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09 July 2012 EMA/CHMP/450916/2012 Committee for Medicinal Products for Human Use (CHMP)

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Guideline on clinical investigation of medicinal products for prevention of stroke and systemic embolic events in patients with non-valvular atrial fibrillation

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Draft

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10 Draft Agreed by Cardiovascular Working Party 1 Adoption by CHMP for release for consultation Start of public consultation End of consultation (deadline for comments)

28 March 2012 09 July 2012 15 August 2012 15 February 2013

11 12 Comments should be provided using this template. The completed comments form should be sent to [email protected] 13 14 Keywords

Stroke, systemic embolism, atrial fibrillation, guidelines, anticoagulant, CHMP

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7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail [email protected] Website www.ema.europa.eu

An agency of the European Union

© European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.

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Guideline on clinical investigation of medicinal products for prevention of stroke and systemic embolic events in patients with non-valvular atrial fibrillation

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Draft

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Table of contents

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Executive summary ..................................................................................... 3

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1. Introduction (background)...................................................................... 3

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2. Scope....................................................................................................... 3

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3. Legal basis .............................................................................................. 3

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4. Assessment of efficacy criteria ................................................................ 4

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4.1. Primary efficacy outcome .................................................................................... 4 4.2. Secondary outcomes .......................................................................................... 4

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5. Methods to assess efficacy ...................................................................... 5

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5.1. Primary efficacy outcome .................................................................................... 5 5.2. Secondary outcomes .......................................................................................... 5

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6. Selection of patients................................................................................ 6

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6.1. Study population................................................................................................ 6

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6.2. Inclusion criteria ................................................................................................ 6 6.3. Exclusion criteria................................................................................................ 6

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7. Strategy design ....................................................................................... 6

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8. Safety aspects ......................................................................................... 9

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9. References ............................................................................................ 14

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Executive summary

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1–2% of the

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general population. AF confers a 5-fold risk of stroke, and one in five of all strokes is attributed to this

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arrhythmia.

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Current Note for Guidance on Antiarrhythmics (CPMP/EWP/237/95) and its addendum on atrial

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fibrillation and flutter (EMA/CHMP/EWP/213056/2010) do not cover stroke prevention. The aim of this

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guideline is to provide guidance to industry when performing trials to develop drugs in prevention of

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stroke and systemic embolic events (SEE) in patients with AF.

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1. Introduction (background)

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AF is the most common sustained cardiac arrhythmia, occurring in 1–2% of the general population,

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with 45% of diagnoses being in patients 75 years and older [1]. Over 6 million Europeans suffer from

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this arrhythmia, and its prevalence is estimated to at least double in the next 50 years as the

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population ages [2,3]. Based on the presentation and duration of the arrhythmia, AF is classified as:

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first diagnosed, paroxysmal, persistent and permanent AF [2]. Ischaemic strokes in association with AF

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are often fatal, and those patients who survive are left more disabled by their stroke and more likely to

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suffer a recurrence than patients with other causes of stroke. Current recommendations for

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antithrombotic therapy are based on the presence (or absence) of risk factors for stroke and

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thromboembolism [2,4]. The simplest risk assessment scheme in non-valvular AF is the CHADS 2 score

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[cardiac failure, hypertension, age, diabetes, prior stroke or TIA (transient ischaemic attack) (doubled)]

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[1]. The original validation of this scheme classified a CHADS 2 score of 0 as low risk, 1–2 as moderate

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risk, and >2 as high risk. In patients with a CHADS 2 score of ≥2, chronic anticoagulation therapy with

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a vitamin K antagonist (VKA) is currently recommended in a dose adjusted manner to achieve an

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International Normalised Ratio (INR) value in the range of 2.0–3.0 [2]. In these patients, antiplatelet

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therapy could be considered as alternative therapy only when VKA therapy is unsuitable. In patients

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with a CHADS 2 score of 0–1, or where a more detailed stroke risk assessment is indicated, it is

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recommended to use a more comprehensive risk factor-based approach (e.g. CHA 2 DS 2 -VASc score)

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[5].

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Approximately only 30-60% of eligible patients receive oral anticoagulation with VKA and its use in

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clinical practice is challenging for several reasons, including a narrow therapeutic window, variability in

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response, interactions and laboratory standardisation [Ansell et al, 2008]. On average, patients may

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stay within the therapeutic INR range of 2.0–3.0 for 60–65% of the time in controlled clinical trials, but

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many ‘real-life’ studies suggest that this figure may be 25 cm2, or > 100 cm2 if there was a traumatic cause; intramuscular hematoma documented by

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ultrasonography without compartment syndrome; excessive wound hematoma; macroscopic hematuria

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(spontaneous or lasting >24 h if associated with an intervention); epistaxis or gingival bleeding that

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requires tamponade or other medical intervention, or bleeding after venipuncture for >5 min;

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hemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical

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intervention.

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Other non-major bleedings include other overt bleeding events that do not meet the criteria for major

Other non-major bleedings

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bleed or clinically relevant non-major bleed (e.g.: epistaxis that does not require medical attention or

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change in antithrombotic therapy).

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The use of the following composite bleeding endpoints is recommended:

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Composite bleeding endpoints of interest

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bleeding and/or a clinically relevant non-major bleeding. -

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Clinically relevant bleeding: defined as the rate of patients experiencing at least one major Non-major bleeding: defined as the rate of patients experiencing at least one clinically relevant non-major bleeding or other non-major bleeding.

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Total bleeding: defined as the rate of patients experiencing at least one major bleeding, clinically relevant non-major bleeding or other non-major bleeding.

Other parameters related to bleed

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As support for the conclusions drawn from the main safety criteria, other bleedings related parameters

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are recommended to be recorded during the studies e.g.:

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Laboratory parameters: haemoglobin plasma level, haematocrit and red cell count changes during the treatment period,

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Bleeding index (mean, ±SD) calculated in each patient as the number of units of packed red

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cells or whole blood transfused plus the haemoglobin values pre-randomisation minus the

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haemoglobin values at the end of treatment period.

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Patients with bleeding index ≥ 2 at the end of treatment period relative to haemoglobin prerandomisation levels (n, %). Patients receiving transfusion of packed red cells (n, %) (homologous and autologous transfusions need to be distinguished).

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Transfusion volume (mL; mean, ±SD) and transfusion units (U; mean, ±SD) during the treatment period (homologous and autologous transfusions need to be distinguished).

Report and collection of bleeding events and related parameters

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The population included in the assessment of bleeding events should correspond with those subjects

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who have received at least one dose of the study drug (either active or placebo) (i.e.: the safety

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population).

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The period for collection of these data should be identical in all treatment groups, starting at the time

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of the administration of the first dose of study drug (either active or placebo) in any of the treatment

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groups, until the antithrombotic effect of study drugs is not detectable, and after study drugs have

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been cleared from plasma.

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The decrease in the haemoglobin level ≥ 2 g/dL should be considered relative to the pre-randomisation

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level (usually corresponding with the pre-operative haemoglobin).

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The use of a fecal occult blood test (FOBT) at screening visit and during treatment at regular intervals

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is encouraged, since long-term antithrombotic therapy may be associated with unperceived

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gastrointestinal blood loss.

The need for specific antidote and laboratory monitoring

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The development of a specific antidote for new antithrombotics when given at high doses for long-term,

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as in stroke prevention in AF, is highly recommended given the potential for life-threatening bleeding

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events in standard practice. Phase I studies are likely to provide a neutralising dose, but they are not

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expected to address the complex interplay of physiology, concomitant measures (i.e.: blood

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transfusions, use of plasma expanders, etc) and potential for increased thrombogenicity after

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administration of the antidote in patients who experience life-threatening bleed. This can be followed

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by a proof-of-principle study in a small subset of patients with life-threatening bleeding to demonstrate

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the efficacy and safety in a heterogeneous population. A post authorisation safety study (PASS) will be

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needed to provide further data. A randomised clinical study will be difficult to perform taking into

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account the heterogeneity of the population and differences in standard care between the various

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centres. Furthermore, the potential comparator is difficult to be established, since, up to date, non-

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specific procoagulant agents are not licensed for reversal of the new agents and may be associated

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with an increased risk of thrombosis.

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The development of a test for laboratory monitoring of the anticoagulant effect of new agents is highly

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recommended as well. Even if the new drugs have no monitoring requirements and monitoring has not

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been applied in pivotal studies, there are potential situations in standard practice where this

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information might be useful (e.g.: impaired renal function, clinically relevant drug-drug interactions,

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overdose, measurement of treatment compliance, etc.) that will recommend having it.

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8.2

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The mechanism of action and pharmacological class of the medicinal product under investigation may

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suggest specific aspects of safety evaluation (e.g. platelet counts, antibody detection, renal and liver

Other events

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function parameters, hypercoagulability markers to assess a possible rebound hypercoagulation after

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treatment cessation, etc.) that should be considered for incorporation into the entire development

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programme.

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If there is a potential for drug-induced liver injury (DILI) with the study drugs (experimental and/or

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control), an algorithm for hepatic monitoring has to be included in the protocol [13]. Available

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regulatory guidance on DILI should be followed [17].

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Special attention should be paid to hypersensitivity reactions of the skin and other organs (especially

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liver, kidney, lungs), changes in blood cells, and hepatitis.

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For biotechnology derived product(s), immunogenicity should be evaluated prospectively. The type of

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antibody (e.g. neutralising) and incidence of immune mediated adverse events should be assessed and

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clearly documented.

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This should be assessed as dictated by the product and the target population.

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In general, the following groups might require specific evaluation:

8.3 Special populations

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elderly

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renal insufficiency (moderate, severe)

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liver disease

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Regarding the elderly, it is important to determine whether or not the pharmacokinetic behaviour,

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pharmacodynamics, disease-drug, drug-drug interactions and clinical response of the drug in this

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population is different from that in younger adults. Therefore, to assess the benefit/risk balance of a

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drug that will be used in the geriatric population, a representative number of patients >65 years and

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>75 years should be appropriately represented in clinical trials (ICH E7).

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The identification of the more appropriate dose in these special populations, in particular in elderly

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patients, is a matter of utmost importance. Any dose adaptation in these populations should be

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appropriately justified.

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As long as there is a reasonable representation of the above sub-groups of patients in the main

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therapeutic study/es, a separate study is not considered necessary.

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Safety in special populations should be prospectively assessed for inclusion of the sub-groups in SPC.

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9. References

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1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting

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stroke: results from the national registry of atrial fibrillation. JAMA. 2001; 285: 2864-70.

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2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task

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Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart

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J. 2010; 31: 2369-429.

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3. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the Prevention of Stroke in Patients With Stroke

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or Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart

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Association/American Stroke Association. Stroke. 2011; 42: 227-76.

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4. Stroke in AF working group. Independent predictors of stroke in patients with atrial fibrillation: a

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systematic review. Neurology. 2007; 69: 546–54.

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5. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and

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thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey

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on Atrial Fibrillation. Chest 2010; 137: 263–72.

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6. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists:

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American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest.

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2008; 133(6 Suppl): 160S-198S.

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7. Lip GY, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation

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patients: a position document from the European Heart Rhythm Association, endorsed by the European

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Society of Cardiology Working Group on Thrombosis. Europace. 2011; 13: 723-46.

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8. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk

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of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010; 138: 1093-

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100.

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9. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared

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with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale

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and design of the ROCKET AF study. Am Heart J. 2010; 159: 340-7.

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10. Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in

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patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial

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fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011; 50: 675-86.

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11. Rosendaal F, Cannegieter S, van der Meer F, et al. A method to determine the optimal intensity of

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oral anticoagulant therapy. Thromb Haemost. 1993; 69: 236-9.

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12. Connolly SJ, Pogue J, Eikelboom J, et al; ACTIVE W Investigators. Benefit of oral anticoagulant

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over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio

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control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;

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118: 2029-37.

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13. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation

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of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009; 157: 805-

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10.

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14. Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and

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Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of

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major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J

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Thromb Haemost. 2005; 3: 692-4.

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15. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute

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coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494–502.

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16. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban

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compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective

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aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial

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Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010; 160: 635-41.

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17. Food and Drug Administration. Guidance for Industry. Drug-Induced Liver Injury: Premarketing

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Clinical Evaluation. Available at: http://www.fda.gov

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