Diabetes andPlatelet Reactivity

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Number of people with diabetes by IDF Region, 2013

Source: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf

Diabetes is a huge and growing problem, and the costs to society are high and escalating

Source: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf

Top 10 countries / territories of number of people with

diabetes (20-79 years), 2013Diabetes caused 5.1 million deaths in 2013.Every six seconds a person dies from diabetes.

Source: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf

Cardiovascular disease is the most common cause of death and disability among people with diabetes. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction (heart attack), stroke, peripheral artery disease, and congestive heart failure. In people with diabetes, high blood pressure, high cholesterol, high blood glucose and other risk factors contribute to the increased risk of cardiovascular complications.

Prevalence (%) of diabetes (20-79 years) by income group and age

Source: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf

All nations – rich and poor – are suffering the impact of the diabetes epidemic.

WHO’s10 Facts About Diabetes1.About 347 million people worldwide have diabetes.2.Diabetes is predicted to become the seventh leading cause of

death in the world by the year 2030.3.There are two major forms of diabetes.4.A third type of diabetes is gestational diabetes.5.Type 2 diabetes is much more common than type 1 diabetes.6.Cardiovascular disease is responsible for between 50% and 80% of

deaths in people with diabetes.7.In 2004, an estimated 3.4 million people died from consequences

of high fasting blood sugar.8.80% of diabetes deaths occur in low- and middle-income countries.9.Diabetes is a leading cause of blindness, amputation and kidney

failure.10.Type 2 diabetes can be prevented.

Source: http://www.who.int/features/factfiles/diabetes/facts/en/index9.html

Impact of Diabetes on the Blood SystemDifferent systems involved in the maintenance of vascular integrity and patency are impaired in DM

•Platelet function•Endothelial function•Coagulation pathways•Fibrinolysis

More importantly, the alterations in

• the coagulation cascade – with a shift towards a more prothrombogenic state

• platelet function increasing platelet aggregation and adhesion

Patti G et al. Circ J 2014; 78: 33 – 41.

Diabetic patients are at higher risk of recurrent ischemic events following PCI and

ACSDiabetes has been associated with a higher

baseline platelet reactivity described as

“Diabetesthrombocytopathy”

Patti G et al. Circ J 2014; 78: 33 – 41.

Platelets of patients with DM have been proven to be hyper-reactive, which leads to intensified adhesion,

activation and aggregation

Patti G et al. Circ J 2014; 78: 33 – 41.

Diabetes is associated with increased risk of Thrombosis

Michael T. Johnstone, Aristidis Veves. Diabetes and Cardiovascular Disease. Pg.no.109.

Potential Impact of Insulin Resistance and Diabetes on ThrombosisFactors predisposing to thrombosis

•Increased platelet mass•Increased platelet activation

o Platelet aggregationo Platelet degranulation

•Decreased platelet cAMP and cGMPo Thromboxane synthesis

•Increased procoagulant capacity of platelets•Elevated concentrations and activity of procoagulants

o Fibrinogeno von Willebrand factor and procoagulant activityo Thrombin activityo Factor VII coagulant activity

•Decreased concentration and activity of anti-thrombotic factorso Anti-thrombin III activityo Sulfation of endogenous heparino Protein C concentration

cAMP- Cyclic adenosine monophosphate; cGMP- Cyclic guanosine monophosphate

Cardiovascular Disease and Diabetes

•Diabetic patients are 2–4 times more likely to have heart disease or suffer a stroke than non-diabetic patients[NICE 2008:A,B]

•80% of patients with type 2 diabetes die of CV disease[Chiquette 2002:A]

•Dyslipidaemia and insulin resistance in diabetic patients have been linked to an increased risk of atherosclerosis[Turner 1998:A–D; Dunn 2005:A–C]

▫Insulin resistance leads to vascular endothelial cell dysfunction, enhanced platelet activation and aggregation, and proatherogenic cellular processes[Dunn 2005:A–C]

•Other common co-morbidities in patients with type 2 diabetes may also contribute to an increased risk of atherosclerosis

▫Hypertension[Turner 1998:A–D]

▫Obesity[Wilson 2008:A,B]

▫Nephropathy[ADVANCE Collaborative Group 2008:A]CV, cardiovascular; HDL, high-density lipoprotein; LDL, low-density lipoprotein.National Institute for Health and Clinical Excellence (NICE). Diabetes treatment guidelines. 2008; Chiquette E, et al. Curr Atheroscler Rep 2002;4:134–142; Dunn EJ, et al. Curr Mol Med 2005;3:323–332; Turner RC, et al. BMJ 1998;316:823–828; Wilson PWF, et al. Circulation 2008;118:124–130;ADVANCE Collaborative Group, et al. N Engl J Med 2008; 358:2560–2572.

Cardiovascular Disease and Diabetes

In patients with diabetes:▫CVD is the primary cause of death among 55% of patients with

diabetes compared with 31% of deaths in the general population.

▫Ischemic heart disease (IHD) accounts for about 40% of deaths in patients with diabetes.

▫The risk of mortality due to diseases of the heart is 2 to 4 times higher among patients with diabetes than in persons without diabetes.

▫Data from a 10-year period show a 37% increase in the number of hospitalizations that listed major CVD as the primary diagnosis and diabetes as a secondary diagnosis.

Geiss LS, et al. In Diabetes in America, 2nd ed. NIH Publication No. 95-1468.1995:243,558.Centers for Disease Control and Prevention. National Vital Statistics Reports. 2000;48:5.

Diabetic patients are at very high Cardiovascular risk

•Patients with diabetes mellitus (DM) show hyper-reactive platelet profiles, Contribute to their higher risk for atherothrombotic events

and Higher prevalence of impaired response to standard dual

anti-platelet therapy (aspirin plus clopidogrel).

•These high-risk features intrinsic to DM underscore the need Optimized anti-platelet strategies in these patients More intensive oral anti-platelet therapy may be of particular

benefit among patients with DM.

Abbreviated Prescribing Information

Ticagrelor Tablets Brilinta® 90 mg

Composition:Each film coated tablets contains:Ticagrelor 90mg Colors: Ferric oxide Yellow USP-NF & Titanium Dioxide I.P.PHARMACEUTICAL FORM90 mg - Round, biconvex, yellow, film-coated tablets. The tablets are marked with “90” above “T” on one side and plain on the otherMechanism of action: BRILINTA contains ticagrelor a member of the chemical class Cyclo Pentyl Triazolo Pyrimidines (CPTP), which is a selective and reversible adenosine diphosphate (ADP) receptor antagonist acting on the P2Y12 ADP-receptor that can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is orally active, and reversibly interacts with the platelet P2Y12 ADP receptor. Ticagrelor does not interact with the ADP binding site itself, but its interaction with platelet P2Y12 ADP-receptor prevents signal transduction.INDICATIONS AND USAGEBRILINTA is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with Acute Coronary Syndromes ([ACS] unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]) including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG).DOSAGE AND ADMINISTRATION: BRILINTA treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily.For oral use: BRILINTA can be taken with or without food. Patients taking BRILINTA should also take ASA daily unless specifically contraindicated. Following an initial dose of ASA, BRILINTA should be used with a maintenance dose of ASA of 75 150 mg. Lapses in therapy should be avoided. A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its ‑scheduled time.Physicians who desire to switch patients from clopidogrel to BRILINTA should administer the first 90 mg dose of BRILINTA 24 hours following the last dose of clopidogrel. Treatment is recommended for at least 12 months unless discontinuation of BRILINTA is clinically indicated. In patients with Acute Coronary Syndromes (ACS), premature discontinuation with any antiplatelet therapy, including BRILINTA, could result in an increased risk of cardiovascular death, or myocardial infarction due to the patient’s underlying disease.Special warnings and special precautions for use Bleeding riskAs with other antiplatelet agents, the use of BRILINTA in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of thrombotic events. If clinically indicated, BRILINTA should be used with caution in the following patient groups: Consideration should be given to the following:Patients with a propensity to bleed (e.g. due to recent trauma, recent surgery, active or recent gastrointestinal bleeding, or moderate hepatic impairment). The use of BRILINTA is contraindicated in patients with active pathological bleeding and in those with history of intracranial haemorrhage, and severe hepatic impairment. Patients with concomitant administration of medicinal products that may increase the risk of bleeding (e.g. non-steroidal anti-inflammatory drugs (NSAIDS), oral anticoagulants and/or fibrinolytics within 24 hours of BRILINTA dosing). No data exist with BRILINTA regarding a haemostatic benefit of platelet transfusions; circulating BRILINTA may inhibit transfused platelets. Since co administration of BRILINTA with desmopressin did not decrease template bleeding time, desmopressin is unlikely to be effective in managing clinical bleeding events. Anti-fibrinolytic therapy (aminocaproic acid or tranexamic acid) and/or recombinant factor VIIa may augment haemostasis. BRILINTA may be resumed after the cause of bleeding has been identified and controlled.Surgery:If a patient requires surgery, physicians should consider each patient's clinical profile as well as the benefits and risks of continued antiplatelet therapy when determining when discontinuation of BRILINTA treatment should occur. Because of the reversible binding of BRILINTA, restoration of platelet aggregation occurs faster with BRILINTA compared to clopidogrel. In the OFFSET study, mean Inhibition of Platelet Aggregation (IPA) for BRILINTA at 72 hours post-dose was comparable to mean IPA for clopidogrel at 120 hours post-dose. The more rapid offset of effect may predict a reduced risk of bleeding complications, e.g, in settings where antiplatelet therapy must be temporarily discontinued due to surgery or trauma. In PLATO patients undergoing CABG, BRILINTA had a similar rate of major bleeds compared to clopidogrel at all days after stopping therapy except Day 1 where BRILINTA had a higher rate of major bleeding. If a patient is to undergo elective surgery and antiplatelet effect is not desired, BRILINTA should be discontinued 5 days prior to surgery.

Patients with moderate hepatic impairment:Caution is advised in patients with moderate hepatic impairment because BRILINTA has not been studied in these patients. Use of BRILINTA is contraindicated in patients with severe hepatic impairment. Patients at risk for bradycardiac events:Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardiac events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardiac-related syncope) were excluded from the main study evaluating the safety and efficacy of BRILINTA. Therefore, due to the limited clinical experience in these patients, caution is advised. Dyspnoea:Dyspnoea, usually mild to moderate in intensity and often resolving without need for treatment discontinuation, is reported in patients treated with BRILINTA (approximately 13.8% ). The mechanism has not yet been elucidated. If a patient reports new, prolonged or worsened dyspnoea this should be investigated fully and if not tolerated, treatment with BRILINTA should be stopped. Other:Based on a relationship observed in PLATO between maintenance ASA dose and relative efficacy of ticagrelor compared to clopidogrel, co-administration of ticagrelor and high maintenance dose ASA (>300 mg) is not recommended. Renal impairment: No dosing adjustment is needed in patients with renal impairment. No information is available concerning treatment of patients on renal dialysis. Pregnancy and lactation:No clinical study has been conducted in pregnant or lactating women. Limited clinical data on exposure to BRILINTA during pregnancy are available. BRILINTA should be used during pregnancy only if the potential benefit to the mother justifies any potential risks to the foetus.ContraindicationsHyper-sensitivity to ticagrelor or any of the excipients.Active pathological bleedingHistory of intracranial haemorrhageSevere hepatic impairmentADVERSE REACTIONS: The most commonly reported adverse events in patients treated with ticagrelor were dyspnoea, headache, and epistaxis and these events occurred at higher rates than in the clopidogrel treatment group. During the treatment period, the BRILINTA group had a higher incidence of discontinuation due to adverse events than clopidogrel (7.4% vs. 5.4%).List of excipients: Tablet core: Mannitol, Dibasic calcium phosphate, Magnesium stearate, Sodium starch glycolate, Hydroxypropyl cellulose.Tablet Coat : Talc, Titanium dioxide, Ferric oxide yellow, Polyethylene glycol 400, Hypromellose. Incompatibilities: Not applicable. Shelf life: refer outer pack. Storage: Do not store above 300C. Pack size: refer to outer carton BRILINTA is a trademark of the AstraZeneca group of companies.For Further Information Contact:AstraZeneca Pharma India LimitedAvishkar”, Off Bellary road, Hebbal,BANGALORE – 560 024, Date of revision of text: October 2013.V1: 08/10/2013For more information refer full prescribing information For the use of a Cardiologist and Internal Medicine Specialities or a Hospital or a Laboratory only.

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