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By M. Ateras. Centenary College of New Jersey.

Although it had a significant proportion of subjects with New York Heart Association Class II symptoms buy adalat 30mg visa, the mean ejection fraction was similar to that of CIBIS-II generic adalat 30 mg with amex. MERIT-HF was well-designed and well-conducted and had clear-cut overall reductions in Beta blockers Page 34 of 122 Final Report Update 4 Drug Effectiveness Review Project overall mortality cheap adalat 30 mg with visa, death from cardiac causes buy 20 mg adalat with amex, sudden death, and heart transplantation, as well as a reduction in all-cause hospitalization (RR, 0. The MERIT-HF investigators defined a “high risk” group consisting of the 795 patients who had New York Heart Association class III-IV and ejection fraction <25%. This subgroup had a mean ejection fraction (19%) and placebo group mortality (18. The applicability of the results of any trial to a United States population is a major issue in all of these trials, because heart failure survival depends on other aspects of care. The United States Food and Drug Administration review of the MERIT-HF trial found “a strong suggestion of a treatment-by-region (United States compared with Europe) interaction with respect to mortality. The placebo group mortality was higher in Europe (168/1462; 11. Metoprolol succinate reduced all-cause mortality in Europe (hazard ratio, 0. The lack of any trend toward reduced mortality in the United States subgroup is of concern. For carvedilol, relevance to the United States population is not a concern, because the United States Carvedilol Trials were performed in the United States. Rather, the concern is what COPERNICUS adds to what was already known from the United States Carvedilol Trials. About 1 in 5 patients in COPERNICUS were from the United States; the hazard ratio was 0. Statistically, this difference is not meaningful, but that is not the whole story, for 2 reasons. Second, the proportion of United States patients in COPERNICUS was much lower than in MERIT-HF, so it is not surprising that the United States subgroup (n=482) was not a statistical outlier in COPERNICUS. Next to the United States, Russia (n=309) and Poland (n=299) recruited the most patients in COPERNICUS, and carvedilol had larger mortality reductions in these 2 countries than in 9 of 13 others. CIBIS-II was a well-conducted multicenter European study designed to recruit stable 83 subjects with moderate to severe heart failure (New York Heart Association Class III-IV). Most patients were New York Heart Association Class III. The annual placebo mortality rate was 13%, which is higher than the rate projected by the CIBIS-II investigators based on the results of CIBIS-I. Nevertheless, this mortality rate and the average ejection fraction of 27% are closer to those of MERIT-HF, which recruited mostly Class II and III patients, than to those of COPERNICUS, which is thought to have recruited New York Heart Association Class III and IV patients. In CIBIS-II, 752 subjects were New York Heart Association Class III or IV and had an ejection fraction less than 25%, but the results in this subgroup have not been reported completely, although the hazard ratio was said to be 0. For the Class III patients, annual placebo group mortality was about 13%; over the entire study (averaging 1. For the Class IV patients, the annual placebo mortality was about 18%, and the number needed to treat to prevent 1 death over 1. The mortality reduction for Class IV patients was of borderline statistical significance; when measured as a difference of probabilities, the confidence interval was 0. Beta blockers Page 35 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 9. Comparison of major beta blocker trials in heart failure Ejection New York Withdrawal fraction Heart Number Annual rate for Drug and criteria Association of placebo Mortality active drug a Trial target dose (mean) class subjects mortality reduction group Bisoprolol III (81%) CIBIS-II 10mg once <35% (0. Withdrawal rates are also affected by use of an active-drug run-in phase. When program was terminated, more patients were receiving or had completed treatment with carvedilol than placebo (89% compared with 83%, P=0. Beta blockers Page 36 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 10.

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Mixed populations: Primary and secondary progressive multiple sclerosis Glatiramer acetate 2 • In a -site study conducted in a “chronic progressive” patient population order adalat 20 mg on line, glatiramer ® acetate (Copaxone ) was found to be superior to placebo for disease progression and Expanded Disability Status Scale change at 24 months at 1 of 2 centers 20 mg adalat with mastercard. There were no other significant differences between the glatiramer acetate and placebo groups in effectiveness outcomes order 30 mg adalat visa. No studies of beta interferons buy discount adalat 30mg line, natalizumab, or mitoxantrone in a mixed primary and secondary progressive multiple sclerosis population were found. Progressive relapsing multiple sclerosis • No studies were identified that assessed the use of 1 of the included drugs in patients with progressive relapsing multiple sclerosis. Mixed populations: Clinically isolated syndrome + relapsing-remitting multiple sclerosis ® • One small fair-quality study compared interferon beta-1b SC (Betaseron ) to glatiramer acetate and found no difference on relapse related outcomes. Disease-modifying drugs for multiple sclerosis Page 25 of 120 Final Report Update 1 Drug Effectiveness Review Project Detailed Assessment Previously conducted systematic reviews of disease-modifying drugs for multiple sclerosis We found 6 systematic reviews that assessed multiple drugs for the treatment of multiple 31-37 sclerosis. One of these reviews was updated in 2009 but without new evidence of the 38 outcomes of interest this review was not analyzed further. One review focused on treatment of 33 symptoms rather than disease modification and will not be discussed here. Another focused on the association of depression with beta interferon and glatiramer acetate treatment and is 34 discussed under Key Question 3 below. The 4 remaining reviews included beta interferons, glatiramer acetate, and mitoxantrone. The best quality review was the one conducted for the National Institute for Clinical Excellence by Clegg and Bryant and a related article that updated 31, 32 that review. This review assessed the general effectiveness of the interventions compared with placebo. No attempts were made to compare the drugs to one another; however the review will be used in the appropriate sections below. Additional systematic reviews of individual drugs are considered as appropriate below. Relapsing-remitting multiple sclerosis Beta interferons 37 While we found 1 systematic review that directly compared the interferons, 2 additional studies directly comparing beta interferons have since been published, limiting the usefulness of that review for our purposes. Direct evidence Five trials directly compared one beta interferon to another, ranging from 16 to 24 months in 39-43 duration in patients with relapsing-remitting multiple sclerosis. While these were all fair- quality trials, there was variation in their features and risk of bias. However, none met all criteria for good quality, and none presented sets of flaws that appeared to indicate high risk for bias. The EVIDENCE trial compared 2 44 the beta-1a interferons to each other and original data was published in 2002. A crossover phase followed in which all patients were either switched to or continued on interferon beta-1a ® SC (Rebif ). Given the lack of comparative data on this crossover phase, it will only be included 45 in the discussion of harms that follows. The 2 Etemadifar trials compared all 3 beta interferons to another, and in the most recent trial, also to azathioprine. This later study did not report 43 relapse related outcomes. Both Etemadifar studies were small, ≤30 patients per group and as low as 13 in the second trial. In the first trial, the baseline mean or median Expanded Disability Status Scale in the groups ranged from 1. In the second trial the mean baseline Expanded Disability Status Scale score was 1. While dosing for interferon beta-1b SC (Betaseron ) 250 µg every other day and ® interferon beta-1a IM (Avonex ) 30 µg once weekly were consistent across the studies, the ® dosing for interferon beta-1a SC (Rebif ) ranged from 22 µg once weekly to 44 µg 3 times a Disease-modifying drugs for multiple sclerosis Page 26 of 120 Final Report Update 1 Drug Effectiveness Review Project week. Additionally, the Danish Multiple Sclerosis Study Group patients were more severely ill compared with the other studies, and the studies differed in terms of whether the endpoint reported was primary or secondary.

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Since the treatment of constipation symptoms is similar in the two conditions buy adalat 20mg on-line, we reviewed and included clinical trials related to constipation symptoms in these two conditions (IBS-C and chronic constipation) purchase adalat 20mg. Functional constipation is considered one of a group of five functional bowel disorders defined by the Rome III classification system (developed by multinational working teams known as the Rome 8 Committees) adalat 30 mg generic. As a functional disorder buy adalat 30 mg with amex, constipation can stand on its own as a distinct diagnosis of functional constipation or be part of another functional bowel disorder of IBS. IBS is the most common Constipation Drugs Page 6 of 141 Final Report Drug Effectiveness Review Project functional gastrointestinal disorder. It is defined as a combination of chronic or recurrent gastrointestinal symptoms, not explained by structural or biochemical abnormalities. The diagnosis is based on identifying typifying symptoms, using of symptom-based diagnostic criteria, and limited diagnostic tests to exclude other conditions. In order to meet the criteria patients must have abdominal pain or discomfort associated with alterations in stool frequency, form, and passage. IBS is sub-classified as diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or mixed (combination of both), depending on the most prevalent bowel pattern. However, because the predominant symptom often changes over time, it is not uncommon 9 for a patient to alternate between these IBS subgroups. This report focuses on functional constipation and does not cover other IBS associated symptoms such as abdominal pain/discomfort, diarrhea, and bloating. The disorder may be secondary to systemic diseases (e. Another common etiology is the use of prescription or over the counter (OTC) medications that slow down the intestinal transit (Table 2). Chronic primary or idiopathic constipation is primarily a diagnosis of exclusion which is made when the other possible etiologies have been ruled out. Once primary idiopathic constipation has been diagnosed and “red flags” suggesting other serious diseases such as colon or rectal cancer have been eliminated, empiric treatment may be started with an appropriate follow-up to assess the response. Medications associated with constipation Prescription Over the counter (OTC) Opiates Antacids, especially calcium containing Anticholinergics Calcium supplements Tricyclic antidepressants Iron supplements Calcium channel blockers Antidiarrheal agents Antiparkinsonian drugs NSAIDS Sympathomimetics Antipsychotics Diuretics Antihistamines Constipation Drugs Page 7 of 141 Final Report Drug Effectiveness Review Project Approach to Management I. Initial recommendations In clinical practice patients with milder symptoms are usually offered behavioral, diet and lifestyle modifications as the first step of treatment. Despite the lack of controlled clinical trials to support these recommendations patients are often encouraged to increase their fluid intake, get involved with moderate increase in exercise, and use the bathroom daily in response to feeling of urge for a bowel movement or at a specific time, particularly after meals. Patients with more severe symptoms or those who do not respond to this initial treatment are usually offered an empiric medication treatment with fiber supplements and “simple laxatives. Evaluation of chronic primary constipation The initial evaluation is based on careful history and physical evaluation. Important historical features include bowel frequency, stool consistency, need for straining, and feeling of incomplete evacuation. Presence of abdominal pain/discomfort can suggest a diagnosis of other functional disorders (e. Patients’ medications should be reviewed carefully and initial limited laboratory tests should be performed to exclude medications (e. The majority of patients with constipation are seen by primary care physicians. Those who are more difficult-to-manage or fail to respond to the initial medical therapy are referred to GI specialists or tertiary care centers. In these settings, patients with primary constipation can be further evaluated for the underlying pathophysiological mechanism(s) of their constipation. Using functional tests of the colon and anorectum, primary constipation can be divided into three separate subgroups: 1. Obstructed defecation Slow transit Constipation refers to a decrease in colonic transit particularly in its proximal parts (i. Normal transit constipation refers to patients who meet the criteria for chronic functional constipation but testing of their colonic transit is between normal limits. These patients often have misperceptions of normal bowel movements and some may have psychosocial disorders. Obstructed defecation refers to organic/mechanical obstruction at the level of the rectosigmoid colon or Constipation Drugs Page 8 of 141 Final Report Drug Effectiveness Review Project pelvic floor, or functional obstruction due to failure of the anorectal and pelvic floor muscles to relax during defecation. In clinical practice only a small minority of patients with primary constipation undergo formal physiologic testing to identify the underlying pathophysiology and subgroup to which they belong.

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ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors References and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 1 purchase adalat 20mg visa. A randomized comparison expert consensus document on reducing the gastrointestinal risks of of antiplatelet and anticoagulant therapy after the placement of coronary- antiplatelet therapy and NSAID use discount adalat 20mg otc. Cytochrome P450 2C19 loss-of- antithrombotic-drug regimens after coronary-artery stenting order 20mg adalat with mastercard. N Engl function polymorphism is a major determinant of clopidogrel responsive- J Med purchase 20 mg adalat with visa. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic 21. Effects of clopidogrel in addition to aspirin in CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacody- patients with acute coronary syndromes without ST-segment elevation. Cytochrome P450 2C19 aspirin and fibrinolytic therapy for myocardial infarction with ST- 681G A polymorphism and high on-clopidogrel platelet reactivity segment elevation. Addition of clopidogrel to aspirin in ous coronary intervention with drug-eluting or bare-metal stents. JAm 45,852 patients with acute myocardial infarction: randomised placebo- Coll Cardiol. Impact of P-glycoprotein on phisms and Response to Clopidogrel. Association of cyto- major determinant of clopidogrel efficacy. Cuisset T, Morange PE, Quilici J, Bonnet JL, Gachet C, Alessi MC. Genetic determinants of Paraoxonase-1 and clopidogrel efficacy. Relation of cytochrome P450 CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and 2C19 loss-of-function polymorphism to occurrence of drug-eluting in vivo antiplatelet response. Cytochrome P450 2C19 loss-of- metabolization, and antiplatelet effects of 300-, 600-, and 900-mg function polymorphism and stent thrombosis following percutaneous loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoro- coronary intervention. Effects of CYP2C19 genotype on and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Preven- outcomes of clopidogrel treatment. The relationship between polymorphisms on the effect of high- and standard-dose clopidogrel CYP2C19 polymorphisms and ischaemic and bleeding outcomes in after percutaneous coronary intervention: the GIFT (Genotype Informa- stable outpatients: the CHARISMA genetics study. Paraoxonase-1 is not a major genotype, clopidogrel metabolism, platelet function, and cardiovascular determinant of stent thrombosis in a Taiwanese population. CYP2C19 genotype and cardiovascu- variant and response to clopidogrel and prasugrel [abstract]. Plavix (clopidogrel bisulfate) tablets: prescribing infor- variant, platelet aggregation, bleeding events, and stent thrombosis in mation. Genetic variants in ABCB1 and based on CYP2C19 genotype and the effect on platelet reactivity in CYP2C19 and cardiovascular outcomes after treatment with clopidogrel patients with stable cardiovascular disease. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospec- 35. Effect of CYP2C19 and ABCB1 single tive, randomised, proof-of-concept trial. No association of paraoxonase-1 (Clopidogrel and Response Variability Investigation Study 2). JACC Q192R genotypes with platelet response to clopidogrel and risk of stent Cardiovasc Interv. Paraoxonase-1 Q192R P2Y12 receptor antagonist activity. Campo G, Ferraresi P, Marchesini J, Bernardi F, Valgimigli M. First analysis of the relation variants influence clopidogrel pharmacokinetics, pharmacodynamics, between CYP2C19 genotype and pharmacodynamics in patients treated and clinical efficacy in post-myocardial infarction patients. Circ Cardio- with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND vasc Interv. Predicting clopidogrel lar Angiography and Interventions. Effect of PON1 Q192R genetic Implementation Consortium guidelines for CYP2C19 genotype and polymorphism on clopidogrel efficacy and cardiovascular events in the clopidogrel therapy: 2013 update.

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