By O. Gambal. Alverno College. 2019.
The British Guidelines (2010) recommend treatment initiation when HIV-2 plasma RNA is above 1 order 10 mg sarafem otc pregnancy portraits,000 copies/ml buy sarafem 10 mg on-line pregnancy clothes. The preferred first-line regimen is TDF+FTC plus lopinavir/r discount sarafem 20mg line womens health york pa, alternatives are AZT+3TC and darunavir/r (Gilleece 2010). There is an uncertainty whether all patients with HIV-2 infection showed receive ART, regardless of their immune status. This applies in particular to elite controllers that are seen in considerable proportions in this setting. Overall, clinical and immunologic and virologic outcomes in HIV-2 infected indi- viduals treated with ART are suboptimal. There is a need for controlled trials to improve the management and outcomes (Ekouevi 2014). HIV-2 Infection 519 References Andersson S, Norrgren H, da Silva Z, et al. Plasma viral load in HIV-1 and HIV-2 singly and dually infected indi- viduals in Guinea-Bissau, West Africa: significantly lower plasma virus set point in HIV-2 infection than in HIV-1 infection. Arch Intern Med 2000; 160: 3286–3293 Arvidson N, Gisslen M, Albert J, et al. Cerebrospinal fluid viral load, virus isolation, and intrathecal immuno- activation in HIV type 2 infection. AIDS Research and Human Retroviruses 2004; 20: 711–715 Benard A, van Sighem A, Taieb A, et al. Immunovirological response to triple nucleotide reverse-transcriptase inhibitors and ritonavir-boosted protease inhibitors in treatment-naive HIV-2-infected patients: The ACHIEV2E Collaboration Study Group. High level of APOBEC3F/3G editing in HIV-2 DNA vif and pol sequences from antiretroviral-naïve patients. AIDS 2015, 29;779-784 Burgard M, Jasseron C, Matheron S, et al. Mother-to-Child Transmission of HIV-2 Infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1. Special aspects of the treatment of HIV-2-infected patients. Intervirology 2012; 55: 179-183 Carvalho A, Valadas E, França L et al. Population mobility and the changing epidemics of HIV-2 in Portugal. HIV Med 2012, 13:219-25 Charpentier C, Visseaux B, Bénard A, et al. Transmitted drug resistance in French HIV-2-infected patients. AIDS 2013, 27:1671-4 Charpentier C, Camacho R, Ruelle J, et al. HIV-2EU-Supporting Standardized HIV-2 Drug-Resistance Interpretation in Europe: An Update. Clavel F, Guetard D, Brun-Vezinet F, Chamaret S, Rey MA, Santos-Ferreira O. Isolation of a new human retrovirus from West African patients with AIDS. Science 1986, 233: 343 Clavel F, Guyader M, Guetard D, et al. Molecular cloning and polymorphism of the human immune deficiency virus type 2. In vitro phenotypic susceptibility to nucleoside reverse transcriptase inhibitors of HIV-2 isolates with the Q151M mutation in the reverse transcriptase gene. Antivir Ther 10, 861–865 de Mendoza C, Caballero E, Aguilera A, et al. HIV-2 and HTLV-1 infections in Spain, a non-endemic region. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother 2008, 52:1545-8 Descamps D, Peytavin G, Visseaux B, et al. Dolutegravir in HIV-2-Infected Patients With Resistant Virus to First- line Integrase Inhibitors From the French Named Patient Program. CID 2015, 60:1521-7 Drylewicz J, Matheron S, Lazaro E, et al. Comparision of viro-immunological marker changes between HIV-1 and HIV-2 infected patients in France AIDS 2008, 22: 457-68. Maintenance of HIV-specific CD4+ T cell help distinguishes HIV-2 from HIV-1 infection. Antiretroviral therapy response among HIV-2 infected patients: a sys- tematic review. Comparison of HIV-1 and HIV-2 infectivity from a prospective cohort study in Senegal. Stat Med 2003, 22:573-93 Gilleece Y, Chadwick DR, Breuer J et al. British HIV Association guidelines for antiretroviral treatment of HIV-2 positive individuals 2010. HIV Medicine 2010, 11, 611-619 Gottlieb GS, Sow PS, Hawes SE, et al. Equal plasma viral loads predict a similar rate of CD4+ T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa. Lower levels of HIV RNA in semen in HIV-2 compared with HIV-1 infec- tion: implications for differences in transmission. Baseline plasma viral load and CD4 cell percentage predict survival in HIV- 1- and HIV-2-infected women in a community-based cohort in The Gambia. JAIDS 2005; 38: 335–341 Hegedus A, Nyamweya S, Zhang Y, et al. Protection versus pathology in aviremic and high viral load HIV-2 infec- tion-the pivotal role of immune activation and T-cell kinetics. Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau. AIDS Research and Human Retroviruses 2005; 21: 560–564 Jallow S, Alabi A, Sarge-Njie R et al. Virological response to highly active antiretroviral therapy in patients infected with HIV-2 and in patients dually infected with HIV-1 and HIV-2 in the Gambia and emergence of drug-resistant variants.
These include the need for preauthorization of NOACs followed by 20 mg daily buy 20 mg sarafem mastercard menstruation occurs when there is a decrease in. The principal safety outcomes of major and departments and among practitioners responsible for follow-up order sarafem 10mg with visa women's health center queens blvd. In the continued-treatment study order sarafem 20mg menstruation japanese word, rivaroxa- NOACs will replace heparin and vitamin K antagonists as ban reduced the recurrence rate by 82% compared with patients on standard therapy for the majority of patients with an initial placebo, albeit with a small increased risk of major (0. In the AMPLIFY trial, a ﬁxed-dose Antidotes and laboratory monitoring regimen of apixaban alone for 6 months was also shown to be There is no speciﬁc antidote available to reverse the anticoagulant noninferior to standard therapy for the treatment of symptomatic effect of dabigatran, but an approach using a monoclonal antibody is VTE, but was associated with signiﬁcantly less bleeding. Rivaroxaban and apixaban are both highly warfarin); it may reduce the costs of treating VTE by reducing the protein bound and therefore cannot be removed by hemodialysis. A post hoc analysis of pooled data from the results from high drug levels or another etiology (eg, bleeding from 2 trials did not ﬁnd any difference in outcomes among “fragile” a discrete anatomic site, coagulopathy resulting from liver disease, patients (age 75 years or creatinine clearance 50 mL/min or or disseminated intravascular coagulation) and before some surgical body weight 50 kg), those with active cancer, or those with large procedures (eg, neurosurgery, cardiac surgery). The percentage of cancer patients enrolled in thrombin time have been developed and appear to be sufﬁciently the trials was also relatively small ( 5%) because oncologists sensitive. However, a normal measurement Adherence, anticoagulation clinics, and medication provides assurance that a signiﬁcant drug concentration is no longer costs present. Dabigatran prolongs the partial thromboplastin time (PTT), Perhaps the most signiﬁcant concern with the NOACs is medication but the effects are not dose dependent; although a prolonged PTT adherence. Issues speciﬁc to vitamin K antagonists have led to the may indicate the presence of dabigatran, it will not provide an exact development of anticoagulation clinics (so-called Coumadin clin- level of anticoagulant activity. For therapeutic doses of oral factor ics) in many parts of the world, which play a very important role in Xa inhibitors, the prothrombin time (PT) is more sensitive than the optimizing the safety and efﬁcacy of vitamin K antagonists. PTT; however, the results are dependent on the PT reagent used in Warfarin’s long half-life of 40 hours is an advantage for patients the assay and apixaban has less effect on the PT than rivaroxaban. Furthermore, the twice-daily dosing schedules of some provide sensitive and speciﬁc assays for measuring drug concentra- NOACs may be more difﬁcult for some patients to adhere to than a tions of oral direct factor Xa inhibitors. The lack of a requirement for recombinant factor VIIa are available for overcoming their antico- regular coagulation monitoring may eliminate the initial and agulant effect in the management of severe bleeding episodes. Healthcare systems are now grappling with how to handle the threatening hemorrhage. If NOACs are prescribed appropriately, the adherence issue with the NOACs. One approach is to have patients current lack of a speciﬁc antidote may not be a great drawback in on NOACs be followed by anticoagulation or thrombosis manage- most bleeding situations because there will be relatively few ment clinics. Reports of thrombotic and hemorrhagic complications circumstances in which a reversal agent will be required. This will be an added burden for clinics that are apixaban, respectively, are renally eliminated as active drug. However, with better care coordination and NOAC and this is best done by calculating creatinine clearance bundled payment systems, there should be an impetus for incorporat- using the Cockcroft-Gault formula, which incorporates body weight ing patients on NOACs into these clinics to optimize outcomes (as opposed to other formulas that provide estimates for a body (including reduced need for hospitalizations and emergency depart- surface area of 1. Pharmacists/nurses/physicians with special expertise in All of the trials evaluating dabigatran etexilate or rivaroxaban anticoagulation management can provide the oversight to ensure excluded patients with a creatinine clearance 30 mL/min, whereas that NOACs are prescribed appropriately based upon an individual the ARISTOTLE trial excluded patients with creatinine clearance patient’s history and clinical characteristics. In patients with a creatinine clearance of 30 to 49 Cushman recommended that institutions adopt protocols for NOAC mL/min, the dose of rivaroxaban was reduced to 15 mg, whereas no use in acute VTE that address 6 key components: patient preference, adjustments were made in the RE-LY trial for either the 150 or 110 patient selection, drug interactions, compliance, follow-up, and mg doses of dabigatran etexilate. Based on pharmacokinetic consider- taken into consideration. Even among patients with insurance that ations, a reduced dose of 75 mg BID was approved by the FDA for covers drugs, prescribers should ascertain how much patients pay patients with atrial ﬁbrillation and a creatinine clearance of 15 to 29 out of pocket (copayment) compared with warfarin. High drug costs mL/min in the absence of efﬁcacy and safety data. The FDA also can contribute to reduced medication adherence: patients are known approved rivaroxaban at a dose of 15 mg daily for atrial ﬁbrillation to not ﬁll prescriptions they regard as too expensive or skip/split patients with a creatinine clearance of 15 to 29 mL/min. The FDA also extended the substantial cost for healthcare systems. Many clinicians with The vitamin K antagonists will remain an important anticoagulant expertise in anticoagulant therapy were surprised by these option. They remain the medication of choice for patients with decisions by the FDA, particularly given the current absence of a mechanical heart valves. Therefore, many believe that NOACs have minimal, if any, long-term effects on organ systems and should not be prescribed at any dose in patients with a creatinine physiologic processes other than blood coagulation. JAm mentation Laboratory, Boehringer Ingelheim, Pﬁzer, Bristol- Coll Cardiol. Meyers Squibb, Janssen Pharmaceuticals, Bayer Healthcare, and 16. Off-label drug use: Dabigatran and apixaban for the botic therapy to prevent stroke in patients who have nonvalvu- prevention and treatment of VTE. Beneﬁt of oral anticoagulant over antiplatelet therapy in atrial ﬁbrillation Correspondence depends on the quality of international normalized ratio control Kenneth A. Bauer, MD, Beth Israel Deaconess Medical Center, 330 achieved by centers and countries as measured by time in Brookline Avenue, Boston, MA 02215; Phone: 617-667-2174; Fax: therapeutic range. Comparison of outcomes among patients randomized to warfarin therapy according to References anticoagulant control: results from SPORTIF III and V. Recent progress in anticoagulant therapy: oral with atrial ﬁbrillation. Kirley K, Qato DM, Kornﬁeld R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 3. New oral anticoagulants: which one should versus enoxaparin for thromboprophylaxis after hip arthro- my patient use? Newer oral anticoagulants rivaroxaban versus short-term enoxaparin for the prevention of should be used as ﬁrst-line agents to prevent thromboembolism venous thromboembolism after total hip arthroplasty: a double- in patients with atrial ﬁbrillation and risk factors for stroke or blind, randomised controlled trial. New oral anticoagulants should not be used as enoxaparin for thromboprophylaxis after total knee arthro- ﬁrst-line agents to prevent thromboembolism in patients with plasty. Eisert WG, Hauel N, Stangier J, Wienen W, Clemens A, van versus enoxaparin for thromboprophylaxis after total knee Ryn J. Dabigatran: an oral novel potent reversible nonpeptide arthroplasty (RECORD4): a randomised trial. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The prevention of venous thromboembolism after hip or knee discovery and development of rivaroxaban, an oral direct arthroplasty. Jensen CD, Steval A, Partington PF, Reed MR, Muller SD. Return to theatre following total hip and knee replacement, 11. Dabigatran versus before and after the introduction of rivaroxaban: a retrospec- warfarin in patients with atrial ﬁbrillation. Einstein Investigators, Bauersachs R, Berkowitz SD, et al.
The mean intensity of vaginal dryness buy generic sarafem 10mg on line womens health knoxville tn, involuntary loss of urine discount sarafem 20 mg on-line breast cancer socks, and pain during intercourse decreased from baseline to 24 weeks in both groups effective sarafem 20mg 4 menstrual stages. There were some baseline differences among groups in vaginal irritation and itching (more severe in placebo group) and vaginal dryness (greater in placebo and 100 mcg vaginal ring groups). There was significant improvement in vaginal dryness at 4 and 8 weeks in the E2 vaginal ring 100 mcg group, and significant improvement in pain during intercourse at week 4 in both E2 groups and at week 13 in the E2 100 mcg group. There was a nonsignificant trend toward greater improvement of other urogenital symptoms in both E2 groups compared with placebo. In a subgroup of 60 women (18% of total) with signs and symptoms of vaginal atrophy at baseline, the maturation index was improved in both E2 groups compared with placebo at week 13. A trial of transdermal E2, utilizing responses on the McCoy Sex Scale Questionnaire, 95 indicated improvement in responses to five of nine items compared to placebo. A correlation between improved sexual life and a quality-of-life questionnaire was also reported in this study. These findings were supported by another trial of transdermal E2 that indicated improvement in 76 sexual problems and dysfunction as measured with the McCoy Sex Scale compared to placebo. Another trial of transdermal E2 indicated improvement in vaginal dryness, but not dyspareunia, 96 frequent urination, dysuria, stress incontinence, and nocturia, compared to placebo. Another trial comparing transdermal E2 and placebo indicated no differences between groups for 73 symptoms of vaginal discomfort, loss of libido, and incontinence. There are two brief reports from one head-to-head study that measured sexual functioning and sexual quality-of-life in 186 women randomized to transdermal E2 or oral E2. One of these 97 98 is an abstract and the other a poster presentation. On some, but not all, measures of sexual function and sexual quality of life, there was more improvement in women who used transdermal E2 compared with oral E2. This study is not published in full-text form and the brief reports do not provide sufficient detail to assess quality. A trial of CEE reported significantly improved vaginal dryness and urinary frequency, but no significant improvement on six other items related to sexual function on a General Health 61 Questionnaire compared to placebo. The HERS trial found that women with at least one episode of incontinence per week at baseline who received CEE/MPA had worsening 99 incontinence after approximately 4 years of follow up compared to women taking placebo. The WHI reported on genital symptoms, as noted above under the section ‘Hot 81 flashes/flushes’. In Update #3, the ULTRA study found no differences between treatment with low-dose 30 39 transdermal estradiol on vaginal dryness or on urinary incontinence. There was a reduction in Hormone therapy Page 38 of 110 Final Report Update 3 Drug Effectiveness Review Project investigator-assessed vaginal atrophy, dryness, and friability for estradiol acetate compared with 37 placebo (p<0. A Cochrane systematic review compared efficacy and safety of intra-vaginal estrogen preparations (creams, pessaries, tablets, and estradiol-releasing ring) for the relief of symptoms 100 of vaginal atrophy (vaginal dryness, itching, discomfort, and painful sexual intercourse). Overall, the author concluded that the preparations appear to be equally effective for the symptoms of vaginal atrophy. CEE cream caused more side effects compared to estradiol tablets (uterine bleeding, breast pain, and perineal pain) or estradiol vaginal ring (endometrial overstimulation). For the comparison of the estradiol ring to CEE vaginal cream, there was no difference between groups in patient assessment of vaginal dryness or withdrawals due to adverse events, but there was more improvement in pruritis with the ring. For the comparison of estradiol ring versus estradiol tablet, vaginal dryness was improved more with tablets, but there was no difference between groups in genital pruritis or withdrawals due to adverse events. Symptom improvement was similar for tablet versus cream, but there were fewer withdrawals due to adverse effects with tablets compared with cream. There was no difference among all treatment comparisons for dysuria, nocturia, urgency, urge incontinence, participant symptom improvement in dryness, soreness, and irritation, loss of libido, and vaginitis. Quality-of-life A head-to-head comparison of CEE vs. A trial comparing oral E2 and intravaginal ring E2 found significant improvement on the Greene Climacteric Scale among 102 both treatment groups but no between-group differences. One trial of oral E2 conducted in HRT-naive women in Thailand observed no difference in mean Greene score 83 improvement compared with placebo after 12 months of treatment. A trial of low-dose oral E2 103 (1 mg per day) reported significant improvement from baseline at 6 and 12 weeks on six of nine domains of the Women’s Health Questionnaire (vasomotor symptoms, sexual behavior, depressed mood, somatic symptoms, anxiety/fear, and sleep problems). There was no difference between control and treatment groups on the memory concentration, menstrual symptoms, and attractiveness items of the scale. Seven trials of transdermal E2 and placebo indicated improved health related quality-of- life and well-being measured by various instruments: Nottingham Health Profile, Psychological General Well-Being Index, Women Health Questionnaire, Kupperman’s index, McCoy Sex 68, 70, 73, 74, 76, 96, 104 Scale, and psychological general well-being index. One trial indicated that women with high well-being and no vasomotor symptoms at baseline had no improvement with 105 treatment as measured by the Psychological General Well-Being Index. The HERS trial (CEE), using non-validated quality of life instruments (Duke Activity Status Index, RAND Mental Health Inventory, among others), found that quality of life scores were significantly lower among women who were older, had diabetes, hypertension, chest pain, 91 or heart failure, and that use of CEE had little effect. One trial found a significant decrease in 59 Kupperman’s index among women treated with E2V compared with placebo. A trial of Hormone therapy Page 39 of 110 Final Report Update 3 Drug Effectiveness Review Project esterified estrogens reported improvement in the Quality of Life Menopause Scale compared to 106 placebo. Health-related quality of life (HRQL) measures were collected on a subgroup of women 85 enrolled in the WHI randomized to CEE plus MPA or to placebo (n=16,608). Quality of life and functional status were assessed using the RAND 36-item Health Survey, which includes items about general health, physical functioning, limitations on usual role-related activities due to physical health problems, bodily pain, energy and fatigue, limitations on usual role-related activities due to emotional or mental problems, social function, and emotional or mental health. At 1-year follow-up, there were small but statistically significant positive effects of CEE/MPA on physical functioning (0. There were no differences from placebo in any other HRQL measure and by 3 years of follow-up (n=1511) there were no significant differences from placebo on any HRQL measure. Subgroup analyses detected no statistically significant interactions between baseline age, race, ethnicity, body mass index, or menopausal symptoms and HRQL. In a post hoc analysis of women 50 to 54 years of age who reported moderate-to-severe vasomotor symptoms at baseline, there was a positive effect on sleep disturbance, but no effect on other HRQL measures, despite significant improvement in vasomotor symptoms. At 1-year follow-up, there was a small positive effect of CEE on sleep disturbance (0. At 1- year follow-up of women who had moderate-to-severe vasomotor symptoms at baseline, 72. In a subsample (n=1,189) examined at 3-year follow-up there were no significant differences in any HRQL measure between treatment groups. For Update #3, none of the three new studies reporting HRQL or related outcomes showed significant effects between the treatment and placebo groups. The ULTRA study of 78 low-dose transdermal estrogen reported no significant improvements in the SF-36 subscales of 29 physical and mental function. The findings of Dayal and colleagues were similar in that conjugated equine estrogen did not improve vitality, general health status, or quality of life at 12- week follow-up.
Antihistamines Page 11 of 72 Final Report Update 2 Drug Effectiveness Review Project METHODS Study Selection and Inclusion Criteria Populations • Adult or pediatric outpatients with the following conditions: o Seasonal allergic rhinitis o Perennial allergic rhinitis o Urticaria (acute and chronic) • Subgroups of interest included discount 10 mg sarafem fast delivery women's health clinic tualatin, but were not limited to buy sarafem 20 mg on-line breast cancer 7 mm, different races quality 10mg sarafem contemporary women's health issues for today and the future 5th edition, ages (older adult compared with younger adult), concomitant use of other medications (in consideration of drug-drug interactions), persons with various comorbidities (pregnancy and consideration of drug-disease interactions), and sex. Interventions Drugs included in this review are listed below. This review is restricted to drugs currently available on the United States and Canadian markets. No black box warnings were found for any of the included drugs. Active ingredient Brand name Cetirizine hydrochloride Zyrtec , Reactine Loratadine Claritin Fexofenadine hydrochloride Allegra Desloratadine Clarinex a Levocetirizine Xyzal a,b Azelastine Astelin , Astepro a,b Olopatadine Patanase a Not available in Canada. Outcomes The following were the primary outcomes for this review: • Efficacy and effectiveness o Symptoms (nasal congestion, rhinorrhea, sneezing, itching and pain from skin irritations) o Functional capacity (physical, social and occupational functioning, quality of life) o Time to relief of symptoms (time to onset, duration of relief) o Duration of effectiveness (switch rate) • Harms o Total withdrawals o Withdrawals due to adverse events Antihistamines Page 12 of 72 Final Report Update 2 Drug Effectiveness Review Project o Serious adverse events or withdrawals due to specific adverse events (central nervous system effects, sedation, gastrointestinal effects, dry mouth, urinary retention) Study Design 1. Randomized controlled trials, controlled clinical trials, and systematic reviews of fair or better quality. Direct comparisons (head-to-head studies) were preferred over indirect comparisons using active or placebo-controlled trials. Inclusion of indirect evidence will be considered where there is insufficient direct evidence. Studies conducted in artificial study settings (for example, antigen exposure chambers) were not be included. Abstracts and conference proceedings are also excluded. Randomized controlled trials, controlled clinical trials, pre-compared with post- design studies, and observational studies with comparative groups. To be included, reports about overall harms or adverse events had to report total withdrawals, withdrawals due to specific adverse events (for example, central nervous system effects, sedation, gastrointestinal effects, dry mouth, urinary retention, etc. Literature Search To identify articles relevant to each key question, we searched the Cochrane Library (3rd Quarter 2005), MEDLINE (1966 to August Week 4 2005), EMBASE (1991 to August Week 4, 2005), the 2 dossiers received from pharmaceutical companies for fexofenadine HCL (Allegra ) and desloratadine (Clarinex ), and reference lists of review articles. For Update 2, we searched Ovid MEDLINE (1996-November Week 3, 2009), the Cochrane Database of Systematic Reviews th th (4 Quarter 2009), the Cochrane Central Register of Controlled Trials (4 Quarter 2009), and th Database of Abstracts of Reviews of Effects (4 Quarter 2009). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. The complete search strategy for electronic searches for Update 2 is in Appendix B. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote XI, Thomson Reuters). Data Abstraction Two reviewers abstracted the following data from included trials: study design, setting, population characteristics (including sex, age, race/ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparison group treatment; numbers screened, Antihistamines Page 13 of 72 Final Report Update 2 Drug Effectiveness Review Project eligible, enrolled, and lost to follow-up; methods of outcome ascertainment; and results for each outcome. Any discrepancies in abstraction were resolved through discussion and consensus was achieved. We recorded intention-to-treat results if available and if the trial did not report high overall loss to follow-up. Study Selection Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for inclusion using the criteria below. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by both reviewers. Results published only in abstract form were not included because inadequate details were available for quality assessment. Validity Assessment We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix C. These criteria are based on the US Preventive Services Task Force and the National 24, 25 Health Service Centre for Reviews and Dissemination (United Kingdom) criteria. We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. A particular randomized trial might receive 2 different ratings, one for effectiveness and another for adverse events. Appendix C also shows the criteria we used to rate observational studies of adverse events. These criteria reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria. Included systematic reviews were also rated for quality (see Appendix C). We rated the internal validity based a clear statement of the questions(s); reporting of inclusion criteria; methods used for identifying literature (the search strategy), validity assessment, and synthesis of evidence; and details provided about included studies. Again, these studies were categorized as good when all criteria were met. The overall strength of evidence for a body of evidence pertaining to a particular key question or outcome reflects the risk of bias of the studies (based on quality and study designs), consistency of results, directness of evidence, and precision of pooled estimates resulting from Antihistamines Page 14 of 72 Final Report Update 2 Drug Effectiveness Review Project the set of studies relevant to the question. Strength of evidence is graded as insufficient, low, moderate, or high. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated one newer antihistamine against another provided direct evidence of comparative effectiveness and adverse event rates. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes. In theory, trials that compare newer antihistamines with other drug classes or with placebos can also provide evidence about effectiveness.