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1. ยา Pitavastatin กับการ Reverse โรคหลอดเลือดหัวใจตีบ 2. Tertiary source : Micromedex Pitavastatin Calcium Diabetes mellitus - Hyperlipidemia Hyperlipidemia Diabetes mellitus - Hyperlipidemia a) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence favors efficacy Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS b) Summary: Pitavastatin did not meet the noninferiority margin when compared with atorvastatin for reduction of LDL-C in patients with type II diabetes mellitus and combined dyslipidemia in a multicenter, randomized, double-blind, phase 3 trial (n=410) [2]. Effective in one small study [8] c) Adult: 1) Pitavastatin did not meet the noninferiority margin when compared with atorvastatin for reduction of LDL-C in patients with type II diabetes mellitus and combined dyslipidemia in a multicenter, randomized, double-blind, parallel group, phase 3 trial (n=410). After a 6 to 8 week, wash-out/dietary lead-in period, patients were randomized to either pitavastatin 4 milligrams daily or atorvastatin 20 mg daily for 12 weeks. Noninferiority of pitavastatin was declared if the lower limit of the 95% confidence interval for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. At week 12, the mean percent change from baseline in LDLC was -41% vs -43% in the pitavastatin compared with atorvastatin groups, respectively, yielding a mean treatment difference of -2% (95% CI, -6.2% to 1.5%), thus noninferiority was not achieved [2]. 2) In non-insulin-dependent (type 2) diabetic patients with hyperlipidemia, a dose of 2 milligrams (mg) daily reduced total and LDL cholesterol levels by 25% and 36%, respectively, and increased HDL-cholesterol by 5 mg/dL after 8 weeks of treatment in one study (n=28). Triglyceride levels were reduced by 29%. Other results of this study suggested a decrease in small-dense LDL particles during therapy. There was no effect of pitavastatin on glycemic control [8]. Hyperlipidemia FDA Labeled Indication a) Overview FDA Approval: Adult, yes; Pediatric, no Efficacy: Adult, Effective Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS b) Summary: Pitavastatin is indicated for the treatment of primary hyperlipidemia and mixed dyslipidemia as an adjunct to diet control [1]. Pitavastatin was noninferior to atorvastatin and simvastatin and superior to pravastatin (elderly patients) for reduction of LDL-C in randomized, 12-week, double-blind studies [2]. In a 12-week, multicenter, randomized, double-blind, double-dummy trial, pitavastatin was noninferior to simvastatin with regards to low density lipoprotein C cholesterol reduction in patients with primary hyperlipidemia or mixed dyslipidemia (n=857) [3]. In a multicenter, open-label, 52-week (wk) extension trial (n=1353), the long-term safety and efficacy of pitavastatin were demonstrated in patients with primary hypercholesterolemia or combined dyslipidemia [4]. The efficacy of pitavastatin 2 milligrams (mg) daily with respect to LDL-lowering effects has been greater than observed with pravastatin 10 mg daily in primary hypercholesterolemia [5]. c) Adult: 1) Dose-Range Trial a) In a multicenter, randomized, 12-week double-blind study involving Japanese patients with primary hypercholesterolemia (total cholesterol 220 milligrams/deciliter (mg/dL) or greater (n=251), pitavastatin produced dose-dependent reductions in total and LDL cholesterol. Mean reductions in total cholesterol by 23%, 26%, and 31% were observed at the end of treatment with doses of 1, 2, and 4 mg once daily, respectively. Corresponding dose-dependent reductions in mean LDL cholesterol were 32%, 36%, and 43%, respectively. Reduction in triglyceride levels were 15%, 19% and 18%, respectively, but were not dose-dependent. Mean levels of high-density lipoprotein (HDL) cholesterol were increased significantly (5 to 8 mg/dL from baseline), with no evidence of a dose- response relationship. The most common adverse events reported (2% or greater) in at least one marketed dose were myalgia, back pain, diarrhea, constipation and pain in the extremity [6][2]. b) Oral pitavastatin 1 to 4 milligrams (mg) daily has shown efficacy in patients with familial heterozygous or nonfamilial hypercholesterolemia and mixed dyslipidemia, producing significant and dose-dependent decreases in total and low-density lipoprotein (LDL) cholesterol; in short-term studies (up to 16 weeks) with 2 and 4 mg once daily, reductions in LDL cholesterol of approximately 40% and 47%, respectively, have been reported [5][7][6][8][9]. Reductions in triglyceride levels, usually significant and possibly dose-related, were also reported in these studies. Similar reductions in total and LDL cholesterol levels have been observed with 1 mg twice daily and 2 mg once daily [8]. 2) Active-Comparator Trials a) Atorvastatin 1) Pitavastatin was noninferior to atorvastatin for reduction of LDL-C in patients with primary hyperlipidemia or mixed dyslipidemia in a multicenter, double-blind, randomized, phase 3 trial (n=817). The regimen comparisons included pitavastatin 2 milligrams (mg) once daily (n=315) compared with atorvastatin 10 mg daily (n=102) and pitavastatin 4 mg daily (n=298) compared with atorvastatin 20 mg daily (n=102). The treatment duration was 12 weeks. Noninferiority of pitavastatin was declared if the lower limit of the 95% confidence interval for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. At week 12, the mean change from baseline in LDL-C was -38% for both pitavastatin 2 mg and atorvastatin 10 mg groups, yielding a mean treatment difference of 0% (95% CI, -3% to 3%). Similarly, at week 12, the mean change from baseline in LDL-C was -45% vs -44% in the pitavastatin 4 mg compared with atorvastatin 20 mg groups, respectively, yielding a mean treatment difference of 1% (95% CI, -2% to 4%). The most common adverse events reported (incidence of 2% or greater) in at least one marketed dose were myalgia, back pain, diarrhea, constipation and pain in the extremity [2]. b) Pravastatin 1) Pitavastatin was superior to pravastatin for reduction of LDL-C in elderly patients with primary hyperlipidemia or mixed dyslipidemia in a 12-week, multicenter, randomized, double-blind, parallel group, phase 3 trial (n=942). After a 6 to 8 week, wash-out/dietary lead-in period, elderly patients (65 years or older) were randomized to pitavastatin 1, 2, or 4 milligram (mg) once daily or to pravastatin 10, 20 or 40 mg once daily. Noninferiority of pitavastatin was declared if the lower limit of the 95% confidence interval for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. The pairwise dose comparisons were 1 mg vs 10 mg, 2 mg vs 20 mg and 4 mg vs 40 mg for pitavastatin compared with pravastatin, respectively. At week 12, all doses of pitavastatin were superior to pravastatin for reduction in LDL-C. The mean treatment differences were 9% (95% CI, 6% to 12%), 10% (95% CI, 7% to 13%) and 10% (95% CI, 7% to 13%), in the 1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg groups, respectively [2]. 2) Pitavastatin 2 milligrams (mg) once daily was compared with pravastatin 10 mg once daily in patients with primary hyperlipidemia (total cholesterol 220 mg/dL or greater, triglycerides less than 400 mg/dL, n=240) in a 3-month, double-blind study . Mean falls in total and LDL cholesterol from baseline were significantly greater in the pitavastatin group (28% and 38%, respectively) compared to those receiving pravastatin (14% and 18%) at the end of treatment. Target LDL cholesterol levels (less than 140 mg/dL) were achieved in significantly more patients treated with pitavastatin (75% versus 36%). At week 12, triglyceride levels were decreased similarly with either drug (by about 22%) in patients with a baseline level of at least 150 mg/dL, whereas reductions in apolipoprotein B, C-II, C-III, and E were significantly greater in the pitavastatin group. Both agents produced similar increases in HDL cholesterol (about 9 mg/dL). Adverse effects were similar in each group [5]. c) Simvastatin 1) In a multicenter, randomized, double-blind, double-dummy trial, pitavastatin was noninferior to simvastatin with regards to low density lipoprotein C cholesterol (LDL-C) reduction in patients with primary hyperlipidemia or mixed dyslipidemia (n=857). Following a 6- or 8- (if previously on lipid lowering therapy) week wash-out and dietary run in (European Atherosclerosis Society (EAS) recommended diet), patients with mean LDL-C levels that ranged from 160 to 220 milligrams (mg)/deciliter (dL) and mean triglyceride (TG) levels less than or equal to 400 mg/dL were eligible for enrollment. Concomitant use of other lipid lowering therapy or drugs that may alter the pharmacokinetics of statins was not permitted. Patients (mean age, 58 years) were randomized 3:3:1:1 to receive oral doses of pitavastatin 2 mg daily (n=315), pitavastatin 4 mg daily (n=323), simvastatin 20 mg daily (n=108), or simvastatin 40 mg daily (n=111) for 12 weeks. Patients in the higher dose groups received the lower dose for 4 weeks before titrating up to the higher dose. Efficacy was assessed in the full analysis set (FAS; those who received at least 1 study dose and had at least 1 on-treatment lipid assessment) and the per-protocol (PP) set. Noninferiority of pitavastatin was declared if the lower limit of the 95% confidence interval for the mean treatment difference (mean percent change in LDL-C from baseline) was greater than -6%. At week 12 in the FAS, the mean change from baseline in LDL-C was -39% in the pitavastatin 2-mg group compared with -35% in the simvastatin 20-mg group, corresponding to an adjusted mean treatment difference of 4.1% (95% confidence interval, 0.8% to 7.3%). Similarly, at week 12, the mean change from baseline in LDL-C was -44% and -43% in the pitavastatin 4-mg and simvastatin 40-mg groups, respectively (adjusted mean treatment difference, 1.1%; 95% CI, -2.1% to 4.3%). Analysis of the PP population confirmed the FAS results (data not provided). There were no significant differences between the groups for most of the secondary endpoints (including changes from baseline in high density lipoprotein cholesterol (HDL-C), TG, apolipoprotein B and A1, and C-reactive protein); however, more patients in the pitavastatin 2mg group compared with the simvastatin 20-mg group achieved target LDL-C goals per EAS guidelines (59.6% vs 48.6%; p=0.049). Additionally, the mean percent change in total cholesterol (-27.9% vs -25.4%; p=0.041) and non-HDL-C (-35.8% vs -32.3%; p=0.021) was significantly greater in the pitavastatin 2-mg group compared with the simvastatin 20-mg group. Adverse events were similar across all of the treatment groups; the most common (approximately 2% or greater) treatment emergent adverse events reported were headache and myalgia [3]. 2) Pitavastatin was noninferior to simvastatin for reduction of LDL-C in patients with primary hyperlipidemia or mixed dyslipidemia with 2 or more risk factors for coronary heart disease in a multicenter, randomized, double-blind, phase 3 trial (n=351). After a 6- to 8-week, wash-out/dietary lead-in period, patients were randomized to either pitavastatin 4 milligrams (mg) daily or simvastatin 40 mg daily for 12 weeks. Noninferiority of pitavastatin was declared if the lower limit of the 95% confidence interval for the mean treatment difference was greater than -6% for the mean percent change in LDL-C. At week 12, the mean change from baseline in LDL-C was -44% for both pitavastatin and simvastatin groups, yielding a treatment difference of 0% (95% CI, -2% to 3%) [2]. 3. Secondary source : Pitavastatin กับการลดระดับไขมันในเลือด 4. Primary source 1 : Sciencedirect 5. Primary source 2 : The 7th Statin : ReversingCoronary artery disease? จากวารสาร Medical time ปี ที่ 13 ฉบับที่ 292 ประจาวันที่16-31 ธ.ค.2554 6. คาตอบ : ยา Pitavastatin มีการค้ นคว้ าวิจยั ตังแต่ ้ อดีตมีทงหมด ั้ 9 ชนิด แต่ที่ใช้ กนั ในปั จจุบนั มี 7 ชนิด ยากลุม่ นี ้ใช้ ลดระดับCholesterol ในเลือดสูง สามารถลดขนาด Lipid plaqueลงได้ และอาจสามารถreverse โรคหลอดเลือดหัวใจตีบได้ ใช้ กนั มานานในญี่ปนโดยในการศึ ุ่ กษาเกี่ยวกับการลดขนาด artherosclerotic plaque Japan-ACS study ศึกษาการใช้ ยา Pitavastatin เปรี ยบเทียบกับ Atorvastatin ในผู้ป่วย Acute coronary syndrome พบว่ายาทัง้ 2 ชนิดลดขนาด Plaque volume ลงได้ โดยเป็ นเพียงการชลอการตีบตันของหลอดเลือดเท่านัน้ สรุปว่าลดขนาดของ Plaque volume ได้ ไม่ด้อยกว่า Atorvastatin และในอีกการศึกษาหนึง่ ได้ ทาการศึกษาใน ผู้ป่วย โรคCoronary artery disease ผู้ป่วยต้ องมีลกั ษณะ Plaque ที่เป็ น “Yellow plaque” พบว่ายา statin ชลอการขยายขนาดของ Plaqueแต่ไม่สามารถลดขนาดของ Plaqueได้ ผลของยาPitavastatin น่าจะมีฤทธิ์ Stabilize plaque โดยที่ Stabilizeคือการเปลีย่ นแปลงสีของPlaque แสดงว่ายา Pitavastatin มีฤทธิ์ Anti-inflammatoryด้ วย นอกเหนือจาก การลดระดับไขมัน http://www.thomsonhc.com/micromedex2/librarian/ND_T/evidencexpert/ND_PR/evidencexpert/C S/7EF823/ND_AppProduct/evidencexpert/DUPLICATIONSHIELDSYNC/D0E0B1/ND_PG/evidencexpert /ND_B/evidencexpert/ND_P/evidencexpert/PFActionId/evidencexpert.DisplayDrugdexDocument?do cId=2290&contentSetId=31&title=Pitavastatin+Calcium&servicesTitle=Pitavastatin+Calcium&topicId =dosingInformationSection&subtopicId=adultDosageSection http://pdn.sciencedirect.com/science?_ob=MiamiImageURL&_cid=271064&_user=1184727&_pii=S 0021915011008288&_check=y&_origin=search&_zone=rslt_list_item&_coverDate=2011-1231&wchp=dGLzVlt-zSkzV&md5=9f9a2f24a77242d6dc0cd86672333f9d/1-s2.0-S0021915011008288main.pdf