Atherosclerosis is a disease in which fatty plaques accumulate on the sides of blood vessels. It is also called “hardening of the arteries” since the fatty plaques become hard due to calcification. Eventually, an artery can become 100% blocked by the plaque, or a clot of blood can stick in the space left by the plaque, thereby shutting off blood flow.
A large number of medications have been developed to combat the different factors that contribute to atherosclerosis. One class of drugs prescribed for atherosclerosis is the ADP inhibitors. These drugs reduce the release of adenosine diphosphate (ADP) from platelets, resulting in several positive effect, including less intracellular calcium (less calcification) and less frequent binding of ADP to the P2Y12 receptor. The ADP-P2Y12 binding is an essential part of arterial thrombosis; therefore, the antagonistic effect of clopidogrel (Plavix) and other ADP inhibitors is highly important.
Ticlopidine (Ticlid) is the first ADP inhibitor discovered for atherosclerosis (1). Chemically, it is in the thienopyridine family. It has been mostly supplanted by its successor, clopidogrel, because ticlopidine causes increased risk of neutropenia, agranulocytosis and thrombotic thrombocytopenic purpura (TTP).
Srinivas et al (2) studied the efficacy of clopidogrel (Plavix) in atherosclerotic rats (fed a high fat diet for one month before beginning clopidogrel) and determined that clopidogrel was able to reverse atherosclerotic calcification in the aorta, as well as reduce cholesterol levels by half and increase urine creatinine to near-normal levels. A study that compared ticlopidine and clopidogrel to aspirin for stroke prevention revealed that both ticlopidine and clopidogrel were able to produce a statistically significant decrease in the risks of a serious cardiovascular event such as a stroke (3). Ticlopidine was more likely to cause side effects such as skin rash and diarrhea, as well as life-threatening events including neutropenia and TTP(1).
Prasugrel was developed to enhance the beneficial effects of clopidogrel. In the TRITON-TIMI 38 study, prasugrel was shown to have significantly lower occurrence of CV death, nonfatal MI, and nonfatal stroke than that obtained using clopidogrel. However, the rate of major bleeding increased with prasugrel, including dangerous but ultimately nonfatal bleeding as well as fatal bleeding events (4). Another study, called (PRINCIPLE)-TIMI 44, used a crossover methodology to compare responses to the two drugs in patients who had undergone PCI. Again, prasugrel inhibited platelets significantly more effectively that clopidogrel. Response to prasugrel as measured by time to peak platelet inhibition and time to platelet aggregation steady state was found to be significantly faster than response to clopidogrel (5).
The latest drug in the ADP inhibitor family is ticagrelor (Brilinta), which was shown to be significantly more effective at preventing cardiovascular events (CV death, MI, or stroke) than clopidogrel (6). Deaths from all causes were reduced by 22% in the double-blind randomized study with over 18, 000 participants (7). Ticagrelor has not yet been approved for general use by the FDA or European and British regulatory organizations. Another new PDP inhibitor, elinogrel, has shown fast-acting inhibition of platelets in phase 1 clinical trials, and is now being evaluated in phase 2 (8). If it proves as efficacious as research so far suggests, and if it has an adequate safety profile, intravenous elinogrel may become the preferred treatment for acute coronary syndrome (9).
Although drugs can be very effective in the treatment of atherosclerosis, they come at a price, both financial and physical. All of the drugs discussed here have side effects, some of which are dangerous. Organizations such as the American Heart Society and the National Institutes of Health continue to recommend lifestyle changes before the use of drugs or surgery in atherosclerosis.
References
(1) Sudlow CL, Mason G, Maurice JB, Wedderburn CJ, Hankey GJ. (2009).Thienopyridine derivatives versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev.(4)
(2) Srinivas M, Annapurna A, Reddy YN. (2008). Anti-atherosclerotic effect of atorvastatin and clopidogrel alone and in combination in rats. Indian Journal of Experimental Biology 46:698-703.
(3) Tsukahara K, Kimura K, Morita S, Ebina T, Kosuge M, Hibi K, Okuda J, Iwahashi N, Maejima N, Nakachi T, Ohtsuka F, Hashiba K, Tahara Y, Sugano T, Umemura S. (2010). Impact of High-Responsiveness to Dual Antiplatelet Therapy on Bleeding Complications in Patients Receiving Drug-Eluting Stents. Circulation Journal. 2010 Feb 20. [Epub ahead of print]
(4) Reinhart KM, White CM, Baker WL. (2010). Prasugrel: A Critical Comparison with Clopidogrel. Pharmacotherapy 29(12):1441-1451.
(5) Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. Jan 2007;153(1):66 e69-16.
(6) Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): A randomised double-blind study Lancet 2009; 62191-7.
(7) James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. Apr 2009;157(4):599-605.
(8) Gurbel PA, Bliden KP, Antonino MJ, et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to cyp 2c19*2 genotype: first experience in patients. J Thromb Haemost. Oct 11 2009
(9) Berger JS, Roe MT, Gibson CM, Kilaru R, Green CL, Melton L, Blankenship JD, Metzger DC, Granger CB, Gretler DD, Grines CL, Huber K, Zeymer U, Buszman P, Harrington RA, Armstrong PW. (2009). Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J. 158(6):998-1004.e1