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The evidence was largely applicable to patients with relapsing-remitting multiple sclerosis of moderate severity order apcalis sx 20 mg otc. The comparative evidence was limited to treatment for 1 year and did not reflect changes beyond that time apcalis sx 20 mg lowest price. Outcomes related to disability progression may require 2 or more years to evaluate. The conclusions about benefit or harm relative to other disease-modifying drugs were limited only to interferon beta-1a. Trials in Progress According to the US Food and Drug Administration documents, there are 5 studies currently on- going. One of these is a 2 year placebo-controlled trial of 0. This study is very 22 similar to the recently published placebo-controlled study, except that it includes additional safety measurements such as ophthalmologic testing, high resolution computerized tomography, pulmonary function tests, and echocardiography. A smaller placebo-controlled trial in patients with relapsing-remitting multiple sclerosis is also being conducted in Japan, and a multi-country trial is being conducted in patients with primary progressive multiple sclerosis comparing 1. In addition there are 2 ongoing extension studies (one reported above). MS drugs addendum: fingolimod 25 of 32 Final Original Report Drug Effectiveness Review Project Table 9. Summary of the evidence by key question Strength of Key question evidence Conclusion Key Question 1. Differences were not found between the lower dose of fingolimod and the higher dose. Rates of confirmed disability progression were low, and similar between groups. Moderate while a higher rate of increased alanine aminotransferase All others: Insufficient (RR, 3. The rate of herpes zoster infections was similar between fingolimod 0. The risk of discontinuing drug due to an adverse event increased with fingolimod 1. Are there Age, gender, baseline Differences in efficacy based on age, gender, or baseline subgroups of patients disability score: disability score were not found with fingolimod. Abbreviations: NNH, number needed to harm; NNT, number needed to treat; RR, relative risk. MS drugs addendum: fingolimod 26 of 32 Final Original Report Drug Effectiveness Review Project CONCLUSIONS In patients with relapsing-remitting multiple sclerosis, fingolimod 0. Progression of disability was not different between the treatments. Ongoing concerns with the safety of fingolimod included the risk of macular edema, the effect of lung function, cancers, and serious viral infections. Further studies are underway to better determine the risk with fingolimod. MS drugs addendum: fingolimod 27 of 32 Final Original Report Drug Effectiveness Review Project REFERENCES 1. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Drug class review: Disease-modifying drugs for multiple sclerosis. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Current methods of the US Preventive Services Task Force: a review of the process. Grading the strength of a body of evidence when comparing medical interventions. Methods Guide for Comparative Effectiveness Reviews. Grading the strength of a body of evidence when comparing medical interventions-Agency for Healthcare Research and Quality and the Effective Health Care Program. Methods for Meta-Analysis in Medical Research: John Wiley & Sons, Inc. Explaining heterogeneity in meta-analysis: a comparison of methods.
In the updated review several additional trials provided evidence on macrovascular outcomes and on mortality order 20mg apcalis sx, with 5 trials providing additional evidence on pioglitazone buy apcalis sx 20 mg free shipping. The primary endpoint was the change in carotid artery intima-media thickness after 72 weeks. Secondary endpoints included the composite of cardiovascular mortality, non-fatal myocardial infarction, or nonfatal stroke, and the composite of these outcomes plus coronary revascularization, carotid endarterectomy/carotid stenting, hospitalization for unstable angina, or hospitalization for heart failure. There were few events reported, and no cardiovascular deaths. There were 2 instances of the first composite endpoint in the glimepiride group and none in the pioglitazone group. On the second composite endpoint, there were 10 events in the glimepiride group (8 of which were coronary revascularization) and 4 in the pioglitazone group (3 coronary revascularization). PERISCOPE was another trial of pioglitazone compared to glimepiride designed to 128 measure progression of atherosclerosis in patients with type 2 diabetes. After 18 months of follow-up, there was no difference between groups in the occurrence of clinical endpoints, including the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (2. There were 3 cardiovascular deaths in the pioglitazone group and 1 in the glimepiride group (P=0. In a small, fair-quality, randomized controlled trial (N=47), patients with impaired glucose tolerance or type 2 diabetes (combined in the analysis) in addition to nonalcoholic steatohepatitis, received either pioglitazone 45 mg daily or placebo, in addition to a weight loss 180 intervention. Glycemic control improved with pioglitazone compared with placebo (P<0. Plasma aspartate and alanine aminotransferase levels and hepatic fat content all decreased with treatment compared with placebo (P<0. Histologic changes in the liver also improved significantly with pioglitazone. At 6- months follow-up these researchers demonstrated that late luminal loss was less in the pioglitazone group than in the control group (P=0. Major cardiac events (myocardial infarction or revascularization of the target lesion) were significantly decreased in the pioglitazone group at 6 months compared with the control group (7. Takagi and colleagues compared pioglitazone with placebo in 44 patients with type 2 182 diabetes who had undergone coronary stent implantation. After 6 months of follow-up, angiographic in-stent restenosis (19% compared with 46%; P=0. There was no difference in HbA1c levels at follow-up in this study (See Key Question 1). The updated search identified several important recent trials of rosiglitazone reporting 146, 157 147 vascular or mortality outcomes: the RECORD trial and ADOPT. The RECORD trial was an open-label, multicenter, noninferiority, randomized controlled trial (N=4447). Subjects who were already taking metformin or a sulfonylurea were randomized to add-on rosiglitazone 4 mg daily (titrated up to 8 mg daily) or to metformin (titrated up to 2550 mg daily) plus a sulfonylurea (glyburide, gliclazide or glimepiride, depending on physician preference). The primary outcome for the RECORD study was time to first occurrence of cardiovascular hospitalization or cardiovascular death. The hazard ratio for rosiglitazone (plus metformin or a sulfonylurea) compared with metformin plus a sulfonylurea was 0. Heart failure causing admission to the hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group(hazard ratio 2. Subjects with significant renal or hepatic disease, unstable or severe angina, or congestive heart failure of any New York Heart Association class were excluded. Approximately half of subjects 156 had hypertension, 81% had metabolic syndrome, and 45% were smokers. The number of deaths from all causes was similar across the 3 groups, but more cardiovascular events were reported in the rosiglitazone group (4. Congestive heart failure events were higher with rosiglitazone than with glyburide (further details are presented in Key Question 8). The lower rates of cardiovascular events in the glyburide group were primarily due to lower rates of nonfatal myocardial infarction and congestive heart failure in this group. Several additional, smaller rosiglitazone trials were also identified in the updated 174, 176 search. In a very small (N=16), poor-quality, randomized controlled trial, subjects with coronary stent implantation were randomized to rosiglitazone 4-8 mg daily or placebo for 6 months. Rosiglitazone did not reduce in-stent restenosis and there were no differences in cardiac 174 events between the groups. Fixed-dose Combination Products (FDCPs) or Dual Therapy Summary of findings for FDCPs or Dual Therapy Evidence in children • We did not find any evidence meeting inclusion/exclusion criteria for children (insufficient strength of evidence). Evidence in adults • We found no studies that focused on health outcomes as the primary outcomes for any available FDCP. Two studies reported health outcomes among other secondary outcomes 183, 184 or in the adverse events section. Overall evidence was insufficient to determine how FDCPs compare with other treatments for their impact on health outcomes.
The then re-enters below piriformis through the lesser sciatic foramen to ureter passes forwards under this ligament best 20 mg apcalis sx, but above and lateral to the enter the pudendal canal together with the pudendal nerve apcalis sx 20mg without prescription. The broad liga- • Uterine artery: passes medially on the pelvic ﬂoor and then over the ment contains the following structures: ureter and lateral fornix of the vagina to ascend the lateral aspect of the • Fallopian tube. Branches of the posterior trunk • Round ligament: is a cord-like ﬁbromuscular structure which is the • Superior gluteal artery: contributes a supply to the gluteal muscles. It passes from the It leaves the pelvis through the greater sciatic foramen. These arteries, in turn, bifur- cava behind the right common iliac artery but anterolateral to the body cate into external and internal iliac branches anterior to the sacro-iliac of L5. The overall arrangement of pelvic venous drainage reciprocates joints on either side. The external iliac artery gives rise to branches Sacral plexus (see p. These include the: deep cir- The pelvis IIbthe contents of the pelvis 57 25 The perineum Dorsal vein Corpus cavernosum Corpus spongiosum Muscles with urethra Ischiocavernosus Crus Penile Bulbospongiosus Bulb Perineal membrane Superficial transverse perineal muscle Perineal body Levator ani External sphincter ani Gluteus maximus Fig. It forms a diamond- lower vagina drains to the superﬁcial inguinal nodes. The blood supply shaped area when viewed from below that can be divided into an anter- to the vagina is from the vaginal artery (branch of the internal iliac ior urogenital region and a posterior anal region by a line joining the artery) and the vaginal branch of the uterine artery. In addition to the sphincter, two glands of Cowper are also • Anal sphincter: comprises external and internal sphincter compon- contained within the deep pouch. The internal anal sphincter is a continuation of the inner circular forwards to drain into the bulbous urethra. Inferior to the perineal mem- smooth muscle of the rectum. The external anal sphincter is a skeletal brane is the superﬁcial perineal pouch which contains the: muscular tube which, at its rectal end, blends with puborectalis to form • Superﬁcial transverse perineal muscles: run from the perineal an area of palpable thickening termed the anorectal ring. The lat- • Ischiorectal fossae: lie on either side of the anal canal. The fossae are ﬁlled with ramus to cover the corpus cavernosum. The anococcygeal body separates the fossae posteriorly; however, sinuses within these cavernosa that generate and maintain an erection. The pudendal (Alcock’s) canal is a sheath crura which are supplied by branches of the internal pudendal artery. It conveys the pudendal The erectile penile tissue is enclosed within a tubular fascial sheath. At nerve and internal pudendal vessels from the lesser sciatic notch to the the distal end of the penis the corpus spongiosum expands to form the deep perineal pouch (see below). On the tip of the glans the urethra opens as the external pudendal nerve and internal pudendal vessels course transversely urethral meatus. The foreskin is attached to the glans below the meatus across the fossa to reach the anus. Urogenital region The scrotum The urogenital region is triangular in shape. The perineal membrane is The skin of the scrotum is thin, rugose and contains many sebaceous a strong fascial layer that is attached to the sides of the urogenital tri- glands. A longitudinal median raphe is visible in the midline. In the male it is pierced by the urethra and, in females, by the skin lies a thin layer of involuntary dartos muscle. The mons The testes are responsible for spermatogenesis. Their descent to an extra- pubis is the fatty protuberance overlying the pubic symphysis and abdominal position favours optimal spermatogenesis as the ambient pubic bones. The labia majora are fatty hair-bearing lips that extend scrotal temperature is approximately 3°C lower than body temperature. The labia minora lie internal to the labia • Structure: the testis is divided internally by a series of septa into majora and unite posteriorly at the fourchette. Each lobule contains 1–3 seminiferous minora form the prepuce and split to enclose the clitoris. The clitoris tubules which anastomose into a plexus termed the rete testis. It has a similar structure in that it is tubule is coiled when in situ, but when extended measures approxim- made up of three masses of erectile tissue: the bulb (corresponding to ately 60 cm. Efferent ducts connect the rete testis to the epididymal the penile bulb) and right and left crura covered by similar but smaller head. They serve to transmit sperm from the testicle to the epididymis.
Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Bomhof 96 (did not take study 1999 medication) Carpay 1997 NR/NR Triptans Page 5 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1 cheap 20 mg apcalis sx overnight delivery. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Charlesworth Multicentre discount apcalis sx 20 mg on line, DB, Double- 42 centers in 1547 Mean age=19. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Charlesworth History of basilar, ophthalmoplegic AstraZeneca NR 1547/1383/1372 2003 migraine reported non-migraine > 10 days/month 6 months before study pregnancy, lactation, inadequate conception in women ischaemic heart disease, arrhythmias/cardiac accessory uncontrolled hypertension, use of monoamine oxidase-A inhibitors, methylergometrine within 2 weeks of study clinically significant abnormal laboratory result recent history of drug/alcohol abuse known hypersensitivity/adverse reaction to study treatments/triptans existing serious medical condition participation in another clinical study at same time of this study risk of transmitting Hep B/HIV Colman, 2001 Subjects could not have uncontrolled Pharmacia Rescue medications NR/NR/1255 Spierings, hypertension, defined as a diastolic allowed at 2 hours 2001 blood pressure higher than 95 mm Hg or a systolic blood pressure higher than 160 mm Hg, or clinically significant disease affecting any system but especially the cardiovascular or gastrointestinal tract Triptans Page 7 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Charlesworth 66/8 2003 Colman, 2001 NR/NR Spierings, 2001 Triptans Page 8 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Diez Multicenter, randomized, open, NR 436 Mean age: 36. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Diez Complex forms of migraine, pregnancy, Almirall Prodesfarma Rescue medication NR/436/372 2007 lactation, hypersensitivity to any permitted (NSAIDs) component of the study medications, history signs or symptoms of ischemic heart disease, cerebrovascular accidents, transient ischemic attack or peripheral vascular disease. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Diez 54/10 2007 DowsonDowson 32(14. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Gallagher Multicenter, multiple-dose Not stated 1212 39 years IHS criteria; 1 For women, use of reliable 1999, 2000 analysis of DB RCT, 6 month 85% female year history of contraception. Patients who had study; conducted in Europe of race/ethnicity migraine 2 or more migraines included in zolmitriptan vs. Garcia-Ramos Multicenter, single-attack, DB Not stated 548 Mean age=36. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Gallagher H/o ischemic heart disease, arrhythmia, Zeneca, co-investigator Some permitted NR 1999, 2000 hypertension, some types of migraine; drug or alcohol abuse, abnormal lab tests Garcia-Ramos 1) Coronary artery disease, heart failure, Pfizer Rescue medication 563 screened/548 2003 uncontrolled hypertension or abnormal allowed by 4 hours post- randomized/483 treated an UK/Latin ECG; dose (excluding any other attack America 2) frequent migraine or concommitant triptan, ergotamine, or nonmigrainous headache (<6 per month), ergotamine-like substance) Fair quality migraine variants (e. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Gallagher 233 who had only 1 1999, 2000 headache Garcia-Ramos 65 not treated/4 2003 withdrawn/1 (0. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Geraud Multicenter, single-dose DB Outpatient 1311 38 years IHS criteria; 1 Average of 1-6 attacks per 2000 RCT conducted in Europe and 85% female year history of month for the 6 months Australia of zolmitriptan vs. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Geraud H/o ischemic heart disease, arrhythmias, Maker of zolmitriptan, co- Permitted NR 2000 uncontrolled hypertension, use of investigator psychoactive drugs, history of drug or alcohol abuse; certain types of migraine; any condition that could interfere with efficacy assessments, pregnant or breastfeeding Goadsby Hemiplegic or basilar migraine, tension- Almirall Prodesfarma Rescue medication (other NR/NR/1298 2007 type headache >4 days/month, inability than triptans) was to distinguish between tension-type and permitted migraine headache, history of ischaemic heart disease, severe or uncontrolled hypertension, cerebrovascular disease, peripheral artery disease, moderate to severe renal or hepatic disease, pregnancy, lactation, history of abuse of analgesics or ergot derivatives or triptans, allergy or sensitivity to sulfonamides or triptans Goadsby, 2000 >6 migraine attacks per month, frequent Pfizer, Ltd. Rescue medication NR/NR/857 Jackson, 1998 tension-type headaches, recent history allowed after 2 hours of alcohol or other substance misuse, serious allergic reactions to drugs, use of any experimental drug within the past month, pregnant or breastfeeding women, severely limited gastrointestinal absorption, any medical condition that might interfere with the interpretations of the study results, coronary artery disease, heart failure, uncontrolled hypertension, and receiving medication specifically contraindicated with sumatriptan Triptans Page 16 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Geraud 253; 225 did not take 2000 medication, 28 were lost to follow-up Goadsby 122/NR 2007 Goadsby, 2000 157/849 (18. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Gruffyd-JonesGruffydd-Jones Multicentre, randomized, open, NRMulticenter, double-dummy Not stated 1787401 Age range=18-42 years IHS criteriaMale or female Average of 1-6 attacks perHistory of migraine for at least 2001 RCT conducted in 21 countries 86% female 18-65 men and month for 2 months preceding of zolmitriptan vs. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Gruffyd-JonesGruffydd-Jones Pregnancy, lactating, inadequateNR Astra-Zeneca, funderNR Most prohibitedRescue medication: 414/401/388NR 2001 contraception in females, ischemic heart disease, arrhythmias, cardiac accessory pathway disorders, hypertension, use of MAO inhibitors, recent history of alcohol or drug abuse, abnormal clinical lab result, STDs, hepatitis B. Havanka History suggestive of cardiovascular or Glaxo, co-investigator Prophylactic medications NR 2000 cerebrovascular disease; hypertension; stopped 1 week before the pregnant or lactating; history of drug or study; rescue drugs not alcohol or ergotamine abuse; use of permitted MAO inhibitors, SSRIs, lithium, or flunarizine. Triptans Page 19 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Gruffydd-JonesGruffyd-Jones 620, many because109/30% 2001 they did not have 6 attacks Havanka NR 2000 Triptans Page 20 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Kolodny 2004 Multicenter, randomized, NR 1288 mean age: 40 Male or female At least 6 month history of (b) placebo, crossover, DB years, adults, aged migraine White: 87% over 18 years good health standing Female: 86% that met IHS criteria for migraine Kolodny Multicenter, randomized, NR 1447 Mean age: 40 Male or female At least 6 month history of 2004(a) placebo, crossover, DB years, adults, aged migraine White: 87% over 18 years good health standing Female: 86% that met IHS criteria for migraine Lainez Randomized, open, crossover NR 439 Adults aged 18 Be in good health, 1 to 8 2006 to 65 years who migraines/month met IHS criteria for migraine Lines Multicenter single-dose DB Not stated 792 40 years I H S criteria 6-month history of migraine; 1-8 1997 RCT conducted in Sweden, 80% women 18-65 men and attacks per month Lines Norway, the United Kingdom ethnicity NR women. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Kolodny 2004 Use of monoamine oxidase inhibitors, Merck Standard antimigraine 1287/1287/1287 (b) methysergide/propranolol, participation prophylactic (with in study 1 exception of non-steroidal anti-inflammatory drugs, daily analgesics, or propranolol) Kolodny Use of monoamine oxidase inhibitors, Merck Standard antimigraine 1447/1447/1447 2004(a) methysergide/propranolol prophylactic (with exception of non-steroidal anti-inflammatory drugs, daily analgesics, or propranolol) Lainez Preponderance of mild attacks, baslar or NR Rescue medication 509/506/439 2006 hemiplegic migraines, difficutly permitted (NSAIDs) distinguishing migraine from tension or other interval headache, cardiovascular disease, ECG abnormality, uncontrolled hypertension, renal, hepati or other systemic disease Lines NR Merck, co-investigator Escape medications, NR 1997 consisting of standard Lines analgesics or anti-emetics, 2001 were allowed from 2 hours onwards. Triptans Page 22 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Kolodny 2004 NR/NR (b) Kolodny 13/18 2004(a) Lainez 67/0 2006 Lines 141 (did not take study 1997 medication) Lines 2001 Triptans Page 23 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Loder 2001 Multicenter, randomized, open, NR 384 Mean age=37. Triptans Page 24 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Loder 2001 History or clinical evidence of Merck NR 524/524/384 cardiovascular disease, clinically significant electrocardiogram abnormality, resting systolic blood pressure of more than 160mm Hg evidence of significant systemic disease previously exposed to rizatriptan or sumatriptan hypersensitivity to other 5-HT receptor agonists currently taking methysergide or propranolol history of drug alcohol abuse within 1 year, pregnancy/lactation, unable to distinguish migraine vs non- migraine exposure to investigational compound Mathew Concurrent nonmigrainous headache or Pfizer, Ltd. Rescue medication NR/NR/2421 treatment-resistant migraine; migraine allowed after 2 hours variants; coronary artery disease; heart failure; uncontrolled hypertension; abnormal ECG; clinically significant medical illness or laboratory abnormality; severe reduction in gastrointestinal absorption; Pascual Cardiovascular disease, hypertension, Merck, co-investigator Recent propranolol, ergot, NR 2000 EKG abnormality; drug or alcohol abuse; (maker of rizatriptan) MAO inhibitor, opiates pregnant or breast-feeding prohibited; other prophylaxis permitted; NSAIDs and opiates permitted for rescue Triptans Page 25 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1. Characteristics of head-to-head trials Number Author withdrawn/ Year lost to follow-up Loder 2001 2/NR Mathew 308(12. Characteristics of head-to-head trials Age Author Number Gender Year Design Setting randomized Ethnicity Patients Inclusion criteria Sandrini, 2002 Multicenter, three-attack, DB NR 1008 38. Characteristics of head-to-head trials Number screened/ Author Funding sources eligible/ Year Exclusion criteria and role of funder Other medications enrolled Sandrini, 2002 Patients who had previously taken oral Pfizer, Ltd. Rescue medication 1013/NR/1008 Pryse-Phillips, eletriptan or any formulation of allowed two hours after 1999 sumatriptan were excluded from the trial, optional second dose of as were patients who had taken any study medication experimental drug within the previous month; patients with frequent nonmigrainous headache, atypical migraine that had not previously responded to therapy, migraine with prolonged aura, familial hemiplegic migraine, basilar migraine, or migrainous infarction were excluded from the trial; patients with a history of heart disease, uncontrolled hypertension, cardiac arrhythmias, abnormalities on laboratory tests or EKGs, documented allergic reactions to drugs or any other clinically significant disease Schoenen Presence of frequent concurrent non- Pfizer Rescue medication 323/NR/311 2005 migraine and/or treatment-resistant permitted- list NR migraine known history of coronary artery disease clinically significant arrhythmia, heart failure or uncontrolled hypertension, poor tolerance to sumatriptan, clinically significant Triptans Page 28 of 184 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 1.