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Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis.
Blanc, JF, Khemissa, F, Bronowicki, JP, Monterymard, C, Perarnau, JM, Bourgeois, V, Obled, S, Abdelghani, MB, Mabile-Archambeaud, I, Faroux, R, et al
Hepatology international. 2021;(1):93-104
Abstract
BACKGROUND AND AIMS There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child-Pugh B cirrhosis. METHODS PRODIGE 21 was a multicentric prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib-pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS). RESULTS 160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 [95% CI: 2.4-6.5], 3.1 [95% CI: 1.9-4.3], 4.0 [95% CI: 3.2-5.5] and 3.5 months [95% CI: 2.2-5.4] in arms A, B, C and D, respectively. Median OS was 4.0 months [95% CI: 3.3-5.5] for patients treated with sorafenib, vs 2.9 months [95% CI: 2.2-3.9] for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months [95% CI: 3.8-8.3] in patients treated with sorafenib vs 3.1 months [95% CI: 1.9-4.8] for patients not treated with sorafenib. CONCLUSION In the overall Child-Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib. CLINICAL TRIAL REGISTRATION The study was referenced in clinicaltrials.gov (NCT01357486).
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Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML).
Advani, AS, Li, H, Michaelis, LC, Medeiros, BC, Liedtke, M, List, AF, O'Dwyer, K, Othus, M, Erba, HP, Appelbaum, FR
Leukemia research. 2018;:17-20
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Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.
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The effect of fasting status on lipids, lipoproteins, and inflammatory biomarkers assessed after hospitalization for an acute coronary syndrome: Insights from PROVE IT-TIMI 22.
Steen, DL, Umez-Eronini, AA, Guo, J, Khan, N, Cannon, CP
Clinical cardiology. 2018;(1):68-73
Abstract
BACKGROUND For decades, fasting for 8 to 12 hours has been recommended for measurement of lipid profiles. The effect of fasting on low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) has been described in healthy cohorts and those with stable disease states. Recently, guidelines suggested that fasting may not be necessary due to its small effect on lipid measures. Little is known, however, regarding whether the impact of fasting is altered in the setting of an acute coronary syndrome (ACS). HYPOTHESIS We hypothesized that the post-ACS period would minimally effect the impact of fasting status on lipid measurements. METHODS We evaluated the association of fasting on lipid and other biomarkers at the randomization visit, which occurred at a median of 7 days after the onset of an ACS, as well as during follow-up, in a cohort of 4177 subjects from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. RESULTS Fasting samples were independently associated with a higher LDL-C of 4.1 mg/dL and apolipoprotein-B 100 of 2.6 mg/dL as well as a lower TG of 21.0 mg/dL and high-sensitivity C-reactive protein of 0.48 mg/dL. The relative difference was 3.8% for LDL-C and -11.3% for TG. Fasting did not change total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), or apolipoprotein C-III. CONCLUSIONS Although fasting does impact lipid measurements, the effect on LDL-C is small (about 4 mg/dL), both early after ACS and during follow-up. These data provide support for recent guidelines that no longer advocate for fasting lipid samples, including in the setting of ACS.
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Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV.
Toribio, M, Fitch, KV, Sanchez, L, Burdo, TH, Williams, KC, Sponseller, CA, McCurdy Pate, M, Aberg, JA, Zanni, MV, Grinspoon, SK
AIDS (London, England). 2017;(6):797-806
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OBJECTIVE Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population. DESIGN Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites. METHODS Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066). RESULTS One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ± 0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/μl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin). CONCLUSION Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.
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The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study.
Hosomi, N, Nagai, Y, Kohriyama, T, Ohtsuki, T, Aoki, S, Nezu, T, Maruyama, H, Sunami, N, Yokota, C, Kitagawa, K, et al
EBioMedicine. 2015;(9):1071-8
Abstract
BACKGROUND Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. METHODS This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FINDING Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. INTERPRETATION Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FUNDING This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.
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Which lipid measurement should we monitor? An analysis of the LIPID study.
Glasziou, PP, Irwig, L, Kirby, AC, Tonkin, AM, Simes, RJ
BMJ open. 2014;(2):e003512
Abstract
OBJECTIVES To evaluate the optimal lipid to measure in monitoring patients, we assessed three factors that influence the choice of monitoring tests: (1) clinical validity; (2) responsiveness to therapy changes and (3) the size of the long-term 'signal-to-noise' ratio. DESIGN Longitudinal analyses of repeated lipid measurement over 5 years. SETTING Subsidiary analysis of a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study-a clinical trial in Australia, New Zealand and Finland. PARTICIPANTS 9014 patients aged 31-75 years with previous acute coronary syndromes. INTERVENTIONS Patients were randomly assigned to 40 mg daily pravastatin or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES We used data on serial lipid measurements-at randomisation, 6 months and 12 months, and then annually to 5 years-of total cholesterol; low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and their ratios; triglycerides; and apolipoproteins A and B and their ratio and their ability to predict coronary events. RESULTS All the lipid measures were statistically significantly associated with future coronary events, but the associations between each of the three ratio measures (total or LDL cholesterol to HDL cholesterol, and apolipoprotein B to apolipoprotein A1) and the time to a coronary event were better than those for any of the single lipid measures. The two cholesterol ratios also ranked highly for the long-term signal-to-noise ratios. However, LDL cholesterol and non-HDL cholesterol showed the most responsiveness to treatment change. CONCLUSIONS Lipid monitoring is increasingly common, but current guidelines vary. No single measure was best on all three criteria. Total cholesterol did not rank highly on any single criterion. However, measurements based on cholesterol subfractions-non-HDL cholesterol (total cholesterol minus HDL cholesterol) and the two ratios-appeared superior to total cholesterol or any of the apolipoprotein options. Guidelines should consider using non-HDL cholesterol or a ratio measure for initial treatment decisions and subsequent monitoring.
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In search for genetic determinants of clinically meaningful differential cardiovascular event reduction by pravastatin in the PHArmacogenetic study of Statins in the Elderly at risk (PHASE)/PROSPER study.
Postmus, I, Johnson, PC, Trompet, S, de Craen, AJ, Slagboom, PE, Devlin, JJ, Shiffman, D, Sacks, FM, Kearney, PM, Stott, DJ, et al
Atherosclerosis. 2014;(1):58-64
Abstract
BACKGROUND Statin therapy is widely used in the prevention and treatment of cardiovascular events and is associated with significant risk reductions. However, there is considerable variation in response to statin therapy both in terms of LDL cholesterol reduction and clinical outcomes. It has been hypothesized that genetic variation contributes importantly to this individual drug response. METHODS AND RESULTS We investigated the interaction between genetic variants and pravastatin or placebo therapy on the incidence of cardiovascular events by performing a genome-wide association study in the participants of the PROspective Study of Pravastatin in the Elderly at Risk for vascular disease--PHArmacogenetic study of Statins in the Elderly at risk (PROSPER/PHASE) study (n = 5244). We did not observe genome-wide significant associations with a clinically meaningful differential cardiovascular event reduction by pravastatin therapy. In addition, SNPs with p-values lower than 1 × 10(-4) were assessed for replication in a case-only analysis within two randomized placebo controlled pravastatin trials, CARE (n = 711) and WOSCOPS (n = 522). rs7102569, on chromosome 11 near the ODZ4 gene, was replicated in the CARE study (p = 0.008), however the direction of effect was opposite. This SNP was not associated in WOSCOPS. In addition, none of the SNPs replicated significantly after correcting for multiple testing. CONCLUSIONS We could not identify genetic variation that was significantly associated at genome-wide level with a clinically meaningful differential event reduction by pravastatin treatment in a large prospective study. We therefore assume that in daily practice the use of genetic characteristics to personalize pravastatin treatment to improve prevention of cardiovascular disease will be limited.
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Rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke: the Japan Statin Treatment Against Recurrent Stroke (J-STARS).
Nagai, Y, Kohriyama, T, Origasa, H, Minematsu, K, Yokota, C, Uchiyama, S, Ibayashi, S, Terayama, Y, Takagi, M, Kitagawa, K, et al
International journal of stroke : official journal of the International Stroke Society. 2014;(2):232-9
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BACKGROUND Although statin therapy is beneficial for preventing first strokes, the benefit for recurrent stroke and its sub-types remains unknown in Asian populations. The aim of this study is to examine the role of pravastatin in the secondary prevention of stroke in Japanese patients. METHODS This is a multicenter, randomized, open-label, parallel group study of patients with noncardioembolic ischemic stroke (atherothrombotic infarction, lacunar infarction, and infarction of undetermined etiology). All patients were diagnosed with hyperlipidemia and with a total cholesterol level between 180 and 240 mg/dl at enrollment. Patients in the treatment group receive 10 mg/day of pravastatin, and those in the control group receive no statin treatment. The primary end-point is the recurrence of stroke, including transient ischemic attack. The secondary end-points include the onset of respective stroke sub-types and functional outcomes related to stroke. The patients were enrolled for five-years and will be followed up for five-years. RESULTS A total of 1578 eligible patients (age: 66·2 years, men: 68·8%), including 64·2% with lacunar infarction, 25·4% with atherothrombotic infarction, and 10·4% with infarction of undetermined etiology were included in this study. Lipid levels were generally well controlled (total cholesterol: 210·0 mg/dl, low density lipoprotein cholesterol: 129·5 mg/dl) at baseline. In addition, the disability of patients was relatively mild, and cognitive function was preserved in the majority of patients. CONCLUSION This article reports the rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke. Follow-ups of patients are in progress and will end in 2014.
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Change in carotid intima-media thickness in a high-risk group of patients by intensive lipid-lowering therapy with rosuvastatin: subanalysis of the JART study.
Yokoi, H, Nohara, R, Daida, H, Hata, M, Kaku, K, Kawamori, R, Kishimoto, J, Kurabayashi, M, Masuda, I, Sakuma, I, et al
International heart journal. 2014;(2):146-52
Abstract
Carotid intima-media thickness (IMT), a measure of atherosclerosis, is modulated by multiple risk factors. Accordingly, comprehensive control of risk factors is indispensable for management of atherosclerosis. In this study, as a posthoc analysis of the JART Study we planned two analyses. In the main analysis, we evaluated the effect of intensive lipid-lowering therapy with rosuvastatin on carotid IMT in high-risk patients. We also evaluated efficacy in the presence or absence of each risk factor using the full analysis population in the JART Study. Patients with low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL and max-IMT ≥ 1.1 mm were randomized to rosuvastatin or pravastatin therapy for 12 months. Dosages were allowed to increase to 10 mg/day and 20 mg/day to achieve LDL-goals (aggressive goals for rosuvastatin group and guideline goals for pravastatin group). For the main analysis, we assessed 200 high-risk patients (105 in the rosuvastatin group), as category III or secondary prevention according to the Japan Atherosclerosis Society guideline 2007, whereas we assessed 289 patients in the other analysis. Rosuvastatin significantly slowed the percentage change in mean-IMT at 12 months compared with pravastatin (1.40 ± 10.03% versus 6.43 ± 13.77%, P = 0.005). LDL-C was reduced by 48.1% in the rosuvastatin group and 27.9% in the pravastatin group. The rate of achieving the LDL-C goal was significantly greater in the rosuvastatin group compared with the pravastatin group (P < 0.001). Rosuvastatin slowed the change in mean-IMT in the presence of every risk factor. Thus, intensive lipid-lowering therapy reduced progression of carotid IMT in high-risk patients.
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Pravastatin and cardiovascular outcomes stratified by baseline eGFR in the lipid- lowering component of ALLHAT.
Rahman, M, Baimbridge, C, Davis, BR, Barzilay, JI, Basile, JN, Henriquez, MA, Huml, A, Kopyt, N, Louis, GT, Pressel, SL, et al
Clinical nephrology. 2013;(4):235-48
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BACKGROUND/AIMS: The role of statins in preventing cardiovascular outcomes in patients with chronic kidney disease (CKD) is unclear. This paper compares cardiovascular outcomes with pravastatin vs. usual care, stratified by baseline estimated glomerular filtration rate (eGFR). METHODS Post-hoc analyses of a prospective randomized open-label clinical trial; 10,151 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) were randomized to pravastatin 40 mg/day or usual care. Mean follow-up was 4.8 years. RESULTS Through Year 6, total cholesterol declined in pravastatin (-20.7%) and usualcare groups (-11.2%). Use of statin therapy in the pravastatin group was 89.8% (Year 2) and 87.0% (Year 6). Usual-care group statin use increased from 8.2% (Year 2) to 23.5% (Year 6). By primary intention-to-treat analyses, no significant differences were seen between groups for coronary heart disease (CHD), total mortality or combined cardiovascular disease; findings were consistent across eGFR strata. In exploratory "as-treated" analyses (patients actually using pravastatin vs. not using), pravastatin therapy was associated with lower mortality (HR = 0.76 (0.68 - 0.85), p<0.001) and lover CHD (HR=0.84 (0.73-0.97), p=0.01), but not combined cardiovascular disease (HR=0.95 (0.88-1.04), p=0.30). Total cholesterol reduction of 10 mg/dl from baseline to Year 2 was associated with 5% lower CHD risk. CONCLUSIONS In hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing total mortality or CHD independent of baseline eGFR level. However, exploratory "as-treated" analyses suggest improved mortality and CHD risk in participants using pravastatin, and decreased CHD events associated with achieved reduction in total cholesterol. Potential benefit from statin therapy may depend on degree of reduction achieved in total and LDL-cholesterol and adherence to therapy.