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The cumulative incidence risk of SPMs was greater for the UK) in the MRC IX MM trial purchase vardenafil online from canada. The due to an anti-MM effect of bisphosphonates vardenafil 20 mg visa, but an exact cumulative incidence risk of progressive disease (P vardenafil 10mg without prescription. All patients benefited from lenalidomide maintenance Lenalidomide maintenance after autologous HSCT has been re- regardless of remission status or prior exposure to thalidomide or ported in 3 studies (Table 4), all of which showed a PFS or time to lenalidomide during induction. Lenalidomide maintenance after autologous HSCT Study N Initial dose, mg Maintenance versus no maintenance Benefit EFS/OS McCarthy et al55 460 10 EFS or PFS or TTP: 46 vs 27 mo OS at 34 mo median follow-up: / (P. Treatment recommendations for transplantation-eligible patients Induction* ASCT† Consolidation‡ Maintenance§ Standard-risk patients (RVD, VCD, VTD) Single (tandem) VTD, V (RVD, R) T, R, V, VT High-risk patients (RVD, VCD, VTD) Single (tandem) VTD, V (RVD, R) R, V (RVD) Recommendationsinparenthesesareintheabsenceofphase3comparativestudiesintheeraofnovelagents. RVD and VCD appear to generate deeper responses than 2-agent induction regimens. Early reports suggest that very recent regimens may generate even deeper responses, but this remains to be studied in phase 3 trials. Specific treatment recommendations: for renal failure patients: bortezomib and dexamethasone; for del(13), t(4;14)cytogenetic abnormality: bortezomib-containing regimens. GEP-70 positive, del(17p), del(1p), 1q, and plasma cell leukemia patients are very high risk and are candidates for trials examining novel agents or allogeneic HSCT in younger patients. VTinonestudyimprovedPFS but not in high-risk disease. Two years of bortezomib maintenance was not significantly different from thalidomide in standard-risk disease. Lenalidomide maintenance until progression improved PFS in standard-risk patients. Lenalidomide and bortezomib have been shown to improve outcome in some patients with high-risk disease and in all respondingpatients(inCRandnotinCR). Very-high-risk patients with plasma cell leukemia; t(14;16), del(17p), del(1p), and 1q cytogenetic abnormalities; or GEP 70 positivity: RVD in maintenance doses should be consideredforthesepatientsbecausetheydonotdowellwithsingle-agentmaintenance. Patients with very-high-risk features such as tenance had improved TTP. A new analysis was conducted and del(17p) may be considered for up-front investigational approaches presented at the International Myeloma Workshop (IMW) in the to long-term disease control. The TTP, PFS, and OS benefit were still present on an intent-to-treat analysis despite the crossover by the majority of 56 Induction the placebo arm patients. The IFM 05-02 trial randomized 605 MM patients to lenalidomide 10 mg daily (dose range, 5-15 mg) There have been no phase 3 studies that have compared newer versus placebo until progression after single (79%) or tandem induction regimens including RVD, VCD, and VTD. Based on autologous HSCT (21%) and a 2-cycle consolidation with lenalido- phase 2 results, RVD, VCD, and possibly VTD appear to generate mide for all patients before randomization. The induction regimens deeper responses than 2-drug regimens such as VD or RD/Rd. Approximately Therefore, a 3-drug regimen is recommended for induction therapy. Replacing IV dexamethasone, cyclophosphamide, etoposide, and cisplatin. The administration of bortezomib with subcutaneous bortezomib as part median PFS was 41 months for the lenalidomide arm and 23 months of induction therapy has been shown to decrease neuropathy without any impact on outcomes. The 4-year PFSs was 43% for the lenalidomide arm and 22% for the placebo arm (P. The OS response, followed by autologous PBSC collection. The Up-front autologous HSCT is recommended because there is a PFS study was unblinded at 22 months before the above analysis, and benefit for early transplantation based on one phase 3 study. Placebo arm patients did not HSCT would be detrimental, and autologous HSCT after first cross over to lenalidomide maintenance at unblinding. There was an disease progression is another treatment option. A single autologous increased incidence of SPMs in the lenalidomide arm compared HSCT is recommended, although patients achieving less than a with placebo (4. Lenalidomide maintenance was found to benefit therapy or a second transplantation to deepen response. Two all patient subclassifications, including cytogenetic risk and remis- ongoing trials will help to update and refine the evidence for sion status, in the IFM 05-02 study. The third lenalidomide up-front versus delayed autologous HSCT and help to determine maintenance study of 402 patients has been reported in abstract which patient populations should proceed to autologous HSCT and form and, in addition to comparing maintenance versus no mainte- 33 which patient populations can defer transplantation. The Dana nance, compared chemotherapy versus tandem autologous HSCT. Farber Cancer Institute trial in conjunction with the IFM will The median PFS was 37. The IFM group has completed accrual from diagnosis was 76% for maintenance and 68% for no mainte- nance (P. The 81% for maintenance and 72% for no maintenance, respectively U. There was no difference in SPM rates between the This will provide an indirect comparison of the effect of 1-year maintenance and no maintenance arms. The European Myeloma Network (EMN) will examine the role of chemotherapy versus single versus tandem autologous HSCT. In all Table 557 lists current treatment recommendations for MM. Risk arms, the maintenance of lenalidomide 3 weeks per month is given stratification at diagnosis will help with selecting treatment and until progression. Other strategies are ongoing to incorporate vaccina- autologous HSCT. It tion against MM antigens, along with immunomodulatory agents remains to be determined whether RVD consolidation will improve such as IMiDs or the anti-PD-1 antibody. The incorporation of new outcome after single autologous HSCT. The BMT-CTN 0702 is a agents into the treatment of MM patients should lead to further phase 3 study examining a single autologous HSCT followed by a prolongation of response and long-term control of the disease. All 3 arms are followed by 3 years of lenalidomide Disclosures maintenance therapy. The and has received honoraria from Celgene and Janssen. Off-label drug use: thalidomide, after chemotherapy and single or tandem transplantation. McCarthy, Roswell Park Cancer Institute, BMT Program, are recommended as the primary agents to be considered for Department of Medicine, Buffalo, NY 14263; Phone: 716-845-4074; long-term maintenance. Bortezomib may be considered for 2 years Fax: 716-845-3272; e-mail: philip. There has been no demonstrated increase in SPMs with 1. Lenalidomide maintenance until disease cation of monoclonal gammopathies, multiple myeloma and progression was shown to improve PFS and OS in the CALGB related disorders: a report of the International Myeloma Work- 100104 study, especially in patients receiving lenalidomide-based ing Group.

Hepatotoxicity has not been reported for donepezil generic vardenafil 10mg on-line, galantamine buy vardenafil 20mg overnight delivery, rivastigmine generic vardenafil 20mg on line, or memantine. Gastrointestinal adverse events and loss of body weight ChEI trials commonly reported nausea and vomiting by more than 10% of patients (and as many as 50% of patients) randomized to active treatment. In the only memantine trial the incidence of nausea and vomiting did not differ between the active drug and placebo. Nausea, vomiting, and diarrhea are thought to reflect excessive activation of intestinal muscarinic cholinergic receptors and tend to be dose related. Anorexia and loss of body weight are associated gastrointestinal adverse events. We did not find any trials directly comparing the incidence of gastrointestinal adverse events among ChEIs and memantine. The odds of having nausea or vomiting with rivastigmine compared to placebo (OR 5. The higher incidence of gastrointestinal events may be related to the significant loss of body weight commonly reported for donepezil-, galantamine-, and rivastigmine-treated patients. Pooled analysis suggests a 2- to 4-fold increase in the risk of anorexia for active treatment compared to placebo. Although tacrine was not included in this analysis, relative trends in gastrointestinal adverse events and loss of body weight reported in tacrine trials 58, 67-69 are consistent with those seen in donepezil, galantamine, and rivastigmine trials. Similarly, the relative proportions of patients who experienced vomiting were 5%, 21% and 28%, respectively; diarrhea occurred in 10%, 16% and 16%, respectively. Data from the Réseau sur la Maladie d’Alzheimer Francais (REAL. FR) cohort was used to assess the risk 83 of weight loss with AChEI. This long-term observational study found the risk of clinically significant weight loss to be similar for Alzheimer’s patients taking AChEIs and patients not taking these drugs (21. However, we excluded this study for reasons of quality because we were unable to assess the similarity or differences between the two populations, and little information was provided with regard to the type, intensity, or duration of drug treatment. Cardiovascular adverse events Bradycardia and subsequent dizziness or syncope originates from central and peripheral muscarinic cholinergic stimulation. Cardiovascular adverse events can lead to falls and other types of injury-causing accidents. We did not find any trials directly comparing the incidence of cardiovascular adverse events among ChEIs and memantine. Cardiovascular adverse events may be of particular concern in patients with cardiac conduction disorders or a sick sinus syndrome. One head-to-head study reports no statistically significant differences in 28 changes of heart rates between donepezil and galantamine. Two open-label comparative trials reported 28 29 no difference in cardiovascular events between donepezil and galantamine and rivastigmine. Most placebo-controlled trials revealed no other significant differences in cardiovascular events, vital signs, or electrocardiogram (ECG) findings. One trial described a statistically significantly larger reduction of heart 43 rate in patients treated with donepezil than in those given placebo. However, the incidence of bradycardia (heart rate < 50 beats per minute) was not significantly different among treatment groups. An analysis of prescription-event monitoring (n = 1,762) in general practice in the UK did not find evidence 84 for cardiac arrhythmias with donepezil treatment. One pooled data-analysis of RCTs including 2,791 patients evaluated ECG results from four clinical trials 85 of rivastigmine; rivastigmine had no apparent effect on heart rate. However, patients with underlying ECG abnormalities did not meet eligibility criteria of the RCTs. Summary of the evidence The overall grade of the evidence on comparative tolerability is poor to fair. Evidence of the comparative incidence of adverse events and tolerability comes from three open-label trials comparing donepezil with 27 28 galantamine and rivastigmine. One 52-week trial and one 12-week trial compared donepezil to galantamine. Although the number of adverse events and loss to follow-up differed between trials, withdrawals and withdrawals because of adverse events were not significantly different in the 52-week trial and only minor differences favoring donepezil were observed in the 12-week trial. In one trial that 29 compared donepezil to rivastigmine, total withdrawals and withdrawals because of adverse events were significantly greater among rivastigmine-treated patients. Gastrointestinal-related events were most commonly reported among rivastigmine-treated patients. Indirect comparison of the pooled mean incidence of adverse events from placebo-controlled trials also suggests a higher rate of gastrointestinal- related events among rivastigmine-treated patients. However, this comparison is limited by the tremendous variability observed among placebo-controlled evidence. Evidence of hepatotoxicity and cardiovascular events comes from comparative trials, meta-analyses, and indirect comparison of placebo controlled evidence. Evidence from one meta-analysis and four placebo- 67, 80 controlled trials indicate substantially higher rates of hepatotoxicity for tacrine. Donepezil, galantamine, rivastigmine, and memantine did not present hepatotoxic effects in placebo controlled trials. Two open-label comparative trials reported no difference in cardiovascular events between donepezil and 28 29 galantamine and rivastigmine. Placebo-controlled trials revealed no other significant differences in cardiovascular events. Age We did not identify any study specifically designed to compare the effect of donepezil, galantamine, rivastigmine, tacrine, or memantine in a younger versus an older population. We did find age-related information in two sources: one subgroup analysis of rivastigmine-treated 35 patients and a placebo-controlled donepezil trial conducted in a population of nursing home residents 47 who were, on average, older than the typical population for donepezil studies. The subgroup analysis pooled data from four rivastigmine trials and reported an age-related treatment effect. Patients 75 years and older revealed a greater benefit of rivastigmine than did patients younger than 75 years; 15% of 35 older patients and 6% of younger patients were considered responders on the ADAS-cog. Overall, no difference in efficacy or adverse events was apparent in the data on the older population compared to data from the trials in younger populations. Race We did not identify any study specifically designed to compare the effect of donepezil, galantamine, rivastigmine, tacrine, or memantine in one racial group compared to another. In general, trials were conducted predominantly in white populations. Treatment response did not differ across racial subgroups. Overall, effect sizes observed in these trials are similar to effect sizes reported in trials conducted predominantly in non-Asian populations.

Pharmacologic treatment of hypertensive disorders in pregnancy purchase discount vardenafil. Beta blockers Page 115 of 122 Final Report Update 4 Drug Effectiveness Review Project 355 discount vardenafil 10mg with amex. Riedinger MS buy vardenafil discount, Dracup KA, Brecht ML, Padilla G, Sarna L, Ganz PA. Quality of life in patients with heart failure: do gender differences exist? Atenolol and/or nifedipine in effort angina: which is the treatment of choice for exercise coronary protection? International Journal of Clinical Pharmacology, Therapy, & Toxicology. Influence of chronic beta-adrenoreceptor blocker treatment on melatonin secretion and sleep quality in patients with essential hypertension. Observations on the efficacy of propranolol for the prophylaxis of migraine. Sexual sequelae of antihypertensive drugs: treatment effects on self-report and physiological measures in middle-aged male hypertensives. Analysis of adverse effects among patients with essential hypertension receiving an ACE inhibitor or a beta-blocker. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Unstable angina pectoris: National cooperative study group to compare surgical and medical therapy. In-hospital experience and initial follow-up results in patients with one, two and three vessel disease. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Calcium channel blockers or beta receptor antagonists for patients with ischaemic heart disease. Angiotensin converting enzyme inhibition and quality of life: A randomized controlled trial. Current Therapeutic Research, Clinical & Experimental. Intravenous streptokinase in the management of a subset of patients with unstable angina: a randomized controlled trial. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. Evaluation of endoscopic variceal ligation (EVL) versus propanolol plus isosorbide mononitrate/nadolol (ISMN) in the prevention of variceal rebleeding: comparison of cirrhotic and noncirrhotic patients. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Transient asymptomatic S-T segment depression during daily activity. Beta blockers Page 116 of 122 Final Report Update 4 Drug Effectiveness Review Project 371. Hemodynamics and exercise tolerance after bisoprolol, nifedipine, and their combination in patients with angina pectoris. Equivalent blood pressure reduction and tolerability with controlled- release metoprolol 50 mg once daily and conventional metoprolol 50 mg twice daily. A double-blind 8-week comparison in hypertensive patients. Comparative effects of alinidine and propranolol in ischaemic heart disease. Comparison of metoprolol and sotalol in preventing ventricular tachyarrhythmias after the implantation of a cardioverter/defibrillator. Senior R, Muller-Beckmann B, DasGupta P, van der Does R, Lahiri A. Shapiro W, Narahara KA, Kostis JB, Thandroyen F, Zohman LR. Comparison of atenolol and nifedipine in chronic stable angina pectoris. A comparative trial of flunarizine and propranolol in the prevention of migraine. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. The Losartan Intervention for Endpoint Reduction (LIFE) trial-have angiotensin-receptor blockers come of age? Effect of gallopamil and propranolol in patients with coronary heart disease and moderately depressed left ventricular ejection fraction. The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11,942 elderly patients with heart failure. Treatment of silent ischemia in unstable angina: A randomized comparison of sustained-release verapamil versus metoprolol. Prophylactic effects of flunarizine versus metoprolol in migraine. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Therapeutic effectiveness of flunarizine and propranolol in the interval therapy of migraine. An open label, randomised, crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation. Beta blockers Page 117 of 122 Final Report Update 4 Drug Effectiveness Review Project 389. Effects of atenolol and diltiazem on exercise tolerance and ambulatory ischaemia. Management of patients with life-threatening sustained ventricular tachyarrhythmias - The role of guided antiarrhythmic drug therapy. Steiner SS, Friedhoff AJ, Wilson BL, Wecker JR, Santo JP. Antihypertensive therapy and quality of life: a comparison of atenolol, captopril, enalapril and propranolol. Short-term clinical trial of phopranolol in racemic form (Inderal), D-propranolol and placebo in migraine. Stephenson LW, MacVaugh HI, Tomasello DN, Josephson ME. Propranolol for prevention of postoperative cardiac arrhythmias: A randomized study. Relationships between self-efficacy and mood before and after exercise training. Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina.

Statins Page 117 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1 purchase 20 mg vardenafil overnight delivery. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Stalenhoef et al buy 10mg vardenafil free shipping. No clinically R buy vardenafil mastercard, DB, MC, not ITT LDL-c reduction from baseline at 18 weeks: significant increases in ALT/AST or CK. Most common treatment-related ADE was musculoskeletal complaints in 1994 LDL-c reduction from baseline at 6 weeks: simva group vs. No details on 3rd 281 patients randomized LDL-c reduction from baseline at 12 weeks: withdrawal. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Stalenhoef et al. R, DB, MC, not ITT 281 patients randomized 12 weeks Statins Page 119 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Sweany et al. Simva 207 mg/dl before baseline and treatment with immunosuppressive drugs. Doses doubled if LDL-c at weeks 6 and 12 were >130 mg/dl, up to a maximum of 40 mg qd for each statin. Misc Gratsianskii N, et al Men and postmenopausal women Recent ACS, receiving statins, and patients with evident systemic Series 1- control vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Sweany et al. Reasons in parva group: R, DB, MC, not ITT LDL-c reduction from baseline at 6 weeks: headache and tinnitus, rash, abdominal pain, GI complaints and dizziness. CK elevation in other HDL-c increase from baseline at 18 weeks: myalgia reports not clinically significant. Trigs reduction from baseline at 18 weeks: parva 14% Nonequivalent doses compared. Prava40 unknown, SC, not ITT (n=25) -23% (atorva10 and prava40 vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Sweany et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Rosuvastatin vs Atorvastatin Ballantyne C, et al 2006 Men and women aged z18 years; high Pregnancy or lactation; history of homozygous familial 6 week dietary lead in, then randomized to (MERCURY II) risk of CHD events; fasting LDL-C percholesterolemia or known hyperlipoproteinemia types I, III, rosuvastatin 20 mg, atorvastatin 10 mg, ≥130 yo<250 mg/dL; fasting TG <400 IV, or V; unstable arterial disease within 3 months of trial entry; atorvastatin 20 mg, simvastatin 20 mg, or RCT, OL, MC, AC, mg/dL uncontrolled hypertension; fasting serum glucose of >180 mg/dL; active simvastatin 40 mg for 8 weeks. Patients either 1993 patients liver disease or hepatic dysfunction; serum creatinine of >2. Further dose titrations up to rosuva 40 mg or aorta 40 mg or 80 mg were performed at weeks 8 and 12 if patients were still not at goal. Statins Page 123 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Ballantyne C, et al 2006 LDL-c change at 8 weeks First 8 weeks n (%) rosuva20 vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Ballantyne C, et al 2006 1 author from (MERCURY II) AstraZeneca RCT, OL, MC, AC, 1993 patients randomized (first 8 weeks rosuva20 = 392, atorva10 = 403, atorva20 = 395, simva20 = 402, simva40 = 401, second 8 weeks rosuva20 = 367, atorva10 = 185, atorva10 to rosuva10 191, atorva20 = 186, atorva20 to rosuva20 = 186, simva20 = 190, simva20 to rosuva10 = 183, simva40 = 191 simva 40 to rosuva20 = 189) Berne et al, Supported by 2005 AstraZeneca URANUS R, DB, MC, not ITT 469 patients randomized 16 weeks Statins Page 125 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Betterridge D, et al Men and non-pregnant women aged Type 1 diabetes; HbA 1c > 9. RCT, (2:1) OL, MC, ITT mg/dL] if LLT-naive or 120 mg/dL if unstable CVD (including unstable angina); active hepatic disease or switching; and triglycerides 400 hepatic dysfunction ; unexplained serum creatine kinase (CK) >3 x ULN; 1506 patients mg/dL)and a 10-year coronary heart women of childbearing age not using contraception, or pregnant or randomized disease (CHD) risk >20% or a history breastfeeding; and current treatment with medications not allowed during (n= rosuvastatin, 1002 of CHD or other established the study (lipid-modifying agents [e. Statins Page 126 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Betterridge D, et al LDL-c change from baseline at 8 weeks: Overall adverse events: 2007 (ANDROMEDA) rosuva -51. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Betterridge D, et al AstraZeneca 2007 (ANDROMEDA) RCT, DB, MC, AC, 509 patients randomized (mITT) (n=254(248) rosuva, 255(246) aorta) 16 weeks Binbrek A, et al 2006 AstraZeneca, (DISCOVERY-Alpha) RCT, (2:1) OL, MC, ITT 1506 patients randomized (n= rosuvastatin, 1002 patients; atorvastatin, 504 patients)) 12 weeks Statins Page 128 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Blasetto et al, 2003; Men and women age 18 or older with Patients were excluded if they had disorders or were taking other Rosuva 5 mg or 10 mg; aorta 10 mg; simva Shepherd et al, 2003 LDL-c ≥ 160 mg/dL and <250 mg/dL medications known to affect lipid values or to present a potential safety 20 mg; parva 20 mg R, DB, MC and triglyceride levels < 400 mg/dL concern 5 trials prospectively designed to allow Mean baseline LDL-c pooling 3 pooled trials of rosuva vs aorta: rosuva 5mg: 188 mg/dL 2153 patients rosuva 10mg: 185 mg/dL randomized (n=394 aorta 10mg: 187 mg/dL rosuva 5 mg, 392 rosuva 10 mg, 396 aorta 10 mg, 2 pooled trials of rosuva vs parva and 240 rosuva 5mg, 226 simva: rosuva 10 mg, 250 rosuva 5mg: 189 mg/dL simva 20 mg, 255 prava rosuva 10mg: 187 mg/dL 20 mg) simva 20mg: 188 mg/dL 12 weeks parva 20mg: 189 mg/dL Statins Page 129 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Blasetto et al, 2003; 3 pooled trials of rosuva vs aorta: No information on adverse events. Shepherd et al, 2003 LDL-C reduction from baseline at week 12: R, DB, MC rosuva 5mg: 41. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Blasetto et al, 2003; Supported by Shepherd et al, 2003 AstraZeneca R, DB, MC 5 trials prospectively designed to allow pooling 2153 patients randomized (n=394 rosuva 5 mg, 392 rosuva 10 mg, 396 aorta 10 mg, 240 rosuva 5mg, 226 rosuva 10 mg, 250 simva 20 mg, 255 prava 20 mg) 12 weeks Statins Page 131 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Bots A, et al, 2005 Aged 18 years with type IIa or type IIb Familial hypercholesterolemia or type III hyperlipoproteinemia, 12- week treatment with rosuvastatin 10 mg, (Dutch DISCOVERY) hypercholesterolemia and a 10-year secondary dyslipidemia (except diabetic dyslipidemia for patients with atorvastatin 10 mg, cardiovascular risk of >20% or a controlled diabetes), uncontrolled diabetes or hypertension, active liver simvastatin 20 mg or pravastatin 40 mg. RCT (3:1:1:1), DB, MC, history of CHD or other established disease or hepatic dysfunction, unstable CVD (including unstable AC, atherosclerotic disease, fasting LDL-C angina), history of hypersensitivity to other statins, unexplained serum 1215 patients of >3. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Bots A, et al, 2005 LDL-c change at 12 weeks: Rosuva vs. Statins Page 133 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Bots A, et al, 2005 AstraZeneca (Dutch DISCOVERY) RCT (3:1:1:1), DB, MC, AC, 1215 patients randomized (n=621 rosuva10, 189 atorva10, 194 simva20, 211 prava40 ) 16 weeks Statins Page 134 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Brown et al, 2002 Men and women ≥18 years with Active hepatic disease or dysfunction, active arterial disease within 3 6-week dietary run-in with NCEP Step 1 R, DB, MC, not ITT LDL-c ≥160 and <250 mg/dl, and months, <10-year history of malignancy (unless basal or squamous diet, then: triglyceride levels ≤400 mg/dL cell skin carcinoma), uncontrolled hypertension, history of rosuva 5 mg or 477 patients randomized ketoacidosis within 5 years, uncontrolled hypothyroidism, serum rosuva 10 mg or (n= 239 rosuva, 118 Mean baseline LDL-c creatine kinase (CK) concentration>3 times the upper limit of normal parva 20 mg or parva vs. Women of childbearing potential not using NCEP (ATP 2) targets or maximum dose of a reliable form of contraception or who were pregnant or lactating rosuva 80 mg, parva 40 mg or simva 80 were also excluded. Clearfield M, et al 2006 Men and women, 18 years or more, History of statin-induced myopathy or a serious hypersensitivity to 6 week dietary lead in then 6 weeks of RCT (PULSAR) hypercholesterolemia and either a statins; patients considered to be unstable after a myocardial infarction rosuva vs.. Statins Page 135 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Brown et al, 2002 Efficacy analysis for 472 patients. Withdrawals due to treatment-related adverse events:7 rosuva 5 mg, 7 rosuva R, DB, MC, not ITT LDL-c reduction at 12 weeks: 10 mg, 6 parva, 7 simva. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Brown et al, 2002 3 authors employed by R, DB, MC, not ITT AstraZeneca 477 patients randomized (n= 239 rosuva, 118 parva vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Davidson et al, 2002 Men and women age 18 and older Active arterial disease within 3 months of trial entry, familial 6-week dietary run-in with NCEP Step 1 R, DB, MC, PC. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Davidson et al, 2002 LDL-c reduction from baseline at week 12: Withdrawals due to adverse events: 4 (3. No serious rosuva 5 mg: 17% adverse event was considered by the investigators to be related to study drug. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Davidson et al, 2002 Supported by a grant R, DB, MC, PC.