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By U. Rasarus. Frostburg State University. 2019.

Chest radiography (exclusion of a pulmonary KS) Treatment If KS is newly diagnosed in an HIV+ patient naïve to antiretroviral therapy buy discount aricept 10 mg line, ART should be initiated: in early KS aricept 10mg on line, additional chemotherapy is only required in 20% of cases (Bower 2009) cheap aricept 5 mg with mastercard. In patients on ART without complete suppression of HIV plasma viremia, ART should be optimized. With decreasing HIV plasma viremia and immune 414 AIDS reconstitution, many KS lesions stabilize or even resolve completely without any specific treatment. Among 213 ART-naïve patients with early KS stages who were treated with ART alone, overall survival at five years was 95%, while progression-free survival was 77% (Bower 2014). In one Italian study in 22 ART-naïve KS patients, the overall clinical response rate to ART alone was 91%: 18 complete and 2 partial responses were achieved, and only two patients experienced disease progression. Complete remission was sustained in all 18 patients with complete response (Cattelan 2005). Animal and in vitro experiments have suggested a direct anti-proliferative effect of PIs (Sgadari 2002, Gantt 2011). There is some evidence that PIs may reduce oral shedding of HHV-8 (Gantt 2014) and that KS incidence is reduced with longer PI use (Kowalkowski 2015). However, there is no ART combination of choice for KS patients. PIs are not required necessarily as NNRTI-based regimens are also effective with regard to KS regression (Grabar 2006, Martinez 2006). With ART, there is also an improvement of the humoral response against HHV-8 (Sullivan 2010) and HHV-8 viremia rapidly decreases (Cattamanchi 2011). ART inter- ruptions should be avoided in patients with current or previous KS. In the SMART study, KS was among the most frequent AIDS-defining illnesses during treatment interruptions, in particular among patients with a history of KS (Silverberg 2007). ART as the only therapy is not recommended in all cases. In patients with rapidly progressive disease (especially in the setting of IRIS), with KS-related symptoms, or with visceral disease or lymphoedema, ART should be combined with cytotoxic chemotherapy (Grabar 2006). There are different options: Chemotherapy: Pegylated liposomal doxorubicin hydrochloride (Caelyx or Doxil) at a dosage of 20 mg/m² body surface is the treatment of choice (Di Trolio 2006). With Caelyx complete remission rates of up to 80% are possible (Lichterfeld 2005). Usually 6-8 cycles are required to achieve a good clinical response. Relapses during Caelyx therapy occur rarely and particularly during the first year (Martin-Carbonero 2008). During treat- ment, myelotoxicity and cardiotoxicity of doxorubicin should be considered. Although the latter is rare and occurs only above cumulative doses of 450 mg, echocardiography (ejection fraction? Another important side effect of Caelyx is palmo- plantar erythrodysesthesia (PPE, “hand-foot-syndrome”), which becomes apparent as painful erythemas at hands and feet (Lorusso 2007). In August 2011, Janssen-Cilag reported a shortage of Caelyx (Doxil) due to pro- duction delays at a contract manufacturer. Intermittent capacity constraints were seen during the following months. In the setting of this shortage, liposomal daunoru- bicine (DaunoXome) is an alternative. However, DaunoXome appears to be less effective than Caelyx (Cooley 2007). Of note, non-liposomal and non-pegylated forms of doxorubicin are not bioequivalent. Beside doxorubicin and daunorubicin, paclitaxel (Taxol) is also effective in KS (Tulpule 2002, Dhillon 2005, Stebbing 2006, Cianfrocca 2010). However, paclitaxel is more myelotoxic and leads almost always to complete alopecia, often during the very first cycle (patients must be informed! Paclitaxel should be used only if KS lesions show progression during therapy with Caelyx or when Caelyx or DaunoXome are not available. Docetaxel (Taxotere) is also effective according to uncontrolled studies (Autier 2005, Lim 2005). It should be mentioned that signifi- cant interactions may exist between the taxanes and ART. Paclitaxel levels may increase significantly when combined with PIs (Bundow 2004, Cianfrocca 2011). Kaposi’s Sarcoma 415 For the treatment cases refractory to doxorubicin, beside taxanes, oral etoposide (Evans 2002), irinotecan (Vaccher 2005) and the ABV regimen, a combination of adriamycin, bleomycine and vincristine, may be considered. According to a retro- spective study from Kenya, even gemcitabine has promising activity in KS (Strother 2010). Immunotherapy: With interferons (IFN) acceptable remission rates are reached. However, CR rates seem to be lower than with pegylated liposomal doxorubicin (Kreuter 2005). The effect mechanism of IFN on KS is not fully clarified. Apart from an immune modulating effect, IFN probably induces the apoptosis in KS cells. It is important to note that the effectiveness depends on the immune status. In patients with more than 400 CD4 T cells/µl, remission rates during IFN are at least 45%, com- pared with only 7% in patients with less than 200 CD4 T cells/µl. There may be other factors to predict response to IFN such as endogenous IFN levels, which are increased in the advanced stages of HIV infection. Table 1: Specific therapies for KS when ART is not sufficient Therapy Dosage Comments Pegylated liposomal 20 mg/m2 IV Treatment of choice, beware of myelotoxicity, doxorubicine every 2 weeks cardiotoxicity, hand-foot syndrome (Caelyx™ or Doxil™) Liposomal 40 mg/m2 IV Slightly less effective than Caelyx™, daunorubicin every 2–3 weeks seldom used during the past decade. SC or IM Considerable side effects, less efficacy than (Roferon™) 3x/week with doxorubicin. Use only when CD4 T cells are >200/μl and limited disease Pegylated 50 μg SC weekly Tolerability improved compared to Interferon- 2b conventional IFN- (2a,b), but lack of data in (PegIntron™) AIDS KS, off-label use!

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Clinically sufficient window of time to confirm PCR positivity in an indepen- relevant threshold transcript levels were defined order aricept 5mg mastercard, with studies dent sample and to initiate preemptive therapy to prevent progres- consistently showing that relapse can be predicted by persistently sion to frank relapse with its associated risk of fatal bleeding safe aricept 10mg. MRD monitoring to guide early intervention has been shown to reduce the risk of induction of hyperleukocytosis and the associated NPM1 mutant AML buy aricept 10 mg without a prescription. Frameshift mutations in exon 12 of the differentiation syndrome as compared with treatment in the context NPM1 gene are found in approximately one-third of AML cases, of frank relapse. Mutation-specific prim- been recommended in the National Comprehensive Cancer Network ers can be readily designed to allow MRD detection in AML guidelines to inform treatment approach. The NPM1 mutant transcript is typically highly treated in clinical trials, particularly those including ATO as expressed in diagnostic AML samples, affording sensitivities typi- frontline therapy, the value of routine sequential monitoring for cally higher (median 1 in 105) than observed with RT-qPCR assays PML-RARA transcripts beyond the postconsolidation time point has for other molecular subtypes of AML, with RNA-based assays been increasingly questioned. In APL (presenting WBC 10 109/L) who rapidly achieve molecu- accordance with the findings in CBF leukemia, RT-qPCR assess- lar remission, based on current evidence there appears to be limited ment of MRD can distinguish patients at markedly differing risk of benefit for sequential MRD monitoring beyond the end of treatment relapse based on response kinetics. On the other hand, there remains a predicted in individual patients based on persistent high level PCR case for stringent assessment of MRD in the subgroup of patients positivity after frontline therapy or by a rising NPM1 mutant presenting with high-risk disease (WBC 10 109/L), who have a transcript level after an initial molecular response (Figure 4D). The significant risk of relapse ( 25%) after conventional all-trans recent study by Shayegi and colleagues also highlighted the retinoic acid and anthracycline-based therapy and can benefit from potential of serial MRD monitoring to predict outcome after serial molecular monitoring to guide early salvage with ATO. Considering that a RUNX1-RUNX1T1 and CBFB-MYH11 detection in CBF significant proportion of AML cases lack an informative leukemia- leukemias. Established EAC RT-qPCR assays have also been specific target (ie, chimeric fusion gene, NPM1 mutation, Figure 3), evaluated in large cohorts of clinical trial patients with core-binding there has been interest as to whether WT1, which is overexpressed in Hematology 2014 227 228 American Society of Hematology the majority of AML cases, could provide a universal molecular of applicability and sensitivity in the substantial proportion of AML MRD marker. However, there has been inconsistency in the patients in whom MRD tracking is not feasible using an established literature concerning the utility of this approach to MRD assess- leukemia-specific RT-qPCR assay. This issue has been addressed by an ELN study that systematically evaluated 9 WT1 Defining the mutational landscape by high-throughput sequencing RT-qPCR assays, leading to selection of an assay that amplified a of AML genomes has broadened the scope of potential molecular region outside the mutational hot spots and exhibited the best methods for MRD detection. Although it is possible to design performance profile. Moreover, because of the marked level MRD from normal background. In contrast to leukemia- heterogeneity of mutations already described in AML, developing a specific markers (eg, PML-RARA, NPM1 mutation) in which BM catalog of standardized assays to cover every patient would be generally provides a more sensitive and reliable sample source for completely unrealistic. Therefore, several groups have started to MRD assessment (Figure 4D), in the case of WT1 PB is more explore the use of next-generation sequencing (NGS) technologies informative because of the much higher background level of as a further platform to detect MRD. To provide proof of principle, expression in normal marrow. Taking this into account, based on the Heuser and colleagues used targeted sequencing to successfully analysis of a large cohort of diagnostic AML samples (n 620), the detect FLT3-ITD and NPM1 mutations in remission samples and to track the emergence of relapsing disease. Measurement of kinetics of WT1 response after approaches to enable detection of subclinical disease in subsets of induction therapy in informative patients can provide independent AML that are not informative for one of the established leukemia- prognostic information. Because this approach is scalable, ment, this platform seems unlikely to be widely adopted into routine with increasing read depth, it may be possible to achieve further clinical practice, particularly because flow cytometry (see previous improvements in sensitivity. However, there are several other sections) and, potentially, newer sequencing-based approaches (see technical issues that need to be taken into consideration in the the following section) are expected to be more informative in terms application of NGS for MRD detection, including background Figure 4. Development of leukemia-specific RT-qPCR assays to track treatment response is dependent upon molecular characterization of diagnostic material to determine the most appropriate assay, with MRD monitoring strategies informed by maximal achievable sensitivity, optimal sample type, and typical kinetics of disease relapse. For example, in 5% of acute promyelocytic leukemia cases, the standard EAC assays are not suitable because of occurrence of rarer breakpoints within the PML locus requiring design of patient-specific forward primers to be used in conjunction with the standard EAC probe and reverse primer (both located in RARA). This can be measured as the difference in the number of PCR cycles ( Ct) to detect fluorescence above background from amplification of the leukemic transcript and the control gene at the threshold (set at 0. The detection limit of PCR is taken as 40 cycles (equivalent to 1 copy), with 1-log being equivalent to 3. Assuming ABL amplification at cycle threshold (Ct) value of 24, the observed Ct value for amplification of the leukemic target in blasts at diagnosis indicates the maximal theoretical sensitivity for detection of MRD in that particular patient. The Ct value of the MRD target equating with a given level of sensitivity (10 1 to 10 5) is marked based on an ABL Ct value of 24. For example, MRD can be detected at a sensitivity of at least 1 in 104, where CtTarget-ABL is 2. Detection of MRD at a sensitivity of 1 in 105 is possible when the MRD target is more highly expressed than ABL, with a Ct of 1. Rn, normalized reporter signal (change in fluorescence intensity). Figure panel adapted from Freeman et al26 with permission. Examination of diagnostic BM samples from primary leukemia samples using standardized assays developed within the EAC program demonstrates marked variation in the level of leukemic transcripts both between and within different molecular subsets, which impacts on the sensitivity to detect MRD in any given patient (right panel). For example, in APL, the median increment in PML-RARA fusion transcripts is 1-log/month. For PCR-negative samples, data points are plotted according to the maximal sensitivity afforded by the follow-up sample based on the respective level of ABL control gene expression and taking into account the difference in expression between the NPM1 mutant allele and ABL in leukemic cells at diagnosis ( CtNPM1mut-ABL), as described in panel B. In this patient, rapid PCR negativity was achieved in the PB. However, serial BM samples afforded greater sensitivity, revealing that the patient failed to achieve molecular remission after frontline therapy, with relapse preceded by a rapid rise in NPM1 mutant transcripts. The PB MRD assay only converted to PCR positivity at the time of diagnosis of clinical relapse. Proposal as to which platforms are now ready for “prime time” according to AML disease subtype and clinical context Timing of MRD assessment Sequential MRD Early risk monitoring (longitudinal Platform stratification postconsolidation) Applicability Comments Flow cytometry * † 90% Ready to be used for assessing CR status MRD analysis needs to be conducted in expert laboratories with standardization RT-qPCR Fusion genes/NPM1 mutation Marker-dependent * 32–62%‡ Standardized assays for leukemia-specific targets available and widely validated WT1 expression § † 45% Assays insensitive and not leukemia- specific, but can predict outcome Next-generation sequencing † † To be established Promising preliminary data Digital PCR † † To be established Potentially applicable to detect mutations and fusion genes *Validatedinlargestudieswithinclinicaltrials. Moreover, considering the Digital PCR is another highly promising approach to detect limited sensitivity of conventional chimerism testing and the dismal mutations that merits further investigation. This involves partition- outcome of frank relapse after allogeneic transplantation, there ing of sample DNA within the PCR mixture using droplet genera- could be significant benefits to more widespread uptake of MRD tion or nanofluidic chips depending on the platform, allowing many surveillance posttransplant to identify residual disease at an early individual PCRs to be conducted in parallel. The fluorescent the question, what is the “best” method? However, given the readout of each well/droplet is measured individually, allowing heterogeneity of AML in terms of mutational and immunopheno- precise calculation of the percentage of mutant allele copies in the typic profile, a “one size fits all” approach (eg, as used in chronic original sample. This methodology is capable of achieving sensitivi- myeloid leukemia) is completely unrealistic, with the most appropri- ties comparable to quantitative PCR, with enhanced capability to ate assay depending upon the characteristics of the leukemia and distinguish single base mutations from normal background se- clinical circumstances (Table 1). MFC-MRD and genomic DNA-based assays (qPCR, NGS, ized RT-qPCR assays in chronic myeloid leukemia. Unlike RT-qPCR, flow Discussions with respect to MRD assessment in AML often seem cytometric assays have not been validated for tracking reemergence polarized, with questions raised as to whether the information of leukemia posttherapy. There is, however, some evidence that this provided (1) adds anything to what is already known about a is feasible, particularly if the flow cytometric approach takes into patient’s prognosis based on conventional risk factors, increasingly account the immunophenotypic changes that result from the evolu- complemented by molecular profiling data; and (2) can realistically tion of resistant clones from heterogeneous leukemia popula- tions. These aspects are being leukemic transcript expression and therefore provide an estimate investigated in the UK National Cancer Research Institute AML17/ rather than a direct measure of the burden of residual leukemia.

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However order 10 mg aricept overnight delivery, the group randomized to standard tablets had statistically significantly higher rates of complete emesis control (0 episodes and no rescue medications over 3 days cheap aricept 5mg without a prescription, 72% compared with 52% generic aricept 10 mg line, respectively, P=0. This study was small (N=134), however, and may suffer from recall bias. The main method of recording the number of episodes of emesis or nausea was patient interview after 3 days. Patients were also given diaries to record these episodes, but only 44% completed the diaries. Using only data from completed diaries, the proportion of patients who had complete response was similar Antiemetics Page 28 of 136 Final Report Update 1 Drug Effectiveness Review Project between groups, and the difference was no longer statistically significant (65% with standard tablets and 54. Placebo-controlled and active-control trials Head-to-head trials lacked good evidence for quality-of-life and functional capacity outcomes. Numerous placebo-controlled and active-control trials were reviewed to address these gaps, but none were found that reported functional capacity outcomes in patients undergoing chemotherapy. Quality of life Five fair-quality active-control trials of ondansetron reported the effects of antiemetic treatment on quality of life in women undergoing moderately to severely emetic chemotherapy (Table 7 77-81 and Evidence Tables 5 and 6). However, these trials do not provide any information regarding the indirect comparative efficacy of 5-HT3 antagonists. Ondansetron was found to be associated with higher quality of life than alizapride (not available in the United States) but not prochlorperazine, and the quality of life associated with ondansetron compared with 77, 78, 80 metoclopramide is less clear. Quality-of-life outcomes in active-control trials of ondansetron Ondansetron Hesketh QOL Trial dose Comparator Cancer type Scale Results Bhatia 2004 Metoclopramide 4-5 8 mg IV Rotterdam No differences (N=80) 20 mg IV Head/neck Lachaine 21 mg (route Metoclopramide 4 EORTC 1999 No differences unclear) 306 mg Breast QLQ-C30 (N=52) O superior on Soukop Metoclopramide 3 or higher psychological 1992 8 mg IV Rotterdam 60 mg IV Breast subscale across 6 (N=187) courses Prochlorperazine Crucitt 1996 16 mg po (8 mg 4 20 mg po (10 mg FLIE No differences (N=57) bid) Breast bid) Day 1: Alizapride Clavel 1995 All days: 8 mg 150 mg IV (50 4 FLIE O superior (N=254) po (tablet) bid mg po bid after Breast day 1) Abbreviations: bid, twice daily; EORTC, European Organization for Research and Treatment of Cancer; FLIE, Functional Living Index-Emesis; IV, intravenous; O, ondansetron; po, by mouth, orally; QLQ-C30, Quality of Life Questionnaire (EORTC); QOL, quality of life. Children Direct comparisons 52, 82-86 Six head-to-head trials included children (Evidence Tables 1 and 2). One was poor quality due to a combination of flaws that indicate probable bias, including lack of blinding, unclear randomization and allocation concealment methods, uncertainty regarding between-groups balance of baseline characteristics, and analyses that excluded a proportion of the original patient Antiemetics Page 29 of 136 Final Report Update 1 Drug Effectiveness Review Project 83 population. A small study comparing intravenous ondansetron with oral disintegrating tablets 85 in children receiving any chemotherapeutic regimen was poor quality for multiple reasons. Randomization resulted in uneven groups, with 56 assigned to intravenous formulation and 39 assigned to oral disintegrating tablet. A smaller proportion of children received chemotherapy with a Hesketh score of 3 to 4 in the intravenous group than the oral disintegrating tablet group (58% compared with 76%). Granisetron compared with ondansetron Two trials comparing granisetron and ondansetron in children found no significant differences in 52, 82 82 efficacy outcomes. Evaluation of efficacy outcomes was based on patient days as the unit of measurement, rather than number of patients, and it is unknown whether the distribution of baseline patient characteristics remained balanced between groups in this type of analysis. Results were stratified by age and the subgroup analysis of 51 (26%) participants under age 18 (mean age not reported) is reported here. Granisetron and ondansetron, respectively, were associated with 0. Between-groups balance of baseline and prognostic factors is unknown because patient-related information was only provided for the group as a whole. Oral ondansetron syrup compared with intravenous ondansetron There were no significant differences in complete response between oral ondansetron syrup compared with intravenous ondansetron (78% compared with 81%) in younger children (mean age 8 years) undergoing moderately to highly emetogenic chemotherapy for various 84 malignancies. Children received loading doses of either oral ondansetron syrup 8 mg or 2 intravenous ondansetron 5 mg/m. Then, all patients then 4 mg of oral ondansetron syrup plus 2- 4 mg of oral dexamethasone every 6 to 8 hours for up to 8 days and 4 mg of oral ondansetron oral solution twice daily for the 2 days that followed cessation of the chemotherapy. Palonosetron compared with ondansetron 2 Intravenous palonosetron 0. Mean age of the children was 11 years and 69% were male. Rates of complete control were 92% for palonosetron and 72% for ondansetron (P=0. There was no significant difference between palonosetron and ondansetron in rate of complete control on days 4 to 7. At baseline there was a significantly greater proportion of undernourished children in the palonosetron group (20% compared with 8%, P=0. Consequently, risk of emetic events in the palonosetron group may have been greater at baseline. Yet despite this imbalance, the palonosetron group had better control of emetic events. If the groups initially were more balanced, the advantage of Antiemetics Page 30 of 136 Final Report Update 1 Drug Effectiveness Review Project palonosetron might have been even greater. However, randomization resulting in uneven groups is indicative of a flawed randomization process, which could bias result in unknown ways. Therefore, we suggest that these results be interpreted with caution. Prevention of nausea and vomiting associated with radiation therapy Adults Direct comparisons No study evaluated the direct comparative efficacy of newer antiemetics in adults undergoing radiation therapy. One small study evaluated both oral granisetron 2 mg (N=18) and oral ondansetron 8 mg (N=15), but only as each compared with a historical control group who did not 87 receive any 5-HT3 antagonists (N=90). Significantly more patients in the granisetron and ondansetron groups had complete control compared to the historical control group (27. Based on our analyses using the Fisher’s exact test (StatsDirect software), direct comparison of complete control rates for granisetron and ondansetron did not find a significant difference between the 5-HT3 antagonists. Placebo-controlled and active-control trials We identified a number of placebo-controlled and active-control trials of dolasetron, granisetron, 2, 88-97 95 and ondansetron (Evidence Tables 7 and 8). Four of the trials of granisetron and 89-91 ondansetron, plus 1 incompletely published trial comparing ondansetron with 98 99 metoclopramide, were previously analyzed in a good-quality systematic review. This review by Tramer et al (1998) made no indirect comparisons and noted that the evidence was limited by variability in underlying risk (wide ranges in placebo response rates), clinical setting, drugs compared, radiation therapy regimen, and endpoints. Conclusions were that (1) ondansetron is consistently efficacious in preventing acute vomiting after total body or upper abdominal 90, 98 irradiation (number needed to treat = 3); (2) limited evidence suggests that ondansetron is 90, 98 efficacious in preventing acute nausea; and (3) there was no difference between granisetron or ondansetron and any placebo or active control in delayed protection from vomiting or 90, 95, 98 nausea. Although our review adds identification of trials that have been published since the final 2, 88, 97 search date for the Tramer review (January 1997), earlier trials that were not in the Tramer 2, 88, 93, 94, 96, 97 review for unknown reasons, and a placebo-controlled trial of the oral disintegrating tablet form of ondansetron, we also were unable to make any indirect comparisons due to the variability described above. Children Head-to-head trials of newer antiemetics for prevention of radiation-associated nausea and vomiting in children were not found.

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How do statins and fixed-dose combination products containing a statin and another lipid lowering drug compare in their ability to raise high-density lipoprotein cholesterol? Are there doses for each statin or fixed-dose combination product containing a statin and another lipid lower drug that produce similar percent increase in high-density lipoprotein cholesterol between statins? How do statins and fixed-dose combination products containing a statin and another lipid lowering drug compare in their ability to reduce the risk of nonfatal myocardial infarction purchase aricept 5 mg with mastercard, coronary disease (angina) aricept 10mg mastercard, coronary heart disease mortality buy aricept 10mg line, all-cause mortality, stroke, hospitalization for unstable angina, or need for revascularization (coronary artery bypass graft, angioplasty, or stenting)? Are there differences in effectiveness of statins and fixed-dose combination products containing a statin and another lipid lowering drug in different demographic groups or in patients with comorbid conditions (e. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid lowering drug when used in the general population of children?. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid lowering drug when used in special populations or with other medications (drug-drug interactions)? Percent reduction in low-density lipoprotein cholesterol with statins....................................... Doses of statins that result in similar percent reductions in low-density lipoprotein a cholesterol............................................................................................................................................ Percent reduction in low-density lipoprotein cholesterol with fixed-dose combination products................................................................................................................................................. Achieving target low-density lipoprotein cholesterol goals...................................................... Achievement of National Cholesterol Education Program low-density lipoprotein cholesterol goals of fixed-dose combination products............................................................................................. Outpatient and community-based placebo-controlled trials of statins with coronary heart disease endpoints.................................................................................................................................. Placebo-controlled trials in patients with diabetes................................................................. Inpatient trials of acute myocardial infarction or unstable angina (statins compared with placebo or usual care)........................................................................................................................... Studies of atherosclerotic progression that reported coronary heart disease outcomes...... Low-density lipoprotein cholesterol lowering in placebo-controlled trials of statins in children with familial hypercholesterolemia......................................................................................................... High-density lipoprotein cholesterol increases in placebo-controlled trials of statins in children with familial hypercholesterolemia......................................................................................................... Black box warnings for US Food and Drug Administration-approved drugs................... We also thank Trish Thieda, MA and Miranda Walker, MA for assistance with data abstraction and quality assessment of studies, and Theresa Nguyen for retrieval of articles and assistance with editing and formatting. Suggested citation for this report Smith MEB, Lee NJ, Haney E, Carson S. Drug class review: HMG-CoA reductase inhibitors (statins). These organizations selected the topic of the report and had input into its Key Questions. The content and conclusions of the report were entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Statins Page 6 of 128 Final Report Update 5 Drug Effectiveness Review Project INTRODUCTION In the United States, coronary heart disease and cardiovascular disease account for nearly 40% of all deaths each year. Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity among North Americans. In 2006, coronary heart disease claimed 1 607 000 lives, translating into about 1 out of every 5 deaths in the United States. High levels of cholesterol, or hypercholesterolemia, are an important risk factor for coronary heart disease. The 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, also known as statins, are the most effective class of drugs for lowering serum low-density lipoprotein cholesterol concentrations. They are first-line agents for patients who require drug therapy to reduce serum low-density lipoprotein cholesterol concentrations. Statins work by blocking the enzyme HMG-CoA reductase, the rate-limiting step in the manufacture of cholesterol. Statins reduce low-density lipoprotein cholesterol, total cholesterol, and triglycerides and slightly increase high-density lipoprotein cholesterol. Statins may also have 2 anti-inflammatory and other pleiotroptic effects. A recent good-quality systematic review found that all statins are equally effective at lowering C-reactive protein levels, but do not affect 3 fibrinogen or several other markers of inflammation. The third report of the Expert Panel on Detection, Evaluation, and Treatment of High 4 Blood Cholesterol in Adults (Adult Treatment Panel III) was released in September 2002 and 5 updated in August 2004 to include evidence from more recent trials. The report stressed that the intensity of treatment should be directed by the degree of cardiovascular risk. Target low-density lipoprotein cholesterol levels depend on the patient’s risk of heart disease, medical history, and initial low-density lipoprotein cholesterol level. For most patients who are prescribed a statin, the target will be less than 130 mg/dL or less than 100 mg/dL. In the Adult Treatment Panel III, patients who have type 2 diabetes without coronary heart disease, peripheral or carotid vascular disease, and patients who have multiple risk factors and a 10-year risk of coronary heart disease of greater than 20% are said to have “coronary heart disease equivalents. A low-density lipoprotein cholesterol goal of less than 70 mg/dL for high-risk patients is a therapeutic option. Factors that place patients in the category of very high risk favor a decision to reduce low-density lipoprotein cholesterol levels to less than 70 mg/dL. These factors are the presence of established cardiovascular disease plus (1) multiple major risk factors (especially diabetes), (2) severe and poorly controlled risk factors (especially continued cigarette smoking), (3) multiple risk factors of the metabolic syndrome (triglycerides greater than 200 mg/dL plus non-high-density lipoprotein cholesterol greater than 130 mg/dL with low high-density lipoprotein cholesterol [less than 40 mg/dL]), and (4) patients with acute coronary syndromes. The optional goal of less than 70 mg/dL does not apply to individuals who are not high risk. The 2006 update of the American Heart Association/American College of Cardiology consensus statement on secondary prevention states, “…low-density lipoprotein cholesterol (LDL-C) should be less than 100 mg/dL for all patients with coronary heart disease and other clinical forms of atherosclerotic disease, but in addition, it is reasonable to treat to LDL-C less than 70 mg/dL in such patients. Furthermore, if it is not possible to attain low-density lipoprotein cholesterol <70 mg/dL because of a high baseline low-density lipoprotein cholesterol, it generally is possible to achieve low-density lipoprotein cholesterol reductions of >50% with either statins or low-density lipoprotein cholesterol–lowering drug combinations. Moreover, this guideline for patients with atherosclerotic disease does not modify the recommendations of the 2004 Adult Treatment Panel III update for patients without atherosclerotic disease who have diabetes or multiple risk factors and a 10-year risk level for coronary heart disease >20%. In the latter 2 types of high-risk patients, the recommended low- density lipoprotein cholesterol goal of <100 mg/dL has not changed.