Frontiers in Cardiovascular Drug Discovery

Volume: 2

Novel Oral Anticoagulants for Thromboprophylaxis in Non- Valvular Atrial Fibrillation: Focus on Randomized Clinical Trials

Author(s): Tatjana S. Potpara, Marija M. Polovina, Marina M. Licina, Milica S. Prostran and Gregory Y.H. Lip

Pp: 134-230 (97)

DOI: 10.2174/9781608059683115020005

* (Excluding Mailing and Handling)

Abstract

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which were the most effective stroke prevention treatment and the only available drugs for oral anticoagulation for a long time. The oral direct thrombin inhibitors and oral direct inhibitors of factor Xa have recently emerged as a viable alternative to VKAs for stroke prevention in AF. These drugs act rapidly and have a predictable, dose-related anticoagulant effect with a few clinically relevant interactions with other drugs. The novel oral anticoagulants are used in fixed doses with no need for a regular laboratory monitoring of anticoagulation intensity.

Several phase III randomized trials with novel oral anticoagulants for stroke prevention in AF have been completed recently: the RE-LY trial with dabigatran, the ROCKET-AF with rivaroxaban and the ARISTOTLE trial with apixaban, and all 3 trials compared the novel drug with warfarin. The AVERROES trial, which included AF patients who have failed or were unsuitable for warfarin, compared apixaban versus aspirin for stroke prevention in AF. Altogether, the novel oral anticoagulants showed impressive performance in these trials and have already been implemented into clinical practice worldwide. In addition, many more novel anticoagulants are at various stages of clinical investigation.

In this chapter, we present a brief summary of clinical trials with oral vitamin K antagonists for stroke prevention in AF and the caveats regarding these trials. We further present a detailed overview of the recently completed phase III randomized trials on the novel oral anticoagulants along with clinical implications of the results and summarize the current knowledge on the investigational oral anticoagulants which are under development.


Keywords: Novel oral anticoagulants, stroke prevention, thromboprophylaxis, atrial fibrillation, oral anticoagulation, clinical trials, warfarin, dabigatran, rivaroxaban, apixaban.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740516393 and j.to_date >= 1740516393 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6994) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740516393 and j.to_date >= 1740516393 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6994) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316567616 and j.to_ip >=316567616 )) and ((j.from_date <= 1740516393 and j.to_date >= 1740516393 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6994)
      890μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1675 and `b`.`banner_from_date` <= 1740516393 and `b`.`banner_to_date` >= 1740516393 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.45msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1675
      • 3: 1740516393
      • 4: 1740516393
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='0796f3c1b4d79dfa854a13d7aeceb399'
      300μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    10Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        io2AVoAjqBgwBxH9DMaPos8WBzmrnRHXp3r8w50p
        uc_cart_id
        0796f3c1b4d79dfa854a13d7aeceb399
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6994" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/6994
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6InNMTDI4b25BQUZCTUdJNHk3cnNwR3c9PSIsInZhbHVlIjoiQTFqQmZKMUFxVkZpSnQyaHcvOTNwUEM4V2ZySktDYVppY1pwMHNlcTY5RT0iLCJtYWMiOiIxZjFmMzVmMDk5ODg0MjJiMzQyZjUzNjNjYzdmMTA2NjcxM2NiNzY5YmFiMDllMjlhOGZkMWU2Y2RkMmJkNGM2IiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6InNMTDI4b25BQUZCTUdJNHk3cnNwR3c9PSIsInZhbHVlIjoiQTFqQmZKMUFxVkZpSnQyaHcvOTNwUEM4V2ZySktDYVppY1pwMHNlcTY5RT0iLCJtYWMiOiIxZjFmMzVmMDk5ODg0" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 20:46:33 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IitRaXZiUTJNOWJBTHVMVEM2MWtkUHc9PSIsInZhbHVlIjoiZ09Kem5ONVd0KzN4NlpvUzE5VDRJWlpBRDBlWmgzUGZ3elM5OGR0a0Vnb1hBWk9qSFBLRHUvS29qQ1FHNnBxY2JBOGtyTmI0YkcxT2E1NUV2SVB1RHhWdklwdlZjcDQ1NjVzajR1ZFRoc0l4MklHY3RtWllVRXVhVjVGN3ZPME8iLCJtYWMiOiJjYjMyMTU4YWY2MmQwNDQ2Yzc3Mzg1ZmNkMTE2OWI5ZmU2MzFlYWY3OGJhZWMxOTg5ZjE5MjZkZWUzZDQyZGNhIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 08:46:33 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IitRaXZiUTJNOWJBTHVMVEM2MWtkUHc9PSIsInZhbHVlIjoiZ09Kem5ONVd0KzN4NlpvUzE5VDRJWlpBRDBlWmgzUGZ3elM5OGR0a0Vnb1hBWk9qSFBLRHUvS29qQ1FHNnBxY2JBOGtyT" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImkrM1cxczFqaGhXckNQK0NCTTFLWnc9PSIsInZhbHVlIjoiSVVXNHAxRTZPS2FSUVpmMW9lczlSY25pTUE4dWwxSWU4M29JbFRqcUNRYzQybS8zeWhlTjh4VFNQUWVsckx4ZHllMGorU0t0dnFKQ3ZERUdWbzNJZWRDcmtoRzBaSENXQnlKMWFER0x4K21keklOb3ZodmExT1RHQzRaSkZYaVYiLCJtYWMiOiI3NzdhZTFmYWRkYjI1ODA5M2NjNzk3NjdlODE3NDBkYWE5OWNiMmQ1YzcxODllMWZhZjFmYjBiYjBkODk3YzliIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImkrM1cxczFqaGhXckNQK0NCTTFLWnc9PSIsInZhbHVlIjoiSVVXNHAxRTZPS2FSUVpmMW9lczlSY25pTUE4dWwxSWU4M29JbFRqcUNRYzQybS8zeWhlTjh4VFN" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IitRaXZiUTJNOWJBTHVMVEM2MWtkUHc9PSIsInZhbHVlIjoiZ09Kem5ONVd0KzN4NlpvUzE5VDRJWlpBRDBlWmgzUGZ3elM5OGR0a0Vnb1hBWk9qSFBLRHUvS29qQ1FHNnBxY2JBOGtyTmI0YkcxT2E1NUV2SVB1RHhWdklwdlZjcDQ1NjVzajR1ZFRoc0l4MklHY3RtWllVRXVhVjVGN3ZPME8iLCJtYWMiOiJjYjMyMTU4YWY2MmQwNDQ2Yzc3Mzg1ZmNkMTE2OWI5ZmU2MzFlYWY3OGJhZWMxOTg5ZjE5MjZkZWUzZDQyZGNhIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 08:46:33 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IitRaXZiUTJNOWJBTHVMVEM2MWtkUHc9PSIsInZhbHVlIjoiZ09Kem5ONVd0KzN4NlpvUzE5VDRJWlpBRDBlWmgzUGZ3elM5OGR0a0Vnb1hBWk9qSFBLRHUvS29qQ1FHNnBxY2JBOGtyT" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImkrM1cxczFqaGhXckNQK0NCTTFLWnc9PSIsInZhbHVlIjoiSVVXNHAxRTZPS2FSUVpmMW9lczlSY25pTUE4dWwxSWU4M29JbFRqcUNRYzQybS8zeWhlTjh4VFNQUWVsckx4ZHllMGorU0t0dnFKQ3ZERUdWbzNJZWRDcmtoRzBaSENXQnlKMWFER0x4K21keklOb3ZodmExT1RHQzRaSkZYaVYiLCJtYWMiOiI3NzdhZTFmYWRkYjI1ODA5M2NjNzk3NjdlODE3NDBkYWE5OWNiMmQ1YzcxODllMWZhZjFmYjBiYjBkODk3YzliIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImkrM1cxczFqaGhXckNQK0NCTTFLWnc9PSIsInZhbHVlIjoiSVVXNHAxRTZPS2FSUVpmMW9lczlSY25pTUE4dWwxSWU4M29JbFRqcUNRYzQybS8zeWhlTjh4VFN" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "io2AVoAjqBgwBxH9DMaPos8WBzmrnRHXp3r8w50p" "uc_cart_id" => "0796f3c1b4d79dfa854a13d7aeceb399" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6994" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:46:33GET/chapter/69941121912