|Year : 2016 | Volume
| Issue : 4 | Page : 130-137
Antiplatelet therapies: An overview
Gundu H R Rao PhD
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Nuwill Research and Innovations, Bengaluru, Karnataka, India
|Date of Web Publication||20-Oct-2016|
Gundu H R Rao
Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
Source of Support: None, Conflict of Interest: None
The role of blood components including platelets, in initiating inflammation, endothelial dysfunction, atherosclerosis, thrombus formation, thrombus growth, and acute vascular ischemic events, is well established. Given this recognized role played by platelets, there is a considerable interest in understanding the physiology and function of platelets, as well as in the development of novel platelet function-inhibitory drugs. The generation of the second messengers, calcium mobilization, shape change, adhesion, aggregation, contraction, release of granule contents, thrombus development, thrombus growth, and formation of hemostatic plug at the injured vessel surfaces, in brief, constitute platelet activation. Some of the known compounds that inhibit platelet activation include inhibitors of arachidonic metabolism (cyclooxygenase-1 inhibitors; aspirin, ibuprofen, etc.), adenosine diphosphate receptor antagonists (P2Y 12 inhibitors), adenylyl and guanylyl cyclase stimulators, calcium antagonists, and GP11b/111a receptor antagonists. Since platelets have multiple mechanisms of achieving in vivo activation, it is difficult to design a novel drug that offers total protection for developing acute ischemic vascular events, without compromising coagulation mechanisms. Given this complexity, any aggressive antiplatelet therapy results in increased bleeding episodes. Having said that, we feel that there is a great window of opportunity for developing novel antiplatelet therapies. There is also scope for the development of fixed-dose combinations for the primary and secondary management of chronic diseases such as hypertension, heart disease, and type-2 diabetes.
Keywords: Antiplatelet therapies, aspirin, clopidogrel, fixed-dose combinations, P2Y 12 inhibitors, platelet activation, platelet pharmacology, ReoPro
|How to cite this article:|
Rao GH. Antiplatelet therapies: An overview. J Clin Prev Cardiol 2016;5:130-7
| Introduction|| |
Atherosclerosis is a chronic, complex, inflammatory disease of the blood vessels, which leads to the narrowing and hardening of the arteries.  Thrombosis is another associated multifactorial disease that causes reduction and blockage of the flow of blood to the tissues, causing ischemia and tissue injury. Together, these vascular diseases leading to heart attacks and stroke are the leading causes of morbidity and mortality worldwide. , A variety of risk factors contribute to the pathogenesis of these diseases. Some of the well-known risk factors include smoking, inflammation, endothelial dysfunction, hypertension, diabetes, repeated injury of the vascular tissues, elevated levels of low-density lipoproteins, low levels of high-density lipoproteins (HDL), visceral adiposity, and sedentary lifestyle. Some of the newer emerging risk factors include increased levels of fibrinogen, elevation of circulating activating factor, circulating endothelial cells, increased stress, depression, decreased levels of Vitamin B 12 , Vitamin D, elevated blood phosphorous, C-reactive protein, platelet microparticles, platelet hyperfunction, and hypercoagulability. Since the time Framingham trials listed the predictors of risk (http://www.framinghamheartstudy.org/risk) (age, diabetes, smoking, systolic blood pressure (BP), total cholesterol, HDL cholesterol, and body mass index) for acute vascular events, there has been a great interest in reducing modifiable risks with appropriate intervention. In spite of decades of research in this field, the role of platelets in the initiation of inflammation, vascular dysfunction, atherosclerosis, ischemic heart disease, and stoke is not very well defined. In this overview, an attempt is made to provide some evidence to support the hypothesis that platelets play a very significant role in the promotion of events leading to acute coronary and cerebrovascular events. ,,,,,,,,,,,,,,,,, Unlike other reviews on the subject, no attempt will be made to catalog the results of all the clinical studies. On the other hand, we will try to explain why we have not reaped the benefits of antiplatelet therapy and shed some lights on some novel approaches. 
| Platelet Physiology|| |
Blood platelets interact with a variety of soluble agonists such as epinephrine and adenosine diphosphate (ADP), many insoluble cell matrix components, including collagen, laminin, and biomaterials, used for the construction of invasive medical devices.  These interactions stimulate specific receptors and glycoprotein-rich domains (integrins and nonintegrins) on the plasma membrane and lead to the activation of intracellular effector enzymes. The majority of the regulatory events appear to require free cytosolic calcium. Ionized calcium is the primary bioregulator, and a variety of biochemical mechanisms modulate the level and availability of free cytosolic calcium. ,, Major enzymes that regulate the free calcium levels via second messengers include phospholipase C, phospholipase A 2 , and phospholipase D, together with adenylyl and guanylyl cyclases. Activation of phospholipase C results in the hydrolysis of phosphatidyl inositol 4, 5 bisphosphate (PIP 2 ) and formation of the second messengers such as 1, 2-diacylglycerol and inositol 1, 4, 5 trisphosphate (IP 3 ) [Figure 1].
|Figure 1: Structure of inositol trisphosphate (1P3). Activation of phospholipase C results in the hydrolysis of inositol bisphosphate and generation of the second messengers such as diacylglycerol and inositol trisphosphate|
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Diglyceride induces the activation of protein kinase C, which plays a crucial role in signal transduction for a variety of biologically active substances (Nishizuka Y: Nature 308, 693-698, 2016). Inositol trisphosphate mobilizes cytosolic calcium from internal membrane stores. Elevation of cytosolic calcium stimulates phospholipase A 2 and liberates arachidonic acid. Free arachidonic acid is transformed to a novel metabolite, thromboxane A 2 , by fatty acid synthetase (cyclooxygenase-1 [COX-1]). Thromboxane A 2 is the major metabolite of this pathway and plays a critical role in platelet recruitment, granule mobilization, and secretion. ,
Secretory granules contain a variety of growth factors, mitogens, and inflammatory mediators. Secretion of granules promotes p-selectin expression on the platelet membrane. Furthermore, activation also promotes the expression of acidic lipids on the membrane and tissue factor expression, thus making these cells pro-coagulant. Fully activated platelets can modulate the function of other circulating blood cells such as leukocytes, monocytes, macrophages as well as vascular endothelial cells. Agonist-mediated stimulation of platelets promotes the expression of an epitope on glycoprotein 11b/111a receptors. Activation of this receptor is essential for the binding of circulating fibrinogen. Fibrinogen forms a bridge between individual platelets and facilitates the thrombus formation. Von Willebrand factor (vWF) binds platelet GP1b1X complex only at high shear rate unlike fibrinogen, which can bind platelets at low shear [Figure 2].
|Figure 2: Agonist-mediated activation of platelets results in the mobilization of cytosolic calcium. Cytosolic calcium levels are modulated by the second messengers such as cyclic adenosine monophosphate and cyclic guanosine monophosphate|
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Upregulation in signaling pathways will increase the risk for clinical complications associated with acute coronary events. Downregulation of signaling pathways may precipitate bleeding diathesis or hemorrhagic stroke. Based on this knowledge about various activation mechanisms, the current antiplatelet drugs are being developed for therapeutic applications. , Having said this, I would like to mention here that aspirin is one of the most researched drugs in the world, and it was used for the prevention of cardiovascular and cerebrovascular diseases, long before its mechanism of action was researched and the results were published by Professor John Vane in 1971. According to Clinical Pharmacist (September 2014), an estimated 700-1000 trials are conducted each year. As far as its use as an antiplatelet drug is concerned, Antithrombotic Trialists (ATT) Collaboration has done meta-analysis of all clinical trials of aspirin and summarized their findings. The results of these studies will be discussed along with the other newer antiplatelet therapies.
| Clinical Conditions Needing Antiplatelet Therapy|| |
Cardiovascular disease (CVD) is the leading cause of death, accounting for 17.5 million deaths per year that is expected to exceed 24 million by 2030. Worldwide prevalence of stroke was 33 million in 2010, with some 17 million people with the first stroke. Stroke is the second leading cause of death with 12 million deaths worldwide. Given these statistics from the American Heart and Stroke Association data, it is clear that antiplatelet therapies play an important role in the management of these diseases. Having said that, we should give credit to the significant role primary prevention has played in the reduction of morbidity and mortality. Nearly, half of the decline in coronary artery disease (CAD) deaths has been attributed to population-wide risk reduction and another half due to intervention with medical therapies specific to risk factors. Antiplatelet therapies play a significant role in the risk reduction strategies. ,
| Pharmacological Approaches for the Development of Antiplatelet Drugs|| |
Major pharmacological approaches for the prevention of platelet activation include the use of compounds that inhibits the release of arachidonic acid (Vitamin E), development of receptor antagonists for potent agonists (thromboxane receptor antagonists), COX inhibitors (aspirin, indomethacin, and trifusal), stimulators of adenylyl cyclases (adenosine, PGE 1 , and PGI 2 ) and guanylyl cyclases (nitric oxide), calcium chelators, calcium antagonists, and calcium channel blockers [Figure 3].
|Figure 3: Major pharmacological approaches include the development of drugs that inhibit cyclooxygenases, receptor antagonists, and modulators of cyclases|
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Before discussing studies related to the major antiplatelet therapies, for the sake of providing readers some knowledge of the type of antiplatelet studies that have been explored before, we will list a few examples for each class of platelet function-inhibitory drugs. ,, COX inhibitors include aspirin, phenylbutazone, ibuprofen, fenoprofen, fluribuprofen, naproxen, butylhydroxyanisole, butylated hydroxytoluene, and diphenylamine. Thromboxane synthetase inhibitors include benzydamine, imidazole congeners, 9,11-azo-13oxa-15 hydroxyprostanoic acid, and 9,11-azoprosta-5-13dienoic acid (U-51605). Thromboxane receptor antagonists include vapiprost (SN309), 13 azaprostanoic acid, isoprostane (8epi-PGF 2 alpha), and (3-pyridinyl) alkanoic acids. Stimulators of cyclases include aCyclases; PGE 1 , PGI 2 , adenosine, forskolin, coleonol gCyclases; nitric oxide, nitroglycerine, nitroprusside, Sin-1, nitrosoglutathione, and free radicals. Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors include dipyridamole and related compounds such as RA233, RA433, VK744, VK774, methylxanthines, theophylline, caffeine, papaverine, and aminophylline. Serine protease inhibitors include heparin, hirudin, low molecular weight heparins, and synthetic biosimilars. Calcium antagonists include cAMP, cyclic guanosine monophosphate, verapamil, nifedipine, diltiazem, quin-2AM, BAPTA-AM, mepacrine, and trifluoperazine. Studies from our laboratory as well as that of others have demonstrated that none of these agents are capable of effectively blocking platelet interactions with vessel wall or with cell matrix components.  In addition, we have to remember that in vivo platelet activation is accomplished by a variety of small molecules, enzymes, peptides, proteins, and cell matrix components. Just blocking one receptor or one pathway will not be able to inhibit platelet activation in acute clinical conditions. ,,
| Clinical Complications Needing Antiplatelet Therapies|| |
Clinical applications of antiplatelet drugs include conditions such as CAD (acute myocardial infarction, unstable angina, and re-occlusive restenosis), cerebrovascular disease (transient ischemic attack, complete stroke, and carotid-endarterectomy), peripheral vascular disease (peripheral arterials disease and peripheral venous disease), small vessel disease, and situations where thrombus formation needs to be prevented on medical implants, artificial surfaces, preoperational conditions, and before and during cardiac and cerebrovascular interventional procedures. ,,,,,,,,,
One of the great success stories of modern day discovery of a drug on evidence-based science is the development of GP11b/111a antagonists. Professor Barry S. Coller and his associates did extensive work in the development of a monoclonal antibody (10E5) that blocked fibrinogen binding to platelets. Experiments that led to this discovery and the clinical studies that helped them to develop a potent antiplatelet therapy make a superb story in the modern day drug discovery initiatives. We were fortunate to have Prof. Coller as our chief guest at the SASAT-1996 conference in Bengaluru. The GP11b/111a receptor complex numbers between 60,000 and 80,000 copy per platelet and play a critical role in fibrinogen binding and aggregation of platelets. The clinical data supporting the use of these classes of inhibitors were first established with abciximab (EPIC and EPILOG trials) and eptifibatide (IMPCT 11 and ESPIRIT) trials. Both were found to achieve significant improvements in reducing the mortality in patients undergoing percutaneous coronary interventions (PCIs). ,,,,,, Glycoprotein 11b/111a inhibitors are antiplatelet drugs that are commonly used in treating patients who have unstable angina, certain types of heart attacks, and in combination with angioplasty with or without stent placement. These drugs are given in combination with heparin or aspirin to prevent clotting before and during invasive cardiac and cerebrovascular procedures. Specific inhibitors of this class of drugs in use include abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These drugs are usually administered as intravenous injections or IV infusion during hospitalization.
What are some of the concerns related to the use of this class of drugs in antiplatelet therapies? Currently, use of these types of drugs is limited because of the need to administer them by constant intravenous infusion. Since it is not easy to reverse their effect, there are chances of increased bleeding if the dosage is not well within the required limit. There is also some concern about immunogenicity. The second-generation drugs of this class are the group of synthetics that target a GP11b/111a recognition site for an Arg-Gly-Asp sequence found in fibrinogen. When these classes of drugs occupy the receptor site, GP11b/111a is no longer functional as the aggregation promoting receptor. There is continued effort to develop orally active arginine-glycine-aspartic mimics for therapeutic applications. There is a window of opportunity for synthetic chemists to develop novel organic molecules, which can compete for this active site on the platelet membrane and provide an alternate for ReoPro-like molecules, which can be used only by IV route and as such have limited clinical application.
Another class of drugs that were developed on the basis of available scientific evidence is ADP receptor antagonists. Since the time studies by Hellem (1960) observed that small molecules from red cells caused platelets to adhere to the glass and aggregate, there is considerable interest in the development of ADP receptor antagonists. ,,,,,,,, Clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of acute vascular events. CAPRIE steering committee concluded that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin. ,
| Clinical Trials of Antiplatelet Drugs|| |
Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing clinical vascular complications. Data for aspirin as a drug of choice for the primary prevention strategies come from ATT' Collaboration, which evaluated 95,456 patients in six clinical trials.  The current ACC/AHA guidelines recommend the use of low-dose aspirin for primary prevention.  Both aspirin and clopidogrel as the drugs of choice have been quite effective. ,,,,,,,, The ATT was set up to provide updated information about the benefits and hazards, among particular types of patients, of antithrombotic therapy. In the 2002 analyses, 200,000 high-risk individuals in 287 studies were compared. Aspirin was the most widely studied antiplatelet drug. Indirect and direct comparisons suggested that doses of 75-100 mg daily were at least as effective as higher daily doses. In the 2009 analyses, 95,000 low-risk individuals in six primary prevention trials were compared. In the primary prevention trials, the absolute risk of a serious event was an order of magnitude less than in the secondary prevention trials. In the secondary prevention trials, aspirin is of substantial benefit. It reduces nonfatal events by much more than it would increase major extracranial bleeds (BMJ: 2002:234:71-86, lancet 2009; 373:1849-60). In an earlier article, Sudlow and Baigent (ao GHR: Handbook of Platelet Physiology and Pharmacology, 1999 Kluwer Publication) reviewed all the available randomized trial evidence for the effects of antiplatelet therapy in the treatment and prevention of major vascular outcomes as summarized by the ATT Collaboration in 1994. The 2002 ATT analyses showed that aspirin or some other antiplatelet regimen was of clear net benefit for those who have occlusive vascular disease. For primary prevention, however, the balance between risks and benefits was less clear. ,,,
Given the fact that ATT Collaboration does not discuss the controversial area of aspirin and clopidogrel resistance, I have briefly discussed this phenomenon. In recent years, several studies have reported the existence of a strange phenomenon of resistance to these drugs. , However, if one looks at these studies, one can see the flaw in these studies. Aspirin, for instance, is an irreversible inhibitor of COX, an enzyme, which converts substrate arachidonic acid to active metabolites, prostaglandin endoperoxides. The bioactive molecules are further converted to thromboxanes, which are the real agonists that induce platelet activation. In our experience of four decades, we have never found anyone whose platelet COXs are resistant to the action of aspirin.  However, we have demonstrated that if platelets are first exposed to short-acting ibuprofen, those platelets are resistant to the action of aspirin.  Majority of studies, describing aspirin resistance, have based their conclusion on results obtained by functional studies using various platelet agonists other than arachidonic acid. Similarly, clopidogrel studies also should be done, using the specific agonist ADP, to titrate platelet aggregation response, postclopidogrel treatment. Having said that, we would like to bring the attention of the readers to the observations in several clinical studies, in which those individuals, who have increased urinary metabolites of thromboxane, in spite of aspirin prophylaxis, are at risk for developing acute CVD events. Given these reports, it is important to customize the antiplatelet prophylaxis with functional studies as well as by monitoring urinary metabolites.
A new meta-analysis of clopidogrel clinical trials has shown that patients with either one or two loss-of-function CYP2C19 alleles, undergoing PCI on normal doses of clopidogrel, have an increased risk of cardiovascular events, compared with noncarriers. In these studies, the researchers explain that the CYP2C19 enzyme plays a key role in clopidogrel metabolism, and the carriers of reduced function variants in the CYP2C19 gene have lower active clopidogrel metabolite levels and diminished platelet inhibition. The findings of this collaborative meta-analysis demonstrate that common genetic variants in the CYP2C19 gene are associated with almost one in three patients not receiving ideal protection from ischemic events, when treated with the standard doses of clopidogrel for PCI. Given how widely clopidogrel is used to treat patients with CVD, determination of the optimal antiplatelet treatment doses or regimens for individual patients is needed to tailor the therapy appropriately. The total knowledge base on this topic now shows a definite increased risk of stent thrombosis and other cardiac events in the carriers of CYP2C19 loss-of-function alleles. It is widely known that poor platelet function suppression is associated with poor outcomes. 
To customize antiplatelet therapy of the two most commonly used antiplatelet drugs (aspirin and clopidogrel), one needs to do the following studies. For aspirin prophylaxis, determine the platelet aggregation response to arachidonic acid and determine the ability of aspirin-treated platelets to generate thromboxane or monitor urinary metabolites of thromboxane. For clopidogrel prophylaxis, determine the ADP-mediated platelet aggregation response or determine CYP2C19 functional alleles. Alternately, use new clopidogrel (Plavix) point-of-care assay for the rapid determination of antiplatelet activity (Bansal et al.; Trauma 2011;70:65-9). However, various guidelines published by major professional societies do not advocate such studies for the optimization of standard of care with antiplatelet therapy. Lack of an easy-to-do assay for monitoring platelet function limits the validation/optimization of antiplatelet therapies. There is a great need for the development of a point-of-care assay to monitor the status of circulating blood in terms of its thrombotic state or otherwise, similar to monitoring of the effect of anticoagulation therapy with INRs (Rao GHR: Stroke: 2009;40:2271-72). We at the University of Minnesota have validated a platelet reaction-monitoring device, which uses shear-induced activation of platelets and clotting time (Rao GHR: New point-of-care methods for monitoring antiplatelet therapy. A symposium Sponsored by Eli Lilly and Company: XX1 st Congress of the International Society on Thrombosis and Hemostasis, Geneva, Switzerland, 2007) [Figure 4].
|Figure 4: Platelet reactivity monitor uses a drop of fresh blood to monitor shear-induced activation and clotting time. Disposable cassettes with capillary are used to generate flow and required shear force. Courtesy: Blood Biocompatibility Laboratory, University of Minnesota|
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Based on the results of 11 clinical studies, an extensive guideline has been developed and published recently on the duration of dual antiplatelet therapy (DAPT) (DAPT: Aspirin plus a P2Y 12 inhibitors; clopidogrel, prasugrel, or ticagrelor) in patients with CAD. Among P2Y 12 inhibitors, cilostazol, ticagrelor, and cangrelor are direct-acting drugs, and prasugrel and clopidogrel are prodrugs. When it comes to the clinical application of DAPT for studies of long duration for an additional 18-36 months after drug-eluting stent placement, there was an absolute decrease in late stent thrombosis and ischemic complications.  As far as DAPT for coronary artery bypass graft (CABG) was concerned, it was associated with a significant lower vein graft occlusion at 1 year versus antiplatelet monotherapy, but with no such improvement in arterial graft patency. Of course, major bleeding was more frequent with DAPT compared to monotherapy. Aspirin remains the drug of choice for antiplatelet therapy for patients with acute coronary syndrome (ACS). DAPT recommendation beyond a minimum recommended period was associated with increased bleeding and thereby offsets the benefits of DATP. ,, Therefore, careful monitoring of patients and customization of therapy are essential.
DAPT with aspirin and P2Y 12 inhibitors are the antiplatelet therapy choices worldwide for the care of ACS patients and those undergoing coronary interventional procedures such as PCI or CABG. These classes of antagonists inhibit only two specific pathways of platelet activation and minimally affect other pathways of platelet activation. These limitations may explain why even patients with DAPT experience recurrent ischemic events. Given these observations, currently, two oral thrombin receptor antagonists (PAR-1) are under clinical evaluation. , From time to time, several other agents that target various platelet signaling pathways have been developed and evaluated in Phase 1 and Phase 2 trials. They include glycoprotein V1 antagonist (6B4-Fab antibody), serotonin receptor inhibitor (saprogrelate, APD791), prostaglandin E receptor antagonist (DG-041), nitric oxide donors (LA846, LA419), nitric oxide substrate, L-arginine, and phosphatidylinositol 3-kinase inhibitors (TGX-221). Prostaglandin/thromboxane receptor antagonists such as GR32191, ifetroban, and sulotorban had disappointing results in Phase 1 and Phase 2 clinical trials. Antiplatelet drugs that are in preclinical studies include inhibitors of platelet adhesion; vWF (Mab, aptamer), GP1b/V/1X (peptide, MAB), GP V1 (Mab, small molecule), collagen (protein) P13K inhibitors, intracellular targets; cytoplasmic tail of Beta3-integrin, and tyrosine kinase inhibitors (Src, Syk). Dual antiplatelet therapy has become the standard of care in the management of a variety of platelet-related clinical complications. However, emerging antiplatelet therapies are aimed at developing more potent novel drugs, which would offer better protection by reducing ischemic events, without increased bleeding. Currently, prasugrel, ticagrelor, cangrelor, oral thrombin antagonist SCH 530348, and elinogrel are undergoing extensive testing worldwide. We have made no attempt to review the development of oral anticoagulants. Readers are urged to refer to recent reviews on this topic for additional information. ,, As mentioned in the introduction, this is not a comprehensive review on this subject. Readers are urged to refer to the current guidelines and reviews by the experts. ,,,,,,,,,,,,,,,,,,,
The Ministry of Health and Family Welfare, India, has banned recently over 350 fixed-dose combinations (FDCs) as unsafe or ineffective. On the other hand, there are currently several ongoing international clinical studies with various FDCs for the management of hypertension and type-2 diabetes. For hypertension, a combination of benazepril plus amlodipine or hydrochlorothiazide has been tested. For the management of type-2 diabetes, the fixed-drug combinations include metformin with sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor, or meglitinide as well as thiazolidinedione-sulphonylurea. , Professor Salim Yusuf of Population Health Research Institute of Ontario, Canada, has hypothesized that a combination of four drugs (aspirin, B-blocker, a statin, and an angiotensin-converting enzyme inhibitor) could reduce CVD events by 75% in those with vascular disease.  Wald and Law have proposed a polypill containing three BP-lowering drugs for different classes with each, at half doses, aspirin, a statin and folic acid, for all individuals with established CVD and older than 55 years without CVD and have estimated that this approach will reduce CVD events by 88% and stroke by 80%.  The Central Drugs Standard Control Organization (CDSCO), India, has approved 41 FDC formulations for type-2 diabetes. This approval by the CDSCO has resulted in 500-marketed brands. According to an article in the Lancet (Valerie E, Pollock AM: Doi.org/10.1016/52213-8587 (14) 70239-6), most of the FDCs sold in India have not been shown to be safe and effective for the treatment of diabetes.
Various national and international health organizations such as the WHO, National Institutes of Health, USA, National Heart, Lung and Stroke, UK; Centers for Disease Control, USA, have advocated the development and validation of different FDCs. ,,, For a comprehensive review on this subject, readers are urged to refer to the work of Lonn et al. and associates.  In their overview on this subject, they conclude, "On the basis of available data on the individual component drugs, the polypill could potentially be widely used in secondary prevention and in selected high-risk individuals without CVD (e.g., those with hypertension or diabetes with additional risk factors). " The question that arises from this need for a cost-effective medication for managing "at risk" individuals and lack of robust clinical trial data on FDCs is how do we find an acceptable way to validate the comparative safety and efficacy of these FDCs? Authors of the Lancet article on FDCs conclude, "None of the metformin FDC trials meet WHO guidelines for approval as FDCs and recommended criteria for efficacy and safety. With such large volumes of metformin FDCs in the India market, this inadequate control is deeply worrying."
The role of platelets in the pathogenesis of inflammation, atherosclerosis, thrombosis, and stroke is well recognized. Variety of agonists are capable of mediating platelet activation including shear force in the circulating blood. , Activation of platelets by agonists initiates a series of biochemical events leading to the formation of second messengers, elevation of cytosolic calcium, shape change, contraction, release of pro-aggregatory components, and formation of hemostatic plug for the arrest of bleeding at the injured sites. Since the activation of GP11b/111a receptors and fibrinogen binding is considered the common pathway for aggregation, thrombus formation, and growth, several effective antiplatelet therapies have been developed related to this mechanism of activation. Similarly, antiplatelet therapies also have been developed using ADP receptor antagonists. As we have explained earlier, platelets are activated by a variety of external stimuli, and as such, there is a need to develop antiplatelet therapies that can offer better protection than these two inhibitory pathways and yet will not promote bleeding. There is a great window of opportunity for the development of novel antiplatelet therapies including FDCs. 
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