Wednesday, June 20, 2012

Salah Kaprah: Mi Instan Ditakuti, Mi Lain Digemari

http://health.kompas.com/read/2012/06/20/17115136/Salah.Kaprah.Mi.Instan.Ditakuti.Mi.Lain.Digemari
Dr. Widodo Judarwanto Sp.A






KOMPAS.com - Pihak Kepolisian sekali lagi berhasil menggerebek pabrik mi yang beromzet besar dan sudah beroperasi puluhan tahun kedapatan menggunakan bahan pengawet formalin dan perwarna berbahaya dalam kandungan mi produksinya. Mungkin saja banyak industri rumahan lainnya harus lebih diawasi dan dimonitor ketat tentang penggunaan bahan pengawet berbahaya yang dapat menekan ongkos produksi tetapi sangat berbahaya bagi masyarakat. Faktanya, masyarakat justru tak pernah kawatir dengan bahaya yang mengancam ini. Tetapi uniknya, justru masyarakat sangat fobi  dengan bahaya mi instan buatan pabrik ternama yang sudah dijamin keamanannya oleh BPOM.

Sampai saat ini, para orang tua bahkan sebagian dokter masih khawatir dan takut akan bahaya mi instan. Padahal berkali-kali BPOM mengatakan mi instan dijamin aman, pengawetnya aman dan tidak berbahaya dikonsumsi dalam jumlah tertentu atau kewajaran. Tetapi inilah keunikan klasik masyarakat Indonesia, masyarakat sangat fobi dengan mi instan kemasan yang sudah berstandar Internasional tetapi tidak khawatir dengan mi produksi lain berupa mi tradisonal dan mi kemasan “home product” lainnya yang masih tidak diketahui jenis dan jumlah bahan pengawetnya.

Makanan favorit masyarakat ini selalu saja setiap waktu dihantui ketakutan berlebihan. Bukan kali ini saja penggemar mi instant dicekam berita yang mengkhawatirkan. Meski berkali-kali badan POM menjelaskan bahwa mi instant aman, tetapi seperti sebelumnya berbagai berita yang tidak jelas tetap sering dituding bahwa mi instan mengandung lilin, menyebabkan operasi pemotongan usus dan berbagai hal menyeramkan lainnya. Anehnya, orangtua tampaknya tetap merasa aman dengan mi industri lain yang juga banyak dikonsumsi untuk rumah makan, restoran dan penjaja mi goreng keliling. Padahal produk mi instant diawasi ketat melalui standarisasi internasional yang ditetapkan Codex Alimentarius Commission (CAC), sedangkan produk lainnya tersebut belum tentu mengikuti standarisasi yang ketat.

Justru mi buatan “home industry” yang dijual di pinggir jalan, di pasar tradisional atau bahkan dijual di super market saat ini tidak ada yang tahu jumlah dan jenis bahan pengawetnya. Apakah berbhaya atau tidak ? Padahal faktanya sudah banyak dijumpai mi seringkali dicampur pengawet makanan yang berbahaya seperti borax atau formalin. Bahkan sudah sering disaksikan di media masa petugas kepolisian menggerebek “home Industri” pembuat mi yang menggunakan bahan berbahaya. Padahal pabrik tersebut sudah puluhan tahun beroperasi dan memproduksi sangat bannmyak mi yang dikonsumsi oleh banyak masyarakat tidak disadari. Belum lagi zat warna yang digunakan saat ini tidak ada yang mengetahui apakah jenisnya berbaya atau tidak. Justru zat warna yang kuning terang itu biasanya menggunaklan zat warna yang berbahaya. Sekali lagi, masyarakat tidak pernah trauma bahkan sangat lahap makan mi seperti itu, tetapi sebaliknya masyarakat sangat trauma dengan mi instan. Padahal mi instan tertentu yang sudah berstandar Internasional selalu menerapkan prinsip aman dalam berproduksi. Sehingga jelas tahu komposisi kandanungan bahan yang digunakan dan dijamin aman karena sudah diirekomendasikan oleh instansi tertentu yang berwenang dan kredibel.

Bahan pengawet

Sebenarnya penggunaan pengawet makanan dalam industri makanan adalah hal yang biasa. Dapat dikatakan hampir 90% industri makanan kemasan tidak terlepas dalam penggunaan bahan pengawet. Bahkan penggunaan bahan pengawet makanan berbagai industri makanan yang tidak mencantumkan label BPOM mungkin justru malah lebih menyeramkan. Tetapi, bila isu ini mengusik keamanan mi instan akan semakin menghebohkan karena mi instan adalah merupakan salah satu makanan instant yang paling banyak dikonsumsi.

Penggunaan mi instan pada usia anak cukup tinggi. Karena sekitar 30% anak usia di bawah 9 – 12 tahun mengalami gangguan mengunyah dan menelan. Pada kelompok anak seperti ini seringkali mengalami pilih-pilih makanan. Biasanya, anak-anak tidak menyukai makanan yang sulit dikunyah dan ditelan seperti makanan berserat keras seperti sayur, daging sapi dan nasi. Sebaliknya makanan yang tidak berserat seperti mi, telor, nugget , biskuit, krupuk dan makanan crispy lainnya lebih banyak digemari. Hal inilah tampaknya yang mendasari mengapa pada anak-anak lebih sering mengkonsumsi mi.

BPOM sudah mengumumkan bahwa memang mi instan di pasaran beberapa di antaranya memakai bahan pengawet methyl p-hydroxybenzoate dan benzoic acid. Sebenarnya bahan pengewet tersebut sebenarnya masih aman dan diperbolehkan digunakan dalam kadar tertentu. Dalam industri makanan modern saat ini, diperlukan penggunaan teknologi pengawetan pangan untuk membuat makanan menjadi tahan lama dan tetap berkualitas, Salah satu dari beberapa teknik pengawetan pangan adalah memberikan bahan tambahan pangan (BTP) untuk pengawetan, hal ini dilakukan dengan menambahkan suatu bahan kimia tertentu dengan jumlah tertentu yang diketahui memiliki efek mengawetkan dan aman untuk dikonsumsi manusia.

Jenis dan jumlah pengawet yang diijinkan untuk digunakan telah dikaji keamanannya. Indonesia menganut Standarisasi internasional yang ditetapkan Codex Alimentarius Commission (CAC). Forum CAC (Codex Alimentarius Commission) merupakan organisasi perumus standar internasional untuk bidang pangan. Berbagai produk dan industri makanan yang ada di Indonesia harus dibuat berdasarkan CAC.
Menurut Permenkes No.722/1988, bahan pengawet yang diizinkan digunakan dalam makanan dalam kadar tertentu adalah Asam Benzoat, Asam Propionat, Asam Sorbat, Belerang Dioksida, Metil p-Hidroksi Benzoat, Kalium Benzoat, Kalium Bisulfit, Kalium Meta Bisulfit, Kalium Nitrat, Kalium Nitrit, Kalium Propionat, Kalium Sorbat, Kalium Sulfit, Kalsium Benzoit, Kalsium Propionat, Kalsium Sorbat, Natrium Benzoat, Metil-p-hidroksi Benzoit, Natrium Bisulfit, Natrium Metabisulfit, Natrium Nitrat, Natrium Nitrit, Natrium Propionat, Natrium Sulfit, Nisin dan Propil-p-hidroksi-benzoit.
Salah satu bahan tambahan yang diatur adalah nipagin (methyl p-hydroxybenzoate) yang berfungsi sebagai pengawet dengan batas maksimum penggunaan. Selain Nipagin, ada beberapa jenis pengawet lain yang diizinkan BPOM untuk digunakan dalam mie instan misalnya asam benzoat dan propeonat. Methylparaben nama teknisnya methyl p-hydroxybenzoate (disebut juga methyl parahydroxybenzoate) juga terdapat dalam makanan instant dan makanan lainnya. Untuk makanan seperti mie instan, asalkan tidak melebihkan kadar maksimum yang ditentukan Badan POM, yakni 250 mg per kg.

Waspadai pada anak

Sebagai manusia modern di masa depan takkan pernah terlepas dari pengaruh bahan kimia yang merugikan bagi organisme hidup. Bahan kimia tersebut dalam jumlah dan jenis tertentu akan saling berinteraksi dengan suatu cara-cara tertentu untuk menimbulkan respon pada sistem biologi yang dapat menimbulkan kerusakan pada sistem biologi tersebut. Salah satu unsur toksikologi adalah agen-agen kimia atau fisika yang mampu menimbulkan respon pada sistem biologi. Selanjutnya, cara-cara pemaparan merupakan unsur lain yang turut menentukan timbulnya efek-efek yang tidak diinginkan ini. Tetapi mekanisme tubuh sudah demikian sempurna. Berbagai zat berbahaya tersebut dalam jumlah tertentu dapat dibuang ke luar tubuh manusia melalui organ hati sebagai alat detoksifikasi tubuh manusia.

Bahaya bahan paparan bahan makanan tersebut sangat tergantung dari jenis bahan, jumlah paparan dan kondisi setiap individu. Dalam jumlah tertentu dan bahan tertentu tubuh masih bisa mentolerir. Tetapi pertanyaannya, seberapa banyak jumlah tertentu tersebut aman dapat dikonsumsi. Hal ini sulit dijawab karena banyak faktor yang berpengaruh dan belum ada data ilmiah yang menunjukkan efek samping jangka panjang bahan pengawet tersebut. Sehingga rekomendasi untuk tidak mengkonsumsi mi instan berlebihanpun selalu dikemukakan. Hal ini wajar terjadi karena berbagai konsumsi makanan lainnya pun selalu ada batas toleransi jumlah yang harus dikonsumsi seperti alkohol, kopi, atau makanan tertentu lainnya. Dalam jumlah berlebihan makanan tertentu akan mengganggu tubuh manusia.

Kondisi tubuh setiap individu juga sangat berpengaruh. Pada manusia sehat pada umumnya mungkin zat pengawet tersebut tidak terlalu berdampak karena sistem tubuh yang baik dapat mengeliminasi dan mengeluarkan zat kimia tersebut dalam tubuh. Tetapi pada penderita tertentu khususnya usia anak, sistem tubuhnya tidak berjalan sempurna, sehingga zat kimia tersebut sulit dibuang dari tubuh dan akan tersimpan dan menganggu fungsi tubuh lainnya.
Hal ini harus diwaspai pada usia anak dengan gangguan saluran cerna seperti hipermeabilitas Intestinal atau dikenal dengan Leaky Gut Syndrome. Gangguan hipersensitifitas saluiran cerna ini biasanya terjadi pada penderita alergi makanan, seliak, intoleransi makanan, penderita Autism, ADHD dan berbagai penderita gangguan metabolisme lainnya. Pada gangguan hipersensitivitas saluran cerna tersebut terjadi ketidakmatangan saluran cerna. Pada penderita seperti ini sebaiknya lebih mewaspadai penggunaan bahan pengawet termasuk mi instan. Gejala gangguan hipersensitifitas saluran cerna yang harus diwaspadai adalah gangguan BAB berupa kesulitan atau sering buang air besar. Gejala saluran cerna lainnya adalah mudah muntah, nyeri perut, mulut berbau, sering kembung, sering buang angin, air liur berlebihan, lidah sering kotor dan putih dan berbagai gejala lainnya.

Berbagai berita yang menghebohkan tersebut sebenarnya bila dikaji dengan fakta ilmiah yang ada tidak seperti yang dikhawatirkan. Bahaya dan efek samping bagi tubuh akibat pengaruh methyl p-hydroxybenzoate dan benzoic acid bagi tubuh secara jangka panjang sampai saat ini masih belum diketahui secara pasti. Beberapa opini yang menyebutkan bahwa mi instan menyebabkan pemotongan usus, penyebab kanker dan berbagai hal menyeramkan lainnya tersebut sampai sekarang juga masih belum ada bukti ilmiah yang menyebutkannya. Kalaupun opini tersebut muncul mungkin saja hanya berdasarkan hipotesa beberapa klinisi yang belum terbukti. Hanya terdapat laporan ilmiah bawa konsumsi berlebihan dapat mengganggu lambung. Fenomena ini juga terjadi pada fobia pada MSG (monosodium glutamate). Ternyata ketakutan pada MSG juga sampai 100 tahun penggunaannya di dunia hingga sekarang tidak ada bukti ilmiah yang menunjukkan bahwa MSG berbahaya bagi tubuh.

Badan Pengawas Obat dan Makanan AS (FDA) menggolongkan methylparaben dalam kategoriGenerally Recognized as Safe (GRAS). Artinya, bahan kimia ini bisa dan aman untuk digunakan pada sebagian besar produk makanan. Sebagai pengawet makanan, methylparaben memiliki keunggulan dibanding pengawet lain yaitu lebih mudah larut air. Oleh karenanya, senyawa ini sering dipakai karena dinilai lebih aman saat terlibat kontak dengan cairan. Kelebihan lainnya, methylparaben tidak hanya mencegah pertumbuhan bakteri pada makanan instan dan awetan. Lebih dari itu, senyawa ini juga bisa membantu menjaga kestabilan rasa sehingga makanan dapat disimpan dalam waktu yang lebih lama. Di dalam tubuh, senyawa ini juga relatif aman karena mudah dimetabolisme. Karena mudah diserap, baik melalui saluran pencernaan maupun kulit, senyawa ini juga lebih cepat dikeluarkan dari dalam tubuh.

Bahan pengawet berbahaya ini justru tampak lebih berisiko sering dijumpai pada mi buatan industri rumahan karena pengawasannya yang lemah dari pihak berwenang. Pengawet berbahaya seperti formalin yang mengancam di sekitar masyarakat justru kesannya sangat diabaikan. Jika kandungan formalin dalam tubuh tinggi, akan bereaksi secara kimia dengan hampir semua zat di dalam sel, sehingga menekan fungsi sel dan menyebabkan kematian sel yang menyebabkan kerusakan pada organ tubuh. Formalin merupakan zat yang bersifat karsinogenik atau bisa menyebabkan kanker. Beberapa penelitian terhadap tikus dan anjing pemberian formalin dalam dosis tertentu jangka panjang secara bermakna mengakibatkan kanker saluran cerna seperti adenocarcinoma pyloruspreneoplastic hyperplasia pylorus dan adenocarcinoma duodenum. Penelitian lainnya menyebutkan pengingkatan resiko kanker faring (tenggorokan), sinus dan cavum nasal (hidung) pada pekerja tekstil akibat paparan formalin melalui hirupan.

Ciri mi yang berbahan pengawet berbahaya dan bahan pewarna berbahaya adalah biasanya mi tampak berwarna kuning terang, kenyal dan keras dan awet sampai beberapa hari. Sebakliknya mi yang tanpa bahan pengawet berbahaya biasanya justru warnanya tidak menarik, pucat, lembek dan lunak.

Bagaimana menyikapinya

Berbagai berita menghebohkan tersebut merupakan suatu peringatan bagi manusia modern bahwa ternyata banyak paparan bahan kimia di sekitar yang harus diwaspadai. Sebenarnya kewaspadaan ini justru bukan pada mi instan tetapi berbagai paparan bahan kimia lain yang lebih berbahaya dan tidak terlihat mengancam kita tanpa disadari yang justru terdapat pada mi home industri lainnya. Berbagai produk mi lain atau bahan makanan lain yang tidak masuk standar SNI justru harus menjadi perhatian masyarakat. Karena, kandungan jenis dan kadar pengawetnya justru tidak diketahui secara pasti.

Manusia modern tidak akan terlepas dari paparan bahan kimia tersebut dalam berbagai jenis makanannya. Selama jumlah dan jenis bahan kimia tersebut tidak berbahaya dan dapat ditoleransi oleh tubuh maka kekwatiran berlebihan tersebut seharusnya tidak terjadi. Meski data ilmiah belum ada bukti yang menunjukkan bahaya methyl p-hydroxybenzoate dan benzoic acid yang dikatakan aman tersebut bukan berarti tidak ada bahaya jangka panjang hanya belum diketahui. Karena keterbatasan data ilmiah tersebut maka sulit menentukan batasan dosis yang berbahaya yang boleh dikonsumsi bagi manusia.

Justru karena hal tersebut paling tidak masyarakat dapat menjadikan pelajaran dalam kasus ini. Bahwa meski bahaya yang mengancam tersebut masih belum kelihatan nyata secara fakta ilmiah tetapi perilaku konsumsi makanan dengan “back to nature” adalah paling aman dan ideal bagi kesehatan tubuh. Mi instan yang dikenal enak, praktis dan murah sulit untuk dilepaskan dari kebiasaan konsumsi anak-anak. Berdasarkan fakta ilmiah yang ada juga bukan berarti bahwa harus menghindari konsumsi mi instan. Karena sejauh ini masih belum ada bukti ilmiah bahaya pengawet tersebut dalam jangka panjang. Tetapi sebaiknya berbagai lembaga terkait seperti BPOM, lembaga konsumen atau institusi ilmiah untuk melakukan prioritas penelitian terhadap dampak mi instan bagi tubuh manusia baik jangka pendek maupun jangka panjang khususnya terhadap usia anak.
Sebaiknya orangtua harus sangat selektif dalam membeli makanan instan. Pembelian makanan instan sebaiknya harus dipilih yang mencantumkan label ijin BPOM. Dengan data tersebut pihak yang berwenang dalam hal ini BPOM dapat menentukan dengan pasti batas keamanan suatu bahan pengawet yang digunakan. Bila hal itu dilakukan maka anak-anak penggemar mi instan dapat melahap kenikmatan instan tanpa harus dihantui kecemasan pada orangtuanya. Meski pengawet dalam mi instan dalam jumlah tertentu aman, tetapi bila sering konsumsi dalam jumlah besar atau jangka panjang sebaiknya lebih sering tanpa memakai bumbu dalam mi tersebut. Karena justru pengawetnya ada pada bumbu yang terkandung bukan dalam bahan minya. Jadi sebaiknya orangtua memakai bumbu bawang merah, bawang putih dan garam. Jadi tampaknya kekhawatiran masyarakat selama ini yang salah alamat harusnya dapat dikoreksi dan lebih dicermati lagi.

Studi: Kurang Tidur Memicu Risiko Stroke

 http://kosmo.vivanews.com/news/read/323992-studi--kurang-tidur-memicu-resiko-stroke
SELASA, 12 JUNI 2012, 09:23 WIB
Wuri Handayani


Kurangnya jam tidur membuat tekanan darah meingkat dan juga stress






VIVAlife - Pemenuhan jam tidur menjadi hal yang patut mendapatkan perhatian sekarang ini. Di saat semakin sempitnya waktu, yang lebih banyak Anda habiskan untuk bekerja.
Sebuah penelitian terbaru mengatakan, terutama mereka yang berusia paruh baya dengan jam tidur tidak teratur atau kurang, secara signifikan meningkatkan risiko stroke. Penelitian ini diberitakan melaluiHealth Day News, hari ini.
Sebanyak empat kali lipat peningkatan stroke justru terlihat pada mereka yang memiliki berat badan normal, dan jarang sekali mengalami gangguan tidur. Hanya saja, waktu tidur mereka kurang dari enam jam setiap harinya.
Sedangkan pada mereka yang tergolong obesitas, justru menempati posisi ke dua terhadap resiko ini, seperti dilansirivillage.com.
"Tidur sangat penting," demikian dikatakan Megan Ruiter, pemimpin penelitian di University of Alabama dan Birmingham's School of Medicine. Terbukti kurang tidur juga meningkatkan gangguan ketidak normalan pada sistem tubuh.
Seperti peradangan dan juga meningkatkan tekanan darah dan pelepasan hormon yang menyebabkan stress yang lebih besar. Ini yang memicu terjadinya stroke.
Hasil penelitian ini dijadwalkan akan dipresentasikan pada pertemuan tahunanAssociated Professional Sleep Societies di Boston.
Pada penelitian yang dilakukan selama tiga tahun ini, Ruiter bersama tim-nya mengumpulkan data dari 5.600 responden. Mereka tidak menemukan hubungan antara obesitas dan stroke, justru sebaliknya, stroke menjadi lebih mengancam orang-orang dengan berat tubuh normal yang mengalami kurang tidur.
Dr. Michael Frankel, direktur neurologi pembuluh darah di Emory University dan juga direktur di Stroke Marcus & Neuroscience Center di Grady Hospital, Atlanta, berkomentar bahwa "Meskipun sulit untuk menentukan mengapa hal ini mungkin terjadi, seseorang dapat berspekulasi tentang kemungkinan mekanisme terkait terhadap perubahan tingkat kortisol. Yakni hormon stress yang sangat mungkin meningkat saat seseorang tidak memiliki waktu tidur yang benar".
Peningkatan kadar hormon ini memicu disfungsi sel yang melindungi pembuluh darah, sehingga stroke lebih mudah menghampiri, jelasnya. Ini mengapa orang-orang tanpa gangguan vascular seperti obesitas, hipertensi, dan diabetes juga memungkinkan terkena stroke.
"Bagi kita yang bekerja hingga larut, mungkin perlu mempertimbangkan temuan baru ini, dan menyesuaikan diri dengan gaya hidup yang lebih sehat untuk mengurangi resiko terkena stroke," ujar Frankel.
Rutin melakukan pemeriksaan tekanan darah, makan rendah kalori, diet seimbang, olahraga, berhenti merokok, dan tidur teratur, adalah saran dari Frankel untuk menjaga kesehatan pembuluh darah.
Pakar lain, Dr Keith Siller, direktur medis dari NYU Comprehensive Stroke Care Center di New York City, menyepakati bahwa tidur merupakan faktor penting untuk kesehatan. "Saya melihat ini sebagai pesan umum bahwa tidur yang cukup juga merupakan bagian dari hidup sehat," katanya.
Bagaimana dengan waktu tidur Anda, apakah sudah cukup? (eh)

Sunday, June 17, 2012

E Waste: Dampak Pada Kesehatan dan Lingkungan

http://www.gatra.com/nasional-cp/1-nasional/14229-dampak-pada-kesehatan-dan-lingkungan
SUNDAY, 17 JUNE 2012 11:30


Sejumlah e-waste berdampak buruk pada kesehatan. Dampaknya tergantung kondisi tubuh dan lama-tidaknya terpapar limbah. Berikut ini dampak kesehatan dari limbah elektronik:


Thursday, June 14, 2012

Banyak Penghuni ''Kebun Binatang'' di Tubuh Kita

http://www.tempo.co/read/news/2012/06/15/095410738/Banyak-Penghuni-Kebun-Binatang-di-Tubuh-Kita
JUM''AT, 15 JUNI 2012 | 07:59 WIB


foto


TEMPO.COSan Fransisco - Sebuah upaya besar yang didanai pemerintah federal Amerika Serikat menghasilkan sebuah laporan yang sangat rinci tentang makhluk-makhluk super kecil yang menumpang di tubuh kita. Ilmuwan merilis foto-foto triliun koloni makhluk ini dalam tubuh kita untuk pertama kalinya.

Dua makalah utama penelitian diterbitkan di jurnal ilmiah Nature dan satu lagi diterbitkan dalam jurnal lain, Science.

Para peneliti menemukan banyak variasi dalam populasi mikroba dalam sampel 242 orang yang mereka teliti. Namun, apakah ada polanya? Studi ini tidak menemukannya, tetapi jumlah mereka sangat tergantung pada pada jenis kelamin, indeks massa tubuh, tekanan darah, dan suhu tubuh manusia. Ras atau etnis tak begitu berpengaruh. 

Satu hal yang belum diteliti lebih jauh adalah paparan lingkungan, seperti di mana seseorang dibesarkan atau apa yang dimakannya ketika bayi.

Gerombolan bakteri paling banyak ditemukan di kulit. Ini adalah tempat lain pada tubuh di mana para ilmuwan menemukan banyak variasi bakteri yang berbeda antara satu orang dengan yang lainnya. Hal ini, kata ilmuwan, sangat bisa dipahami, "Kulit paling mudah terganggu oleh lingkungan," kata Curtis Huttenhower dari Harvard, salah satu ilmuwan yang terlibat dalam penelitian, dalam sebuah wawancara. Kulit juga menjadi "padang pasir" mikroba. Dibandingkan dengan bagian lain dari tubuh, hanya ada nutrisi lebih sedikit di sana, lebih kering, dan tidak "ramah".

Para ilmuwan tidak menemukan perbedaan bakteri pada kulit yang berhubungan dengan usia (responden berusia 18-40 tahun). Bakteri tertentu dari kelompok besar yang disebut Firmicutes menurun jumlahnya seiring pertambahan usia yang pada sampel diambil dari belakang telinga.

Bagian tubuh yang paling miskin variasi mikroba adalah vagina wanita. Area ini didominasi oleh hanya satu jenis bakteri Lactobacillus saja. Namun ada kondisi yang mengubah komposisinya dan membuat masuk mikroba lain, yaitu kadar pH. makin tinggi kadarnya, yang artinya kadar asam berkurang, maka jumlah Lactobacillus menurun dan keanekaragaman mikroba akan naik.

Ketika seorang wanita hamil, microbiome vagina menjadi lebih kurang beragam. Para ilmuwan melaporkan dalam makalah yang diterbitkan dalam jurnal PLoS ONE setelah membandingkan flora vagina dari 24 wanita hamil yang sehat dengan 60 wanita yang tidak hamil. Ada bakteri lebih sedikit di sana juga. Para ilmuwan berspekulasi bahwa perubahan mungkin memiliki peran dalam melindungi bayi yang akan segera bergerak melalui saluran vagina dari kemungkinan infeksi.

Meskipun bakteri merupakan bentuk kehidupan yang dominan dalam microbiome, ada makhluk mikroskopis lainnya dalam diri kita, yaitu jamur. Dalam sebuah makalah yang diterbitkan pekan lalu, David Underhill dari Cedars Sinai Medical Center dan rekan-rekannya menjelaskan bagaimana beberapa dari mereka terkait dengan ulcerative colitis, penyakit inflamasi usus.

Virus juga berada dalam tubuh kita, meskipun proyek ini tidak secara optimal membahasnya. Peneliti melihat kemungkinan adanya hubungan antara virus dan demam yang tidak jelas pada anak-anak berusia di bawah tiga tahun. Meskipun virus umumnya diduga menjadi penyebabnya, mereka biasanya tidak diuji dan ada banyak antibiotik yang diresepkan untuk sakit jenis ini. Padahal antibiotik tidak membasmi virus. Analisis DNA menemukan bahwa anak-anak dengan demam memiliki 1,5 kali lebih jumlah materi genetik virus daripada mereka yang sehat.

Thursday, June 7, 2012

Association of Aspirin Use With Major Bleeding in Patients With and Without Diabetes

http://jama.jamanetwork.com/article.aspx?articleID=1172042
JAMA. 2012;307(21):2286-2294. doi:10.1001/jama.2012.5034


Giorgia De Berardis, MSc; Giuseppe Lucisano, MSc; Antonio D’Ettorre, MSc; Fabio Pellegrini, MSc; Vito Lepore, MD; Gianni Tognoni, MD; Antonio Nicolucci, MD



ABSTRACT

Context  The benefit of aspirin for the primary prevention of cardiovascular events is relatively small for individuals with and without diabetes. This benefit could easily be offset by the risk of hemorrhage.
Objective  To determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes taking aspirin.
Design, Setting, and Participants  A population-based cohort study, using administrative data from 4.1 million citizens in 12 local health authorities in Puglia, Italy. Individuals with new prescriptions for low-dose aspirin (≤300 mg) were identified during the index period from January 1, 2003, to December 31, 2008, and were propensity-matched on a 1-to-1 basis with individuals who did not take aspirin during this period.
Main Outcome Measures  Hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage occurring after the initiation of antiplatelet therapy.
Results  There were 186 425 individuals being treated with low-dose aspirin and 186 425 matched controls without aspirin use. During a median follow-up of 5.7 years, the overall incidence rate of hemorrhagic events was 5.58 (95% CI, 5.39-5.77) per 1000 person-years for aspirin users and 3.60 (95% CI, 3.48-3.72) per 1000 person-years for those without aspirin use (incidence rate ratio [IRR], 1.55; 95% CI, 1.48-1.63). The use of aspirin was associated with a greater risk of major bleeding in most of the subgroups investigated but not in individuals with diabetes (IRR, 1.09; 95% CI, 0.97-1.22). Irrespective of aspirin use, diabetes was independently associated with an increased risk of major bleeding episodes (IRR, 1.36; 95% CI, 1.28-1.44).
Conclusions  In a population-based cohort, aspirin use was significantly associated with an increased risk of major gastrointestinal or cerebral bleeding episodes. Patients with diabetes had a high rate of bleeding that was not independently associated with aspirin use.
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Figures in this Article
Therapy with low-dose aspirin is used for the treatment of cardiovascular disease. It is recommended as a secondary prevention measure for individuals with moderate to high risk of cardiovascular events (ie, for patients with multiple risk factors such as hypertension, dyslipidemia, obesity, diabetes, and family history of ischemic heart disease).The American Diabetes Association recommends low-dose aspirin use (75-162 mg/d) for adults with diabetes and no previous history of vascular disease but who have a 10-year risk of cardiovascular disease events greater than 10% and who do not have an increased risk for bleeding.1
A meta-analysis based on individual patient data demonstrated that the benefits of low-dose aspirin for the primary prevention of cardiovascular disease are modest.Any benefit of low-dose aspirin might be offset by the risk of major bleeding.It is known that aspirin is associated with gastrointestinal and intracranial hemorrhagic complications.However, randomized controlled trials have shown that these risks are relatively small.,6
Randomized controlled trials evaluate selected patient groups and do not necessarily generalize to an entire population. They are particularly limited when evaluating relatively rare events.7Observational studies suggest an excess of approximately 1 to 2 major bleeding episodes annually for every 1000 patients treated with low doses of aspirin. The bleeding risk sharply increases in individuals older than 70 years.8
A meta-analysis by the Antithrombotic Trialists' Collaborationsuggested that diabetes, in addition to being an independent risk factor for cardiovascular disease, also increases the risk of extracranial hemorrhage. These estimates were derived from a limited number of events within randomized trials. Hence, the risk-to-benefit ratio for the use of low-dose aspirin in the presence of diabetes mellitus remains to be clarified. To increase the number of observations, we used administrative data to determine the bleeding rate attributable to prophylactic aspirin use and how it is influenced by the presence of diabetes. The objectives of this study were to estimate the incidence of major bleeding events in individuals with diabetes and in those without diabetes and how these events were affected by aspirin use.

METHODS

We conducted a population-based cohort study, using a record-linkage analysis of hospital discharge records, prescription databases, and the civil registry, including data on 4.1 million citizens in 12 local health authorities in Puglia, Italy.
Data Sources
All Italian citizens have equal access to health care services and are cared for by a general practitioner as part of the National Health System. Hospital and pharmaceutical services are provided free or at a minimum charge. Aspirin for the prevention of cardiovascular events is available to all citizens at high cardiovascular risk only by prescription and is free of charge. Prescription databases provide data on all the community prescriptions reimbursed by the National Health System with drugs coded according to the Anatomical Therapeutic Chemical classification system.9
Hospital discharge records cover all the admissions in public and private hospitals and include information on primary diagnoses and up to 5 coexisting conditions, performed procedures (diagnostic and therapeutic interventions), date of hospital admission and discharge, and in-hospital death. All diagnoses are coded according to the International Classification of Diseases, Ninth Revision,Clinical Modification (ICD-9-CM).10
Data sources, such as hospital discharge records and prescription databases, and the reliability of record linkage to produce epidemiological information have been validated and described elsewhere.11 17 All security and protection measures for data from patients were performed according to national law.18
Study Design
We identified new users of low-dose aspirin (≤300 mg) (Anatomical Therapeutic Chemical code B01AC06) during the index period from January 1, 2003, to December 31, 2008. The date of the first filled prescription for aspirin was considered the patient's index date. Patients had to be at least 30 years old on the index date with no prescription for aspirin in the past year. Current low-dose aspirin users were defined as those who had the last prescription of aspirin at least 75 days before hospitalization for major bleeding events or the end of follow-up; this allowed for a tolerance of 15 days between prescriptions, each covering a period of 60 days of treatment. All those individuals who did not receive aspirin throughout the study period were considered controls, and were assigned an index date corresponding to the same year of the cases.
Former aspirin users, who were those who had prescriptions for aspirin at the beginning of follow-up but had their last prescription of aspirin more than 75 days before an event, were excluded from the analyses.
Outcome Variables
The outcomes of interest were hospitalization for major gastrointestinal bleeding (ICD-9-CM codes 531-535 and 578.9) or cerebral hemorrhage (ICD-9-CM codes 430-432) occurring after the initiation of antiplatelet therapy. All patients were followed up from their index date to the earliest hospitalization for gastrointestinal or intracranial hemorrhages, death (derived from the civil registry), or the end of the study period, providing a maximum follow-up of 6 years.
Possible Confounding Factors
To control for confounding, drugs considered either to promote or conversely to be protective against bleeding events were taken into account. Patients with diabetes were defined as individuals exposed to antidiabetic agents in the year before the index date together with those that began to be exposed to antidiabetic agents during the follow-up period. To allow a more accurate definition of individuals with diabetes, those treated before cohort entry but with no antidiabetic prescriptions during follow-up were excluded from the cohort. Cases of gestational diabetes (treated with insulin for only a few months) would have been erroneously considered as cases of diabetes.
Individuals were considered as affected by hypertension if they were exposed to at least 3 prescriptions of antihypertensive agents (eg, centrally acting antiadrenergic agents, α-blockers, thiazide-type diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) in the previous year with respect to index date. Previous hospitalizations for cardiovascular events during the year prior to the index date also were considered (ICD-9-CM codes for myocardial infarction: 410, 786.51, 786.52, 786.50, 36.0, 36.1, 36.2, and 36.3; for ischemic stroke: 434, 436, 38.11, and 38.12).
Current use of the following medications was identified: other antiplatelet agents, anticoagulants, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin as an analgesic agent, systemic corticosteroids, selective serotonin reuptake inhibitors (SSRIs), proton pump inhibitors (PPIs), and statins. In line with previous studies,19 current use was defined as individuals with a prescription of such drugs in the previous 3 months from an event or the end of follow-up; for PPIs and statins, a period of 6 months was chosen. Models also were adjusted for occurrence of hospitalization for gastrointestinal complications (ICD-9-CM codes 531-535, 556, and 578) during the year prior to the index date.
Statistical Analyses
From the overall sample of 4.1 million individuals, a sample of 598 418 patients receiving low-dose aspirin was identified. Furthermore, individuals younger than 30 years, those with former aspirin use, and those with diabetes without antidiabetic prescriptions during the study period were excluded from the low-dose aspirin cohort, leaving a sample of 241 844 patients. Following the same exclusion criteria, a sample of 845 707 controls (20% of the overall sample of individuals) was selected at random. To allow an unbiased comparison between patients currently treated with aspirin and those who never took aspirin, a propensity score–matching algorithm on a 1-to-1 basis was used.20 21
A logistic regression model including age, sex, diabetes, previous hospitalization for cardiovascular disease, use of antihypertensive agents, NSAIDs, PPIs, SSRIs, and statins as covariates was used to predict the probability (propensity score) to receive aspirin. An 8-to-1 greedy matching algorithm21 was eventually used to identify a unique matched control for each aspirin-treated patient according to the propensity score. Adequacy of balance for the covariates in the matched sample was assessed via standardized mean difference between the 2 groups, considering differences less than 10% as good balance, as well as graphical methods (ie, quantile-quantile plots, side-by-side box plots, and nonparametric density plots).22
Characteristics of the study population are reported as percentages, mean (standard deviation), or median (interquartile range). Incidence rates (IRs) with 95% confidence intervals of hospitalization per 1000 person-years were estimated for both cohorts. Using Poisson regression, we first estimated crude IR ratios (IRRs) of hospitalization in the cohort with aspirin use compared with the cohort who never took aspirin. The IRRs were then adjusted for all the other covariates within multivariate models. The latter included the following covariates: age, sex, exposure to antidiabetic agents, hospitalization for cardiovascular or gastrointestinal problems in the year prior to study entry, or prescription for antihypertensive agents, other antiplatelet agents, anticoagulants, NSAIDs, aspirin as an analgesic agent, systemic corticosteroids, SSRIs, PPIs, or statins. Both individual (gastrointestinal and intracranial bleeding) and composite end points were assessed; in the latter case, the first occurrence of bleeding event was considered.
Risks were reported as IRRs along with their 95% confidence intervals and P values. For subgroup analyses according to sample characteristics, P values for interaction also were assessed. A sensitivity analysis also was performed after exclusion of ICD-9-CM code 578.9, which was considered less specific for the identification of upper gastrointestinal bleeding. The cumulative proportion of patients developing major bleeding events during follow-up according to diabetes status and use of aspirin was estimated by life table methods and log-rank tests were reported. Pvalues were 2-sided, and values of .05 or less were considered statistically significant. All statistical analyses were performed using SAS version 9.1 (SAS Institute Inc).

RESULTS

From the initial cohort of 241 844 individuals with aspirin use, 186 425 were selected using propensity score matching (Figure 1). Prematching characteristics widely differed between those with aspirin use and those without aspirin use, but propensity score matching led to a satisfactory balance for all the characteristics considered (eTable). The cohort with aspirin use included patients aged 30 to 95 years who had received the first dose of aspirin in the period considered.
Figure 1. Screening and Enrollment of Participants in the Study
Overall, a total of 1.6 million person-years of observation was accumulated with a median follow-up of 5.7 years (interquartile range, 2.4-6.0 years); the mean (SD) age was 69 (12) years and 53% of cases were female, 57% were identified as affected by hypertension, 15% were treated with hypoglycemic agents, 2.0% had experienced a hospitalization for a cardiovascular event, and 0.9% had experienced a hospitalization for gastrointestinal complications. General characteristics of the study population according to aspirin use are reported in Table 1.
Table 1. Study Cohort Characteristics
Risk of Bleeding Associated With Aspirin Use
During 6 years, 6907 first episodes of major bleeding requiring hospitalization were registered; of which there were 4487 episodes of gastrointestinal bleeding and 2464 episodes of intracranial hemorrhage (both events were registered on the same date for 44 individuals). The overall IR of total hemorrhagic events was 5.58 (95% CI, 5.39-5.77) per 1000 person-years for those with aspirin use and 3.60 (95% CI, 3.48-3.72) per 1000 person-years for those without aspirin use (IRR, 1.55; 95% CI, 1.48-1.63). In particular, the use of aspirin was associated with an excess risk of gastrointestinal (IRR, 1.55; 95% CI, 1.46-1.65) and intracranial (IRR, 1.54; 95% CI, 1.43-1.67) bleeding.
Table 2 shows IRs by aspirin use and their IRRs, according to the different characteristics. Among those without aspirin use, incidence increased steeply with age. The IRs exceeding the upper limit of the 95% confidence interval for the estimate relative to the whole population were observed in men (IR, 4.50; 95% CI, 4.30-4.70) per 1000 person-years, in individuals with diabetes (IR, 5.35; 95% CI, 4.97-5.76) per 1000 person-years, hypertension (IR, 4.23; 95% CI, 4.06-4.40) per 1000 person-years, previous hospitalization for cardiovascular problems (IR, 5.91; 95% CI, 4.78-7.31) per 1000 person-years or gastrointestinal complications (IR, 12.00; 95% CI, 10.03-14.44) per 1000 person-years, among those treated with other antiplatelet agents (IR, 5.03; 95% CI, 4.55-5.56) per 1000 person-years, anticoagulants (IR, 5.59; 95% CI, 5.10-6.12) per 1000 person-years, systemic corticosteroids (IR, 4.07; 95% CI, 3.65-4.53) per 1000 person-years, PPIs (IR, 4.09; 95% CI, 3.90-4.28) per 1000 person-years, SSRIs (IR, 4.09; 95% CI, 3.90-4.28) per 1000 person-years, and among those not treated with statins (IR, 4.08; 95% CI, 3.93-4.22) per 1000 person-years.
Table 2. Incidence Rates of Major Bleeding Events and Relative Incidence Rate Ratios by Sample Characteristics
The use of aspirin was associated with a greater risk of bleeding in most of the subgroups evaluated. Significant interactions were detected between the magnitude of risk conferred by aspirin and sex, age, presence of diabetes, hypertension, previous hospitalization for cardiovascular or gastrointestinal problems, and use of several concomitant treatments including anticoagulants and PPIs.
The risk of bleeding associated with the use of aspirin was particularly high in individuals younger than 50 years (IR, 3.17; 95% CI, 1.99-5.05) per 1000 person-years, in individuals not treated for hypertension, and in those treated with aspirin as an analgesic (statistical significance was not reached). On the other hand, the presence of diabetes, a previous hospitalization for cardiovascular events or gastrointestinal problems, or treatment with PPIs or SSRIs were not associated with an increased hemorrhagic risk.
As an additional analysis, we evaluated the risk of bleeding associated with the use of aspirin when administered in combination with other antiplatelet agents and/or anticoagulants. Compared with those without aspirin use, the risk was 2.6 times higher in individuals treated with aspirin and other antiplatelet agents (IRR, 2.56; 95% CI, 2.15-3.04), 2 times higher when aspirin was administered in association with anticoagulants (IRR, 1.92; 95% CI, 1.65-2.24), and almost 3 times higher when all 3 classes were administered in concomitance (IRR, 2.89; 95% CI, 1.71-4.88).
Risk of Bleeding Associated With Diabetes
The cumulative IR of major bleeding according to the presence of diabetes and use of aspirin is reported in Figure 2.The baseline risk of bleeding in the absence of aspirin therapy was higher among individuals with diabetes than those without diabetes, whereas the use of aspirin was associated with a higher bleeding risk only among individuals without diabetes.
Figure 2. Cumulative Proportion of Patients Developing Major Bleeding Events During Follow-up According to Diabetes Status and Aspirin Use
In the cohort with diabetes, there were 704 major bleeding events in 131 535 person-years for the no aspirin use group (incidence rate [IR], 5.35; 95% CI, 4.97-5.76) and 549 events in 94 232 person-years for the aspirin use group (IR, 5.83; 95% CI, 5.36-6.33). In the cohort without diabetes, there were 2821 major bleeding events in 848 631 person-years for the no aspirin use group (IR, 3.32; 95% CI, 3.20-3.45) and 2818 events in 509 565 person-years for the aspirin use group (IR, 5.53; 95% CI, 5.33-5.74).
Among individuals not taking aspirin, the IR of major bleeding was 3.32 (95% CI, 3.20-3.45) per 1000 person-years in those without diabetes and 5.35 (95% CI, 4.97-5.76) per 1000 person-years for those with diabetes (IRR, 1.61; 95% CI, 1.49-1.75). Individuals with diabetes had an increased risk of 59% for gastrointestinal bleeding (IRR, 1.59; 95% CI, 1.45-1.79) and 64% for intracranial bleeding (IRR, 1.64; 95% CI, 1.43-1.89). Further adjustment for other covariates within multivariate Poisson regression models confirmed that diabetes was associated with an excess risk of major bleeding (IRR, 1.58; 95% CI, 1.46-1.72), gastrointestinal bleeding (IRR, 1.61; 95% CI, 1.45-1.78), and intracranial bleeding (IRR, 1.54; 95% CI, 1.34-1.77).
Among aspirin users, the IR of major bleeding was 5.53 (95% CI, 5.33-5.74) per 1000 person-years in those without diabetes and 5.83 (95% CI, 5.36-6.33) per 1000 person-years for those with diabetes (IRR, 1.05; 95% CI, 0.96-1.15). Similar estimates were found for both gastrointestinal bleeding (IRR, 1.08; 95% CI, 0.97-1.21) and intracranial bleeding (IRR, 1.01; 95% CI, 0.86-1.18). Further adjustment for other covariates within multivariate Poisson regression models showed that diabetes was associated with a small excess risk of major bleeding (IRR, 1.13; 95% CI, 1.03-1.24) and gastrointestinal bleeding (IRR, 1.15; 95% CI, 1.03-1.29), and a nonsignificant increased risk of intracranial bleeding (IRR, 1.11; 95% CI, 0.95-1.30).
The sensitivity analyses performed after the exclusion of the less-specific ICD-9-CM code 578.9 increased the risk estimate associated with the use of aspirin. In fact, the IRRs for those with aspirin use vs those without aspirin use were 1.62 (95% CI, 1.53-1.70) for the whole sample, 1.73 (95% CI, 1.63-1.84) for individuals without diabetes, and 1.15 (95% CI, 1.01-1.30) for individuals with diabetes.
Other Factors Associated With the Risk of Bleeding
In addition to aspirin use and the presence of diabetes, the risk of bleeding increased with age and was higher in men, individuals treated with antihypertensive agents, NSAIDs, other antiplatelet and antithrombotic agents, and in those with previous hospitalization for gastrointestinal and cardiovascular problems. Furthermore, the use of PPIs and statins was associated with a reduction in the risk of hemorrhagic events (Table 3).
Table 3. Factors Associated With Hospitalization for Major Bleeding Events From Multivariate Analysis
Of note, the use of statins was associated with a significant reduction of both gastrointestinal (IRR, 0.65; 95% CI, 0.60-0.71) and intracranial (IRR, 0.69; 95% CI, 0.64-0.74) bleeding. The introduction of the aspirin × diabetes interaction term in the model yielded a statistically significant result (P < .001), thus confirming a differential bleeding risk associated with aspirin use and diabetes.

COMMENT

This study provides information for the evaluation of the risk-benefit balance of aspirin use in a real-world setting. Our study demonstrated that the incidence of major bleeding events is much higher than that recorded in randomized, prospective clinical trials. Data from the meta-analysis by the Antithrombotic Trialists' Collaborationreported an IR of major gastrointestinal and other extracranial bleeding of 0.10% per year in patients treated with aspirin and 0.07% in those not treated with aspirin in a population with a comparable age range (ie, 19-94 years). In comparison with these estimates, we found a 5-time higher incidence of major bleeding leading to hospitalization among both aspirin users and those without aspirin use.
In line with existing evidence,,23 the use of aspirin was associated with a 55% relative risk increase in major bleeding; this translates to 2 excess cases for 1000 patients treated per year. In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10% and 20%.3
The increase in the risk of hemorrhages associated with the use of aspirin was present in the majority of subgroups evaluated; the exceptions were patients with diabetes and those previously admitted to the hospital for gastrointestinal or cardiovascular problems. In the latter 2 subgroups, the lack of excess risk of bleeding can at least partially be attributable to the concomitant use of PPIs in line with existing recommendations,24 whereas diabetes deserves additional consideration.
To our knowledge, this is the first longitudinal study that specifically examined the role of diabetes in the incidence of major bleeding in a cohort of individuals, irrespective of the use of aspirin. In a systematic review, Feigin et al25 reported a protective effect of diabetes on the incidence of subarachnoid hemorrhages; the authors justified this unexpected finding by pointing out the high risk of death from other causes in the population with diabetes and therefore the chance of developing such hemorrhages was smaller than in individuals without diabetes.
A case-control study in Japan reported similar results showing that diabetes decreased the risk of subarachnoid hemorrhage in older women.26 As for gastrointestinal bleeding, a British case-control study on patients with bleeding peptic ulcers indicated that diabetes was associated with an increased relative risk for this condition (odds ratio [OR], 3.1; 95% CI, 1.2-4.3).27 Possible mechanisms include vascular disease impairing mucosal integrity in diabetes.27
The meta-analysis by the Antithrombotic Trialists' Collaboration reported that some of the risk factors for cardiovascular disease also increase the risk of extracranial hemorrhages, suggesting that those at higher cardiovascular risk are also at higher risk of bleeding. Individuals with diabetes showed a more than 50% increased risk compared with those without diabetes.3
Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes. These findings were confirmed in multivariate analyses taking into account a number of potential confounders and further reinforced by the highly significant interaction term tested within the multivariate model. These results can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population. An accelerated platelet turnover in diabetes28 could explain the reduced incidence of adverse effects related to aspirin, as well as its limited efficacy in preventing major cardiovascular events.,29
Our study also provides important information regarding bleeding risk factors other than aspirin use. In line with existing literature, individuals with a previous hospital admission for gastrointestinal problems19 ,30 31 show the highest risk of major bleeding. Increasing age,,19male sex,,19 ,32 diabetes,hypertension,,25 and previous cardiovascular problems,19 also were confirmed as independent risk factors for major bleeding. As for other medications, the use of both antiplatelet agents or oral anticoagulants was associated with a significant increase in the risk of bleeding, whereas the use of NSAIDs only marginally affected such a risk.
Our data are in line with an Italian population-based study showing an inverse association between an increased consumption of PPIs and reduction of hospitalization for gastrointestinal events.33However, the cost-effectiveness of PPIs associated with aspirin use needs to be verified. A recent study demonstrated that the addition of a PPI to aspirin is cost-effective only for men at increased risk for gastrointestinal bleeding.34 On the other hand, recent data suggest that use of PPIs might increase the risk of cardiovascular events in patients treated with antiplatelet agents.35 37
Another important finding of our study is the substantially lower risk of both gastrointestinal and intracranial hemorrhages associated with the use of statins. As for gastrointestinal bleeding, an apparent protective effect of statins was postulated in a post hoc analysis of the Orbofiban in Patients with Unstable coronary Syndromes–Thrombolysis in Myocardial Infarction 16 (OPUS-TIMI 16) trial.38 In this trial of patients with acute coronary syndromes who were treated with aspirin alone or in combination with orbofiban, the use of statins was associated with a lower risk of major bleeding (OR, 0.71; 95% CI, 0.44-1.14) and total gastrointestinal bleeding (OR, 0.68; 95% CI, 0.45-1.04). Such a protective effect was not confirmed in a population-based case-control study, although a borderline significant protective effect was observed in users of low-dose aspirin (OR, 0.43; 95% CI, 0.18-1.05).39 An increase in systemic prostacyclin and prostaglandin E2 production by statins has been advocated as the possible protective effect on gastric mucosa.39
The effect of statins on intracranial bleeding is more controversial. A large, randomized trial suggested that statins may increase the risk of intracranial hemorrhage.40 More recently, a meta-analysis of published and unpublished data was unable to confirm a significantly increased risk for intracerebral hemorrhage in relation to statins.41 Our results, based on more than 2000 episodes of intracranial bleeding, strongly suggest a protective effect of statins and call for further investigation in this area.
Our study has limitations. Despite adjustment for a wide range of potential bleeding risk factors, it was not possible to consider variables not routinely captured in the claims database, including lifestyle factors such as obesity, smoking, high alcohol consumption, or use of over-the-counter NSAIDs. Also, we could not take into account over-the-counter aspirin use. Nevertheless, misclassification of exposure status is unlikely because long-term use of aspirin for cardiovascular protection is reimbursed by the national health care system.
In conclusion, weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high-risk populations. In this population-based cohort, aspirin use was significantly associated with an increased risk of major bleeding, but this association was not observed for patients with diabetes. In this respect, diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy

AUTHOR INFORMATION

Corresponding Author: Antonio Nicolucci, MD, Consorzio Mario Negri Sud, Via Nazionale 8/a, 66030 S Maria Imbaro, Italy (nicolucci@negrisud.it).
Author Contributions: Dr Nicolucci had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: De Berardis, Tognoni, Nicolucci.
Acquisition of data: D’Ettorre, Lepore.
Analysis and interpretation of data: De Berardis, Lucisano, Pellegrini, Lepore, Tognoni, Nicolucci.
Drafting of the manuscript: De Berardis, Lucisano, D’Ettorre, Nicolucci.
Critical revision of the manuscript for important intellectual content: Pellegrini, Lepore, Tognoni.
Statistical analysis: De Berardis, Lucisano, Pellegrini, Nicolucci.
Administrative, technical, or material support: D’Ettorre.
Study supervision: Lepore, Tognoni.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Mr D’Ettorre reported receiving consulting fees from Bristol-Myers Squibb. Dr Tognoni reported receiving a research grant from Bayer. Dr Nicolucci reported receiving a research grant and fees for lectures including service on speakers bureaus from Bayer. Ms De Berardis, Messrs Lucisano and Pellegrini, and Dr Lepore did not report any financial disclosures.
Additional Contributions: We thank the Regional Health Agency and the Department of Health of the Puglia Region for the cooperation, general interest, and provision of data.

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