Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment

Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment Anna L Parks , View ORCID Profile Jacquelyn M Lykken , Meghan L Rieu-Werden , Darae Ko , Dae Hyun Kim , Margaret C Fang , Steven M Greenberg , Daniel M Witt , Mark A Supiano , View ORCID Profile Sachin J Shah doi: https://doi.org/10.1101/2025.07.17.25331746 Anna L Parks 1 Division of Hematology and Hematologic Malignancies, University of Utah , Salt Lake City, UT, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jacquelyn M Lykken 2 Division of General Internal Medicine, Massachusetts General Hospital , Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacquelyn M Lykken Meghan L Rieu-Werden 2 Division of General Internal Medicine, Massachusetts General Hospital , Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Darae Ko 3 Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School; Boston Medical Center, Section of Cardiovascular Medicine , Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dae Hyun Kim 4 Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife , Harvard Medical School, Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Margaret C Fang 5 Division of Hospital Medicine, University of California San Francisco , San Francisco, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Steven M Greenberg 6 J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital , Harvard Medical School, Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel M Witt 7 Department of Pharmacotherapy, University of Utah College of Pharmacy , Salt Lake City, Utah, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mark A Supiano 8 Division of Geriatrics, University of Utah , Salt Lake City, UT, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sachin J Shah 2 Division of General Internal Medicine, Massachusetts General Hospital , Boston, MA, USA 9 Center for Aging and Serious Illness , Massachusetts General Hospital, Boston, MA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sachin J Shah For correspondence: sshah{at}mgh.harvard.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Objectives Antithrombotic drugs—anticoagulants and thrombolytics— may interact with anti-amyloid monoclonal antibodies (mAbs) to increase intracranial hemorrhage risk, so expert guidance recommends against their co-prescription. We aimed to estimate how many people with mild cognitive impairment (MCI) or dementia develop a new cardiovascular indication for antithrombotic drugs. Methods In a longitudinal cohort of adults ≥65 years old from the Health and Retirement Study (2010-2020) with linked Medicare claims and no prior indication for anticoagulants, cognition was categorized as normal, MCI, or dementia. We fit Fine-Gray separate survival models accounting for competing risk of death to estimate 1-year incidence of atrial fibrillation (AF), deep vein thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction (MI), and stroke. Results Among 12,373 participants (mean age 73 years, 59% female), for MCI, 1-year incidence was 1.7% for AF, 1.2% for DVT, 0.4% for PE, 1.2% for AMI, 2.0% for stroke, and 5.7% for any indication. In dementia, 1-year rates were 1.7% for AF, 1.8% for DVT, 0.3% for PE, 1.0% for AMI, 2.4% for stroke, and 6.7% for any indication. Discussion Our finding inform shared decision-making about the tradeoffs of anti-amyloid mAbs. Introduction The anti-amyloid monoclonal antibodies (mAbs) lecanemab and donanemab modestly slow cognitive decline in people with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease. The major adverse effects of this medication class are amyloid-related imaging abnormalities (ARIA), which rarely can present as intracranial hemorrhage (ICH). Appropriate use recommendations advise against co-prescribing antithrombotic drugs—including anticoagulants and thrombolytics—due to potential interactions with anti-amyloid mAbs that increase ICH risk. 1 , 2 Because new cardiovascular diagnoses, such as atrial fibrillation (AF) or pulmonary embolism (PE), are common in older adults, some people may develop an indication for antithrombotic drugs during an anti-amyloid mAb treatment course. 3 Professional societies, appropriate use recommendations and expert guidance recommend shared decision-making for anti-amyloid mAb treatment decisions. 4 – 8 These discussions require individualized estimates of risks and benefits. Understanding the risk of developing a new condition where antithrombotic drugs are indicated during anti-amyloid mAb therapy is important when considering the tradeoffs of treatment. Our goal was to estimate how many people with MCI or dementia develop a new condition for which anticoagulants or thrombolytics are indicated. Methods Participants We conducted a longitudinal cohort study using data from 2010-2020 from the Health and Retirement Study (HRS). The HRS is a nationally representative, longitudinal cohort of Americans over age 50 with linked Medicare claims. Subjects are interviewed biennially on topics including health and cognition. Proxies are interviewed when participants cannot answer questions due to physical or cognitive impairment. We included HRS participants aged 65 and older with Medicare claims linkage, at least 12 months of continuous Medicare Part A, B, and D enrollment, no diagnosis of AF or anticoagulant prescription in the 12 months prior to a baseline interview, and no missing information on cognition ( Supplementary Figure 1 ). Participants were enrolled when they first met inclusion criteria and censored at disenrollment from Medicare, end of 12-month follow-up, or death. Covariates To assess cognition, HRS researchers administer a validated 27-question neuropsychological battery to participants or an informant questionnaire to proxies when participants cannot be interviewed. 9 We used standardized definitions that categorize participants’ cognition as normal, MCI, or dementia (defined in HRS as moderate or severe cognitive impairment), which correlate with clinically diagnosed MCI and dementia. 10 We used claims-based algorithms ( Supplementary Table 1 ) to define AF, deep vein thrombosis (DVT), PE, myocardial infarction (MI), and stroke. Statistical Analysis After describing the cohort demographics, we fit separate Fine-Gray survival models accounting for competing risk of death to estimate the 1-year incidence of each outcome. Models used a robust sandwich variance estimator accounting for repeated observations. Standard Protocol Approvals, Registrations, and Participant Consents The institutional review board at Mass General Brigham approved the study as exempt, and we followed STROBE reporting guidance. Data Availability Researchers can apply to the Health and Retirement Study ( https://hrs.isr.umich.edu/ ) to access the data used in this study. Results The study included 12,373 participants (mean age 73 years, 59% female), including 2,433 (20%) with MCI, and 1,145 (9%) with dementia ( Table ). Among participants with MCI, the estimated 1-year incidence was 1.7% for AF, 1.2% for DVT, 0.4% for PE, 1.2% for MI, and 2.0% for stroke ( Figure ). The estimated 1-year incidence of developing a new indication for antithrombotic drugs for any reason was 5.7%. Download figure Open in new tab Figure 1: 1-year incidence of cardiovascular disease by cognitive status View this table: View inline View popup Table 1: Cohort sociodemographics, geriatric syndromes, and comorbidities stratified by cognition Among participants with dementia, estimated 1-year incidence was 1.7% for AF, 1.8% for DVT, 0.3% for PE, 1.0% for MI, and 2.4% for stroke. Overall, in those with dementia, 6.7% developed a new indication for antithrombotic drugs for any reason in 1 year. Discussion Over 1 year, 6-7% of people with MCI or dementia in this national sample were newly diagnosed with a cardiovascular disease where anticoagulants or thrombolytics are indicated. As clinicians, patients and caregivers consider anti-amyloid mAbs, these results should be added to the risk-benefit discussion. 11 Other risk factors for ICH in patients on anti-amyloid therapy can be screened for and potentially mitigated either through patient selection (such as cerebral amyloid angiopathy and APOE-ε4 genotype) or treatment intensification (such as hypertension). 12 In addition, clinicians can already use clinical trial and extension-phase data on ICH rates based on these fixed risk factors to inform discussion. In contrast, antithrombotic use is substantially more dynamic and detailed risk estimates have not been available until now. Our results provide estimates of the likelihood of emergent cardiovascular conditions that can be incorporated into the decision to start anti-amyloid mAbs, as well as advance care planning. We found that the 1-year risk of 3 common acute clinical conditions—stroke, PE and MI—was 2.0-2.4%, 0.3-0.4% and 1.0-1.2%, respectively. These conditions at the very least require rapid decision-making and treatment with anticoagulants, and guidelines recommend administration of thrombolytics for patients with stroke who present within the appropriate timeframe, PE who have hemodynamic instability, and MI if percutaneous coronary intervention is not available. Due to the uncertainty and potential for catastrophic ICH, both lecanemab and donanemab appropriate use recommendations recommend against treating patients with anticoagulants or thrombolytics. 2 , 5 Clinicians should discuss the small but potentially fatal or disabling possibility of patients not being able to receive emergent treatment for these acute conditions while receiving anti-amyloid mAbs so that patients and caregivers have a fully informed understanding of the tradeoffs. Our results also inform discussion of the development of non-emergent conditions like a new diagnosis of AF (1.7% per year) or DVT (1.2-1.8%). Most older adults with AF and MCI or dementia will qualify for anticoagulation to prevent ischemic stroke based on their CHA 2 DS 2 -VAS c score. 13 And guideline-recommended therapy for DVT and PE is at least 3 months of anticoagulant treatment and long-term anticoagulation in those with thromboses that occur in the absence of provoking risk factors. 14 Although recommendations about concurrent anticoagulant use may shift over time, most centers currently exclude these patients. Annual risk of stroke is 5-7% in AF without anticoagulation, and the annual risk of recurrent venous thromboembolism is between 3-10%. Thus, our results can be used to discuss with patients the possibility of having to decide between continuing anti-amyloid therapy versus forgoing anticoagulation for these chronic conditions. Our data have limitations. We lack the granularity to determine eligibility for anti-amyloid therapy, and risk estimates may differ for people who qualify for anti-amyloid treatment. Additionally, while not all patients with new cardiovascular conditions would qualify for thrombolytic or anticoagulant therapy, a substantial proportion would meet guideline indications, which justifies consideration of this possibility. The availability of anti-amyloid mAbs is a paradigm shift in dementia care. Incorporating the considerable risk of developing a condition for which antithrombotic drugs are indicated would enhance shared decision-making for these novel therapies. Data Availability Researchers can apply to the Health and Retirement Study (https://hrs.isr.umich.edu/) to access the data used in this study. References 1. ↵ Cummings J , Apostolova L , Rabinovici GD , et al. Lecanemab: Appropriate Use Recommendations . J Prev Alzheimers Dis . 2023 ; 10 ( 3 ): 362 – 377 . doi: 10.14283/jpad.2023.30 OpenUrl CrossRef PubMed 2. ↵ Rabinovici GD , Selkoe DJ , Schindler SE , et al. Donanemab: Appropriate use recommendations . J Prev Alzheimers Dis . 2025 ; 12 ( 5 ): 100150 . doi: 10.1016/j.tjpad.2025.100150 OpenUrl CrossRef PubMed 3. ↵ Ko D , Pascual-Leone A , Shah SJ . Use of Lecanemab for Patients With Cardiovascular Disease: The Challenge of Uncertainty . JAMA . Published online March 15, 2024. doi: 10.1001/jama.2024.2991 OpenUrl CrossRef 4. ↵ Ramanan VK , Armstrong MJ , Choudhury P , et al. Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease . Neurology . 2023 ; 101 ( 19 ): 842 – 852 . doi: 10.1212/WNL.0000000000207757 OpenUrl CrossRef PubMed 5. ↵ Cummings J , Apostolova L , Rabinovici GD , et al. Lecanemab: Appropriate Use Recommendations . J Prev Alz Dis . Published online 2023. doi: 10.14283/jpad.2023.30 OpenUrl CrossRef PubMed 6. Greenberg SM , Aparicio HJ , Furie KL , et al. Vascular Neurology Considerations for Antiamyloid Immunotherapy: A Science Advisory From the American Heart Association . Stroke . 2025 ; 56 ( 1 ): e30 – e38 . doi: 10.1161/STR.0000000000000480 OpenUrl CrossRef PubMed 7. Sarkisian CA , Romanov A , Mafi JN . Talking With Patients About the New Anti-amyloid Alzheimer Disease Medications . Ann Intern Med . 2024 ; 177 ( 2 ): 246 – 248 . doi: 10.7326/M23-3377 OpenUrl CrossRef PubMed 8. ↵ Monoclonal anti□amyloid antibodies for the treatment of Alzheimer’s disease and the hesitant geriatrician - Chin - 2024 - Journal of the American Geriatrics Society - Wiley Online Library . Accessed March 21, 2025 . https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.18652 9. ↵ Crimmins EM , Kim JK , Langa KM , Weir DR . Assessment of Cognition Using Surveys and Neuropsychological Assessment: The Health and Retirement Study and the Aging, Demographics, and Memory Study . J Gerontol B Psychol Sci Soc Sci . 2011 ; 66B ( Suppl 1 ): i162 – i171 . doi: 10.1093/geronb/gbr048 OpenUrl CrossRef PubMed 10. ↵ Langa KM , Plassman BL , Wallace RB , et al. The Aging, Demographics, and Memory Study: study design and methods . Neuroepidemiology . 2005 ; 25 ( 4 ): 181 – 191 . doi: 10.1159/000087448 OpenUrl CrossRef PubMed Web of Science 11. ↵ Widera EW , Brangman SA , Chin NA . Ushering in a New Era of Alzheimer Disease Therapy . JAMA . 2023 ; 330 ( 6 ): 503 – 504 . doi: 10.1001/jama.2023.11701 OpenUrl CrossRef PubMed 12. ↵ Zimmer JA , Ardayfio P , Wang H , et al. Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer Disease: Secondary Analysis of the TRAILBLAZER-ALZ and ALZ 2 Randomized Clinical Trials . JAMA Neurology . Published online March 10, 2025. doi: 10.1001/jamaneurol.2025.0065 OpenUrl CrossRef 13. ↵ Joglar JA , Chung MK , Armbruster AL , et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines . Circulation . 2024 ; 149 ( 1 ): e1 – e156 . doi: 10.1161/CIR.0000000000001193 OpenUrl CrossRef PubMed 14. ↵ Stevens SM , Woller SC , Kreuziger LB , et al. Antithrombotic Therapy for VTE Disease: Compendium and Review of CHEST Guidelines 2012-2021 . CHEST . 2024 ; 166 ( 2 ): 388 – 404 . doi: 10.1016/j.chest.2024.03.003 OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted July 18, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment Anna L Parks , Jacquelyn M Lykken , Meghan L Rieu-Werden , Darae Ko , Dae Hyun Kim , Margaret C Fang , Steven M Greenberg , Daniel M Witt , Mark A Supiano , Sachin J Shah medRxiv 2025.07.17.25331746; doi: https://doi.org/10.1101/2025.07.17.25331746 Share This Article: Copy Citation Tools Rates of new indication for antithrombotic drugs in people with cognitive impairment: implications for anti-amyloid monoclonal antibody treatment Anna L Parks , Jacquelyn M Lykken , Meghan L Rieu-Werden , Darae Ko , Dae Hyun Kim , Margaret C Fang , Steven M Greenberg , Daniel M Witt , Mark A Supiano , Sachin J Shah medRxiv 2025.07.17.25331746; doi: https://doi.org/10.1101/2025.07.17.25331746 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Geriatric Medicine Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15229) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6600) Geriatric Medicine (668) Health Economics (997) Health Informatics (4536) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (541) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3332) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9232) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a0089e99cdb9dfa9',t:'MTc3OTU4NzExMQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();