Module 1: Introduction to venous thromboembolism

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd Medical Information on 0800 731 1736 or [email protected]

Prescribing information for Eliquis (apixaban) can be found at the end of this presentation These slides are promotional in nature and have been produced by the BMS/Pfizer Alliance PP-ELI-GBR-0382

Date of preparation: September 2016

VTE: clot formation within the venous circulation 2

Pulmonary embolism (PE) Thromboemboli detach and travel through the right side of the heart to block vessels in the lungs

Embolus

Migration

1

Thrombus VTE, venous thromboembolism PP-ELI-GBR-0382

Date of preparation: September 2016

Deep vein thrombosis (DVT) Thrombi form predominantly in venous valve pockets and other sites of presumed stasis

Adapted from Tapson VF. N Engl J Med. 2008;358:1037–52. Tapson VF. N Engl J Med 2008;358:1037–52.

VTE is a prevalent and severe disease compared with other public health burdens 600,000

543,454

500,000

Annual no. of deaths

Estimated annual mortality rate in Europe*

400,000 300,000 200,000 86,831

100,000 0

VTE-related deaths

*25 member-state countries

Breast cancer

63,636

53,599

Prostate cancer

Transport accidents

5860 AIDS

Created from Cohen et al. Thromb Haemost 2007;98:756–64.

Implementation of appropriate VTE prophylaxis is a high priority given the high mortality rate associated with VTE in the EU PP-ELI-GBR-0382

Date of preparation: September 2016

Cohen et al. Thromb Haemost 2007;98:756–64.

VTE is a serious medical problem 





DVT is a common disease, often asymptomatic, presenting in about 1.6 per 1,000 people/year1 VTE causes an estimated 60,000 deaths each year in the UK2 Incidence rises with3: Age – incidence ~ 1/100 in patients >80 years Obesity – 2–3 fold in BMI>30 kg/m3 Hospitalisation – 10-fold

60,000

Complications include PE3 PE often results from asymptomatic DVT and may present with clinical complications, even death3

40,000

–

– –  

– – –



Estimated number of deaths in the UK per year (2010)6–9

Fatal PE is under diagnosed because of non specificity of symptoms3 About 10% of hospital deaths were attributed to PE in the UK3,4 Non-fatal PE may delay discharge or require readmission to hospital3

56,167

20,000 2,243

485

267

Traffic accidents

MRSA

HIV

0 VTE

It is estimated that a similar proportion of VTE events occur in hospital and in the community5

1. Khan et al. Dinajpur Med Col J 2014 Jan; 7 (1):52–59; 2. Report of the Independent Group on the Prevention of VTE in Hospitalised Patients. Department of Health 2007; 3.SIGN Guideline 122 Prevention and management of venous thromboembolism; 4. Sandler et al. J R Soc Med 1989; 82:203–5; 5.Select committee on health http://www.publications.parliament.uk/pa /cm200405/cmselect/cmhealth/99/99we07.htm. Last accessed March 2016; 6. Eurostat http://appsso.eurostat.ec.europa.eu/nui/submitViewTableAction.do; 7. Office for National Statistics http://www.ons.gov.uk/ons/rel/subnational-health2/deaths-involving-mrsa/2007-to-2011/index.html . Last accessed March 2016; 8. Cohen et al. Thromb Haemost 2007;98:756–64; 9. Office for National Statistics https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsinvolvingmrsaenglandandwales/2012-08-22. Last accessed March 2016.

PP-ELI-GBR-0382 Date of preparation: September 2016

Pathophysiology of VTE

Hypercoagulability

Virchow’s Triad Endothelial injury

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Stasis of venous blood flow

Adapted from Kyrle PA et al. Blood 2009; 114:1138–39.

Risk factors for VTE1 Risk factors for VTE include: Active cancer or cancer treatment

Age over 60 years

Critical care admission

Dehydration

Known thrombophilias

Obesity (BMI over 30 kg/m2)

One or more significant medical comorbidities (e.g. heart disease; metabolic, Personal history or first-degree relative with endocrine or respiratory pathologies; acute a history of VTE infectious diseases; inflammatory conditions) Use of hormone replacement therapy

Use of oestrogen-containing contraceptive therapy

Varicose veins with phlebitis

Pregnancy

A surgical procedure with a total anaesthetic and surgical time of more than 90 minutes, or 60 minutes if the surgery involves the pelvis or lower limb

Acute surgical admission with inflammatory or intra-abdominal condition

BMI, body mass index PP-ELI-GBR-0382

Date of preparation: September 2016

1. NICE clinical guideline (CG92). Venous thromboembolism: reducing the risk for patients in hospital. January 2010.

Provoked vs unprovoked VTE 



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Provoked VTE – With an antecedent (within 3 months) and transient major clinical risk factor for VTE – for example, surgery, trauma, significant immobility (being bedbound, unable to walk unaided or likely to spend a substantial proportion of the day in bed or in a chair), pregnancy or puerperium, or – Undergoing hormonal therapy (oral contraceptive or hormone replacement therapy) Unprovoked VTE – With no antecedent major clinical risk factor for VTE, who is not having hormonal therapy (oral contraceptive or hormone replacement therapy) or – With no active cancer

Date of preparation: September 2016

1. NICE clinical guideline (CG144). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. July 2012.

VTE is associated with significant morbidity and mortality Morbidity

Mortality

 Without extended treatment after unprovoked VTE, a recurrence may occur in:1

 Nearly 550,000 annual deaths due to VTE across the EU3

– 11% of patients after 1 year – 29.1% of patients after 5 years

 VTE is associated with longterm, clinically significant complications, including post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension2 PP-ELI-GBR-0382

Date of preparation: September 2016

 PE may be responsible for 1 in ~10 hospital deaths4

1. Prandoni et al. Haematologica 2007;92:199–205; 2. Palareti. Scientifica 2012;2012:1–17; 3. Cohen et al. Thromb Haemost 2007;98:756–764; 4. Geerts et al. Chest 2004;126(3 Suppl):338S–400S.

The risk of recurrent VTE is high Risk factors associated with VTE recurrence         

Idiopathic presentation2,3 Thrombophilia2 Presentation of primary DVT2 Cancer3 Residual thrombus mass4 Proximal DVT3,5 Increasing age2,5 Male gender5 D-dimer5

Adapted from Martinez et al. 20141

•

These were patients without active cancer1 PP-ELI-GBR-0382

Date of preparation: September 2016

1. Martinez et al. Thromb Haem 2014;112:255‒263; 2. Prandoni et al. Haematologica 2007;92:199–205; 3. Hansson et al. Arch Intern Med 2000;160:769–774; 4. Prandoni et al. Ann Intern Med 2002;137:955–960; 5. Eichinger et al. Circulation 2010;121:1630–1636.

The incidence of recurrent VTE is highest amongst the young Recurrent DVT - Males

IR of recurrent VTE per 100 person-years

Incidence of recurrent VTE

Recurrent DVT - Females

8 7 6

Recurrent PE - Males Recurrent PE - Females

5 4 3 2 1 0 89

Age (years) Adapted from Martinez et al. 20141

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Date of preparation: September 2016

1. Martinez et al. Thromb Haem 2014;112:255‒263.

Annual event rates of recurrent VTE 

Patients with unprovoked VTE had the highest risk of recurrence Duration of follow-up

Provoked by surgery

Provoked by nonsurgical factor

Unprovoked (idiopathic)

12 months

1.0%/yr

5.8%/yr

7.9%/yr

24 months

0.7%/yr

4.2%/yr

7.4%/yr

Data from Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710–1716.

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Kaatz S et al. Cleve Clin J Med 2011;78(9):609–18.

Clinical presentation: signs and symptoms1-4 Deep vein thrombosis (DVT)     

Pain Swelling Tenderness Discolouration Pitting oedema

Pulmonary embolism (PE)      

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Shortness of breath Cough Chest pain Tachycardia Hypotension Low grade fever

1.Moll S. Arterioscler Thromb Vasc Biol 2008;28:373–9; 2.Pai M et al. http://www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics Accessed March 2016; 3. Thompson et al. http://www.uptodate.com/contents/pulmonary-embolism-beyond-the-basics. Accessed March 2016; Date of preparation: September 2016 4. Goldhaber SZ. Pulmonary Embolism. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 9th ed. Philadelphia, PA: Elsevier, 2012.

Secondary complications of VTE 

Post-thrombotic syndrome (PTS)1 ―

Can occur within 1–2 years after DVT in 20% to 50% of all patients

―

Severe PTS occurs in 25–33% of patients with PTS •



Can lead to deep vein insufficiency and leg ulcers

Chronic thromboembolic pulmonary hypertension (CTPH) —

Can occur after PE and is associated with significant morbidity and mortality2

—

Incidence of CTPH after an acute episode of PE3

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•

1.0% at 6 months

•

3.1% at 1 year

•

3.8% at 2 years

Date of preparation: September 2016

1. Kahn SR, Ginsberg JS. Arch Intern Med 2004;164:17–26; 2. McNeil K, Dunning J. Heart 2007;93:1152–8; 3. Pengo V et al. N Engl J Med 2004;350(22):2257–64.

VTE risk increases with age Overall incidence rate of first VTE:1 • 131.5 [95% CI (130.2–132.9)] per 100,000 person-years • 58.1 % are unprovoked VTE

800

IR of first VTE per 100,000 (years)

600 400 Male Female

200

0 89

Age (years) Adapted from Martinez et al. 2014

Population-based cohort study of 35,373 patients with a first VTE event in the UK between 2001 and 2011 (26.9 million person-years of observation) IR, incidence rate; CI, confidence interval PP-ELI-GBR-0382

Date of preparation: September 2016

1. Martinez et al. Thromb Haem 2014;112:255–263.

The burden of VTE extends beyond the original event 12

10 IR of recurrent VTE per 100,000 persons (years)

First DVT First PE

8 6 4 2 0 0–0.5 0.5–1 1–2

. Data from patients with non-active cancer

2–3

3–4

4–5

5–6

6–7

7–8

8–9 9–10

Follow-up (years) Adapted from Martinez et al. 2014.

IR, incidence rate PP-ELI-GBR-0382

Date of preparation: September 2016

1. Martinez et al. Thromb Haem 2014;112:255–263.

Higher recurrence rates in unprovoked VTE

30

28.4%

25

p2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Cardioversion (NVAF): Patients can stay

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Date of preparation: September 2016

on Eliquis while being cardioverted. Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients listed in SmPC, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding (refer to SmPC). Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter (refer to SmPC). SPECIAL WARNINGS AND PRECAUTIONS: Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). The concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal antiinflammatory drugs (NSAIDs), including acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. Use of thrombolytic agents for the treatment of acute ischemic stroke: there is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered Eliquis. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting. Surgery and invasive procedures: Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable. Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (see SmPC). Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of Eliquis, a time interval of 20-30 hours (i.e. 2 x half-life) between the last dose of Eliquis and catheter

ELIQUIS®(apixaban) 2.5 mg & 5 mg FILM-COATED TABLETS PRESCRIBING INFORMATION (slide 2 of 2) withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of Eliquis may be given at least 5 hours after catheter removal. As with all newer anticoagulant medicinal products, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using Eliquis in the presence of neuraxial blockade. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: efficacy and safety of Eliquis in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established. Renal impairment: see dosage and administration section. Elderly patients: increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: The use of Eliquis is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment). Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see SmPC). Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS: Medicinal products associated with serious bleeding are not recommended concomitantly with Eliquis, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g.clopidogrel), dipyridamole, dextran and sulfinpyrazone. Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION: Pregnancy: Not recommended during pregnancy. Breastfeeding: Discontinue breastfeeding or discontinue Eliquis therapy. UNDESIRABLE EFFECTS: Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common (≥ 1/100 to < 1/10): anaemia, haemorrhage, haematoma, nausea, contusion. Uncommon (≥1/1,000 to < 1/100): thrombocytopenia; specific haemorrhage such as gastrointestinal, post procedural, incision site, operative; haematochezia. Rare (≥1/10,000 to < 1/1,000): hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as eye (including conjunctival), rectal, muscle; haemoptysis. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common (≥ 1/100 to < 1/10): specific

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Date of preparation: September 2016

haemorrhage, such as eye (including conjunctival), gastrointestinal, rectal; haemorrhage, haematoma, epistaxis, gingival bleeding, haematuria, contusion. Uncommon (≥1/1,000 to < 1/100): hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as brain, intraabdominal, abnormal vaginal, urogenital, traumatic, post procedural, incision site; haemoptysis, haematochezia. Rare (≥1/10,000 to < 1/1,000): specific haemorrhage such as respiratory tract, retroperitoneal.. Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common (≥ 1/100 to < 1/10): haemorrhage, haematoma, epistaxis; specific haemorrhage such as gastrointestinal, rectal; gingival bleeding, haematuria, contusion. Uncommon (≥1/1,000 to < 1/100): specific haemorrhage such as eye (including conjunctival), abnormal vaginal, urogenital, traumatic, post procedural, incision site; haemoptysis, haematochezia. Rare (≥1/10,000 to < 1/1,000): specific haemorrhage such as brain, respiratory tract. Please refer to the SmPC for further details of adverse reactions including other types of haemorrhage. LEGAL CATEGORY: POM. PACKAGE QUANTITIES AND BASIC NHS PRICE: Carton of 10 film-coated tablets 2.5mg £9.50, 20 film-coated tablets 2.5mg £19.00, 60 film-coated tablets 2.5mg £57.00, 56 film-coated tablets 5mg £53.20, 28 film-coated tablets 5mg £26.60. MARKETING AUTHORISATION NUMBERS: EU/1/11/691/001-3, EU/1/11/691/008, EU/1/11/691/014 MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb/Pfizer EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH. Telephone: 0800731-1736. DATE OF PI PREPARATION: March 2016. 432UK1600117-01-01. ELQ1118

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd Medical Information on 0800 731 1736 or [email protected]