No Urut (64) RENI (18.11.125)

Akses Publik HHS
Naskah Penulis
J Am Coll Cardiol. Naskah penulis; tersedia di PMC 2021 Agustus 02.
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Diterbitkan dalam bentuk akhir yang diedit sebagai:
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J Am Coll Cardiol. 2020 26 Mei; 75 (20): 2602–2618. doi:10.1016/j.jacc.2020.03.060.
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Ringkasan Rekomendasi yang Diperbarui untuk Pencegahan Primer
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Penyakit Kardiovaskular pada Wanita:
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Tinjauan JACC State-of-the-Art
a b c d
Leslie Cho, MD , Melinda Davis, MD , Islam Elgendy, MD , Kelly Epps, MD , Kathryn J.
e f g h
Lindley, MD , Puja K. Mehta, MD , Erin D. Michos, MD , Margo Minissian, PhD , Carl Pepine,
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MD , Viola Vaccarino, MD , Annabelle Santos Volgman, MDk, ACC CVD Womens Komisi
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Anggota
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a
Cleveland Clinic Foundation, Jantung Vascular Institute, Cleveland, Ohio; bUniversitas Michigan,
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Ann Arbor, Michigan; cDivisi Kardiologi, Rumah Sakit Umum Massachusetts, Harvard Medical
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School, Boston, Massachusetts; dInstitut Jantung dan Vaskular Inova, Gereja Falls, Virginia;
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Washington University School of Medicine, St Louis, Missouri; fEmory Healthcare Network,
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Atlanta, Georgia; gPusat Medis Universitas Johns Hopkins, Baltimore, Maryland; hCedars Sinai, t
saya
Los Angeles, California; Kesehatan UF, Universitas Florida, Gainesville, Florida; jSekolah
Kesehatan Masyarakat Rollins Universitas Emory, Atlanta, Georgia; kSekolah Tinggi
Kedokteran Rush, Universitas Rush, Chicago, Illinois.
Abstrak
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Kardiovaskular penyakit (CVD) masih menjadi penyebab utama morbiditas dan mortalitas bagi perempuan di
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Amerika Serikat dan di seluruh dunia. Belum ada American College of Cardiology (ACC)/
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Pembaruan pedoman American Heart Association khusus untuk pencegahan CVD pada wanita
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sejak 2011. Sejak itu, tubuh data spesifik jenis kelamin telah berkembang, di samping pembaruan
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hipertensi, kolesterol, diabetes, fibrilasi atrium, dan pedoman pencegahan primer . ACC s
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CVD di Komite Perempuan melakukan tinjauan pedoman baru-baru ini dan studi utama untuk
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rekomendasimeringkas berhubungan dengan wanita. Dalam update ini, penulis membahaskhusus,
topik-topik terutama faktor risiko dan perawatan yang telah menyebabkan beberapa kontroversi dan
kebingungan. Secara khusus, faktor risiko terkait jenis kelamin, hipertensi, diabetes, hiperlipidemia,
antikoagulasi untuk fibrilasi atrium, penggunaan aspirin, terapi hormon perimenopause, dan
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masalah psikososial disorot.
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Kata kunci
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Hasilkehamilan yang merugikan; aspirin; fibrilasi atrium; penyakit kardiovaskular; kehamilan

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diabetes
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ALAMAT UNTUK KORESPONDENSI: Dr. Leslie Cho, 9500 Euclid Avenue JB-1, Cleveland, Ohio 44195. chol@ccf.org. Twitter:
@clevealandclinic.
Para penulis membuktikan bahwa mereka mematuhi komite studi manusia dan peraturan kesejahteraan hewan dari lembaga penulis
dan pedoman Administrasi Makanan dan Obat-obatan, termasuk persetujuan pasien jika sesuai. Untuk informasi lebih lanjut,
kunjungiJACC halaman petunjuk penulis.
Cho dkk. Halaman 2
Penyakit kardiovaskular (CVD) tetap menjadi penyebab utama morbiditas dan mortalitas bagi
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wanita di Amerika Serikat dan di seluruh dunia (1). Secara keseluruhan, 1 dari 3 wanita meninggal karena CVD, dan
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45% wanita di atas usia 20 tahun memiliki beberapa bentuk CVD (1).
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Belum ada American College of Cardiology (ACC) / American Heart Association
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(AHA) pedoman pembaruan khusus untuk pencegahan CVD pada wanita sejak 2011.
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pernyataan terakhir untuk mengatasi ini adalah Pedoman Efektivitas Berbasis untuk Pencegahan
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Penyakit kardiovaskular Perempuan-2011 Perbarui diterbitkan oleh AHA (2). Sejak itu,
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tubuh data spesifik jenis kelamin telah berkembang, selain pedoman hipertensi diperbarui pada 2017
(3), pedoman kolesterol diperbarui pada 2018 (4), fibrilasi atrium baru (AF) pedoman tahun
2019 (5) , dan pedoman pencegahan utama CVD ACC/AHA 2019 yang baru (6). Meskipun
pedoman ini memberikan review yang sangat bagus dari ilmu dan pengobatan yang berkaitan dengan
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seluruhpenduduk, kesehatan jantung perempuan dapat dioptimalkan dengan memfokuskankhusus
perhatianpada aspek spesifik jenis kelamin unik dari perawatan.
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ACC CVD pada Wanita Komite melakukan tinjauan pedoman baru-baru ini danutama
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studiuntuk meringkas rekomendasi yang berkaitan dengan perempuan. Dalam pembaruan ini, kami membahas
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topik khusus, terutama faktor risiko dan perawatan yang telah menyebabkan beberapa kontroversi
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dan kebingungan. Secara khusus, kami menyoroti faktor risiko yang berhubungan seks, hipertensi, diabetes,
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hiperlipidemia, antikoagulan untuk AF, penggunaan aspirin, terapi hormon perimenopause,
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dan masalah psikososial. Pembaruan ini tidak nutrisi alamat, diet, olahraga, dan merokok
berhenti, yang baik-tercakup dalam pedoman 2019 pencegahan primer (6), ataumendadak
kematianjantung, yang berada di luar lingkup pedoman pencegahan primer
(Ilustrasi Central).
Sebuah
RISIKO CVD FAKTOR UNIK UNTUK WANITA

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KEHAMILAN-ASOSIASI KONDISI YANG KENAIKAN MASA DEPAN RESIKO CVD.
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hasil kehamilan yang merugikan (APO) terjadi pada 10% sampai 20% dari seluruh kehamilan dan
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terkait dengan 1,8 sampai 4,0 kali lipat risiko CVD masa depan (7,8). Risiko CVD lebih tinggi denganyang lebih
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bentukparah APO atau lebih dari 1 kehamilan rumit oleh APO (9). Studi
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kelainan pembuluh darah pada wanita dengan APO menyarankan disfungsi plasenta, danyang abnormal
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fungsi endotel mungkin jalur umum dan awal indikatorkemudian kardiometabolik
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risiko(10). American College of Obstetrics and Gynecology merekomendasikan bahwa wanita

dengan APO dan/atau faktor risiko kardiovaskular menjalani skrining risiko kardiovaskular dalam waktu 3
bulan pascapersalinan (11) (Gambar 1, Tabel 1).
Sebuah
GANGGUAN KEHAMILAN HIPERTENSI.
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Gangguanhipertensi kehamilan berhubungan dengan perkembangan insiden
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hipertensi setelah melahirkan dan CVD keseluruhan. Sebuah meta-analisis dari 3.488.160 perempuan,
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termasuk 198.252 dengan pre-eklampsia melaporkan bahwa setelah 10 sampai 15 tahun, wanita dengan pra
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eklampsia memiliki risiko 3,7 kali lipat hipertensi, 2,2 kali lipat risiko penyakit jantung iskemik, 1.8-
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kali lipat risiko stroke, dan risiko 1,5 kali lipat dari angka kematian secara keseluruhan (8). Pre-eklampsia dimasukkan
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sebagai
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“risiko-enhancer” dalam update 2018 kolesterol pedoman (4) dan di 2019 ACC / AHA
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Pedoman tentang Pencegahan Primer Penyakit Kardiovaskular (6). Selain itu, semua
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Cho et al. Halaman 3
gangguan hipertensi kehamilan dikaitkan dengan peningkatan risikokronis

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hipertensi(12,13) pada awal tahun pertama setelah melahirkan (13), dua kali risiko CVD
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rawat inap terkait dalam waktu 3 tahun pengiriman (14), dan pengembangan lainnya klasik
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faktor risiko CVD seperti diabetes dan hiperlipidemia (15). Sebuah studi tahun 2019 dari United
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dengan
Raya Biobank kohort menemukan bahwa hipertensi selama kehamilan dikaitkan
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peningkatan risiko penyakit koroner (rasio hazard [HR]: 1,8; 95% confidence interval [CI]: 1,3
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menjadi 2,6; p <0,001) serta peningkatan risiko gagal jantung dan penyakit katup jantung (16).
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The American College of Obstetri dan Ginekologi saat ini merekomendasikan inisiasi
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aspirin dosis rendahpada wanita dengan minimal 1 faktor tinggi risiko (riwayat pre-eklampsia,
kehamilan multifetal, hipertensi kronis, diabetes mellitus I atau II, ginjal kronis penyakit,
atau gangguan autoimun) atau setidaknya 2 faktor risiko sedang (nuliparitas, obesitas,keluarga
riwayatpre-eklampsia, faktor sosial ekonomi, usia> 35 tahun, atau faktor riwayat pribadi)
Sebuah
untuk mengurangi risiko pre-eklampsia (17).
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diabetes mellitus gestasional.
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Wanita dengan riwayat diabetes gestasional berada pada peningkatan risiko CVD masa depan,
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dari
termasuk 1.4 sampai 20 kali lipat peningkatan risiko diabetes melitus tipe 2, risiko 2 kali lipat
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hipertensi, risiko 2 kali lipat dari stroke, dan risiko 2,8 kali lipat dari penyakit jantung iskemik (18).
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KELAHIRAN PRA-JANGKA.
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Kelahiran prematur didefinisikan sebagai persalinan sebelum usia kehamilan 37 minggu; kelahiran prematur idiopatik
dikaitkan dengan peningkatan risiko CVD 2 kali lipat dan kematian yang disebabkan oleh penyakit jantung koroner
(19) bahkan ketika disesuaikan dengan gaya hidup pra-kehamilan dan faktor risiko CVD (20). Risiko CVD
lebih tinggi dengan lebih banyak kelahiran prematur dan kelahiran prematur lebih awal (sebelum 34 minggu).
Sebuah
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RUGI KEHAMILAN.
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Wanita dengan keguguran sebelumnya (keguguran dan bayi lahir mati) berada di sekitar 2 kali lipat
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peningkatan risiko infark miokard (MI), infark serebral, dan renovaskular
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hipertensi (21). Dalam meta-analisis dari 10 studi, keguguran dikaitkan dengan 1.45-
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kali lipat peningkatan risiko CVD, dan lebih dari 1 keguguran dikaitkan dengan risiko 2 kali lipat dari
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CVD (22).
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Pembatasan pertumbuhan intrauterin.— Pembatasan pertumbuhanintrauterin (IUGR) didefinisikan sebagai

perkiraan berat janin <10 persentil untuk usia kehamilan, sering dikaitkan dengansuboptimal
perfusi uterus-plasenta(23). Beberapa faktor ibu berhubungan denganpertumbuhan janin
hambatan, termasuk gangguan hipertensi dan diabetes (23). Wanita denganIUGR sebelumnya
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kehamilanberada pada peningkatan risiko hiperlipidemia, hipertrigliseridemia, dan resistensi insulin
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(24). Selain itu, perubahan jantung ekokardiografi telah diamati di
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wanita selama kehamilan IUGR normotensive, termasuk prevalensi lebih tinggi dari diastolik
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disfungsi dan cadangan kurang jantung dibandingkan dengan subyek kontrol (25). Dosis rendah aspirin
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dimulai pada awal kehamilan dapat mencegah IUGR pada pasien tertentu (26,27).
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Cho et al. Page 4
MODEL PREDIKSI RISIKO.

Sebuah
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Meskipun hasil kehamilan yang merugikan berkaitan dengan risiko kemudian CVD, penambahan
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komplikasi kehamilan untuk standar model prediksi risiko kardiovaskular belum
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secara signifikan meningkatkan kemampuan prediktif (28,29). Karena kehamilan yang merugikan
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merupakan
Hasiljuga terkait dengan faktor risiko lain konvensional kardiovaskular yang
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termasuk dalam model risiko standar, dampak aditif komplikasi kehamilan
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menjadi kurang signifikan, terutama dengan bertambahnya usia. Sebuah riwayat kehamilan yang merugikan
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hasil mungkin paling berguna pada wanita yang lebih muda, sebelum pengembangankonvensional,
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faktor risiko dan penting untuk konseling perempuan tentang pencegahan risiko.
MENOPAUSE PREMATUR.
Menopause dini (usia <40 tahun) dianggap sebagai faktor peningkatan risiko dalam2018
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pedoman kolesterol(4). Menopause meningkatkan risiko CVD karenafisiologis

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responuntuk penarikan estrogen, termasuk perubahan distribusi lemak tubuh, mengurangi
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toleransi glukosa, lipid tidak normal, tinggi tekanan darah (BP), peningkatan tonus simpatik,
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disfungsi endotel, dan peradangan pembuluh darah ( 30). Analisis gabungan tahun 2019 dari 15
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dalam
studi observasional termasuk 301.438 wanita melaporkan peningkatan risiko CVD nonfatal
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wanita dengan menopause dini (HR: 1,55; 95% CI: 1,38-1,73; p <0,0001), awal
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menopause (usia 40-44 tahun; HR: 1,30; 95% CI: 1,22-1,39; p <0,0001), dan relatif
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menopause dini (usia 45 sampai 49 tahun; HR: 1,12; 95% CI: 1,07-1,18; p <0,0001) (31).
Data terbaru dari kohort Biobank Inggris melaporkan menopause dini

(sebelum usia 40 tahun) dikaitkan dengan peningkatan risiko CVD (HR: 1,36; 95% CI: 1,19 hingga
1,56; p <0,001) setelah penyesuaian untuk faktor risiko konvensional (32 ). Interaksi antara
CVD dan menopause sangat kompleks, dan mungkin saja wanita yang berisiko tinggi terkena CVD
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mengalami menopause pada usia yang lebih dini.

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Sindrom ovarium polikistik.
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Sindrom ovarium polikistik (PCOS) adalah gangguan umum endokrin yang mempengaruhi muda
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Wanita dan ditandai dengan disfungsi ovulasi (oligomenore atau amenore),

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hiperandrogenisme, infertilitas, dan resistensi insulin (33). Apakah PCOS dengan sendirinya menganugerahkan
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risikotinggi CVD, atau apakah fitur kardiometabolik terkait adalah alasan untuk
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peningkatan risiko tidak jelas (34). Wanita dengan PCOS berada pada peningkatan risiko untuk pengembangan
fitur sindrom metabolik obesitas abdominal, diabetes, dislipidemia, dan

hipertensi (35). Faktor-faktor ini berkontribusi terhadap disfungsi endotel, yang merupakan penanda
risiko CVD, dan beberapa penelitian telah menunjukkan kelainan fungsi endotel dansubklinis
aterosklerosispada PCOS (36). Variasi etnis pada PCOS juga telah dilaporkan, denganTimur
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wanita Asiadengan PCOS memiliki prevalensi sindrom metabolik tertinggi, meskipun

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indeks massa tubuh lebih rendah dan fitur hiperandrogenik kurang (37). Selain pengobatan
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ketidakteraturan menstruasi dengan kontrasepsi oral, metformin direkomendasikan untuk pasien
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yang memiliki fitur kardiometabolik seperti obesitas abdominal dan resistensi insulin (38).
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Meskipun pedoman 2018 kolesterol tidak termasuk PCOS sebagai penambah risiko (4),
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pedoman internasional untuk PCOS merekomendasikan bahwa semua wanita dengan PCOS harus
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diskrining untuk risiko CVD, termasuk pemantauan ketat untuk berat perubahan setiap 6 sampai 12 bulan,
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setidaknya cek BP tahunan, puasa panel lipid, layar untuk kontrol glikemik, dan penilaian

untuk merokok dan aktivitas fisik (39). Faktor psikologis, seperti kecemasan, depresi,
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dan gangguan makan, yang lazim di PCOS, dan pedoman merekomendasikan bahwa kesehatan
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profesional memperhitungkan kepekaan budaya pertimbangan dan terkait berat badan-stigma di
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wanita saat menyikapi intervensi berdasarkan gaya hidup (38) .
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sebuah
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penyakit autoimun.
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Wanita lebih mungkin untuk memiliki mendasari kondisi autoimun dan inflamasi yang
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menyebabkan risiko CVD meningkat, di luar faktor risiko CVD tradisional. Kondisi seperti
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sebagai systemic lupus erythematosus (SLE) dan rheumatoid arthritis (RA) sangat umum pada
wanita dan berhubungan dengan aterosklerosis dipercepat sertakoroner
disfungsi mikrovaskuler(2,40). SLE lebih umum di Asia, Afrika Amerika,
Karibia Afrika, Amerika Hispanik dibandingkan dengan Kaukasia. Wanita kulit hitam 2 sampai
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4 kali lebih mungkin untuk memiliki SLE dibandingkan wanita kulit putih (41). Penyakit jantung iskemik adalah
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nomor 1 penyebab kematian pada SLE. Satu studi melaporkan bahwa wanita muda dengan SLE (usia
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35 hingga 44 tahun) lebih dari 50 kali lebih mungkin untuk memiliki MI dibandingkan dengan orang-orang darisama
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usia dalam studi Offspring Framingham (42). Ada 50% peningkatan risiko CVD
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sebuah
Mortalitaspada RA dibandingkan dengan populasi umum (43). Selanjutnya, muncul
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data bahwa durasi waktu pada RA flare dikaitkan dengan peningkatan risiko kejadian CVD
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(44). Sebuah paradoks lipid dijelaskan dalam 1 studi menunjukkan bahwatinggi eritrosit
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tingkatsedimentasi dan kadar kolesterol rendah dikaitkan dengan risiko CVD pada pasien RA
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(45). Tingkat peradangan yang lebih tinggi dikaitkan dengan hasil buruk utama meskipunrendah
kadar kolesterolhingga normal dalam penelitian lain (46,47). Terapi dengananti-inflamasi
obatseperti statin, interleukin-1β antagonis reseptor canakinumab, dan colchicine
meningkatkan hasil CVD di berbagai kohort (47-49). Skor risiko ACC/AHA yang diturunkan
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dari persamaan kohort gabungan untuk memperkirakan risiko CVD aterosklerotik tidak memasukkanini
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faktor risiko unikuntuk wanita; Namun, 2018 kolesterol pedoman daftar faktor-faktor ini sebagai
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berisiko meningkatkan faktor-faktor yang harus dipertimbangkan ketika menilai pasien
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risiko CVD (4).
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FAKTOR RISIKO TRADISIONAL
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HIPERTENSI.
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Pedoman ACC/AHA 2017 untuk pencegahan, deteksi, evaluasi, dan pengelolaan

tekanan darah tinggi memberikan panduan spesifik jenis kelamin terbatas dalam pengelolaan hipertensi dan
berfokus terutama pada hipertensi selama kehamilan (3), yang telahsecara ekstensif
ditinjaudalam sebuah makalah yang membahas hipertensi sepanjang umur wanita (50). Namun,
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adaaspek unik tertentu pada wanita dari pencegahan, epidemiologi, evaluasi, dan
manajemen hipertensi. Faktor risiko umum untuk hipertensi pada wanita meliputi:
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obesitas, aktivitas fisik, peningkatan asupan garam, diabetes, dan lebih dari alkoholmoderat
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konsumsi(yaitu,> 1 minuman beralkohol / hari). Kombinasi dari faktor-faktor risiko ini adalah
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dikaitkan dengan risiko lebih tinggi hipertensi, dan obesitas memiliki dampak tertinggi di
kejadian
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hipertensi pada wanita (51). Karena up-regulasi renin-angiotensin
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reseptor setelah menopause, pembatasan garam adalah bermanfaat dalam mengurangi risiko hipertensi.
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Memang, asupan garam mengurangi telah terbukti mengurangi tekanan darah sistolik pada wanita dengan dan
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tanpa hipertensi (52). 2017 ACC / AHA merekomendasikan untuk idealnya membatasi

asupan natrium untuk <1.500 mg/hari atau setidaknya bertujuan untuk pengurangan 1.000 mg/hari, dan untuk
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meningkatkan asupan kalium dari makanan untuk setidaknya 3.500 sampai 5.000 mg/hari (3); Namun,
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tidak ada rekomendasi spesifik berdasarkan jenis kelamin (Gambar 2).
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Perhatian perlu diberikan pada kemungkinan adanya penyebab sekunder hipertensi
a di
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antara wanita premenopause. Secara khusus, wanita account untuk> 90% kasus
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fibromuskular dysplasia, suatu kondisi yang mempengaruhi 3,3% dari populasi umum (53).
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Gabungan kontrasepsi hormonal juga dapat mengakibatkan peningkatan BP, khususnya di kalangan
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wanita dengan diagnosis yang sudah ada hipertensi. Wanita premenopause yang membutuhkan
terapi antihipertensijuga memerlukan konseling tentang potensi teratogenisitas obat,

terutama jika menerima penghambat enzim pengubah angiotensin, penghambat reseptor angiotensin
, atau antagonis reseptor aldosteron (54).
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Prevalensi hipertensi pada wanita premenopause cenderung lebih rendah dibandingkan pria pada
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usia yang sama; namun, hipertensi menjadi lebih umum pada wanita setelah menopause (1).
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Dalam baru-baru seks-spesifik analisis BP longitudinal> 32.000 pasien, wanita ditemukan
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dan
memiliki kenaikan curam di BP dibandingkan laki-laki, yang dimulai pada awal dekade ketiga kehidupan
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bertahan dengan penuaan, bahkan setelah disesuaikan untuk faktor risiko kardiometabolik. Hal ini
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bertentangandengan keyakinan bahwa penyakit vaskular lag 10 tahun atau lebih pada wanita dibandingkan
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saya
dengan laki-laki (55). Karena BP merupakan ukuran diakses sederhana penuaan pembuluh darah dan merupakan
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kontributor yang signifikanuntuk kejadian kardiovaskular di masa depan, temuan ini bisa membantu menjelaskan
beberapa perbedaan dalam presentasi CVD di kalangan perempuan dibandingkan laki-laki, sepertidiastolik
gagal jantung(55,56) .
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Pedoman ACC/AHA 2017 merekomendasikan pemantauanluar kantor untuk
tekanan darah dikonfirmasidan pengelolaan hipertensi terlepas dari jenis kelamin (3). Khususnya, studi
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menyarankan bahwa wanita pasca-menopause cenderung mengalami malam BPnondipping
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pola(didefinisikan sebagai <pengurangan 10% di malam hari BP) (57). Fenomena ini mungkin menjelaskan
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insiden yang lebih tinggi dari kejadian kardiovaskular dikaitkan dengan tekanan darah malam hari diamati pada wanita
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dibandingkan dengan pria (58), menunjukkan bahwa wanita mungkin memperoleh lebih banyak manfaat dari kontrol BP
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menggunakan pengukuran BP rawat jalan dibandingkan dengan pemantauan BP konvensional.
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Berdasarkan temuan SPRINT (Sistolik Tekanan Darah Intervensi Trial), 2017
ACC / AHA pedoman merekomendasikan target BP terapi 130/80 mm Hg terlepas dari

jenis kelamin (3,59). Meskipun prevalensi hipertensi lebih tinggi di antara wanita, SPRINT hanya
mendaftarkan 36% wanita (59). Menariknya, wanita yang terdaftar dalam SPRINT memilikilebih rendah
risiko kardiovaskular yangdaripada pria (60,61). Dua analisis untuk perbedaan spesifik jenis kelamin antara
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strategi penurunan tekanan darah intensif versus strategi penurunan tekanan darah standar dari SPRINT
u
dilakukan (60,61). Satu menunjukkan bahwa perempuan dan laki-laki memperoleh manfaat yang sama dari
t
h
intensif BP penurun strategi (60), sedangkan analisis lain menunjukkan bahwa wanita tidak
o
manfaat dari intensif strategi penurunan tekanan darah setelah pencocokan perbedaan dasar di
M
tetap
kedua kelompok (61). Secara kolektif, ini menunjukkan bahwa target BP terapi pada wanita
n
u
tidak mapan bahkan setelah hasil uji coba SPRINT (62).
s
i
DataAcak percobaan menunjukkan bahwa tidak ada perbedaan besar antara perempuan dan laki-laki dalam
p
kardiovaskular hasil berdasarkan regimen antihipertensi (63), tapi tampaknya

wanita mungkin mengalami lebih banyak efek samping dari obat antihipertensi (63,64).
A
Mungkin thiazide diuretik agen adalah agen hanya jelas menguntungkan pada wanita yang lebih tua karena
u
t
efeknya dalam mengurangi ekskresi kalsium dan mencegah osteoporosis (65).
h
DIABETES.
n
u
Diabetes mellitus (DM) diperkirakan mempengaruhi lebih dari 26 juta orang di Amerika Serikat, dari
s
c
yang 12,8 juta adalah perempuan, dengan sebagian besar memiliki tipe 2 DM (1). Ada
r
p
perbedaan jenis kelamin mencolok prevalensi DM tipe 2 di seluruh jangka hidup serta seks
t
perbedaan hasil CVD.
Menariknya, ada perbedaan dalam kejadian DM tipe 2 sepanjang umur, dengan anak perempuan
memiliki tingkat yang lebih tinggi dari DM tipe 2 di masa muda, sedangkan laki-laki memiliki tingkat yang lebih tinggi
selama paruh baya,
A
dengan kejadian yang sama antara pria dan wanita pada tahap selanjutnya dalam kehidupan (66) . Mekanisme
dari perbedaan jenis kelamin mungkin karena perbedaan jenis kelamin dalam resistensi insulin selama masa remaja dan
u
t
paruh baya, dengan perempuan muda yang memiliki resistensi insulin lebih tinggi pada anak usia dini untuk
h
o
pubertas (66). Temuan ini dari awal-awal dari DM pada pasien wanita, yang diterjemahkan ke dalam
r
M,
durasi penyakit yang lebih lama sepanjang hidup mereka, harus menimbulkan kekhawatiran serius mengingat
-
n
temuan Swedish Heart Registry barubaru ini bahwa mortalitas CVD meningkat secara signifikan untuk
u
s
orang yang didiagnosis dengan DM tipe 2 sebelum usia 40 tahun (67).
c
t
Diabetes meningkatkan risiko memiliki MI atau stroke sebesar 2 kali lipat (66). Dengan adanyatipe
DM2, perbedaan tingkat absolut antara kedua jenis kelamin berkurang secara signifikan, meskipun
tidak sepenuhnya dihilangkan (68,69). Perlindungan jantung yang terjadi pada wanita premenopause
dengan demikian berkurang secara signifikan dengan diabetes. Sebuah tinjauan sistematis baru-baru ini dan
meta-analisisdari
A
lebih5 juta pasien menemukan bahwa risiko relatif gabungan untuk kematian CVD pada pasien dengan
DMadalah 2,42 pada wanita (95% CI: 2,10 hingga 2,78) dan 1,86 (95% CI: 1,70 hingga 2,03). ) pada pria (70).
u
Ada juga tampaknya menjadi kelebihan risiko yang lebih besar dari kematian CVD pada wanita dengan DM dibandingkan
t
o
dengan laki-laki (risiko relatif: 1,30; 95% CI: 1,13-1,49; p <0,001) dalam beberapa pooled disesuaikan
r,
analisis meskipun ada heterogenitas yang signifikan antara studi (70). Baru-baru ini,
M
sebagai
StudiAterosklerosis Risiko Dalam Komunitas ditemukan DM merupakan faktor risiko yang kuat untuk CVD
n
u
serta kematian CVD di antara perempuan Afrika-Amerika dari kalangan Afrika-Amerika
s
r
pria (71). Temuan ini mirip dengan apa yang telah terlihat padapria dan wanita kulit putih
i
t
pasien(71). Selain acara aterosklerosis, memiliki DM meningkatkan terjadinya
gagal jantung kongestif. Dalam studi biobank Inggris dari 468.941 pasien yang diikuti selama 9,0 tahun,
wanita dengan DM tipe 2 memiliki tingkat insiden gagal jantung yang secara signifikan lebih tinggi (HR:
1,73; 95% CI: 1,34 hingga 2,24; p <0,0001) serta mortalitas gagal jantung (HR: 1,92; 95% CI:
1,25-2,94; p = 0,003) dibandingkan dengan laki-laki (72). Terakhir, DM meningkatkan risikokanker
A
kematian akibatsebesar 26% pada wanita (95% CI: 1,16 hingga 1,36) dan sebesar 29% pada pria (95% CI: 1,18 hingga
u
1,42) (70). Tidak ada perbedaan seks dalam hubungan antara diabetes dankanker
t
h
kematian untuk pasien diabetes (70).
o
sebuah
Tampaknya ada beberapa efek spesifik jenis kelamin dari farmakoterapi untuk DM. Sebagai contoh,
n
u
telah melaporkan bahwa GLP-1 agonis reseptor memilikiglikemik yang lebih baik
s
kontrolkalangan laki-laki daripada perempuan; namun, wanita mengalami penurunan berat badan lebih banyak
c
(73).
r
saya
Thiazolidinediones tampaknya memiliki pengurangan glikemik yang lebih baik pada wanita obesitas, sedangkan
p
pria obes menanggapi lebih baik dengan sulfonilurea (74,75). Yang meyakinkan, EMPA-REG
Cho et al. Page 8
(Empagliflozin, Cardiovascular Outcomes, dan Kematian di Diabetes Tipe 2) studi, yang

A
menunjukkan penurunan mortalitas kardiovaskular pada pasien diabetes yang diobati dengan natrium
u
t
glukosa cotransporter 2 inhibitor empagliflozin, menunjukkan tidak ada perbedaan jenis kelamin yang signifikan dalam
h
R
manfaat dengan obat (76).
M
n
Mengingat peningkatan risiko kardiovaskular, semua pasien dengan DM memerlukanfaktor risiko agresif
u
s
pengurangan. Namun, penelitian telah secara konsisten menunjukkan bahwa perempuan kurang terdiagnosis dan
c
r
terobati dibandingkan dengan laki-laki (77,78). Wanita dengan DM memiliki miskin BP, lipid, dan DM
i
t
kontroldibandingkan dengan rekan-rekan pria mereka (66).
Tabel 2 mencantumkan tujuan BP, lipid, antiplatelet, dan hemoglobin A1c untuk pasien diabetes tanpa
CVD. Meskipun ada beberapa target yang berbeda antara masyarakat yang berbeda
(3,4,6,79-81) mengenai target BP, masyarakat konsisten dengan kontrol lipid agresif
A
untuk pasien diabetes. Tidak ada perbedaan jenis kelamin antara pengobatan dantarget
u
rekomendasi. Semua masyarakat setuju bahwa pasien tanpa gejala tidak rutin diskrining
t
h
untuk CAD.
o
DARAH KOLESTEROL MANAJEMEN PADA WANITA

n
s
Meskipun kemajuan kontemporer dalam terapi penurun kolesterol, wanita cenderung
c
i
untuk menerima pedoman-direkomendasikan terapi statin dibandingkan dengan laki-laki. Mereka juga lebih
p
cenderung menurun pengobatan awal dan kurang mungkin untuk melanjutkan terapi statin yang diresepkan (82).
Pedoman multisociety AHA/ACC 2018 tentang pengelolaan kolesterol darah dan
Pedoman ACC/AHA 2019 tentang Pencegahan Primer Penyakit Kardiovaskular menekankan
pentingnya manajemen lipid untuk mengurangi risiko penyakit kardiovaskular aterosklerotik
(ASCVD) dan memasukkan beberapa risiko spesifik jenis kelamin. -meningkatkan faktor untuk membantu lebih lanjut
A
mengidentifikasi
u
wanita pada peningkatan risiko ASCVD (4,6). Selain intervensi gaya hidup dengan diet,
t
berolahraga, dan penurunan berat badan, pedoman merekomendasikan terapi statin sebagai pengobatan andalan
h
r
di 4 kelompok pasien:
M
a
1. ASCVD Klinis;
n
s
2. Hiperkolesterolemia berat (kolesterol low-density lipoprotein [LDL] 190
c
r
mg/dl);
i
3. Diabetes mellitus pada orang dewasa (usia 40 sampai 75 tahun);

4. Pencegahan primer pada orang dewasa berusia 40 hingga 75 tahun dengan risiko tinggi (≥20%) dan beberapa
orang dewasa dengan risiko sedang (≥7,5% hingga <20%) atau risiko ambang (5% hingga <7,5%)
A
berdasarkan adanya peningkat risiko, adanya peningkatankoroner
skor kalsium arterijika diukur, dan diskusi risiko dokter-pasien.
u
t
Manfaat terapi statin telah diterima secara luas untuk pengurangan kejadian CVD untuk
h
r
pencegahan sekunder pada kedua jenis kelamin; Namun, peran terapi statin untukprimer
M
bagian
Pencegahanpada wanita telah diperdebatkan selama dekade terakhir. Kontroversi ini berasal di
n
dari kurangnya data yang kuat tentang khasiat statin untuk pencegahan primer pada wanita, seperti
u
s
bawah keterwakilan perempuan di uji coba terkontrol secara acak meninggalkan studi kurang bertenaga untuk
c
i
memadai menganalisis hasil berdasarkan jenis kelamin. Selain itu, awal meta-analisis terapi statin untuk
p
pencegahan primer menghasilkan data yang bertentangan, dengan beberapa penelitian yang menunjukkan tidak ada
yang signifikan

pengurangan kematian atau kejadian kardiovaskular pada wanita (83). KarenaEfektivitas

A
Pedoman Berbasisuntuk Pencegahan Penyakit Kardiovaskular Perempuan-2011 Perbarui
u
t
(2), 2 lebih besar meta-analisis termasuk lebih dari 40.000 wanita telah menunjukkanyang sama
h
r
manfaat dari terapi statin pada wanita dan laki-laki untuk kedua primer dan pencegahan sekunder, dan
M
a
manfaat ini terlihat pada kedua jenis kelamin di semua tingkat risiko dalam studi pencegahan primer
n
(84,85). Meskipun tidak ada perbedaan jenis kelamin yang signifikan dalam efek samping yang diidentifikasi dalamini,
u
meta-analisis beberapa percobaan statin dilaporkan reaksi obat yang merugikan berdasarkan jenis kelamin. Meskipun
c
kekurangan
r
i
acak data uji, pernyataan konsensus internasional diakui kelamin perempuan sebagai risiko
p
faktor untuk gejala otot statin terkait (86,87). Pada pasien denganterkait statin
gejala otot, tinjauan yang cermat terhadap pengobatan bersamaan dan riwayat rinci harus
diambil untuk memahami faktor-faktor yang dapat berkontribusi terhadap efek samping statin (86,87). Perubahan statin
(hidrofilik vs lipofilik) serta dosis statin intermiten dapat digunakan untuk membantu
Sebuah
mengatasi beberapa gejala otot yang terkait dengan statin (88).
u
Saat ini tidak ada pedoman spesifik jenis kelamin untuk pengelolaan kolesterol darah dengan
t
o
statin terapi. Statin mengurangi kejadian kardiovaskular dan semua penyebab kematian tanpa memandang jenis kelamin,
r
M
dan harus dipertimbangkan pada dosis dianjurkan pada wanita yang memenuhi kriteria untuk 1 dari 4
sebuah
n
populasi pasien pedoman-direkomendasikan (Gambar 3).
u
c
Alasan untuk perbedaan jenis kelamin dalam metrik kualitas pada pasien dan tingkat dokter perlu menjadi
r
t
diteliti lebih lanjut untuk memastikan pencegahan primer dan sekunder yang optimal pada wanita, mengingat
bahwa perbedaan jenis kelamin dalam statin resep pola dan kepatuhan terus ada.
WANITA DENGAN DYSLIPIDEMIA DAN KEHAMILAN
A
Pedoman merekomendasikan bahwa wanita premenopause pada terapi statin perlu menghentikan
u
statin1 sampai 2 bulan sebelum mencoba kehamilan (4). Jika kehamilan tidak direncanakan,
t
statin harus dihentikan segera setelah kehamilan diketahui (4). Optimal manajemen
h
r
kolesterol dengan kebiasaan hidup sehat harus dibicarakan terlebih dahulu pada wanita hamil dengan
M
a
dislipidemia (4). Sequestrant asam empedu disetujui untuk digunakan selama kehamilan.
n
s
ARAH MASA DEPAN, STATIN, DAN KEHAMILAN.
c
i
Keamanan pravastatin telah diteliti untuk pencegahan pre-eklampsia ditinggi
p
risiko wanita hamil (89). Statin diketahui memiliki efek pleiotropik, yang dapat
mengurangi peradangan dan stres oksidatif, meningkatkan angiogenesis, menghambatkoagulasi
kaskade, dan melindungi endotelium (90). Uji klinis manusia sekarang sedang
berlangsung untuk menentukan apakah statin hidrofilik dapat digunakan untuk mencegah preeklamsia pada
Sebuah
wanita berisiko tinggi.
u
t
NONSTATIN TERAPI PADA WANITA
h
Ezetimibe mengurangi penyerapan kolesterol di usus kecil dan sederhana tapi efektif
M
mengalami
Agen penurun lipiduntuk pria dan wanita. Khususnya, bagi wanita yang
n
statin-induced mialgia, ezetimibe adalah alternatif nonstatin untuk pasien yang dianggap
u
r
toleran terhadap terapi statin (didefinisikan sebagai intoleransi terhadap 2 atau lebih statin dan gagal alternatif
i
t
dosis terapi) atau membutuhkan penurunan LDL tambahan selain statin yang dapat ditoleransi maksimum.

Monoterapi dengan ezetimibe akan memberikan pengurangan LDL 18% dan terapi tambahan
A
memberikan pengurangan 25% (4). The MENINGKATKAN IT (Ezetimibe ditambahkan ke Statin setelah akut
u
t
Sindrom Koroner) percobaan, yang divalidasi efektivitas ezetimibe dalam kombinasi
h
r
dengan simvastatin dilakukan dalam pengaturan pencegahan sekunder antara pasca-akut
M
a
coronary syndrome patients, average age over 60 and were predominantly men. Therefore,
n
the effectiveness of ezetimibe in women (in particular midlife women) in the primary
u
c
prevention setting is less understood (91).
r
t
Proprotein convertase subtilisin/kexin type 9 (PCSK9) are monoclonal antibodies with 2
US Food and Drug Administration approved injectables currently available on the market.
Cardiovascular outcome studies of PCSK9 inhibitors using alirocumab (ODYSSEY
Outcomes [Alirocumab and Cardiovascular Outcome after Acute Coronary Syndrome]) and
A
evolocumab (FOURIER [Evolocumab and Clinical Outcomes in Patients with
Cardiovascular Disease]), demonstrated that PCSK9 inhibition added to maximum-tolerated
u
statin significantly reduced LDL cholesterol levels and the rate of major adverse
t
o
cardiovascular events (92,93). Both studies had smaller numbers of women who participated
r
M
in their clinical trials; however, subgroup analysis found no treatment heterogeneity by sex
a
n
(92,93). The OSLER-1 (Open Label Study of Long-Term Evaluation Against LDL-C Trial)
u
s
evaluated longer-term effects of evolocumab during open-label hypercholesterolemia
c
r
treatment for up to 5 years in over 1,000 patients who tolerated evolocumab up to 4 years
i
t
(94). Women accounted for 53% of the cohort and demonstrated excellent tolerability to
evolocumab with an annual 1.4% discontinuation rate. Although there has not been a
primary prevention trial of PCSK9 inhibitors, they seem to be well tolerated and effective at
lowering LDL in both men and women.
A
ASPIRIN THERAPY.
u
t
Among women with established ASCVD, the role of aspirin is well-established; aspirin
h
o
reduces subsequent vascular events by approximately 25% (95). Aspirin reduces the risk of
r
M
athero-thrombosis by irreversibly inhibiting platelet function, but this same mechanism
a
n
comes at a trade-off of increased risk of bleeding, especially in the gastrointestinal tract. In
u
s
primary prevention, the role of aspirin has been controversial and net benefit less certain for
c
r
most healthy women. This is because in primary prevention, the absolute risk of vascular
i
t
events is lower than in secondary prevention, but the complication rates (bleeding) are
comparable.
The 2005 WHS (Women's Health Study), the largest aspirin primary prevention trial,
evaluated low-dose aspirin (100 mg every other day) versus placebo in nearly 40,000 women
A
≥45 years that were free of ASCVD at baseline. The WHS found that low-dose aspirin
u
reduced the risk of stroke over a 10-year follow-up without reducing the risk of MI;
t
h
however, among women age ≥65 years, aspirin significantly reduced risk of major
o
cardiovascular events including both ischemic stroke and MI (96). Longer (15-year) follow
M
a
up suggested that low-dose aspirin was ineffective or harmful for most healthy women, but
n
u
there may be benefit for women over age 65 years when considering both colorectal cancer
s
c
and ASCVD events (97).
r
J Am Coll Cardiol. Naskah penulis; available in PMC 2021 August 02.

Cho et al. Page 11
However, 3 more recent randomized clinical trials, ASCEND (Effects of Aspirin for Primary
A
Prevention in Persons with Diabetes Mellitus), ARRIVE (Use of Aspirin to Reduce Risk of
u
t
Initial Vascular Events in Patients at Moderate risk of Cardiovascular Disease), and
h
r
ASPREE (Effect of Aspirin of All-Cause Mortality in the Healthy Elderly), published in
M
a
2018, found a lack of net benefit, suggesting that prophylactic aspirin should not be used in
n
the routine primary prevention of ASCVD (98–100). The ASCEND trial evaluated low dose
u
c
aspirin versus placebo in over 15,000 adults who had diabetes but no ASCVD and found that
r
i
the absolute benefit for reduction in serious vascular events conferred by aspirin were largely
p
counterbalanced by the increased risk of bleeding (98). The ARRIVE trial, evaluating over
12,000 adults at intermediate estimated ASCVD risk, found no benefit of aspirin for
reducing vascular events but increased risk of gastrointestinal bleeding (99). Finally, the
ASPREE trial of over 19,000 adults age >65 years (including 56% women) found no
A
reduction in cardiovascular events with aspirin, but there was an increased risk of bleeding
u
and risk of death (100,101). Finally, an updated 2019 meta-analysis found that the number
t
needed to treat to cause major bleeding was lower than the number needed to treat to prevent
h
R
an ASCVD event (210 vs. 265), suggesting more harm than benefit (102).
M
n
These findings guided the updated aspirin recommendations in the 2019 ACC/AHA
u
s
Guideline on the Primary Prevention of CVD (6). The 2019 guidelines state that most
c
r
healthy people do not need to take aspirin, and there were no sex-specific recommendations.
i
t
These recommendations differ from prior AHA guidelines, which recommended that aspirin
could be considered for patients with 10-year ASCVD risk ≥10%. There may still be select
patients age 40 to 70 years who have a high ASCVD risk who may benefit from aspirin if
they are at low risk for bleeding. One might consider low-dose aspirin (75 to 100 mg/day)
A
among current smokers, those with a strong family history of premature ASCVD, those with
very elevated cholesterol suboptimally treated with statins, those with subclinical
u
atherosclerosis such as a coronary artery calcium (CAC) scores ≥100, and other select
t
o
patients at high ASCVD risk. However, these decisions are needed in the context of a
r
clinician-patient risk discussion. Clinicians should qualitatively evaluate for bleeding risk
M
n
and withhold aspirin in primary prevention patients with prior gastrointestinal bleeding,
u
s
known bleeding disorder, severe liver disease, thrombocytopenia, concurrent anticoagulation
c
r
or NSAID use, or uncontrolled hypertension.
i
The more recent trials differ than prior trials, since in the modern era, smoking rates are
lower and there is more contemporary preventive therapy, including greater prevalence of
statin use and BP control. The percent of patients taking statins in ASPREE, ARRIVE, and
ASCEND was 34%, 43%, and 75%, respectively (98–100). Population-specific modeling
A
might help identify those anticipated to derive a net benefit of aspirin for primary prevention,
u
but most primary prevention patients are unlikely to benefit (Figure 4) (103).
t
R
STROKE PREVENTION FOR AF.
M
a
Many studies have shown that women are at greater risk for AF-related stroke than men. The
n
u
reason for this higher risk is unclear. Even after adjusting for differences in stroke risk
s
c
factors and stroke prevention treatment with oral anticoagulants, women have about a 20%
r
t
to 30% higher risk of stroke than men with AF (104,105). As a result of this higher risk,

Cho et al. Page 12
female sex was incorporated into the commonly used algorithm, CHA2DS2-VASc score to
A
predict the risk of stroke in patients with nonvalvular AF (106,107).
u
o
In 2018, a consensus statement regarding sex differences in arrhythmias was published by
r
M
the European Heart Rhythm Association and endorsed by the Heart Rhythm Society and
a
n
Asia Pacific Heart Rhythm Society (108). The statement emphasized the residual stroke risk
u
s
in women compared with men using vitamin K antagonists and recommended the use of the
c
r
novel anticoagulants as the first choice (109,110). Compared with men with AF, women
i
t
with AF had worse stroke severity and more permanent disability after a stroke (111). The
statement also highlighted the lower risk of bleeding seen in women compared with men
with the use of the novel anticoagulants (108). The statement noted that since a meta
analysis of all 4 novel anticoagulants showed no significant difference with regard to their
A
safety and efficacy in women compared with dose-adjusted warfarin, the novel anticoagulant
can be used interchangeably in women depending on personalized needs (112).
u
h
The 2019 AHA/ACC/Heart Rhythm Society update on AF guidelines changed the Class I
o
recommendation for anticoagulation, increasing the CHA2DS2-VASc score from ≥2 to ≥3

M
for women and no change in recommendation for men (CHA2DS2-VASc scores of ≥2) (5).
a
u
Table 3 is a comparison of the recommendations of the American and European guidelines
s
c
as well as the updated European recommendations (5,113). Table 4 is key points in atrial
r
t
fibrillation and women.
There are no sex-specific recommendations for left atrial appendage closure devices or
surgical occlusion of the left atrial appendage orifice. However, in a pooled patient-level
analysis of the PROTECT-AF (WATCHMAN Left Atrial Appendage System for Embolic
A
PROTECTion in Patients With Atrial Fibrillation) and PREVAIL (Evaluation of the
u
WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term
t
Warfarin Therapy), in women, LAA closure significantly reduced bleeding compared with
h
R
patients treated with warfarin (HR: 0.17; 95% CI: 0.074 to 0.369; p < 0.001) (114).
M
n
MENOPAUSAL HORMONE THERAPY.
u
c
At this time, there is no role for menopausal hormone therapy (MHT) for CVD prevention.
r
p
This recommendation is consistent with the American College of Obstetrics and Gynecology
t
statement published in 2013 and reaffirmed in 2018 (115). Since the publication of the
HERS (Heart and Estrogen/progestin Replacement Study) (116) secondary prevention trial
of MHT, and WHI (Women's Health Initiative) Study (117), a primary prevention trial of
MHT for CVD, long-term use of MHT for CVD prevention is not recommended, as both
A
trials failed to demonstrate cardiovascular benefit and suggested potential harm.
u
t
However, there has been much discussion regarding the “timing hypothesis” of MHT. In a
h
o
combined analysis of the 2 WHI trials, estrogen + progesterone and unopposed estrogen
r
M
alone, women who started MHT closer to menopausal onset appeared to have lower risk
a
n
developing subclinical atherosclerosis (118,119) and lower risk of developing CVD (118).
u
s
However, these findings have not been seen consistently in other trials (120,121).
c

Cho et al. Page 13
The most recent meta-analysis in 2017 combining similar long-term MHT studies showed
A
that increased risk of MHT outweighs any benefit in regard to prevention of CVD (122). An
u
t
increased risk of venous thromboembolism with hormone therapy has been shown with all
h
r
forms of hormone therapy except for transdermal estrogen (122). Thus, it is imperative that
M
a
even younger patients who are being considered for treatment for post-menopausal
n
vasomotor symptoms with MHT be assessed for personal and familial risk of venous
u
c
thromboembolism.
r
DEPRESSION AND PSYCHOLOGICAL ISSUES IN WOMEN

A large body of epidemiological, experimental, and clinical observations have long linked
acute and chronic emotional stress and psychological disturbances, such as depression, to
A
physiological perturbations of the cardiovascular system and the risk of CVD (123,124).
Psychosocial stress tends to be a more important risk factor for cardiometabolic diseases in
u
women than in men, not only because women in general have higher exposures to
t
o
psychosocial stress and adversity than men, but also because they may be more vulnerable to
r
the effects of such exposures (125). In particular, depression, early-life adversities,

M
a
socioeconomic deprivation, and post-traumatic stress disorder (PTSD) are more prevalent in
n
u
women than in men and tend to show more robust associations with cardiometabolic risk in
s
r
women than in men, especially in younger populations or with early exposure (125).
i
Depression affects approximately 7% of the population each year, and is about 2-fold more
common in women than in men (126). Depression is a recognized risk factor for incident MI
and cardiac death (127). Among women, a clinical diagnosis of depression is associated with
a doubling of risk of CVD even over a period of decades (128,129). Although few studies
A
have examined sex-related differences, available data suggest that depression may be an
u
especially strong risk factor for early-onset CVD in women (130,131).
t
r
Compared with men, women have a higher exposure to severe childhood adversities, such as
M
a
physical and sexual abuse and child neglect, which are increasingly recognized as risk
n
factors for CVD (132). Similar to depression, exposure to adversity in early life appears to
u
s
be a stronger predictor of CVD in women than it is in men (133). These early exposures are
c
i
also predisposing factors for depression and PTSD, as well as strong correlates of adverse
p
t
lifestyle behaviors.
Although general symptoms of anxiety, measured with a variety of scales, have been
associated with incident CVD in a number of studies, individual study results are
A
heterogeneous and the effect sizes are in general modest (134). In contrast, symptoms of
PTSD, a condition previously classified among anxiety disorders, have been consistently
u
related to increased risk of CVD (135). In the United States, PTSD affects 9.7% of women
t
o
(past year prevalence) versus 3.6% of men (136). In a prospective study of women, those
r
with ≥5 PTSD symptoms had an over 3-fold higher risk of ischemic heart disease compared
M
a
with those without PTSD symptoms, independent of CVD risk factors and depression (137).
n
u
In the Nurses' Health Study II, women who reported ≥4 PTSD symptoms had a 60% higher
s
r
risk of CVD; those with a history of trauma but no PTSD symptoms also showed an elevated
i
t
CVD risk (45% higher) (138).

Cho et al. Page 14
There are multiple possible mechanisms linking depression, PTSD, psychological stress, and
A
trauma to CVD. All of these conditions and exposures are associated with poor health
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t
behaviors, such as smoking, poor dietary habits, and physical inactivity. Alterations in
h
r
neurobiological stress response pathways can also play a role, leading to increased
M
a
inflammation, chronic autonomic dysregulation, endothelial dysfunction, and
n
hypercoagulability (122). Therefore, recognition and management of psychosocial stressors
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c
should be useful in promoting a healthy lifestyle and preventing cardiometabolic risk.
r
i
Currently there are no national guidelines or recommendations on the assessment of these
p
factors in preventive cardiology care. Although there is currently limited understanding of

whether interventions addressing psychosocial and emotional disturbances prevent
progression to cardiometabolic diseases, recognition and management of these factors
should help the quality of life of patients with these conditions, many of whom are women.
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CONCLUSIONS
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o
Women have different manifestations of CVD, and studies have shown sex differences in
r
their response to risk factors and treatments. In addition, unique aspects that pertain to
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a
women, such as pregnancy-associated conditions that increase future risk, PCOS, and
n
u
treatment-related issues specific to women, need to be considered when treating women.
s
r
Knowledge of updated guideline recommendations are critical in shared decision-making
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t
plans to treat women and men to improve CVD outcomes.
Acknowledgments
Dr. Cho has received research support from Novartis; has received research support from and served as a consultant
to Esperion and Amgen; and has served as a consultant to AstraZeneca. Dr. Minissian has served as a consultant for
A
Amgen, Medtelligence, and the North American Center for Continuing Medical Education; and has received
research support from the National Institutes of Health and NIHF. Dr. Pepine has received support from the NIH/
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t
NHLBI (WISE HFpEF, HL146158), NIH/NCATS (University of Florida Clinical and Translational Science,
h
UL1TR001427), the Gatorade Trust through the University of Florida Department of Medicine, the McJunkin
o
r
Family Foundation, and the US Department of Defense (WARRIOR, PR161603). Dr. Vogelman has served as a
consultant for the American Heart Association; and has served as a speaker for Aptus Health. All other authors have
M
reported that they have no relationships relevant to the contents of this paper.
a
c
ABBREVIATIONS AND ACRONYMS
r
AF atrial fibrillation
APO adverse pregnancy outcomes
ASCVD atherosclerotic cardiovascular disease

A
BP blood pressure
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t
CVD cardiovascular disease
h
DM diabetes mellitus
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u
HR hazard ratio
s
r
IUGR intrauterine growth restriction
i

Cho et al. Page 15
PCOS polycystic ovarian syndrome

A
u
PTSD post-traumatic stress disorder
t
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Cho et al. Page 23
HIGHLIGHTS
• CVD remains the leading cause of morbidity and mortality in women.
• Women have unique risk factors for CVD—such as PCOS and pregnancy
associated conditions that increase future risk of CVD.
• Women also have different manifestations of CVD, and studies have shown
sex differences in their response to risk factors and treatments.
• Knowledge of unique risk factors in women as well as treatment gap is

critical in lowering cardiovascular risk in women.
ho
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ip
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Cho et al. Page 24
t
h
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FIGURE 1. Recommendations for Cardiovascular Risk Screening After Adverse Pregnancy
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Outcomes
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Adverse pregnancy conditions that require further cardiovascular screening within 3 months
post-partum based on medical history, physical examination, and laboratory. CVD =
cardiovascular disease; DM = diabetes mellitus; HELLP = hemolysis, elevated liver enzyme,
low platelet count; HTN = hypertension; IUGR = intrauterine growth restriction; PMH =
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past medical history.
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c
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Cho et al. Page 25
h
FIGURE 2. Hypertension in Women
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Progression of hypertension from prevalence to prevention, screening, and therapeutic target.
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BMI = body mass index; BP = blood pressure.
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Cho et al. Page 26
p
FIGURE 3. Recommendations for Statin for ASCVD Prevention in Women
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Statin therapy recommendations based on studies and guidelines. ASCVD = atherosclerotic

cardiovascular disease; LDL-C = low-density lipoprotein cholesterol.
* Consider sex-specific risk enhancers: premature menopause and pregnancy-associated
conditions that increase ASCVD risk
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Cho et al. Page 27
n
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FIGURE 4. Recommendation for Aspirin for ASCVD Prevention in Women

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t
Aspirin therapy recommendation based on studies and guidelines. ASCVD = atherosclerotic
cardiovascular disease; CAC = coronary artery calcium; CVD = cardiovascular disease; FHx
= family history; TIA = transient ischemic attack.

Cho et al. Page 28
t
A
CENTRAL ILLUSTRATION. Cardiovascular Disease Risk Factors in Women

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The factors shown in orange are incorporated in the atherosclerotic cardiovascular disease
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risk calculator. However, there are unique sex-specific factors as well as psychosocial factors
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that contribute to CVD risk and adverse outcomes.
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Cho et al. Page 29
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TABLE 3
Comparison and Summary of the Recommendations for Stroke Prevention for Patients With Nonvalvular
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AF = atrial fibrillation; AP HRS = Asia Pacific Heart Rhythm Society; ASA = acetylsalicylic acid; EHRA = European Heart Rhythm Association,
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