Oleh Admin Kalbe Medical pada December 21, 2012 07:43

Clopidogrel untuk Pasien dengan Gangguan Fungsi Alel CYP2C19

Pada pasien dengan penyakit jantung stabil yang memiliki gangguan fungsi alel CYP2C19, pemberian clopidogrel dosis 225 mg sehari, atau tiga kali lipat dosis biasa, menurunkan reaktivitas trombosit (platelet) yang serupa bila dibandingkan dengan pemberian dosis standar 75 mg pada pasien-pasien non-karier (fungsi alel yang normal). Kesimpulan ini merupakan hasil penelitian ELEVATE-TIMI 56 (Escalating cLopidogrEl by InVolving A geneTic stratEgy - Thrombolysis In Myocardial Infarction 56) yang dilakukan oleh dr. Jessica Mega dan rekan dari Brigham and Women's Hospital, Boston, Massachusetts, Amerika Serikat. Hasil penelitian ini telah dipresentasikan pada pertemuan AHA (American heart Associaton) 2011, juga telah dipublikasikan secara berkala di Journal of the American Medical Association (JAMA).

 

Cloipdigrel merupakan obat anti-platelet dengan fungsi menghambat reseptor ADP (adenosin difosfat) P2Y12 pada trombosit. Pemberian clopidogrel, dengan dosis rumatan 75 mg, telah terbukti menurunkan kejadian kardiovaskular pada pasien-pasien dengan SKA (Sindrom Koroner Akut) dan juga pada pasien-pasien yang menjalani prosedur PCI (percutaneous coronary intervention). Clopidogrel merupakan sebuah pro-drug yang harus mengalami proses biotransformasi sehingga dapat terbentuk metabolit aktif. Enzim sitokrom P450 (CYP) memainkan peranan yang sangat penting terhadap metabolisme clopidogrel. Banyak penelitian memperlihatkan bahwa hilangnya fungsi alel CYP2C19, baik secara homozigot maupun heteroszigot, menyebabkan jumlah metabolit clopidogrel aktif yang lebih sedikit, gangguan penghambatan platelet, dan juga peningkatan kejadian kardiovaskular yang lebih besar dibandingkan dengan pasien yang non-carrier (tanpa gangguan fungsi alel CYP2C19). Berdasarkan data-data ini, FDA (Food and Drug Administration) dan EMA (European Medicines Agency) merekomendasikan pengubahan label keamanan yang menganjurkan terapi alternatif lain untuk pasien karier (pasien dengan gangguan fungsi alel CYP2C19).

 

Karena penggunaan clopidogrel sangat luas dalam terapi, dr. Jessica Mega dan rekan melakukan penelitian ELEVATE-TIMI 56 untuk mengetahui apakah clopidogrel 300 mg sehari (dosis rumatan) dapat memperbaiki reaktivitas trombosit pada pasien-pasien carrier dengan gangguan fungsi genotipe CYP2C19 (disebut dengan CYP2C19*2). Penelitian yang dilakukan adalah penelitian multisenter, acak, tersamar ganda, yang melibatkan 333 pasien. Seluruh pasien tersebut diperiksa genotipenya dan diberikan clopidogrel dosis rumatan sesuai genotipe masing-masing. Pada 247 pasien non-karier (tidak memiliki gangguan pada alel CYP2C19*2), diberikan terapi clopidogrel 75 mg dan 150 mg sehari, sementara pada 86 pasien dengan gangguan alel CYP2C19*2 (80 pasien homozigot dan 6 heterozigot), diberikan clopidogrel dengan dosis 75 mg, 150 mg, 225 mg, dan 300 mg sehari. Pada akhir penelitian, fungsi trombosit diperiksa menggunakan tes VASP (Vasolidator Stimulated Phosphoprotein) dan VerifyNow.

 

Hasil penelitian memperlihatkan bahwa pada pasien karier yang diterapi dengan clopidogrel harian 75 mg, reaktivitas trombosit lebih tinggi dibandingkan dengan pasien non-karier. Di antara pasien-pasien karier heterozigot, setiap peningkatan dosis clopidogrel sebesar 75 mg menurunkan indeks reaktivitas trombosit sebesar 8-9% (dengan perhitungan VASP); hasil serupa dijumpai dengan pemeriksaan VerifyNow. Sebaliknya, pada pasien dengan gangguan fungsi homozigot (hilangnya fungsi pada 2 alel), dosis clopidogrel 300 mg pun tidak meningkatkan penghambatan reaktivitas trombosit secara bermakna.

 

“Hasil penelitian ini dapat bermanfaat untuk memberikan arahan bagi para klinisi mengenai alternatif terapi untuk pasien-pasien karier,” ungkap dr. Jessica. “Kalau seorang dokter mengetahui bahwa pasiennya memiliki gangguan (penurunan) fungsi genotipe,” lanjut beliau, “pemberian clopidogrel dosis standar justru akan merugikan pasien. Dengan demikian, dokter dapat memilih untuk meningkatkan dosis atau menggunakan obat anti-platelet lain.

 

 

 

Referensi:

1. J Am Coll Cardiol. 2010;56(12):919-33.

2. J Thromb Haemost. 2007; 5(12):2429-36.

3. JAMA. 2011; 306(20): E1-E8.

4. N Engl J Med. 2005;352(12):1179-89.

 

Image: Illustration

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