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By A. Kor-Shach. Wesleyan College. 2019.

Unduly • Improvement with defecation restrictive diets have not been shown to be effec- • Onset associated with a change in frequency of tive trusted apcalis sx 20 mg. When constipation is troublesome buy generic apcalis sx 20 mg on-line, increasing stool dietary fiber will help; if diarrhea is a problem order apcalis sx 20 mg with mastercard, re- • Onset associated with a change in form (appear- ducing the amount of dietary fructose may help; if ance) of stool. Diagnosis If symptoms are more severe or not controlled IBS is a diagnosis based on symptoms and the by life-style adjustments, specific treatment should exclusion of organic disease. A full history and be offered depending on the most troublesome physical examination will reveal the need for fur- symptoms at the time. If there are none of the follow- symptoms are likely to wax and wane and that ing ‘alarm’ symptoms or signs, then a diagnosis of pharmacological treatment should be discontinued IBS can be made and treatment commenced28. The precise medi- cystograph cation used will depend on local availability. Hyo- • Tuberculosis: general examination + chest X-ray scine butylbromide has been shown to be effective for pulmonary tuberculosis. Staining/culture of and well tolerated for the treatment of recurrent urine for tuberculosis especially if sterile pyuria crampy abdominal pain in a dose of 10mg 3 times • Overactive bladder: women complain that when daily. It is poorly absorbed from the gastrointestinal 30 they feel the need to void they have to rush to tract and exerts its effects mainly by local action. They do not complain of pain Bulking agents and antidiarrheals • Endometriosis: can occasionally affect the These are indicated only if there are associated symp- bladder and would cause hematuria. Bulking agents do clude inflammation, autoimmune mechanisms (there not improve symptoms of IBS unless there is asso- is an association with systemic lupus erythematosus, ciated constipation. Likewise loperamide in a dose of Sjögren’s syndrome and inflammatory bowel dis- 2–4mg up to 4 times daily improves diarrhea, but 32 29 ease), and abnormalities of the bladder wall. Tricyclic antidepressants Diagnosis Amitriptyline in a dose of 10–25mg at night, may The pain of BPS is typically suprapubic, it may be be of benefit for patients whose pain does not im- a sharp pain but can also be more of a burning or prove with the above suggestions. It characteristically occurs as the bladder fills, and is relieved by voiding33. The pain must be accompanied by at least one other urinary BLADDER PAIN SYNDROME symptom, which in practice usually means multiple The bladder is a significant pelvic organ that can be symptoms including urinary symptoms related to involved in a number of disease processes causing intercourse. Sometimes there is referred pain to the chronic pain. In order to clarify the criteria for back, groin or vagina, and pain may be worse dur- diagnosing chronic pain arising in the bladder, the ing menstruation. Physical examination may reveal European Society for the Study of Interstitial bladder tenderness but is otherwise unremarkable. Cystitis in 2008 proposed that the term bladder Urinalysis is normal. The woman ‘Chronic pelvic pain (>6 months), pressure or records her fluid input as well as her perception of discomfort, perceived to be related to the urinary pain and the amount of urine she passes each time bladder is accompanied by at least one other urin- she voids over a 3-day period. Women should also ary symptom such as persistent urge to void or note any foods or drinks that make the pain worse. Confusable diseases that could cause the symptoms should be excluded’31. Treatment The main treatable diseases (‘confusable diseases’) This must begin with a full explanation of the con- that need to be excluded are: dition, that symptoms are likely to fluctuate over • Urinary tract infection: microscopy/culture of time, but worsening is uncommon, and there is no urine (if facilities available) or response to association with later development of bladder can- antibiotics cer. Many sufferers of BPS find that certain foods • Chlamydia infection of the urethra: history, and drinks make their symptoms worse. Acidic and sexual risk factors, swabs or urine tests if avail- spicy foods, coffee, tea, carbonated and alcoholic able (see Chapter 17) drinks seem to be the most troublesome. Avoiding • Schistosomiasis: microscopy urine and stool, these substances may be helpful34. Fluid restriction biopsy of cervix should not be advised as this can increase pain. With this cause of pain, evidence for this is lacking38. It is the woman is encouraged to very slowly increase unlikely that repeat surgery for adhesions will im- the time between each act of voiding, so gently prove chronic pelvic pain and may make it worse. Analgesics such as It is better to counsel the patient, provide pain paracetamol and NSAIDs can be taken if necessary. It dietary advice so that bloating and constipation are works in a number of ways to reduce pain, increase avoided. It is not being prescribed as ovary syndrome’, when an ovary left in situ at the an antidepressant. In both these circumstances ovulation PELVIC FLOOR MUSCLE DYSFUNCTION suppression is usually helpful6. Repeat surgery is likely to be difficult and should not be undertaken The pelvic floor muscles play a vital role in: main- by the inexperienced. Weakening of the pelvic floor muscles as CHRONIC PELVIC PAIN a result of difficult childbirth and/or repeated childbearing can increase the risk of genital pro- If the history and examination do not point to any lapse and urinary stress incontinence. Overactive, specific cause of the pain, reassurance is vital and chronically tense, pelvic muscles are associated with analgesia as described earlier should be made avail- constipation, BPS, dyspareunia and endometriosis able. Hormonal treatment as explained above for and it is often difficult to determine whether the endometriosis is often also helpful. A history of sexual abuse is another risk 37 PSYCHOLOGICAL ASPECTS OF PAIN factor. MANAGEMENT When a muscle becomes chronically tense there is often a specific sensitive area within the muscle The psyche has an important role to play in the per- that can be localized by palpation during vaginal ception of pain. Want- ments and alleviated in certain positions so that ing to know the cause of physical pain is normal. Health workers must likely to improve when associated conditions such explain ‘negative findings’ carefully to their client as IBS, BPS or endometriosis are controlled. Involving a ADHESIONS close relative or friend in the discussion may be beneficial. Adhesions may develop in the pelvis from pelvic inflammatory disease, endometriosis, appendicitis Behavioral and other therapies and after any surgical procedure, such as cesarean section, salpingectomy, ovarian cystectomy and Unfortunately, access to psychological help is not hysterectomy. Although often presumed to be the readily available in under-resourced countries, but 76 Chronic Pelvic Pain if the possibility exists it should be utilized. En- identifiable disease process, but this will only be couraging gentle resumption of activities can be determined after full history taking, physical exami- beneficial together with setting obtainable goals nation and basic investigations. Taking an interest in dromes tend to fluctuate in intensity over time and the client’s progress and keeping the door open for are rarely cured; however they do not progress to them to return if they feel they are not improving become malignant diseases. Clients who are clinically ditions tend to be poorly managed in under- depressed need to be appropriately referred for resourced countries because of the high work load effective management. However caring clinicians can easily help most women, even when only basic resources Traditional healers, complementary therapy are available, resulting in professional satisfaction and and herbal remedies clients who will not be a strain on the health sector. Traditional healers play an important role in the REFERENCES health care of many people in under-resourced countries.

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For persons with pre-diabetes or the metabolic syndrome cheap apcalis sx 20 mg fast delivery, do pioglitazone and rosiglitazone differ from one another or from placebo in delaying or preventing the occurrence of type 2 diabetes? For persons with type 2 diabetes what are the adverse events related to pioglitazone and rosiglitazone purchase apcalis sx 20mg free shipping, and how do these differ from each other discount apcalis sx online, from placebo, and from other oral hypoglycemic agents? Are there subgroups of persons with type 2 diabetes based on demographic characteristics or co-morbidities for which the benefits and adverse effects of pioglitazone or rosiglitazone Thiazolidinediones Page 10 of 193 Final Report Update 1 Drug Effectiveness Review Project differ from those in general populations, compared to each other and to other hypoglycemic agents? Thiazolidinediones Page 11 of 193 Final Report Update 1 Drug Effectiveness Review Project METHODS Literature Search To identify relevant citations for the original report, 2 independent reviewers identified potentially relevant titles and abstracts from the Cochrane Central Register of Controlled Trials rd (3 quarter 2005), Cochrane Database of Systematic Reviews, DARE, MEDLINE (1966 to July, rd week 4, 2005), and EMBASE (3 quarter 2005). All citations were imported into an electronic database (EndNote 9. For the update the original search terms were used, but titles and abstracts and then full- text articles were screened to include additional active-control studies that address the updated key questions and new head-to-head and placebo-controlled studies. Updated searches were conducted in November 2007 (Appendix A). Electronic searches were supplemented by hand searches of dossiers received from the makers of pioglitazone and rosiglitazone, and medical and statistical reviews available on the Food and Drug Administration website. Articles deemed potentially relevant after review of titles and abstracts were retrieved in full-text form. Two independent reviewers achieved consensus on all included and excluded articles. Excluded articles were coded in the EndNote database with the reason for exclusion. Study Selection The pharmacotherapeutic agents reviewed were the 2 thiazolidinediones currently available in the United States: pioglitazone hydrochloride (Actos ) and rosiglitazone maleate (Avandia™). Muraglitazar (Pargluva™) was not reviewed as it was not available in the United States as of January 1, 2008. Participants in included studies were adults with type 2 diabetes, prediabetes, or the metabolic syndrome. As noted above, various definitions exist for the metabolic syndrome. Any study examining persons with the metabolic syndrome was included if the authors used 1 of the widely accepted definitions mentioned above (see Table 1). Included studies examining type 2 diabetes had to present 1 or more of the primary outcomes of interest to this review: glycemic control (A1c), time to initiation of insulin for glycemic control, progression or occurrence of microvascular disease (nephropathy, retinopathy, and neuropathy), progression or occurrence of macrovascular disease (cardiovascular disease, cerebral vascular disease, amputation), other complications of diabetes, mortality, and quality of life. Included studies examined either effectiveness or efficacy of the 2 included drugs. The purpose of this report was primarily to examine effectiveness; however, since there were very few data available on effectiveness, efficacy studies were included and reviewed in detail. For efficacy, effectiveness, and safety, published and unpublished English-language reports in any geographic setting were included if they had a total sample size of ten or more participants. We included letters if primary data were presented and there was sufficient detail to evaluate quality. We excluded abstracts and conference proceedings, as these publications Thiazolidinediones Page 12 of 193 Final Report Update 1 Drug Effectiveness Review Project generally do not have sufficient detail to assess internal or external validity. Theses were not included as the full text is frequently difficult to retrieve. Selection criteria for the original report For the assessment of efficacy and effectiveness in the original report, we included reports of randomized controlled trials and controlled clinical trials. We included trials comparing rosiglitazone and pioglitazone (head-to-head trials), as well as trials comparing either one of these drugs to placebo. We also included trials comparing these drugs to another pharmacotherapeutic agent (active-control trials) only if they examined effectiveness outcomes or population subgroups. For examination of efficacy and effectiveness among subgroups, we expanded our inclusion criteria to encompass all study designs (that is, observational, before-after, case-control studies, and time series) where data were available. We used this approach because few controlled trials were available that examined subgroups; therefore, we expanded our inclusion criteria in order to examine the best available evidence, recognizing that study designs that do not involve randomization are weaker designs and are more likely to be biased or confounded by known or unknown factors affecting the outcomes of interest. For the assessment of tolerability and adverse effects, we included observational studies, including case series with a sample size greater than ten, before-after studies, randomized controlled trials, and controlled clinical trials. Clinical trials are often not designed to assess adverse events, may select low-risk patients (in order to minimize drop-out rates), or may have too short a follow-up period in which to adequately assess safety. Observational studies designed to assess adverse event rates may include broader populations, carry out observations over a longer time period, use higher quality methodological techniques for assessing adverse events, or examine larger sample sizes. Safety and tolerability were examined using data provided on overall and serious adverse events, withdrawals due to adverse effects, and other relevant specific adverse events including hypoglycemia, liver toxicity, heart failure, pulmonary edema, weight gain, and edema. Selection criteria for the updated report For the updated report we expanded our inclusion criteria with respect to study designs for effectiveness outcomes in order to be consistent with criteria used in the Agency for Healthcare Research and Quality report. Most notably, we expanded our examination of active-control comparisons, which was previously restricted by sample size, follow-up interval, or outcomes. These criteria are listed in Table 3, where they are contrasted with those of the prior report and of the Agency for Healthcare Research and Quality report. Thiazolidinediones Page 13 of 193 Final Report Update 1 Drug Effectiveness Review Project Table 3. Inclusion criteria for the original and updated reports Criteria domain and key question Original DERP report Updated DERP report AHRQ report Type 2 diabetes: adults ≥ Type 2 diabetes: adults ≥ Type 2 diabetes: adults ≥ Population 18 years 18 years 18 years Prediabetes: adults ≥ 18 Prediabetes: adults ≥ 18 years years Metabolic syndrome as Metabolic syndrome as defined by ATPIII criteria: defined by ATPIII criteria: adults ≥ 18 years adults ≥ 18 years Interventions Rosiglitazone, pioglitazone Rosiglitazone, pioglitazone Oral hypoglycemic drugs Drugs not on US market if members of their class were in use (voglibose, gliclazide, glibenclamide) Combination of 2 included oral agents st Excluded: 1 -generation SU, insulin, troglitazone Comparisons Rosiglitazone compared Rosiglitazone compared Rosiglitazone compared Within class with pioglitazone with pioglitazone with pioglitazone Rosiglitazone or Rosiglitazone or Rosiglitazone or pioglitazone compared pioglitazone compared with pioglitazone compared with with placebo placebo placebo Rosiglitazone or Rosiglitazone or Rosiglitazone or pioglitazone compared pioglitazone compared with pioglitazone compared with with other active other oral hypoglycemic other oral hypoglycemic Between classes hypoglycemic drug when agents agents st study examined st Exclude: insulin and 1 - Excluded: insulin and 1 - effectiveness outcomes or generation SU generation SU or population subgroups Study designs Study duration and size: ≥3 Excluded: non-English Excluded: non-English months, ≥ 40 subjects General features studies, letters, editorials, studies, letters, editorials, Excluded: non-English abstracts, and theses abstracts, and theses studies, letters, editorials, abstracts, and theses Efficacy RCTs or CCTs RCTs or SRs RCTs RCTs, CCTs or cohort studies with or without a RCTs, CCTs, cohort with Effectiveness RCTs or CCTs comparison group comparison group or SRs Excluded: case reports or case series RCTs, CCTs, cohort RCTs, CCTs, cohort RCTs, CCTs, cohort studies with or without a studies with or without a studies with or without a Adverse events comparison group, case- comparison group, case- comparison group, or case- control studies, case control studies, and SRs control studies series (N>10), or SRs Excluded: case reports Excluded: case reports and Thiazolidinediones Page 14 of 193 Final Report Update 1 Drug Effectiveness Review Project Criteria domain and key question Original DERP report Updated DERP report AHRQ report Excluded: case reports case series As above for efficacy, As above for efficacy, As above for efficacy, Population effectiveness, or effectiveness, or effectiveness, or subgroups adverse events adverse events adverse events Outcomes A1c, postprandial glucose, Efficacy A1c A1c blood pressure, and lipids For prediabetes: incidence For prediabetes: Incidence of type 2 diabetes of type 2 diabetes For type 2 diabetes: CVD events, death, stroke, For type 2 diabetes: durability of control, nephropathy, neuropathy, Effectiveness durability of control, progression or occurrence PVD, amputations, QoL, progression or occurrence of micro- or macrovascular and functional status of micro- or macrovascular disease, mortality, and disease, mortality, and QoL QoL Hypoglycemia, liver failure, Hypoglycemia, liver failure, heart failure, lactic heart failure, lactic acidosis, Hypoglycemia, liver failure, acidosis, anemia, liver anemia, liver function, heart failure, lactic acidosis, Adverse events function, edema, edema, gastrointestinal anemia, liver function, gastrointestinal effects, effects, weight, macular edema, gastrointestinal weight, macular edema, edema, fractures, and effects, and others fractures, and others others Abbreviations: A1c, hemoglobin A1c; AHRQ, Agency for Healthcare Research and Quality; ATP III, Adult Treatment Panel III of the National Cholesterol Education Program; CCTs, controlled clinical trials; CVD, cardiovascular disease; DERP, Drug Effectiveness Review Project; N, sample size; PVD, peripheral vascular disease; QoL, quality of life; RCTs, randomized controlled trials; SRs, good-quality systematic reviews; SU, sulfonylureas. Data Abstraction The following data were abstracted from included trials into a relational database developed for this review: study design; setting; population characteristics (including sex, age, race/ethnicity, diagnosis, duration of type 2 diabetes, A1c, weight, and body mass index); eligibility and exclusion criteria; drug dosage and frequency; treatment duration; comparison group care; numbers screened, eligible, enrolled, and lost to follow-up; and results for each prespecified outcome. Similar data were abstracted for studies that were not controlled trials and which examined adverse events. We recorded results achieved with an intention-to-treat analytic approach, when reported. If only per protocol results were reported, we specified the nature of these results and reported them. In trials with crossover, outcomes for the first intervention were recorded if available. This was because of the potential for bias due to differential withdrawal prior to crossover, the possibility of a “carryover effect” (from the first treatment) in studies without a washout period, and a “rebound” effect from withdrawal of the first intervention. Thiazolidinediones Page 15 of 193 Final Report Update 1 Drug Effectiveness Review Project Quality Assessment We assessed the internal validity (quality) of controlled clinical trials using the predefined criteria listed in the quality assessment tool found in Appendix C. These criteria are based on 29 those used by the US Preventive Services Task Force and the National Health Service Centre 30 for Reviews and Dissemination. For each included trial we assessed methods for the following charateristics: randomization; allocation concealment; blinding of participants, investigators, and assessors of outcomes; the similarity of comparison groups at baseline; adequate reporting of attrition, crossover, adherence, and contamination; post-allocation exclusions; and use of intention-to-treat analysis. We based assessment of observational and other study designs with adverse event data on unbiased selection of patients, loss to follow-up, unbiased and accurate ascertainment of events, and control for potential confounders (Appendix C). These criteria were then used to categorize studies as good-, fair-, and poor-quality studies. Studies that had a significant flaw in design or implementation such that the results were potentially not valid were categorized as “poor”.

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There were no significant differences in exercise tolerance or attack frequency buy 20mg apcalis sx with visa. No significant differences were found between betaxolol 20 mg and metoprolol tartrate 100 mg on 5 of 6 health-related quality-of-life parameters safe 20 mg apcalis sx. Compared with metoprolol tartrate (15%) purchase 20 mg apcalis sx with visa, however, significantly greater numbers of patients on betaxolol 37 improved on the ‘Physical Function’ parameter (43%; P<0. Beta blockers Page 23 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 5. Results of head-to-head trials in patients with angina Trial Sample size Interventions Results Attack frequency and/or Exercise nitroglycerine use (% parameters reduction) Van der Does 1999 Carvedilol 100 mg No difference Not reported N=368 Metoprolol 200 mg Frishman 1979 Pindolol 10-40 mg No difference No difference N=40 Propranolol 40-240 mg Narahara 1990 Betaxolol 20 and 40 mg No difference No difference N=112 Propranolol 160 and 320 mg Dorow 1990 N=40 Atenolol 50 mg 82. Over the long term, beta blockers may differ in their ability to prevent or reduce the severity of anginal attacks. In 1 fair-quality 2-year multicenter European trial, propranolol was 40 better than placebo after 8 weeks but not after 24 weeks of treatment. Specifically, after 8 weeks propranolol 60 to 240 mg reduced the proportion of patients using nitroglycerin (57% compared with 73% in the placebo group; P=0. These effects were transient, however, and propranolol was equivalent to placebo on those parameters after 24 weeks of treatment. Propranolol and placebo had similar effects on the number of weekly angina attacks, the number of attack-free days, maximum workload, and exercise duration at 8- and 24-week endpoints. The relevance of this trial was limited because since the time it was conducted, the rate of progression of angina may have been altered by advances in treatment of atherosclerosis (for example statin therapy). A good-quality meta-analysis identified 72 randomized controlled trials of a beta blocker 41 compared with a calcium channel blocker and 6 trials comparing a beta blocker to a nitrate. This meta-analysis found that, in general, beta blockers had similar efficacy but fewer discontinuations due to adverse events than calcium channel blockers, but the authors did not report results for each beta blocker separately. Beta blockers Page 24 of 122 Final Report Update 4 Drug Effectiveness Review Project Key Question 1c. For adult patients who have undergone coronary artery bypass grafting, do beta blockers differ in efficacy or effectiveness? We did not examine the short-term (4 to 10 days) use of beta blockers to prevent or control atrial 42-46 tachyarrhythmias after coronary artery bypass graft. In addition to the beta blockers included in our review, esmolol, a very short-acting, intravenous beta blocker, is used postoperatively to control tachyarrhythmias. In 7 trials, long-term use of a beta blocker after coronary artery bypass graft did not improve mortality or other outcomes (Evidence Tables 5 and 6). For example, the MACB Study 47 Group conducted a fair-quality trial that randomized 967 patients (85. No differences between metoprolol and placebo were found in mortality (3. For adult patients with recent myocardial infarction, do beta blockers differ in efficacy or effectiveness? Summary Table 6 summarizes evidence from meta-analyses and major trials of beta blockers in patients with recent myocardial infarction. Timolol was the first beta blocker shown to reduce total 48 mortality, sudden death, and reinfarction outcomes in the Norwegian Multicenter Study. In addition, similar benefits in sudden death were reported for propranolol and 51, 52 52 metoprolol tartrate and in reinfarction for metoprolol tartrate. Carvedilol reduced reinfarction rates in the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial, which recruited stable inpatients with recent myocardial infarction and a left ventricular ejection fraction of 40% or less. Carvedilol is the only beta blocker shown to reduce mortality in post-myocardial infarction patients who are already taking an ACE inhibitor. An extended-release form of carvedilol (carvedilol phosphate) was approved by the US Food and Drug Administration in October 2006. No studies of carvedilol phosphate in patients following myocardial infarction were identified through literature searches. Approval of the left ventricular dysfunction following myocardial infarction indication for carvedilol phosphate was based on pharmacokinetic and pharmacodynamic data that demonstrated bioequivalence with carvedilol. Indirect comparisons of beta blockers across these trials must be done with caution because the study populations differed in duration, the presence or absence of left ventricular dysfunction, the dose and timing of therapy, and the use of other medications. Beta blockers Page 25 of 122 Final Report Update 4 Drug Effectiveness Review Project Table 6. Comparison of outcomes of mortality-reducing beta blockers in patients following myocardial infarction Mortality reduction in Mortality general reduction in population of post-myocardial post- infarction myocardial patients with infarction left ventricular Reinfarction Beta blocker patients dysfunction Sudden death reduction reduction Acebutolol Effective Uncertain Insignificant effect Insignificant effect Not Carvedilol Effective Uncertain (trend) Effective established Carvedilol phosphate No evidence No evidence No evidence No evidence Metoprolol tartrate Effective Probable Effective Effective Insignificant effect Propranolol Effective Probable Effective (BHAT, Hansteen 1982) Timolol Effective Uncertain Effective Effective Head-to-Head Trials No consistent differences between beta blockers were found in 3 head-to-head trials in post- 53-55 myocardial infarction patients. A 6-week trial comparing atenolol 100 mg to propranolol 120 53 mg had inconclusive results. The second trial, an open-label study with a median follow-up of 1. Patients in this study had mean left ventricular ejection fraction 53. The primary outcome of the study was the change in left ventricular ejection fraction at 1 year; time to first serious cardiovascular event was a secondary endpoint. No significant difference was found between the 2 interventions in either change in left ventricular ejection fraction (P=NR) or time to occurrence of a serious cardiovascular event 56 (P=0. However, these results are not conclusive, as the study’s authors acknowledge that the study was underpowered to detect such a difference for this secondary outcome. A study of 313 patients comparing metoprolol tartrate 100 mg twice daily to carvedilol 25 mg twice daily for a mean of 13. There were statistically significant differences in 5 of 8 health-related quality-of-life domains measured using the Short Form-36 55 questionnaire (adjusted for age and baseline differences) favoring the carvedilol group. Placebo-controlled Trials Because there are so few comparative trials, inferences about the comparative effectiveness of beta blockers in post-myocardial infarction patients must be made on other grounds. The criteria for making these comparisons might include: 1. Demonstration of reduced mortality in large, multicenter placebo-controlled trials 2. Degree of mortality reduction compared with other beta blockers 3. Improvements in other outcomes Beta blockers Page 26 of 122 Final Report Update 4 Drug Effectiveness Review Project 4. Effectiveness studies and applicability of efficacy studies to current practice. Mortality Three systematic reviews have analyzed over 60 trials of beta blockers after myocardial 57-59 infarction. The first (Yusuf, 1985) analyzed 22 long-term trials of beta blockers in acute myocardial infarction.