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Triptans Page 61 of 80 Final Report Update 4 Drug Effectiveness Review Project Randomized controlled trial: A trial in which two or more interventions are compared through random allocation of participants purchase imitrex 25 mg. Regression analysis: A statistical modeling technique used to estimate or predict the influence of one or more independent variables on a dependent variable discount 25mg imitrex with mastercard, for example buy 25mg imitrex with amex, the effect of age, sex, or confounding disease on the effectiveness of an intervention. Relative risk: The ratio of risks in two groups; same as a risk ratio. Retrospective study: A study in which the outcomes have occurred prior to study entry. Risk: A way of expressing the chance that something will happen. It is a measure of the association between exposure to something and what happens (the outcome). Risk is the same as probability, but it usually is used to describe the probability of an adverse event. It is the rate of events (such as breast cancer) in the total population of people who could have the event (such as women of a certain age). Risk difference: The difference in size of risk between two groups. In intervention studies, it is the ratio of the risk in the intervention group to the risk in the control group. A risk ratio of 1 indicates no difference between comparison groups. For undesirable outcomes, a risk ratio that is <1 indicates that the intervention was effective in reducing the risk of that outcome. Run-in period: Run in period: A period before randomization when participants are monitored but receive no treatment (or they sometimes all receive one of the study treatments, possibly in a blind fashion). The data from this stage of a trial are only occasionally of value but can serve a valuable role in screening out ineligible or non-compliant participants, in ensuring that participants are in a stable condition, and in providing baseline observations. A run-in period is sometimes called a washout period if treatments that participants were using before entering the trial are discontinued. This term (or the term ‘‘safe’’) should not be used when evidence on harms is simply absent or is insufficient. Sample size: The number of people included in a study. In research reports, sample size is usually expressed as "n. Larger sample sizes also increase the chance that rare events (such as adverse effects of drugs) will be detected. Sensitivity analysis: An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used. Side effect: Any unintended effect of an intervention. Side effects are most commonly associated with pharmaceutical products, in which case they are related to the pharmacological properties of the drug at doses normally used for therapeutic purposes in humans. Triptans Page 62 of 80 Final Report Update 4 Drug Effectiveness Review Project Standard deviation (SD): A measure of the spread or dispersion of a set of observations, calculated as the average difference from the mean value in the sample. Standard error (SE): A measure of the variation in the sample statistic over all possible samples of the same size. The standard error decreases as the sample size increases. The treatment or procedure that is most commonly used to treat a disease or condition. In clinical trials, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease. It may also include people who have no known diseases. Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the participants in a trial, such as all females or adults older than 65 years. Superiority trial: A trial designed to test whether one intervention is superior to another. Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important; for example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up.!! Survival analysis: Analysis of data that correspond to the time from a well-defined time origin until the occurrence of some particular event or end-point; same as time-to-event analysis. Systematic review: A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research and to collect and analyze data from the studies that are included in the review. The extent to which a drug’s adverse effects impact the patient’s ability or willingness to continue taking the drug as prescribed. These adverse effects are often referred to as nuisance side effects, because they are generally considered to not have long-term effects but can seriously impact compliance and adherence to a medication regimen. Treatment regimen: The magnitude of effect of a treatment versus no treatment or placebo; similar to “effect size”. Can be calculated in terms of relative risk (or risk ratio), odds ratio, or risk difference. Two-tailed test (two-sided test): A hypothesis test in which the values that reject the null hypothesis are located in both tails of the probability distribution. For example, testing whether one treatment is different than another (rather than testing whether one treatment is either better than another). Triptans Page 63 of 80 Final Report Update 4 Drug Effectiveness Review Project Type I error: A conclusion that there is evidence that a treatment works, when it actually does not work (false-positive). Type II error: A conclusion that there is no evidence that a treatment works, when it actually does work (false-negative).

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Use a cotton swab to remove any discharge purchase imitrex master card, Visual screening method blood or mucus from the cervix cheap imitrex 50 mg. In VIA we inspect the transformation or transition 5 discount imitrex 25 mg online. Apply acetic acid or Lugol’s iodine to the epithelium of the uterine cervix). In a visual test, cervix; wait a minute or two to allow color the provider applies acetic acid (in VIA) or Lugol’s changes to develop. Observe any changes in iodine solution (in VILI) to the cervix, and then the appearance of the cervix. A VIA test is attention to abnormalities close to the transfor- positive if there are raised and thickened white mation zone. Inspect the SCJ carefully and be sure you can positive if there are mustard or saffron-yellow see all of it. Either test is suspicious for cancer if a plaques or aceto-white epithelium if you used cauliflower-like fungating mass or ulcer is noted on acetic acid or saffron-yellow colored areas after the cervix. Visual screening results are negative if application of Lugol’s iodine. Remove any the cervical lining is smooth, uniform and feature- blood or debris appearing during the inspec- less; it should be pink with acetic acid and dark tion. For a schematic overview of the test, brown or black with Lugol’s iodine. Figure 7 shows examples of 324 Cervical Cancer Prevention and Treatment (a) Figure 6 Schematic overview of the cervix and the aceto-white area. Courtesy of Screening Group (SCR), International Agency for Research on Cancer (WHO- IARC) a negative and positive VIA tests and non- invasive cervical cancer. Use a fresh swab to remove any remaining (b) acetic acid or iodine solution from the cervix and vagina. Draw a map of any abnormal findings on the record form. A sample of a record form and map can be found at: http://screening. Discuss the results of the screening test with the patient. If the test is negative, tell her that she should have another test in 3 years. If the (c) test is positive or cancer is suspected, tell her what the recommended next steps are. If she needs to be referred for further testing or treat- ment, make arrangements and provide her with all necessary forms and instructions before she leaves. Other diagnostic tests Biopsy Biopsy is the removal of small areas of the cervix for histopathological diagnosis. It should be done with a punch biopsy forceps (Figure 8); one or more small pieces of tissue (1–3 mm across) are removed Figure 7 Examples of (a) negative (note no aceto-white from the abnormal areas of the cervix identified by areas seen) and (b) positive (note the well-defined opaque colposcopy or VIA (see Chapter 1 on gynecological aceto-white lesion in the anterior lip arising from the SCJ) examination on how to do a biopsy). Bleeding is VIA tests and (c) non-invasive cervical cancer (note dense usually minimal. The samples are placed in a pre- aceto-white area with irregular surface contour). Courtesy servative, such as formalin, and the container of Screening Group (SCR), International Agency for labelled. This is then sent to a laboratory for precise Research on Cancer (WHO-IARC) histopathological diagnosis of the abnormalities, 325 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS patients can be followed up with colposcopy and cytology every 6 months until the lesion regresses to normal, or there is evidence of progression of the abnormality. If progression is noted, or in cases where follow-up is problematic, as well as in older women in whom spontaneous regression is less Figure 8 A cervical biopsy forceps. Source: Compre- likely, immediate treatment should be considered. Geneva: WHO, 200639 Special considerations Pregnancy whether they are pre-cancer or cancer, and their severity and extent, so that treatment can be tailored Women known or suspected to be pregnant should to each case. A biopsy should be performed: not be treated for pre-cancer; they should be advised to return at 12 weeks post-partum for further evalu- • On women with an abnormal screening test ation. If invasive cancer is suspected, the patient • If suspicious lesions are seen on the cervix on should be referred immediately to a specialist. Women who present for treatment during men- Endocervical curettage struation can be treated if the bleeding is slight. It is advisable to delay the procedure if menstruation is If a woman has a positive Pap test, but no abnormal heavy and interferes with visualization of the extent areas are observed with colposcopy, there may be a of the lesion. However, it is important to remem- lesion in the cervical canal. In this case, the endo- ber that she may be bleeding because of cervical cervix can be examined with a special speculum cancer, so an examination should not be deferred and a sample of cells can be obtained with an endo- for longer than a week. Endo- cervical curettage is a simple procedure, in which The woman has a cervical infection or pelvic some of the surface cells are gently scraped from the inflammatory disease cervical canal (See Chapter 1 on gynecological ex- • A cervical infection with no evidence of pelvic aminations). For more information and digital pub- inflammatory disease (PID) (diagnosed clinically lications see http://www. If LEEP or cold knife TREATMENT OF PRE-MALIGNANT conization is to be used, the infection must be LESIONS treated before the procedure. Pre-malignant lesions of the cervix can be treated • If PID is suspected, a full course of appropriate with either cryotherapy, LEEP of cold knife coni- antibiotic treatment should be completed prior zation. In this chapter we describe them with indi- to any treatment (see Chapter 17 on STI). If you want thorough • Whenever a woman is treated for a cervical in- knowledge about the subject you can download fection, with or without PID, her partner also the following publications for free: http://screen- needs to be fully treated to prevent reinfection. Condoms and instructions on their Indications for treatment use need to be provided to all such patients. All biopsy-confirmed CIN 2 and 3 lesions should The woman is HIV infected be treated, because the majority of them persist and may eventually progress to invasive cancer. CIN 1 HIV-positive women should be managed in the is more likely to resolve spontaneously; these same manner as uninfected women. However, 326 Cervical Cancer Prevention and Treatment HIV-positive women are known to have higher 1. Explain the procedure, and why it is important rates of persistence, progression and recurrence of to return for further management as requested. Women with HIV infection Ensure that the woman has understood and should therefore be monitored every 6 months obtain informed consent. Show her the cryotherapy equipment and ent, progressive or recurrent high-grade lesions are explain how you will use it to freeze the detected. At present there is no clear evidence on abnormal areas on the cervix.

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Both trials looked at treatment of only 1 headache per patient and thus did not provide data on consistency of response across multiple headaches buy imitrex 25mg otc. Triptans Page 35 of 80 Final Report Update 4 Drug Effectiveness Review Project Placebo-controlled trials: Naratriptan We found no placebo-controlled trials of naratriptan that reported quality of life buy imitrex 50 mg mastercard, workplace productivity order imitrex 25 mg with visa, or 2-hour or 24-hour pain-free outcomes. We also found no placebo-controlled trials that evaluated consistency of naratriptan across multiple headaches. Reformulated (rapid-release) oral sumatriptan Direct comparisons We found no head-to-head trial directly comparing reformulated (rapid-release) oral sumatriptan tablet with any other triptan. Placebo-controlled trials: Reformulated oral sumatriptan We included placebo-controlled trials of reformulated oral sumatriptan that looked at early 78, 79 treatment of migraine while pain is still mild. We also used data from placebo-controlled trials of reformulated sumatriptan 100 mg and the conventional tablet form of sumatriptan to explore indirect comparisons between the 2 formulations on 2-hour pain-free rates. The efficacy of reformulated sumatriptan 100 mg administered early in a migraine, while pain is mild, was demonstrated in a fair-quality trial of 432 adults who were 78, 79 instructed to administer treatment when pain was still mild and within 1 hour of onset. Rate of 2-hour pain-free was 66% for reformulated sumatriptan 100 mg and 20% for placebo (P<0. At 24 hours, rate of sustained pain-free also was significantly greater for reformulated sumatriptan 100 mg than placebo (40% compared with 10%; P<0. From these data, we calculated a relative risk of 3. Compared with placebo, rate of normal function was significantly greater for reformulated sumatriptan 100 mg at 45 minutes (29% compared with 18%; P<0. At 24 hours, significantly less time was lost on activities other than paid work for reformulated sumatriptan 100 mg (2. However, lost time in paid work was similar for reformulated sumatriptan 100 mg and placebo (2. Indirect comparison of reformulated with the conventional tablet form of sumatriptan. In the absence of head-to-head trials that directly compared reformulated and the conventional tablet form of sumatriptan, we explored indirect comparisons between formulations using data 80 from placebo-controlled trials. Data from placebo-controlled trials of reformulated sumatriptan 36, 37, 45, 81-85 and the conventional tablet form of sumatriptan were pooled, and combined relative risks and numbers needed to treat were generated for each triptan for 2-hour pain-free rates (Table 6). Estimates of relative risk were similar for the conventional tablet form of sumatriptan and reformulated sumatriptan and the large overlap of 95% confidence intervals did not suggest a clear advantage for either formulation over the other. However, the somewhat higher rate of 2- hour pain-free rates in the placebo group of the reformulated sumatriptan trial compared with those of the conventional tablet form of sumatriptan trials suggests the presence of at least some heterogeneity between the 2 sets of trials, likely in patient population or outcome assessment. Therefore, we caution against drawing firm conclusions about the comparison of reformulated and the conventional tablet form of sumatriptan until results from adjusted, quantitative, indirect comparisons, or head-to-head trials become available. Triptans Page 36 of 80 Final Report Update 4 Drug Effectiveness Review Project We also sought results on 24-hour sustained pain-free outcomes from placebo-controlled trials of reformulated and the conventional tablet form of sumatriptan, but insufficient data were available from trials of conventional sumatriptan. Pain-free at 2 hours in placebo-controlled trials: Pooled relative risk and number needed to treat for conventional and reformulated sumatriptan % sumatriptan % placebo Relative risk of 2 Heterogeneity: group pain- group pain- hr pain-free (95% Number Q (degrees of Sumatriptan free at 2 hr free at 2 hr confidence needed freedom), 100 mg (n/N) (n/N) interval) to treat P 7. But because the trials were poor quality, their findings will not be discussed here. We found no head-to-head trials comparing sumatriptan nasal spray with any other triptan. Placebo-controlled trials: Sumatriptan injection Indirect comparisons of subcutaneous sumatriptan to oral formulations of other triptans. Sumatriptan is the only triptan approved in the United States and Canada in an injectable form. Given the lack of fair-quality or good-quality head-to-head trials involving subcutaneous sumatriptan 6 mg, we examined findings of a good-quality systematic review that qualitatively evaluated indirect comparisons between subcutaneous sumatriptan 6 mg and other triptans on the basis of unadjusted estimates of relative risk calculated for each triptan using pooled data from 52 placebo-controlled trials. The main advantage of subcutaneous sumatriptan 6 mg over oral 86-89 90-96 triptans is that it could potentially provide earlier pain relief. In 12 trials, pooled rates of 1-hour pain relief were significantly greater for subcutaneous sumatriptan 6 mg than placebo (70% compared with 22%), which resulted in the largest relative benefit estimate (3. Benefits relative to placebo calculated for other triptans were lower, ranging from 1. Functional capacity, work productivity, and quality of life. Numerous fair-quality, placebo-controlled studies of subcutaneous sumatriptan reported on functional capacity, work 86-90, 92-106 productivity, and quality of life. Subcutaneous sumatriptan consistently reduced time to 86, 89, 90, 94-96, 103 87, 88, 93, 98, 99, 102, 105, 106 return to work, degree of clinical disability, and time to 98 emergency room discharge and improved quality of life-related symptoms (contentment and 102 vitality dimensions of the Minor Symptom Evaluation Profile). Triptans Page 37 of 80 Final Report Update 4 Drug Effectiveness Review Project Frovatriptan Direct comparisons We are aware of 1 head-to-head trial that directly compared frovatriptan 2. However, information about this trial is available only in the form of an abstract, which did not provide adequate methodological detail for assessment of internal validity. Consequently, results from this trial were excluded from our review. Placebo-controlled trials: Frovatriptan Indirect comparisons of frovatriptan to other oral triptans. Two-hour pain-free data from placebo-controlled trials were pooled and a combined risk difference for frovatriptan 2. For the conventional tablet form of sumatriptan 100 mg, we conducted a risk difference meta-analysis of 36, 37, 45, 81-85 8 placebo-controlled trials. Compared with placebo (8%, 57/696), rates of 2-hour pain-free were 20% higher (95% CI, 0. Results of their risk difference meta-analysis indicate that rates of 2-hour pain-free were only 9% higher (95% CI, 0. One fair-quality, placebo-controlled, crossover trial of frovatriptan 2. Rate of 2-hour pain-free was better with frovatriptan 2. Fixed-dose combination tablets containing a triptan compared with triptan monotherapy Direct comparisons ® The only 2 head-to-head trials that involved Treximet were both conducted as part of the new drug application program and were designed to meet the US Food and Drug Administration’s minimum requirement for all fixed-dose combination products that the product show superiority 110 to its individual components. Although sumatriptan tablets are commercially available in only 25 mg, 50 mg, and 100 mg strengths, in order to match the dosage strength for the sumatriptan ® component in Treximet , these trials used an 85 mg dose for sumatriptan monotherapy. Both ® trials demonstrated that Treximet 85 mg/500 mg was superior in efficacy to its individual components, sumatriptan 85 mg and naproxen 500 mg, on the primary outcome of sustained 24- 110 ® hour pain-free response. Treximet was also superior to sumatriptan 85 mg in improving patients’ return to normal function, overall productivity, and satisfaction with overall 111 ® effectiveness. Whether Treximet is superior to monotherapy with the commercially available 100 mg dosage of sumatriptan, or any other triptan, has not yet been directly evaluated in any known head-to-head trial. Triptans Page 38 of 80 Final Report Update 4 Drug Effectiveness Review Project ® Placebo-controlled trials: Treximet ® Placebo-controlled trials provided supplemental evidence on the efficacy of Treximet in early 112-116 treatment of migraine when pain is still mild. Treximet is the most well-studied triptan for early treatment of mild ® migraine. The efficacy of Treximet (rapid-release sumatriptan RT 85 mg/naproxen 500 mg) administered early in a migraine while the pain is still mild has been demonstrated in 6 trials (GlaxoSmithKline Protocols TRX101998, TRX101999, TRX103632, TRX103635, TRX106571, and TRX106573), enrolling a total of over 2700 adults. Methods and results for 2 pairs of protocols (TRX101998 and TRX101999; TRX103632 and TRX103635) are fully published in 2 116, 117 journal articles, respectively. Methods and results for protocols TRX106571 and TRX106573 had not yet been published at the time of this report, but were accessed from the summary reports available on the manufacturer’s clinical trial registry website (http://www.

To what extent these results have an effect on medical care of HIV-infected patients remains unclear purchase 50mg imitrex visa. However order imitrex 25mg on line, the SMART study did show an increase in the cardiovascular event rate in patients in whom ART was discontinued intermittently compared to patients who received ART continuously (El-Sadr 2006) discount imitrex 50 mg with amex. It was suggested that increased inflam- mation during treatment interruption is responsible for this (Kuller 2008). Summing up, the evidence for negative effects of ART on CAD is not strong enough to influence the decision of when to start or switch ART regimens in terms of the cardiovascular risks. HIV+ men exhibited slightly more positive arterial remodel- ing on coronary CT than negative controls (Miller 2015). Also, the prevalence of coronary calcium is higher (Chow 2015). However, in a sonographic controlled study of the development of carotid plaques HIV+ patients with high baseline CD4 T cells did not have an increased risk compared to normal controls. It was concluded that the degree of immunodeficiency might play a role in the progression of atheroscle- rosis. Studies focusing on subclinical atherosclerosis predict an increasing prevalence of CAD in the near future as the population continues to age (Triant 2009, Lo 2010). It has been shown that HIV+ subjects exhibit a marked cardiovascular risk profile (Neumann 2003+2004a+b). Most notably, cigarette consumption is two- to three- fold higher than in non-infected populations. In addition, uncontrolled blood pressure is frequent in HIV+ patients (Nuernberg 2015) and a recent publication revealed that treatment of risk factors is frequently insufficient (Reinsch 2012). Especially patients with known CAD and diabetes exhibit a high risk for subsequent cardiovascular events (CAD: 7. Prevention and treatment of CAD Prevention and early diagnosis of CAD in patients older than 45 years and with an elevated cardiovascular risk profile should, therefore, be routine in current thera- peutic management of HIV infection. Primary and secondary prevention should aim at modifying known risk factors (Lundgren 2008a). Prevention of CAD is based on the most recent general guidelines (Smith 2006, Perk 2012) (Table 1) and EACS guide- lines (Lundgren 2008a). A number of different scores for calculation of the cardio- vascular risk profile is proposed. However, all of them take into account the classi- cal risk factors hyperlipidemia, diabetes, hypertension and smoking. Primary prevention of CAD aims at the control of these risk factors to lower the future risk of cardiovascular events. Primary prevention of CAD starts by modifying lifestyle and comprises cessation of smoking and a balanced diet with a low content of saturated fatty acids and trans- unsaturated fatty acids, a reduced salt intake as well as a high amount of fibers, fruits and vegetables. Moderate intensity physical activity with a cumulative duration of 2. Weight reduction which aims at a BMI of 20–25 is beneficial for the control of blood pressure and metabolic imbalance. If control of blood pressure cannot be achieved with lifestyle modifications only, drug therapy should be initiated. Drug therapy can comprise any of the standard antihypertensives (diuretics, ß blockers, calcium channel blockers, ACE inhibitors angiotensin receptor blockers and renin antagonists) or a combination (caveat: do not combine ACE inhibitors, angiotensin receptor blockers and renin antagonists). When using calcium channel blockers, interactions with ART (boosted PIs! When multiple metabolic risk factors are present, diuretics and ß blockers are not recommended. The aim of blood pressure control should be a sys- tolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg. Hyperlipidemia can be approached with lipid lowering drugs. Statins are the therapy of first choice but might interact with ARVs. In particular, several PIs act as substrates for isoenzyme 3A4, a subgroup of the cytochrome p450 system. Inhibition of the isoenzyme 3A4 can increase the blood concentration of statins and induce side effects. In contrast to most other statins, pravastatin and fluvastatin are not modu- lated by isoenzyme 3A4. Therefore, these two drugs are preferred in HIV+ patients. Simvastatin is contraindicated in patients receiving ritonavir-boosted PI-based ART. The goal of statin therapy is lowering the LDL-cholesterol level to targets shown in HIV and Cardiac Diseases 589 Table 1. In case of insufficient control of LDL cholesterol levels the cholesterol uptake inhibitor ezetrol can be added. Diabetes in HIV+ patients should be treated according to the general guidelines. From the cardiovascular point of view, an HbA1c of <7mg/dl should be aimed for. Table 1: Prevention of coronary heart disease •Stop smoking •Balanced diet •Moderate intensity exercise training (2. The control of risk factors should be a goal in patients with a very high risk of cardiovascular events. In randomized clinical trials, low dose aspirin (100 mg/d), ß blockers, ACE inhibitors and statins decrease the risk of mortality and re-infarc- tion in patients with CAD. If aspirin is not tolerated it may be substituted by drugs that blocks the ADP receptor on platelets such as clopidogrel 75 mg/d. A calcium antagonist, nitrates, ranolazine and/or procoralan can be supplemented for symp- tomatic treatment. In patients with acute coronary syndrome a dual antiplatelet therapy should be maintained for at least 12 months. The indication for invasive vascular diagnostic and intervention depends on current guidelines (http://www. Clear indications for coronary angiography are a documented exercise-induced ischemia, typical clinical symptoms together with ST alterations in the ECG, increases in cardiac enzymes and/or a marked cardiovascular risk profile. It is worth emphasizing that HIV infec- tion is not an exclusion criteria for invasive procedures. Successful coronary inter- ventions have been performed on HIV+ patients, including catheter procedures with implantation of drug-eluting stents (DES) (Saporito 2005, Glazier 2006, Neumann 2010) and coronary artery bypass operations (Filsoufi 2006).

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