A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol
2017; Elsevier BV; Volume: 120; Issue: 4 Linguagem: Inglês
10.1016/j.amjcard.2017.03.255
ISSN1879-1913
AutoresChristie M. Ballantyne, Sukrut Shah, Aditi Sapre, Tanya B. Ashraf, Sandra C. Tobias, Tayfun Şahı̇n, Ping Ye, Yugang Dong, Wayne Huey-Heng Sheu, Duk‐Hyun Kang, Paulo Roberto Ferreira ROSSI, Yulia Moiseeva, Ignacio Rodríguez Briones, Amy O. Johnson‐Levonas, Yale Mitchel,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoThis phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval −42.5, −31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C. This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval −42.5, −31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C. The plasma protein cholesteryl ester transfer protein (CETP) catalyzes the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and atherogenic apolipoprotein (Apo) B–containing lipoproteins (e.g., very low-density lipoprotein [LDL] and LDL particles). Although previous studies have shown that CETP inhibitors favorably modify plasma lipid profiles (i.e., reduce LDL-C and increase HDL-C) when administered in combination with statins, several investigational CETP inhibitors failed to show a benefit on cardiovascular (CV) events in large clinical outcome studies.1Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. Shear C.L. Revkin J.H. Buhr K.A. Fisher M.R. Tall A.R. Brewer B. ILLUMINATE InvestigatorsEffects of torcetrapib in patients at high risk for coronary events.N Engl J Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2610) Google Scholar, 2Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. Leitersdorf E. McMurray J.J. Mundl H. Nicholls S.J. Shah P.K. Tardif J.C. Wright R.S. dal-OUTCOMES InvestigatorsEffects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1560) Google Scholar Anacetrapib is another investigational CETP inhibitor that remains in clinical development. Anacetrapib has been shown to substantially decrease the levels of atherogenic lipoproteins/apolipoproteins (e.g., LDL, ApoB, and lipoprotein(a) [Lp(a)]) and increase HDL-C and ApoA1 levels, with an overall favorable safety profile devoid of off-target effects.3Cannon C.P. Shah S. Dansky H.M. Davidson M. Brinton E.A. Gotto A.M. Stepanavage M. Liu S.X. Gibbons P. Ashraf T.B. Zafarino J. Mitchel Y. Barter P. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease.N Engl J Med. 2010; 363: 2406-2415Crossref PubMed Scopus (681) Google Scholar, 4Kastelein J.J. Besseling J. Shah S. Bergeron J. Langslet G. Hovingh G.K. Al-Saady N. Koeijvoets M. Hunter J. Johnson-Levonas A.O. Fable J. Sapre A. Mitchel Y. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.Lancet. 2015; 385: 2153-2161Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 5Teramoto T. Shirakawa M. Kikuchi M. Nakagomi M. Tamura S. Surks H.K. McCrary Sisk C. Numaguchi H. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia.Atherosclerosis. 2013; 230: 52-60Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 6Krishna R. Anderson M.S. Bergman A.J. Jin B. Fallon M. Cote J. Rosko K. Chavez-Eng C. Lutz R. Bloomfield D.M. Gutierrez M. Doherty J. Bieberdorf F. Chodakewitz J. Gottesdiener K.M. Wagner J.A. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.Lancet. 2007; 370: 1907-1914Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar An ongoing cardiovascular outcome study (NCT01252953) will assess the potential impact of anacetrapib on CV events in statin-treated patients. In contrast to most lipid studies, which include predominantly participants from North America and western Europe, this multicenter, randomized, double-blind study was conducted in the populous countries underrepresented in clinical trials (i.e., Brazil, Russia, China, Korea, Taiwan, Turkey, and Mexico) to compare the lipid-modifying efficacy and safety profile of anacetrapib 100 mg versus placebo added to ongoing optimal statin therapy (±other lipid-modifying therapies [LMTs]) in patients with hypercholesterolemia who were not at their LDL-C goal (as per the National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low HDL-C. This was a phase 3, randomized, double-blind, worldwide, multicenter study consisting of a 24-week placebo-controlled active treatment period followed by a 12-week off-drug safety monitoring phase (Merck & Co., Inc., Kenilworth, New Jersey, MK-0859 Protocol number 022; registered on ClinicalTrials.gov NCT01860729; Supplementary Figure 1). After screening and a 2-week/single-blind placebo run-in period, 583 patients were randomized equally to receive double-blind treatment with anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks. A post-study safety follow-up visit occurred 12 weeks after early discontinuation or the last dose of study drug (i.e., early discontinuation or completion of study drug phase). All patients who discontinued were contacted at their intended week 36 visit date to assess for serious CV adverse events and all-cause death. This study was conducted at 65 sites in 7 countries (Brazil, Russia, China, Korea, Taiwan, Turkey, and Mexico) from May 2013 to August 2015. All participants provided written informed consent, and the study protocol was approved by the appropriate institutional review boards. This study was conducted in accordance with Good Clinical Practice Guidelines, the Declaration of Helsinki and other statutes, and regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. Eligible patients included adult men and women, 18 to 80 years of age, with hypercholesterolemia who were not at their LDL-C goal per their NCEP ATPIII CHD risk category (i.e., LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk, respectively) or with HDL-C ≤40 mg/dl while taking an optimal dose of statin ± other LMTs for ≥6 weeks before screening. Patients were required to remain on their regimen of statin ± other LMT throughout the study. The co-primary efficacy end points were % change from baseline in plasma levels of LDL-C (β-quantification [BQ] method) and HDL-C at week 24. Key secondary end points included % change from baseline in non-HDL-C, ApoB, ApoAI, and Lp(a) at week 24 and change from baseline in HDL-C at week 24 in patients with low HDL-C who were at LDL-C goal at baseline. Lipid and Apo determinations and other study-specific tests were performed by a centralized laboratory (PPD Global Central Laboratories, Highland Heights, Kentucky; Clusterpark, Zaventem, Belgium; or Science Park, Singapore). Lp(a) protein was measured using an ELISA by Northwest Research Laboratory (Seattle, Washington). Plasma cholesterol and TG were quantified by a standardized enzymatic assay. LDL-C was measured using the β-quantification method (primary end point), Friedewald equation (LDL-C = TC – (HDL-C + TG/5); exploratory end point) and a direct method using a detergent-based assay.7Davidson M. Liu S.X. Barter P. Brinton E.A. Cannon C.P. Gotto Jr., A.M. Leary E.T. Shah S. Stepanavage M. Mitchel Y. Dansky H.M. Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib.J Lipid Res. 2013; 54: 467-472Crossref PubMed Scopus (42) Google Scholar HDL-C was measured by the dextran sulfate method. Apo B and Apo A-1 were measured by turbidimetric immunoassay. All patients who received ≥1 dose of study drug and had ≥1 post-drug efficacy measurement and baseline measurement were included in the efficacy analysis. The co-primary and secondary efficacy end points were analyzed using a constrained longitudinal repeated measures model with terms for treatment, week of visit as a categorical value (weeks 0, 8, 16, 24), statin stratum, country, and time-by-treatment interaction. For Lp(a) and TG, a nonparametric analysis was used to estimate the differences in medians due to the known non-normality of these efficacy parameters. Hodges–Lehmann estimate was used to determine the point estimate of the median difference between treatments with a corresponding distribution-free 95% confidence interval (CI) and associated p value determined based on Wilcoxon's rank-sum test. Percent changes from baseline to week 24 were estimated and tested from the model. Multiplicity adjustments were applied to control for type I error across the primary and key secondary end points. All statistical tests were conducted at the 2-sided level, and a p value 99% power to detect a 25% difference in LDL-C (BQ) and a 100% difference in HDL-C between the anacetrapib 100 mg and placebo arms at an overall 5% α level (2 sided). All patients who received ≥1 dose of study drug were included in the safety analysis. The safety and tolerability profile were assessed through the following prespecified safety parameters: physical examinations, vital signs, blood pressure (BP), electrocardiograms, adverse events (AEs), routine hematology, chemistry, and urinalysis surveillance. Laboratory safety measurements included alanine aminotransferase, aspartate aminotransferase, creatine kinase, electrolytes (potassium, sodium, chloride, and bicarbonate), fasting plasma glucose, glycosylated hemoglobin (HbA1c), fasting plasma insulin, and homeostatic model assessment of insulin resistance (HOMA-IR). Serious CV AEs and all-cause deaths occurring during the treatment phase and the protocol-specified safety follow-up phase were adjudicated by an independent adjudication committee. The analysis of safety results followed a tiered approach. Tier 1 safety parameters were identified a priori and underwent inferential testing for statistical significance including prespecified adjudicated CV serious AEs (CV SAEs) and death from any cause. A total of 948 patients were screened, of which 583 were randomized 1:1 to double-blind anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks (Figure 1). All randomized patients received double-blind treatment except for 1 patient in the placebo group. Of the 582 treated patients, 531 (531 of 582; 91%) completed the base study. The groups were well balanced with respect to baseline characteristics and patient demographics (Table 1). Patients who discontinued study medication in the treatment phase or completed the treatment phase were automatically entered into the 12-week, off-drug, reversal phase unless they dropped out of the study (Figure 1). A total of 554 patients entered the reversal follow-up period, of which 531 (531 of 554; 95.8%) completed. Across treatment groups, the discontinuations and reasons for discontinuation were similar in both the treatment and reversal phases.Table 1Baseline demographics and patient characteristics for entire randomized cohortAnacetrapib 100 mg (n=290)Placebo (n=293)Age (years) – mean ± SD60.3 ± 9.160.9 ± 8.9Age ≥65 years102 (35.2%)102 (34.8%)Diabetes Mellitus26 (9.0%)16 (5.5%)Hypertension (history)185 (63.8%)211 (72.0%)CHD risk∗As defined in NCEP ATP III. Very high risk170 (58.6%)169 (57.7%) High risk95 (32.8%)94 (32.1%) Moderate risk16 (5.5%)24 (8.2%) Lower risk9 (3.1%)6 (2.0%)Male221 (76.2%)203 (69.3%)Country Brazil26 (9.0%)34 (11.6%) China68 (23.4%)64 (21.8%) Republic of Korea51 (17.6%)57 (19.5%) Mexico30 (10.3%)27 (9.2%) Russian Federation43 (14.8%)37 (12.6%) Taiwan46 (15.9%)40 (13.7%) Turkey26 (9.0%)34 (11.6%)Race American Indian/Alaska Native7 (2.4%)11 (3.8%) Asian165 (56.9%)161 (54.9%) Black01 (0.3%) Multiracial16 (5.5%)17 (5.8%) White102 (35.2%)103 (35.2%)Body mass index (kg/m2) – mean ± SD27.7 ± 4.327.8 ± 4.2Type of concomitant statin Lovastatin01 (0.3%) Simvastatin48 (16.6%)62 (21.2%) Atorvastatin140 (48.3%)122 (41.6%) Rosuvastatin68 (23.4%)70 (23.9%) Pitavastatin6 (2.1%)6 (2.0%) Pravastatin25 (8.6%)25 (8.5%) Fluvastatin2 (0.7%)5 (1.7%) Missing1 (0.3%)2 (0.7%)Use of other LMT(s) Yes43 (14.8%)40 (13.7%)Type of other LMT(s) Ezetimibe22 (7.6%)21 (7.2%) Niacin2 (0.7%)0 Fibrate17 (5.9%)16 (5.5%) Others2 (0.7%)3 (1.0%)Baseline lipid/lipoprotein values LDL-C (BQ) (mg/dL) – mean ± SD87.2 ± 27.9 (n=273)88.7 ± 30.0 (n=270) HDL-C (mg/dL) – mean ± SD43.5 ± 11.9 (n=290)43.6 ± 11.0 (n=292) Non-HDL-C (mg/dL) – mean ± SD121.0 ± 34.2 (n=285)125.2 ± 36.4 (n=284) ApoA1 (mg/dL) – mean ± SD128.6 ± 23.2 (n=286)129.9 ± 24.3 (n=284) ApoB (mg/dL) – mean ± SD83.6 ± 20.7 (n=286)85.9 ± 23.0 (n=284) Lp(a) (nmol/L) – median ± SD27.7 ± 64.9 (n=285)31.9 ± 73.6 (n=287) Triglycerides (mg/dL) – median ± SD142.5 ± 133.9 (n=290)154.5 ± 83.5 (n=292)Apo = apolipoprotein; BQ = beta-quantification; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LMT = lipid-modifying therapy; Lp(a) = lipoprotein a; non-HDL-C = non-high-density lipoprotein cholesterol; SD = standard deviation.∗ As defined in NCEP ATP III. Open table in a new tab Apo = apolipoprotein; BQ = beta-quantification; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; LMT = lipid-modifying therapy; Lp(a) = lipoprotein a; non-HDL-C = non-high-density lipoprotein cholesterol; SD = standard deviation. Treatment with anacetrapib 100 mg for 24 weeks led to significant placebo-adjusted reductions in LDL-C (BQ) of 37% and increases in HDL-C of 118% (Table 2; Supplementary Figure 2; p <0.001 for both). Near maximal effects on LDL-C (BQ) and HDL-C occurred by week 8 and remained generally stable thereafter through to week 24 (Supplementary Figure 2). In the anacetrapib 100 mg group, LDL-C (BQ) levels appeared to return to baseline at the completion of the 12-week off-drug reversal phase (i.e., week 36). Evidence of a continued drug effect on HDL-C was observed after completion of the 12-week off-drug reversal period.Table 2Percent changes in lipid and lipoprotein levels during the 24-week, double-blind treatment phaseTreatment PhaseN∗Number of patients with both baseline and Week 24 values.Within-Group AnalysisBetween-Group Analysis Difference in LS Mean % Change (95% CI); P-value‡For Lp(a) and TG, based on Wilcoxon's rank sum test.BaselineMean ± SDWeek 24Mean ± SDLS Mean % Change From Baseline (95% CI)†For Lp(a) and TG, median (95% CI), where CI = ± t (0.975, n-1)*SD/sqrt(n), or the Hodges-Lehmann estimate of the median difference between treatments with a corresponding distribution-free CI.LDL-C (BQ; mg/dL) – primary endpoint Anacetrapib 100 mg22987.4 ± 27.860.3 ± 31.4-27.6 (-31.8, -23.4)-36.7 (-42.5, -31.0)<0.001 Placebo20987.1 ± 29.490.8 ± 32.29.1 (4.8, 13.5)HDL-C (mg/dL) – co-primary endpoint Anacetrapib 100 mg25543.6 ± 12.094.6 ± 27.3123.7 (118.2, 129.2)118.2 (110.6, 125.7)<0.001 Placebo23543.5 ± 11.145.2 ± 13.75.5 (-0.1, 11.2)LDL-C (Friedewald; mg/dL) – exploratory endpoint Anacetrapib 100 mg23788.4 ± 28.657.9 ± 33.1-33.6 (-37.6, -29.6)-41.7 (-47.0, -36.3)<0.001 Placebo22291.3 ± 33.194.1 ± 36.38.0 (4.0, 12.1)LDL-C (Direct; mg/dL) – exploratory endpoint Anacetrapib 100 mg25397.5 ± 28.665.4 ± 35.0-31.1 (-34.9, -27.6)-40.8 (-45.7, -35.9)<0.001 Placebo23799.9 ± 32.8105.6 ± 39.49.5 (5.8, 13.2)Non-HDL-C (mg/dL) Anacetrapib 100 mg250121.0 ± 33.783.7 ± 38.5-26.1 (-29.4, -22.7)-32.2 (-36.7, -27.7)<0.001 Placebo229123.6 ± 36.2126.4 ± 40.06.1 (2.7, 9.5)Apo B (mg/dL) Anacetrapib 100 mg24583.4 ± 20.765.4 ± 20.3-19.2 (-23.2, -15.3)-27.9 (-33.4, -22.5)<0.001 Placebo22984.6 ± 22.287.7 ± 28.68.7 (4.6, 12.7)Apo AI (mg/dL) Anacetrapib 100 mg245128.1 ± 22.5183.5 ± 34.145.4 (41.1, 49.7)39.6 (33.7, 45.4)<0.001 Placebo229130.2 ± 23.1134.7 ± 48.15.8 (1.4, 10.2)Lp(a) (nmol/L)§Expressed as median ± SD, where SD is (Q3-Q1)/1.075, where Q3 is the 75th percentile and Q1 is the 25th percentile. Anacetrapib 100 mg24828.2 ± 71.310.0 ± 58.1-45.8 (-51.9, -39.8)-43.1 (-49.3, -36.8)<0.001 Placebo23428.5 ± 69.828.3 ± 65.0-2.4 (-6.7, 2.0)TG (mg/dL)§Expressed as median ± SD, where SD is (Q3-Q1)/1.075, where Q3 is the 75th percentile and Q1 is the 25th percentile. Anacetrapib 100 mg255141.0 ± 92.1122.0 ± 70.7-10.4 (-15.4, -5.4)-5.0 (-11.2, 1.2)0.015 Placebo239153.0 ± 95.8141.0 ± 82.8-3.3 (-9.1, 2.4)Apo = apolipoprotein; BQ LDL-C = LDL-C measured by β-quantification methods; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein a; LS = least-squares; SD = standard deviation; TG = triglycerides.∗ Number of patients with both baseline and Week 24 values.† For Lp(a) and TG, median (95% CI), where CI = ± t (0.975, n-1)*SD/sqrt(n), or the Hodges-Lehmann estimate of the median difference between treatments with a corresponding distribution-free CI.‡ For Lp(a) and TG, based on Wilcoxon's rank sum test.§ Expressed as median ± SD, where SD is (Q3-Q1)/1.075, where Q3 is the 75th percentile and Q1 is the 25th percentile. Open table in a new tab Apo = apolipoprotein; BQ LDL-C = LDL-C measured by β-quantification methods; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein a; LS = least-squares; SD = standard deviation; TG = triglycerides. After 24 weeks of treatment, significantly more patients in the anacetrapib 100 mg versus placebo group reached their LDL-C (BQ) goal (77.8% [98/126] vs 18.3% [22/120]) of <1.81 mmol/L for very-high risk, <2.59 mmol/L for high-risk, <3.36 mmol/L for moderate-risk, and <4.14 mmol/L for low-risk patients. In patients with low HDL-C who were at their LDL-C goal at baseline, treatment with anacetrapib led to a large, significant increase in HDL-C of 162.2 (95% CI 148.4, 176.1) compared with a more modest, nonsignificant increase of 10.8 (95% CI −5.6, 27.2) in the placebo group resulting in a between-group change of 151.5 (95% CI 130.7, 172.3) favoring anacetrapib (p median. Some subgroup analyses, such as the use of concomitant statin and use of concomitant statin + LMT, should be viewed with caution due to small sample sizes. With respect to the other efficacy end points, treatment with anacetrapib resulted in significantly greater reductions in non-HDL-C (p <0.001), Apo B (p <0.001), Apo AI (p <0.001), Lp(a) (p <0.001), and TG (p upper limit of normal (ULN) (11.8% vs 6.6%, respectively; p ULN or potassium values < LLN. A greater incidence of adjudicated CV SAEs was observed in the placebo versus anacetrapib group, primarily driven by an imbalance in adjudicated CV SAEs of unstable angina and nonfatal stroke.Table 3Safety and tolerability during the 12-Week reversal phaseWithin-group analysis- n/N (%)Between-Group Difference- % (95% CI); p-valueAnacetrapib100 mgPlaceboAnacetrapib 100 mg vs. PlaceboPatients with any AE21/280 (7.5%)27/274 (9.9%)-2.4 (-7.2, 2.4)Patients with any drug-related AE0/2800/2740.0 (-1.4, 1.4)Patients with any SAE2/280 (0.7%)10/274 (3.6%)-2.9 (-6.0, -0.6)Patients with any drug-related SAE0/2800/2740.0 (-1.4, 1.4)Patients with any AE leading to discontinuation of treatment0/2800/274--Blood pressure Elevations in SBP ≥10 mm Hg133/280 (47.5%)147/274 (53.6%)-6.1 (-14.4, 2.2); p=0.148 Elevations in SBP ≥15 mm Hg86/280 (30.7%)99/274 (36.1%)-5.4 (-13.2, 2.4); p=0.177 Elevations in DBP ≥10 mm Hg73/280 (26.1%)84/274 (30.7%)-4.6 (-12.1, 2.9); p=0.232Electrolytes Sodium >ULN37/280 (13.2%)22/273 (8.1%)5.2 (0.0, 10.4); p=0.050 Chloride >ULN4/280 (1.4%)5/273 (1.8%)-0.4 (-3.0, 2.0); p=0.708 Bicarbonate >ULN0/2802/273 (0.7%)-0.7 (-2.6, 0.6); p=0.152 Potassium ULN34/289 (11.8%)19/290 (6.6%)5.2 (0.5, 10.1); P=0.030 Chloride >ULN3/289 (1.0%)4/290 (1.4%)-0.3 (-2.6, 1.8); P=0.707 Bicarbonate >ULN0/2891/290 (0.3%)-0.3 (-1.9, 1.0); P=0.318 Potassium 0.564Consecutive elevations of ALT and/or AST ≥3x ULN0/2890/290--CK ≥10x ULN0/2890/2900.0 (-1.3, 1.3)CK ≥10x ULN + muscle symptoms0/2890/2900.0 (-1.3, 1.3)Prespecified adjudicated CV SAE∗The category of prespecified adjudicated CV SAEs includes the composite of CV death, stroke, myocardial infarction, and unstable angina.0/2907/292 (2.4%)-2.4 (-4.9, -1.1); P=0.008 CV death00— Nonfatal stroke02 (0.7%)-0.7 (-2.5, 0.6) Nonfatal MI01 (0.3%)-0.3 (-1.9, 1.0) Unstable angina04 (1.4%)-1.4 (-3.5, -0.1)Deaths1/290 (0.3%)2/292 (0.7%)†Patient experienced a fatal SAE (metastatic lung cancer) that started on the last day of treatment and ended on the day of death, therefore it is unknown if patient entered the reversal phase.--Longitudinal analysis of change from baseline‡Expressed as LS mean ± standard error in first 2 columns and LS mean difference (95% CI) in third column. SBP (mm Hg)1.2 ± 0.72.6 ± 0.8-1.4 (-3.5, 0.7); P=0.192 DBP (mm Hg)0.4 ± 0.51.5 ± 0.5-1.2 (-2.5, 0.2); P=0.091-- = not calculated; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CI = confidence interval; CK = creatine kinase; CV = cardiovascular; DBP = diastolic blood pressure; LLN = lower limit of normal; MI = myocardial infarction; SAE = serious adverse event; SBP = systolic blood pressure; ULN = upper limit of normal.∗ The category of prespecified adjudicated CV SAEs includes the composite of CV death, stroke, myocardial infarction, and unstable angina.† Patient experienced a fatal SAE (metastatic lung cancer) that started on the last day of treatment and ended on the day of death, therefore it is unknown if patient entered the reversal phase.‡ Expressed as LS mean ± standard error in first 2 columns and LS mean difference (95% CI) in third column. Open table in a new tab -- = not calculated; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CI: confidence interval; CK = creatine kinase; CV = cardiovascular; DBP = diastolic blood pressure; LLN = lower limit of normal; SAE = serious adverse event; SBP = systolic blood pressure; ULN = upper limit of normal. -- = not calculated; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; CI = confidence interval; CK = creatine kinase; CV = cardiovascu
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