the market for four years, and ticagrelor for over two years. Despite declared benefits over clopidogrel, including hypothetical cost saving advantages, in real life, the clinical utilisation of both agents is small. Generic clopidogrel, and price differences are claimed as major obstacles to prevent broader prasugrel and ticagrelor use. However, these economic difficulties are barely supported by available evidence, and served mostly to protect questionable management spending, as an exuse to explain why in reality cardiologists are so sceptical about both novel agents, and to convince the sharehoders that their money is not wasted, misleading the owners with regard to future success. Importantly, brand Plavix® is used worldwide 5-10 times more often than new agents, despite heavy generic competition. The future of prasugrel outside Japan, where much lower reasonable dose will be used is not impressive due to lack of further outcome studies, negative results of the latest trials, and less than four years left before patent expiration. The fate of ticagrelor will depend on verification of deaths numbers in the ongoing United States Department of Justice PLATO investigation, and confirmation of the mortality benefit in the PEGASUS TIMI-54 trial.

Acute myocardial infarction occurring while on chronic clopidogrel therapy (‘clopidogrel failure’) is associated with high incidence of clopidogrel poor responsiveness and stent thrombosis

“…Regulatory agencies as well as major cardiac societies recommend the use of novel antiplatelet medications in patients with ACS [ 29 , 30 ]. Nevertheless, due to patent expiration in 2011, enormous generic competition, and the lack of data regarding the use of novel P2Y12 antagonists post PCI for stable coronary artery disease and cerebrovascular disease, clopidogrel is still the most commonly prescribed P2Y12 antagonist [ 14 ]. Thus our findings are still relevant even in the current era after the introduction of novel P2Y12 antagonists.…”

“…However, while clopidogrel hypo-responsiveness is a well-studied laboratory-based pharmacodynamic phenomenon, there is only a limited amount of data regarding the clinically defined phenomenon ‘clopidogrel failure’, which is the occurrence of an ischemic event during clopidogrel therapy [ 6 ]. Although clopidogrel is widely used [ 14 ], the clinical significance of ‘clopidogrel failure’, as well as platelet responsiveness associated with this phenomenon, are largely unknown. The aim of the current study was to describe the clinical and angiographic characteristics, as well as the platelet reactivity of patients sustaining ACS while on chronic clopidogrel therapy.…”

Filing Sources after Oral P₂Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS)

“…Clearly, the prasugrel adverse event profile in FAERS looks superior to both other agents with regard to better vascular safety at the expense of bleeding, although prasugrel-associated reports are several times fewer than events linked to clopidogrel. Importantly, the total quantity of adverse reports for each drug is clearly a reflection of the current clinical utilization of oral P 2 Y12 antiplatelet agents, where clopidogrel is still dominant with about 75% of prescriptions, while prasugrel and ticagrelor equally share the remaining use [7]. This pattern is important, suggesting that distribution of adverse events in FAERS reflects the “real-life” global clinical scenarios.…”

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study

“…Overall, the net benefit of the ischemic/bleeding risk for novel agents is acceptable for clinical use. Although prasugrel or ticagrelor use has been increasing in clinical practice, and the South Korean guidelines match closely with the ESC and ACC/AHA recommendations, the higher response to prasugrel or ticagrelor in East Asians poses a serious concern, and thus clopidogrel is still the most common oral P2Y 12 receptor agent in clinical decision making [7], especially in women with low body weight and patients with renal or hepatic impairment. Therefore, the HOPE-TAILOR study will test whether the low-dose new P2Y 12 receptor inhibitor strategy may be safer and better with regard to clinical outcome and adequate for clinical practice in Korea.…”

“…However, clopidogrel still remains the first-line agent chosen for treatment [7]. Like most cardiovascular medications, P2Y 12 receptor inhibitors exhibited marked interethnic differences regarding pharmacokinetic (PK) and pharmacodynamic (PD) profiles.…”