DailyMed Label: ticagrelor

DailyMed Label: ticagrelor

2020

DailyMed Prescription

ticagrelor

ticagrelor

Amneal Pharmaceuticals NY LLC

NDC: 69238-1134

NDC: 69238-1134

NDC: 69238-1134

NDC: 69238-1134

NDC: 69238-1134

NDC: 69238-1134

Ticagrelor tablets contain ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y 12 ADP-receptor. Chemically it is (1 S ,2 S ,3 R ,5 S )-3-[7-{[(1 R ,2 S )-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3 H -[1,2,3]-triazolo[4,5- d ]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The empirical formula of ticagrelor is C 23 H 28 F 2 N 6 O 4 S and its molecular weight is 522.57. The chemical structure of ticagrelor is: Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 mcg/mL at room temperature. Ticagrelor tablets for oral administration contain 90 mg of ticagrelor and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, talc and titanium dioxide. abc

Ticagrelor tablets are a P2Y 12 platelet inhibitor indicated to reduce the risk of cardiovascular (CV) death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. Ticagrelor tablets also reduce the risk of stent thrombosis in patients who have been stented for treatment of ACS. (1.1) to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events. While use is not limited to this setting, the efficacy of ticagrelor tablets were established in a population with type 2 diabetes mellitus (T2DM). (1.2) Ticagrelor tablets are indicated to reduce the risk of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. Ticagrelor tablets also reduce the risk of stent thrombosis in patients who have been stented for treatment of ACS [see Clinical Studies (14.1) ] . Ticagrelor tablets are indicated to reduce the risk of a first MI or stroke in patients with coronary artery disease (CAD) at high risk for such events [see Clinical Studies (14.2) ]. While use is not limited to this setting, the efficacy of ticagrelor tablets were established in a population with type 2 diabetes mellitus (T2DM).

ACS or History of MI In the management of ACS, initiate treatment with 180 mg oral loading dose. Then administer 90 mg twice daily during the first year. After one year, administer 60 mg twice daily. ( 2.1 ) Patients with CAD and No Prior Stroke or MI Administer 60 mg twice daily. ( 2.2 ) Use ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg. ( 2.3 , 5.2 ) In the management of ACS, initiate ticagrelor tablets treatment with a 180 mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year, administer 60 mg twice daily. Administer 60 mg twice daily. For all patients with ACS [see Dosage and Administration (2.1) ] . Administer ticagrelor tablets with a daily maintenance dose of aspirin of 75 mg to 100 mg [see Warnings and Precautions (5.2)   and  Clinical Studies (14) ] . A patient who misses a dose of ticagrelor tablets should take one tablet (their next dose) at its scheduled time. For patients who are unable to swallow tablets whole, ticagrelor tablets can be crushed, mixed with water and drunk. The mixture can also be administered via a nasogastric tube (CH8 or greater) [see Clinical Pharmacology (12.3) ] . Do not administer ticagrelor tablets with another oral P2Y 12 platelet inhibitor.

Ticagrelor Tablets, 90 mg are supplied as yellow colored, round, biconvex film-coated tablets marked with “A” above “11” on one side and plain on the other side. 90 mg tablets. ( 3 )

History of intracranial hemorrhage. ( 4.1 ) Active pathological bleeding. ( 4.2 ) Hypersensitivity to ticagrelor or any component of the product. ( 4.3 ) Ticagrelor tablets are contraindicated in patients with a history of intracranial hemorrhage (ICH) because of a high risk of recurrent ICH in this population [see Clinical Studies (14.1) , (14.2) ] . Ticagrelor tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see  Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Ticagrelor tablets are contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product.

Dyspnea was reported more frequently with ticagrelor than with control agents in clinical trials. Dyspnea from ticagrelor is self-limiting. ( 5.3 ) Severe Hepatic Impairment: Likely increase in exposure to ticagrelor. ( 5.6 ) Laboratory Test Interference: False negative platelet functional test results have been reported for Heparin Induced Thrombocytopenia (HIT). Ticagrelor is not expected to impact PF4 antibody testing for HIT. ( 5.7 ) Drugs that inhibit platelet function including ticagrelor increase the risk of bleeding [see Adverse Reactions (6.1) ] . If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events [see  Warnings and Precautions (5.4) and Adverse Reactions (6.1) ] . In PLATO the use of ticagrelor with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Therefore, after the initial loading dose of aspirin, use ticagrelor with a maintenance dose of aspirin of 75 mg to 100 mg [see  Dosage and Administration (2.3) and Clinical Studies (14.1) ] . In clinical trials, about 14% (PLATO and PEGASUS) to 21% (THEMIS) of patients treated with ticagrelor developed dyspnea. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment but led to study drug discontinuation in 0.9% (PLATO), 4.3% (PEGASUS), and 6.9% (THEMIS) of patients.  In a substudy of PLATO, 199 subjects underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no indication of an adverse effect on pulmonary function assessed after one month or after at least 6 months of chronic treatment. If a patient develops new, prolonged, or worsened dyspnea that is determined to be related to ticagrelor, no specific treatment is required; continue ticagrelor without interruption if possible. In the case of intolerable dyspnea requiring discontinuation of ticagrelor, consider prescribing another antiplatelet agent. Discontinuation of ticagrelor will increase the risk of myocardial infarction, stroke, and death. If ticagrelor must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with ticagrelor for five days prior to surgery that has a major risk of bleeding. Resume ticagrelor as soon as hemostasis is achieved. Ticagrelor can cause ventricular pauses [see Adverse Reactions (6.1) ] . Bradyarrhythmias including AV block have been reported in the postmarketing setting. Patients with a history of sick sinus syndrome, 2 nd or 3 rd degree AV block or bradycardia-related syncope not protected by a pacemaker were excluded from clinical studies and may be at increased risk of developing bradyarrhythmias with ticagrelor. Avoid use of ticagrelor in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor. There are no studies of ticagrelor patients with severe hepatic impairment [see Clinical Pharmacology (12.3) ] . False negative functional tests for Heparin Induced Thrombocytopenia (HIT) Ticagrelor has been reported to cause false negative results in platelet functional tests (to include, but may not be limited to, the heparin-induced platelet aggregation (HIPA) assay) for patients with Heparin Induced Thrombocytopenia (HIT). This is related to inhibition of the P2Y 12 -receptor on the healthy donor platelets in the test by ticagrelor in the affected patient’s serum/plasma. Information on concomitant treatment with ticagrelor is required for interpretation of HIT functional tests. Based on the mechanism of ticagrelor interference, ticagrelor is not expected to impact PF4 antibody testing for HIT.

The following adverse reactions are also discussed elsewhere in the labeling:

Avoid use with strong CYP3A inhibitors or CYP3A inducers. ( 7.1 , 7.2 ) Opioids: Decreased exposure to ticagrelor. Consider use of parenteral anti-platelet agent. ( 7.4 ) Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. ( 7.5 ) Monitor digoxin levels with initiation of or any change in ticagrelor. ( 7.6 ) Strong CYP3A inhibitors substantially increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromycin) [see Clinical Pharmacology (12.3) ] . Strong CYP3A inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor. Avoid use with strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine and phenobarbital) [see Clinical Pharmacology (12.3) ] . Use of ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of ticagrelor [see  Warnings and Precautions (5.2) and Clinical Studies (14.1) ] . As with other oral P2Y 12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor and its active metabolite presumably because of slowed gastric emptying [see Clinical Pharmacology (12.3) ] . Consider the use of a parenteral anti-platelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists. Ticagrelor increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology (12.3) ] . Ticagrelor inhibits the P-glycoprotein transporter; monitor digoxin levels with initiation of or change in ticagrelor therapy [see Clinical Pharmacology (12.3) ] .

Lactation: Breastfeeding not recommended. ( 8.2 ) Risk Summary Available data from case reports with ticagrelor use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ticagrelor given to pregnant rats and pregnant rabbits during organogenesis caused structural abnormalities in the offspring at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. When ticagrelor was given to rats during late gestation and lactation, pup death and effects on pup growth were seen at approximately 10 times the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicology studies, pregnant rats received ticagrelor during organogenesis at doses from 20 to 300 mg/kg/day. 20 mg/kg/day is approximately the same as the MRHD of 90 mg twice daily for a 60 kg human on a mg/m 2 basis. Adverse outcomes in offspring occurred at doses of 300 mg/kg/day (16.5 times the MRHD on a mg/m 2 basis) and included supernumerary liver lobe and ribs, incomplete ossification of sternebrae, displaced articulation of pelvis, and misshapen/misaligned sternebrae. At the mid-dose of 100 mg/kg/day (5.5 times the MRHD on a mg/m 2 basis), delayed development of liver and skeleton was seen. When pregnant rabbits received ticagrelor during organogenesis at doses from 21 to 63 mg/kg/day, fetuses exposed to the highest maternal dose of 63 mg/kg/day (6.8 times the MRHD on a mg/m 2 basis) had delayed gall bladder development and incomplete ossification of the hyoid, pubis and sternebrae occurred. In a prenatal/postnatal study, pregnant rats received ticagrelor at doses of 10 to 180 mg/kg/day during late gestation and lactation. Pup death and effects on pup growth were observed at 180 mg/kg/day (approximately 10 times the MRHD on a mg/m 2 basis). Relatively minor effects such as delays in pinna unfolding and eye opening occurred at doses of 10 and 60 mg/kg (approximately one-half and 3.2 times the MRHD on a mg/m 2 basis). Risk Summary There are no data on the presence of ticagrelor or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Ticagrelor and its metabolites were present in rat milk at higher concentrations than in maternal plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Breastfeeding is not recommended during treatment with ticagrelor. The safety and effectiveness of ticagrelor in pediatric patients have not been established. About half of the patients in PLATO, PEGASUS and THEMIS were ≥ 65 years of age and about 15% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. Ticagrelor is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. Avoid use of ticagrelor in patients with severe hepatic impairment. There is limited experience with ticagrelor in patients with moderate hepatic impairment; consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor. No dosage adjustment is needed in patients with mild hepatic impairment [see  Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] . No dosage adjustment is needed in patients with renal impairment [see Clinical Pharmacology (12.3) ] . Patients with End-Stage Renal Disease on dialysis Clinical efficacy and safety studies with ticagrelor did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, no clinically significant difference in concentrations of ticagrelor and its metabolite and platelet inhibition are expected compared to those observed in patients with normal renal function [see Clinical Pharmacology (12.3) ] . It is not known whether these concentrations will lead to similar reductions in risk of CV death, myocardial infarction or stroke or similar bleeding risk in patients with ESRD on dialysis as were seen in PLATO, PEGASUS, and THEMIS.

Ticagrelor Tablets, 90 mg are supplied as yellow colored, round, biconvex film-coated tablets marked with “A” above “11” on one side and plain on the other side. They are available as follows: Bottles of 60:                          NDC 69238-1134-6 Bottles of 100:                        NDC 69238-1134-1 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Ticagrelor and its major metabolite reversibly interact with the platelet P2Y 12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent. The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6-week study examining both acute and chronic platelet inhibition effects in response to 20 μM ADP as the platelet aggregation agonist. The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. As shown in Figure 4, IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours, and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 μM ADP. As shown in Figure 5, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert in Figure 5 shows that after 24 hours, IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%), indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel. After 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk or thrombotic risk track with IPA, for either ticagrelor or clopidogrel. Figure 4: Mean inhibition of platelet aggregation (±SE) following single oral doses of placebo, 180 mg ticagrelor or 600 mg clopidogrel Figure 5: Mean inhibition of platelet aggregation (IPA) following 6 weeks on placebo, ticagrelor 90 mg twice daily, or clopidogrel 75 mg daily Transitioning from clopidogrel to ticagrelor resulted in an absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to ticagrelor without interruption of antiplatelet effect [see Dosage and Administration (2) ] . Figure 3 Figure 4 Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers. Absorption Ticagrelor tablets can be taken with or without food. Absorption of ticagrelor occurs with a median t max of 1.5 h (range 1.0 to 4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median t max of 2.5 h (range 1.5 to 5.0). The mean absolute bioavailability of ticagrelor is about 36% (range 30% to 42%). Ingestion of a high-fat meal had no effect on ticagrelor C max , but resulted in a 21% increase in AUC. The C max of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and C max within 80% to 125% for ticagrelor and AR-C124910XX) with a median t max of 1.0 hour (range 1.0 to 4.0) for ticagrelor and 2.0 hours (range 1.0 to 8.0) for AR-C124910XX. Distribution The steady-state volume of distribution of ticagrelor is 88 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (> 99%). Metabolism CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30% to 40% of the exposure of ticagrelor. Excretion The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (58% in feces, 26% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t 1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite. Specific Populations The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented in Figure 6. Effects are modest and do not require dose adjustment. Patients with End-Stage Renal Disease on Hemodialysis In patients with end stage renal disease on hemodialysis AUC and C max of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor was administered immediately prior to dialysis showing that ticagrelor is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function. Figure 6: Impact of intrinsic factors on the pharmacokinetics of ticagrelor Effects of Other Drugs on Ticagrelor CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented in Figure 7 as change relative to ticagrelor given alone (test/reference). Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., cyclosporine) increase ticagrelor exposure. Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. T max was delayed by 1 to 2 hours. Exposure of the active metabolite decreased to a similar extent. Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine. Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition. Figure 7: Effect of co-administered drugs on the pharmacokinetics of ticagrelor Effects of Ticagrelor on Other Drugs In vitro metabolism studies demonstrate that ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgesterol, tolbutamide, digoxin and cyclosporine, see Figure 8. Figure 8: Impact of ticagrelor on the pharmacokinetics of co-administered drugs fugu5 fugu6 Figure 7 In a genetic substudy cohort of PLATO, the rate of thrombotic CV events in the ticagrelor arm did not depend on CYP2C19 loss of function status.

Carcinogenesis Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MRHD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MRHD based on AUC) was not carcinogenic in female rats. Mutagenesis Ticagrelor did not demonstrate genotoxicity when tested in the Ames bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay. Impairment of Fertility Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (> 15-fold the MRHD on the basis of AUC). Doses of ≥ 10 mg/kg/day given to female rats caused an increased incidence of irregular duration estrus cycles (1.5-fold the MRHD based on AUC).

PLATO PLATO (NCT00391872) was a randomized double-blind study comparing ticagrelor (N=9,333) to clopidogrel (N=9,291), both given in combination with aspirin and other standard therapy, in patients with acute coronary syndromes (ACS), who presented within 24 hours of onset of the most recent episode of chest pain or symptoms. The study’s primary endpoint was the composite of first occurrence of cardiovascular death, non-fatal MI (excluding silent MI), or non-fatal stroke. Patients who had already been treated with clopidogrel could be enrolled and randomized to either study treatment. Patients with previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. Patients could be included whether there was intent to manage the ACS medically or invasively, but patient randomization was not stratified by this intent. All patients randomized to ticagrelor received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. Patients in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if clopidogrel therapy had not already been given. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at investigator discretion. A daily maintenance dose of aspirin 75 mg to 100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local judgment. Patients were treated for at least 6 months and for up to 12 months. PLATO patients were predominantly male (72%) and Caucasian (92%). About 43% of patients were > 65 years and 15% were > 75 years. Median exposure to study drug was 276 days. About half of the patients received pre-study clopidogrel and about 99% of the patients received aspirin at some time during PLATO. About 35% of patients were receiving a statin at baseline and 93% received a statin sometime during PLATO. Table 7 shows the study results for the primary composite endpoint and the contribution of each component to the primary endpoint. Separate secondary endpoint analyses are shown for the overall occurrence of CV death, MI, and stroke and overall mortality. Table 7: Patients with outcome events (PLATO) Ticagrelor* N=9,333 Clopidogrel N=9,291 Hazard Ratio (95% CI) p -value   Events / 1000 patient years  Events / 1000 patient years    Composite of CV death, MI, or stroke 111  131  0.84 (0.77, 0.92) 0.0003 CV death 32  43  0.74 Non-fatal MI 64  76  0.84 Non-fatal stroke 15  12  1.24 Secondary endpoints † CV death 45  57 0.79 (0.69, 0.91) 0.0013 MI ‡ 65 76 0.84 (0.75, 0.95) 0.0045 Stroke ‡ 16 14 1.17 (0.91, 1.52) 0.22 All-cause mortality 51 65 0.78 (0.69, 0.89) 0.0003 * Dosed at 90 mg bid. †Note: rates of first events for the components CV Death, MI and Stroke are the actual rates for first events for each component and do not add up to the overall rate of events in the composite endpoint. ‡Including patients who could have had other non-fatal events or died. The Kaplan-Meier curve (Figure 9) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke in the overall study. Figure 9: Time to first occurrence of CV death, MI, or stroke (PLATO) The curves separate by 30 days [relative risk reduction (RRR) 12%] and continue to diverge throughout the 12-month treatment period (RRR 16%). Among 11,289 patients with PCI receiving any stent during PLATO, there was a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%) (HR 0.67, 95% CI 0.50 to 0.91; p =0.009). The results were similar for drug-eluting and bare metal stents. A wide range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcome. Some of these are shown in Figure 10. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the analyses show effects consistent with the overall results, but there are two exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin. These are considered further below. Most of the characteristics shown are baseline characteristics, but some reflect post-randomization determinations (e.g., aspirin maintenance dose, use of PCI). Figure 10: Subgroup analyses of (PLATO) Note: The figure above presents effects in various subgroups most of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Regional Differences Results in the rest of the world compared to effects in North America (US and Canada) show a smaller effect in North America, numerically inferior to the control and driven by the US subset. The statistical test for the US/non-US comparison is statistically significant ( p =0.009), and the same trend is present for both CV death and non-fatal MI. The individual results and nominal p -values, like all subset analyses, need cautious interpretation, and they could represent chance findings. The consistency of the differences in both the CV mortality and non-fatal MI components, however, supports the possibility that the finding is reliable. A wide variety of baseline and procedural differences between the US and non-US (including intended invasive vs. planned medical management, use of GPIIb/IIIa inhibitors, use of drug eluting vs. bare-metal stents) were examined to see if they could account for regional differences, but with one exception, aspirin maintenance dose, these differences did not appear to lead to differences in outcome. Aspirin Dose The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and use patterns were different in US sites from sites outside of the US. About 8% of non-US investigators administered aspirin doses above 100 mg, and about 2% administered doses above 300 mg. In the US, 57% of patients received doses above 100 mg and 54% received doses above 300 mg. Overall results favored ticagrelor when used with low maintenance doses (≤ 100 mg) of aspirin, and results analyzed by aspirin dose were similar in the US and elsewhere. Figure 10 shows overall results by median aspirin dose. Figure 11 shows results by region and dose. Figure 11: CV death, MI, stroke by maintenance aspirin dose in the US and outside the US (PLATO) Like any unplanned subset analysis, especially one where the characteristic is not a true baseline characteristic (but may be determined by usual investigator practice), the above analyses must be treated with caution. It is notable, however, that aspirin dose predicts outcome in both regions with a similar pattern, and that the pattern is similar for the two major components of the primary endpoint, CV death and non-fatal MI. Despite the need to treat such results cautiously, there appears to be good reason to restrict aspirin maintenance dosage accompanying ticagrelor to 100 mg. Higher doses do not have an established benefit in the ACS setting, and there is a strong suggestion that use of such doses reduces the effectiveness of ticagrelor. PEGASUS The PEGASUS TIMI-54 study (NCT01225562) was a 21,162-patient, randomized, double-blind, placebo-controlled, parallel-group study. Two doses of ticagrelor, either 90 mg twice daily or 60 mg twice daily, co-administered with 75 mg to 150 mg of aspirin, were compared to aspirin therapy alone in patients with history of MI. The primary endpoint was the composite of first occurrence of CV death, non-fatal MI and non-fatal stroke. CV death and all-cause mortality were assessed as secondary endpoints. Patients were eligible to participate if they were ≥ 50 years old, with a history of MI 1 to 3 years prior to randomization, and had at least one of the following risk factors for thrombotic cardiovascular events: age ≥ 65 years, diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance < 60 mL/min. Patients could be randomized regardless of their prior ADP receptor blocker therapy or a lapse in therapy. Patients requiring or who were expected to require renal dialysis during the study were excluded. Patients with any previous intracranial hemorrhage, gastrointestinal bleeding within the past 6 months, or with known bleeding diathesis or coagulation disorder were excluded. Patients taking anticoagulants were excluded from participating and patients who developed an indication for anticoagulation during the trial were discontinued from study drug. A small number of patients with a history of stroke were included. Based on information external to PEGASUS, 102 patients with a history of stroke (90 of whom received study drug) were terminated early and no further such patients were enrolled. Patients were treated for at least 12 months and up to 48 months with a median follow up time of 33 months. Patients were predominantly male (76%) Caucasian (87%) with a mean age 65 years, and 99.8% of patients received prior aspirin therapy. See Table 8 for key baseline features. Table 8: Baseline features (PEGASUS) Demographic % Patients < 65 years 45% Diabetes 32% Multivessel disease 59% History of > 1 MI 17% Chronic non-end stage renal disease 19% Stent 80% Prior P2Y 12 platelet inhibitor therapy 89% Lipid lowering therapy 94% The Kaplan-Meier curve (Figure 12) shows time to first occurrence of the primary composite endpoint of CV death, non-fatal MI or non-fatal stroke. Figure 12: Time to First Occurrence of CV death, MI or Stroke (PEGASUS) Ti = Ticagrelor BID; CI = Confidence interval; HR = Hazard ratio; KM = Kaplan-Meier; N = Number of patients. Both the 60 mg and 90 mg regimens of ticagrelor in combination with aspirin were superior to aspirin alone in reducing the incidence of CV death, MI or stroke. The absolute risk reductions for ticagrelor plus aspirin vs. aspirin alone were 1.27% and 1.19% for the 60 mg and 90 mg regimens, respectively. Although the efficacy profiles of the two regimens were similar, the lower dose had lower risks of bleeding and dyspnea. Table 9 shows the results for the 60 mg plus aspirin regimen vs. aspirin alone. Table 9: Incidences of the primary composite endpoint, primary composite endpoint components, and secondary endpoints (PEGASUS)     Ticagrelor * N=7,045 Placebo N=7,067     HR (95% CI) p -value       Events / 1000 patient years Events / 1000 patient years   Time to first CV death, MI, or stroke † 26 31 0.84 (0.74, 0.95) 0.0043 CV Death ‡, § 9 11 0.83 (0.68, 1.01) Myocardial infarction § 15 18 0.84 (0.72, 0.98) Stroke § 5 7 0.75 (0.57, 0.98) All-cause mortality ‡ 16 18 0.89 (0.76, 1.04) CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction; N = Number of patients. * 60 mg BID † Primary composite endpoint ‡ Secondary endpoints § The event rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component. In PEGASUS, the relative risk reduction (RRR) for the composite endpoint from 1 to 360 days (17% RRR) and from 361 days and onwards (16% RRR) were similar. The treatment effect of ticagrelor 60 mg over aspirin appeared similar across most pre-defined subgroups, see Figure 13. Figure 13: Subgroup analyses of ticagrelor 60 mg (PEGASUS) Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 10 10 10 10 10 THEMIS The THEMIS study (NCT01991795) was a double-blind, parallel group, study in which 19,220 patients with CAD and Type 2 Diabetes Mellitus (T2DM) but no history of MI or stroke were randomized to twice daily ticagrelor or placebo, on a background of 75 mg to 150 mg of aspirin. The primary endpoint was the composite of first occurrence of CV death, MI, and stroke. CV death, MI, ischemic stroke, and all-cause death were assessed as secondary endpoints. Patients were eligible to participate if they were ≥ 50 years old with CAD, defined as a history of PCI or CABG, or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery and T2DM treated for at least 6 months with glucose-lowering medication. Patients with previous intracerebral hemorrhage, gastrointestinal bleeding within the past 6 months, known bleeding diathesis, and coagulation disorder were excluded. Patients taking anticoagulants or ADP receptor antagonists were excluded from participating, and patients who developed an indication for those medications during the trial were discontinued from study drug. Patients were treated for a median of 33 months and up to 58 months. Patients were predominantly male (69%) with a mean age of 66 years. At baseline, 80% had a history of coronary artery revascularization; 58% had undergone PCI, 29% had undergone a CABG and 7% had undergone both. The proportion of patients studied in the US was 12%. Patients in THEMIS had established CAD and other risk factors that put them at higher cardiovascular risk; see Table 10. Table 10: Baseline risk factors (THEMIS)   Risk factor   % Patients  Type 2 Diabetes Mellitus  100%  Hypertension  92%  Dyslipidemia  87%  Multi-vessel CAD  62%  Obesity  43%  Heart failure  16%  Current smoking  11%  Chronic kidney disease  9%   Ticagrelor was superior to placebo in reducing the incidence of CV death, MI, or stroke. The effect on the composite endpoint was driven by the individual components MI and stroke; see Table 11. Table 11: Primary composite endpoint, primary endpoint components, and secondary endpoints (THEMIS) Ticagrelor N=9,619 Placebo N=9,601 HR (95% CI) p -value Events / 1000 patient years Events / 1000 patient years Time to first CV death, MI, or stroke * 24 27 0.90 (0.81, 0.99) 0.04 CV death † 12 11 1.02 (0.88, 1.18) Myocardial infarction † 9 11 0.84 (0.71, 0.98) Stroke † 6 7 0.82 (0.67, 0.99) Secondary endpoints CV death 12 11 1.02 (0.88, 1.18) Myocardial infarction 9 11 0.84 (0.71, 0.98) Ischemic stroke 5 6 0.80 (0.64, 0.99) All-cause death 18 19 0.98 (0.87, 1.10)  CI = Confidence interval; CV = Cardiovascular; HR = Hazard ratio; MI = Myocardial infarction.   *  Primary endpoint †  The event rate for the components CV death, MI and stroke are calculated from the actual number of first events for each component.  The Kaplan-Meier curve (Figure 14) shows time to first occurrence of the primary composite endpoint of CV death, MI, or stroke. Figure 14: Time to First Occurrence of CV death, MI or Stroke (THEMIS) The treatment effect of ticagrelor appeared similar across patient subgroups, see Figure 15. Figure 15: Subgroup analyses of ticagrelor (THEMIS)   Note: The figure above presents effects in various subgroups all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. 14 15

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