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Head-to-head trials Adverse events reported in short-term head-to-head trials of different estrogen preparations are shown in Evidence Tables 7 (trials with symptom outcomes) and 8 (trials with bone outcomes) glipizide 10 mg fast delivery diabetes mellitus management. Head-to-head comparison trials provided insufficient evidence to determine the relative adverse effects of different estrogens glipizide 10 mg with amex diabetes in dogs and seizures. One trial of CEE and oral E2 reported that the incidence of possible drug-related adverse experiences ranged from 20% in placebo 10 mg glipizide free shipping diabetes prevention vegan, E2 1 mg/day buy glipizide 10 mg with visa diabetes type 2 japan, and CEE 0. Most head-to-head trials reported similar rates of specific adverse events and withdrawals due to adverse events between treatment groups, with a few exceptions. In one trial, a significantly greater incidence of breast tenderness was found in women randomized to oral E2 2 mg plus NETA versus CE 5 mg plus MPA, and more women in the E2/NETA group withdrew 19 from the trial during the first 3 months (17. A trial of a vaginal ring releasing E2 compared with an E2 vaginal tablet found more withdrawals in the vaginal ring group, mainly occurring during the first 3 months of treatment and due to abdominal discomfort, 25 lower back pain, and slippage of the ring. In a head-to-head trial of an intravaginal ring delivering E2 compared with oral E2 for treatment of vasomotor symptoms, there were no 24 significant differences between groups in the frequency of the most common adverse events. Placebo-controlled trials Withdrawals due to adverse effects and withdrawals due to specific adverse effects in placebo controlled trials are summarized in Evidence Table 9 for trials of hot flashes and Evidence Table 10 for trials of bone density and fractures. Specific adverse effects include atypical bleeding and endometrial hypertrophy, nausea and vomiting, breast tenderness, headache, weight change, dizziness, venous thromboembolic events (VTE), cardiovascular events, rash and pruritus, cholecystitis, liver effects, and others including breast cancer and additional problems. These outcomes were reported unevenly across studies and could not be combined in summary statistics. Among trials with placebo groups, comparisons between types of estrogens cannot be made with the data provided. The most notable differences between estrogen and placebo groups were breast tenderness and vaginal bleeding; both symptoms were more frequent among women with higher compared to lower doses of estrogen regardless of type of estrogen. Reports of bleeding varied depending on concomitant progestin/progesterone use and regimen (cyclic or continuous). Several of the other symptoms, such as headache and mood changes, were common for both estrogen and placebo groups. Adverse skin reactions were most common among women using transdermal forms of E2. Withdrawals were often high among the placebo group Hormone therapy Page 50 of 110 Final Report Update 3 Drug Effectiveness Review Project in the hot flash trials because of lack of treatment effect among women who were enrolled based on the presence of symptoms. In Update #3, among placebo-controlled trials examining efficacy/effectiveness of 31, 34-36, 38 estrogen projects on symptoms, five studies reported harms. All efficacy trials with bone density outcomes reported some information on harms. We identified an additional four studies which reported adverse effects without reporting efficacy or effectiveness (Evidence 195-198 Tables 9 and 10). Oral estrogen/progesterone regimens increased vaginal spotting and atypical vaginal 31, 34, 38, 121, 122, 141, 170, 198, 199 bleeding compared with placebo. Withdrawal rates due to vaginal bleeding specific to treatment group were not reported in most studies, however. In a trial of BMD outcomes, 18% of women taking E2 1 mg plus intermittent norgestimate withdrew due to 121 uterine bleeding. A study of estradiol/drospirenone reported one woman with severe bleeding 36 198 requiring hysterectomy, revealing adenomyosis and leiomyomata. Langer and colleagues reported no cases of endometrial hyperplasia in the treatment or placebo group; one case of endometrial cancer occurred in the placebo group. Rates in year 2 were also similar (between-group p-value 0. Focal atypical endometrial hyperplasia developed in 1/188 women in treatment group and in 0/177 in the placebo group. One adenosarcoma of the uterus developed in the treatment group and none with placebo. Breast tenderness was reported significantly more frequently with conjugated equine 170, 171 34 estrogen with medroxyprogesterone than with placebo. Headache and dizziness or 31, 34 disorientation were reported at similar rates between estrogen users and the placebo group, 31 31 as was the percentage of study subjects gaining weight. Greenspan and colleagues reported that the incidence of venous thromboembolic disease, endometrial and colon cancer, hospitalizations, myocardial infarction, and clinical fractures was similar between subjects receiving conjugated equine estrogen with medroxyprogesterone and placebo. Speroff and 38 colleagues reported that rates of headache, breast tenderness, vaginal bleeding, and palpitations were evenly distributed between treatment with ethinyl estradiol/norethindrone acetate and placebo (n=266). In a small study (n=40), similar rates of unspecified gastrointestinal adverse effects and headache were reported between the group using CEE and the placebo group (no 35 statistics provided). In the WHI (see Table 11, summary table), vaginal bleeding was frequent among the 81 CEE plus MPA treatment group, occurring in 42. In contrast, reports of bleeding never exceeded 8% in the placebo group. Among women asymptomatic at baseline, the treatment group also reported more breast tenderness at 1- year follow-up (CEE+MPA 9. This group also reported more vaginal discharge (CEE+MPA 4. In Update #3, six new trials were identified which examined the effects of hormone 26, 31, 32, 40, 43, 78 therapy on cognitive function with follow-up between 12 weeks and 3 years, all demonstrating no differences between groups at up to 2-year followup. The fair-quality ULTRA 78 trial found no significant differences at 2-year follow-up between treatment with low-dose transdermal estradiol and placebo for multiple measures of cognitive function: Mini Mental Hormone therapy Page 51 of 110 Final Report Update 3 Drug Effectiveness Review Project State Exam, logical memory, Brief Visual Spatial Memory Test, memory and recall of words, and verbal fluency. Similar negative results were found in a small, fair-quality study of estradiol 32 patch. In the fair quality study (n=373), the Folstein Mini-mental State Examination did not differ between the hormone replacement group (conjugated equine estrogen with or without progesterone depending on uterine status) and placebo at 3-year follow-up. Self-reported 31 function and physical activity levels also did not differ significantly between groups. A poor-quality study did not find differences between treatment group for multiple measures of 43 cognitive function either. A fair-poor quality study reported improvement in 1 of 5 measures 40 of cognitive function at 12-week follow-up (p=0. What is the comparative safety of different hormone therapy preparations for long-term use (5 or more years)? Summary points - In the WHI CEE/MPA study, coronary heart disease (CHD) events increased significantly, although CHD mortality did not at 5. In the WHI CEE-only study, CHD events were not increased. Global cognitive function and mild cognitive impairment did not differ from placebo groups in either WHI study. Rates of cardiovascular mortality were not increased - In the WHI CEE-only study, a significant increase was noted in the hazard ratio (unadjusted for multiple comparisons) for stroke and venous thromboembolism. Rates of probable dementia, cardiovascular events or mortality, and invasive breast cancer were not increased. The WHI was designed as a primary prevention trial, not a trial of menopausal symptom treatment.
Diseases
- Hyperinsulinism, focal
- Familial hyperlipoproteinemia type III
- PARC syndrome
- Hypolipoproteinemia
- Deafness, neurosensory nonsyndromic recessive, DFN
- Willebrand disease
- Human granulocytic ehrlichiosis
Moreover buy 10 mg glipizide visa joslin diabetes diet guidelines, other studies did not find an association between number of resistance mutations and mortality (Lucas 2004) generic glipizide 10 mg otc diabetes type 2 or 1. With good CD4 T cell counts order glipizide 10 mg without prescription diabetic vasculopathy, even despite TCR viruses purchase 10mg glipizide otc diabetes control quotes, the risk of developing AIDS is relatively small (Ledergerber 2004). TCR viruses have less ability to replicate and are probably less aggressive (Prado 2005). New drug classes such as attachment or maturation inhibitors but also neutralizing antibodies will represent new options. It is, however, important that patients with MDR viruses are very carefully moni- tored and undergo regular (monthly) full-body exams – something that is often neg- 6. Salvage therapy 225 lected these days in the discussions on blood values and resistance testing, etc. Loss of weight, Stage B symptoms, oral candidiasis, OHL and cognitive worsening are early signs of disease progression that need to be watched for. If possible, these patients should be treated in large centers that have access to clinical studies. Salvage with the newer drugs A wide range of agents for the treatment of patients with limited options has been licenced in the last few years. These agents include the PIs tipranavir/r and darunavir/r, the NNRTI etravirine, the CCR5 antagonist maraviroc and the integrase inhibitors raltegravir and, more importantly, dolutegravir. They have revolutionized salvage therapy and have become indispensable in the struggle against resistant viruses. The most important results on salvage therapy from large-scale studies within the last few years are shown in Tables 9. In some studies inclusion was coupled to certain resistance mutations, others included triple-class failure. There were great differences in patient populations and the definition of TCF was not con- sistent. The proportion of patients additionally receiving T-20 ranged from 20–44%. Different resistance scores were also used in order to determine the number of active agents in background therapy. Accordingly, response rates vary considerably even in the placebo arms. The rates of all patients with a plasma viremia less than 50 copies/ml at 48 weeks ranged from 10% to 40%, with addition of T-20 from 11% to 62%. The response rates of patients who had received only one active agent and placebo varied from 1–24%. Cross-trial comparisons regarding the efficacy of the new agents need to be avoided, although this is attempted for marketing reasons. According to these trials, darunavir/r is not better than tipranavir/r. Raltegravir does not have a higher efficacy than maraviroc. However, in many of these trials, patients were not as heavily pretreated as in the above mentioned trials such as TORO, MOTIVATE or BENCHMRK (Table 9. In the 145-Study, in which raltegravir and elvitegravir were tested in a double-blinded design (with similar results), the main inclusion criteria were a viral load of more than 1. In the SAILING Study, in which superiority of dolutegravir over raltegravir was shown, patients were enrolled when they had at least 400 copies/ml and RAMs against only two classes. At least one fully active agent was required (Cahn 2014). However, studies like SAILING, although not conducted in “true” salvage patients, provide practical information for the concrete treatment of these patients (see below). What to do in patients with TCR First of all, a resistance test should be available that was not done during a treatment interruption. Resistance mutations detected earlier presumably still exist even if they are no longer detected. It is also important to check incompatibilities of the last years to spare the patient unneces- sary side effects and dangerous re-exposure. Some pilot studies reported success when only new drugs are used. In the French TRIO study, 103 extensively pretreated patients with TCF were treated with RAL+ETV+MVC, out of which 86% achieved plasma viremia below 50 copies/ml at 48 weeks (Yazdanpanah 2009). In a smaller Italian study with 28 patients on the same combination RAL+ETV+MVC, this got to 96% after 4 years (Nozza 2014). Before switching, physicians should go over the classes, one by one, depending on the individual resistance profile, even the old ones. Consider AZT and TDF simultaneously, due to diverging resistance pathways NNRTIs At <3 NNRTI mutations, consider etravirine (approved only with a boosted PI/r), otherwise discontinue NNRTIs PIs Darunavir/r (good data with etravirine) or tipranavir/r Maraviroc Tropism test? Due to non-detected dual-tropic viruses, use 2 definitively active agents such as raltegravir and T-20 (if nothing else works), remember dose adaptions when boosting with PIs INSTIs At least 1–2 active agents additionally needed, be aware of rapid resistance development, dolutegravir most potent T-20 Consider when uncertain that at least one other agent beyond dolutegravir or maraviroc is active NRTIs: Even if 3TC or FTC are no longer effective according to the resistance test, it might make sense in many cases to continue treatment with them. In this way, HIV is forced to conserve the M184V mutation, which reduces the replication fitness (Eron 2004, Campbell 2005, Castagna 2006). Due to diverging resistance pathways, another consideration may be to use AZT and TDF. This also applies when patients have already been treated with these agents. By adding AZT, viral load can be decreased to below detection in the presence of resensitizing K65R (Stephan 2010). However, recent studies evaluating if partially active or inactive NRTIs contribute to treatment response have yielded conflicting results (Imaz 2011, Scherrer 2011). NNRTIs: In the case of NNRTIs, with less than three NNRTI resistance mutations, etravirine seems to be a good option in combination with a boosted PI (most effec- tive with darunavir/r). In other cases it is recommended to discontinue NNRTIs. There is little doubt that once generated, resistance remains. However, with preg- nant women who have received nevirapine once for transmission prophylaxis there was no elevated rate of treatment failure on nevirapine-containing regimens if ART was initiated more than 6 months after delivery – at least theoretically, it seems pos- sible for NNRTI resistances to disappear provided one waits a long enough time (Lockman 2007). However, there is no other data on recycling NNRTIs besides those for transmission prophylaxis. PIs: In the case of PIs, the boosted PIs darunavir and tipranavir are strongly recom- mended. These PIs probably have distinct resistance profiles. When resistance find- ings are unclear, they should be discussed with the virologist. If darunavir/r and tipranavir/r are not available or if they are not tolerated, one can try lopinavir/r; other PIs are probably not suitable. INSTIs: in patients naïve to INSTIs, all three agents, namely raltegravir, elvitegravir and dolutegravir can be considered.
For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study cheap glipizide 10mg with visa diabetes type 2 patient education. However generic 10mg glipizide with visa blood glucose 110, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients buy 10 mg glipizide with mastercard diabetes medications and weight gain. For these reasons discount 10mg glipizide otc diabete zuccheri consentiti, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient. Long-acting opioid analgesics 8 of 74 Final Update 6 Report Drug Effectiveness Review Project Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of study results to their practice and should note where there are gaps in the available scientific information. Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment. In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice. Scope and Key Questions The key questions and scope of the review were originally developed and refined by the Oregon Evidence-based Practice Center with input from a statewide panel of experts (pharmacists, primary care clinicians, pain care specialists, and representatives of the public). Subsequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review: 1. What is the comparative effectiveness of different long-acting opioids in reducing pain and improving functional outcomes in adult patients being treated for chronic noncancer pain? Long-acting opioid analgesics 9 of 74 Final Update 6 Report Drug Effectiveness Review Project 2. What is the comparative effectiveness of long-acting opioids compared with short-acting opioids in reducing pain and improving functional outcomes when used for treatment of adults with chronic noncancer pain? What are the comparative harms (including addiction and abuse) of different long-acting opioids in adult patients being treated for chronic noncancer pain? What are the comparative harms of long-acting opioids compared with short-acting opioids in adult patients being treated for chronic noncancer pain? Are there subpopulations of patients (specifically by race, age, sex, socioeconomic status type of pain, or comorbidities) with chronic noncancer pain for which one long-acting opioid is more effective or associated with fewer harms? Are there subpopulations of patients (specifically by race, age, sex, socioeconomic status, type of pain, or comorbidities) with chronic noncancer pain for which long-acting opioids are more effective or associated with fewer harms than short-acting opioids? Several aspects of the key questions deserve comment: Population. The population included in this review was adult (18 years old or greater) patients with chronic noncancer pain. We defined chronic noncancer pain as continuous or recurring pain for at least 6 months. Cancer patients and patients with HIV were excluded from this review. We included oral or transdermal long-acting opioids. Although dosing frequency varies for an individual formulation of morphine, we refer to dosing twice daily in a trial as “sustained- release” and once daily as “extended-release”. Black box warnings of the included drugs are provided in Appendix B. Although extended-release tapentadol is available in Canada and Europe, the participating organizations of Drug Effectiveness Review Project elected to exclude it from this review because it is not yet available in the United States. Extended-release Tramadol was also excluded because its mechanism of action is different from the other included long-acting opioids. It is believed that tramadol works through binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Long-acting opioid analgesics 10 of 74 Final Update 6 Report Drug Effectiveness Review Project Table 1. Included drugs Recommended usual dosing Drug Trade name(s) Forms frequency (times per day) Buprenorphine Butrans™ ER transdermal film Every 7 days a Codeine Codeine Contin ER oral tablet 2 b Dihydrocodeine DHC Continus Oral tablet 2 Fentanyl Duragesic ER transdermal film Every 72 hours Hydromorphone Exalgo ER oral tablet 1 c Levorphanol Generic Oral tablet 3-4 Methadone Dolophine Oral tablet 2-3 Avinza ER oral capsule 1 Kadian ER oral capsule 1-2 Morphine MS Contin ER oral tablet 1-3 Oramorph SR ER oral tablet 2-3 Morphine sulfate and naltrexone Embeda™ ER oral capsule 1-2 hydrochloride Oxycodone OxyContin ER oral tablet 2 c Oxymorphone Opana ER ER oral tablet 2 Abbreviations: ER, extended release; SR, sustained release. The main efficacy measures were pain intensity, pain relief, and function. There is no single accepted standard regarding how to measure these outcomes. Most studies measure pain intensity using either visual analog or categorical pain scales. Visual analog scales consist of a line on a piece of paper labeled 0 at one end, indicating no pain, and a maximum number (commonly 100) at the other, indicating excruciating pain. Patients designate their current pain level on the line. An advantage of visual analog scales is that they provide a continuous range of values for relative severity. A disadvantage is that the meaning of a pain score for any individual patient depends on the patient’s subjective experience of pain. This poses a challenge in objectively comparing scores between patients, and even different scores from the same patient.
