Delfini Group, LLC Evidence & Value based Solutions For Health Care Clinical Improvement Consults, Content, Seminars, Training & Tools

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1 Delfini Group, LLC Evidence & Value based Solutions For Health Care Clinical Improvement Consults, Content, Seminars, Training & Tools Explicit Evidence based Clinical Practice Guideline Resource Information Irritable Bowel Syndrome (IBS) Information & Decision Aid for Adult Patients and Clinicians Original creation date: March 2003 Updates 07/06: Herbal Preparations 04/07: Medication Withdrawal 06/09: ROME III Criteria (see Guideline) Delfini Group, LLC, All Rights Reserved Worldwide

2 Legal Information & Disclaimers These materials are not meant to replace the clinical judgment of any health care professional or establish a standard of care. The information contained in this document may not be appropriate for use in all circumstances. Decisions to utilize this information must be made by consumers and health care professionals in light of individual circumstances. Before prescribing any medication, review full prescribing information such as from the Physicians Desk Delfini Group, LLC, MAKES AND USER RECEIVES NO WARRANTY EXPRESS OR IMPLIED ABOUT THIS WORK, AND ALL WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE ARE EXPRESSLY EXCLUDED. Information & Decision Aid Page 2

3 Did you know? 1. Irritable bowel syndrome or IBS is a common problem. Millions of Americans experience IBS every day. Not everyone who has IBS chooses to see their doctor about it but many do. It is estimated that over 10% of visits to primary care physicians and almost 30% of visits to gastroenterologists are for IBS. 10%-15% of the US population experiences IBS 2. Information about IBS and how to manage it is available and helpful. There are steps you can take yourself to manage IBS which may help you improve your quality of life. These are called self care approaches which we describe in this guide to IBS. 3. If you have IBS, there are ways your doctor can help you. If you wish for information and assistance from a doctor, you will want one who understands the condition, its management and follow up. In this guide to IBS we include information for you to share with your doctor. In this guide we have also included some addresses of websites that may be of help to you as well. 4. Making choices that are right for you depend on many factors How many symptoms you have, how severe your symptoms are and how frequently you have them. Your individual circumstances and preferences. How effective medication might be for you. People react differently to the same medication a medication that works well for one person might not be the best choice for you and vice versa. 5. Many choices can be used in combination. We have put together the following information to help you understand your options and make treatment decisions. This information is based on the best research available today that has been analyzed by scientific and medical experts. Some of these sections are best shared with your doctor. Information & Decision Aid Table of Contents I. How We Prepared this Information for You Aid Page 4 II. Quick Reference Guide About the Scientific Evidence on Treatments for IBS 5 III. Information About IBS 6 IV. For You & Your Doctor: Information About Treating IBS 8 V. Benefits, Risks and Uncertainties of the Newest IBS Treatments Lotronex (alosetron) 16 VI. For You & Your Doctor: Scientific Information About the principles and processes we used to analyze this information 17 Delfini Validity & Usability Scales 19 Information & Decision Aid Page 3

4 I. How We Prepared This Information for You We have reviewed the medical literature, as of March 2003, to evaluate the scientific quality of published research studies. We do this to find the best available evidence so far for the treatment of IBS. Medical research ranges in quality and results. Research is done to try and find the truth of what will help people. Not every person responds to treatment in the same way. High quality scientific studies can best help you and your doctor understand your chances of benefit and risk. Poorly done scientific studies sometimes do get published, even in high quality medical journals. Using them can result in wrong information which may mislead you and your doctor about your chances of being helped or harmed or to know the right thing to do. Also there are many areas in medicine where no good scientific studies have been done or the results of the studies are weak or contradictory. When there is no evidence or weak evidence, we are uncertain about how to best help you learn your chances of what might work for you or what might put you at risk of harm. We use a rating system to tell you how good we believe the research is or our confidence in the results. (You can read more about our ranking system in the section, Delfini Evidence and Usability Scale, if you want more detailed information.) We also give you our interpretation of what we believe the research says. The fact that there is little or no evidence, or even uncertain evidence, does not mean something will not work. It just means we are uncertain and do not know. Delfini Information Quality Ratings Grade A Useful: To the best of our belief, we are reasonably certain that these research results can be relied upon as true. This is the highest quality research we can find. High quality research helps us feel more certain that the research findings are actually true. Grade B Possibly Useful: We are somewhat less certain that these research results are true. We have some questions or concerns about the research or results that keep us from giving it top rating, but we believe it might possibly be of help. For Grade B evidence, we feel less confident that the research results can be relied upon. Grade U Uncertain Usefulness: We are not certain how true these research results may be. We have so many questions or concerns about the research that we feel the research results might not be accurate. This continues to be an area of medical uncertainty. Lack of evidence, however, is not proof that a drug or intervention is not effective. In those instances where there is no evidence of known harms, you might choose to try certain strategies anyway in case they are helpful to you. Information & Decision Aid Page 4

5 II. Quick Reference Guide About the Scientific Evidence on Treatments for IBS Delfini Information Quality Ratings Grade A Useful Scientific Evidence Grade B Possibly Useful Grade U Uncertain Usefulness Treatment Options for IBS Abdominal Pain Constipation Diarrhea Gas & Bloating Dietary Changes Herbal Preparations STW 5 (9 herbs sold under the name IberogastAA, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany; distributed in the United States by Enzymatic Therapy, Green Bay, WI [independent health food stores] and PhytoPharmica, Green Bay, WI [pharmacies and healthcare professionals]). STW 5 contains bitter candytuft plant (a.k.a. clown s mustard; Iberis amara L., Brassicaceae), German chamomile flower (Matricaria recutita L., Asteraceae), peppermint leaves (Mentha x piperita L., Lamiaceae), caraway fruit (Carum carvi L., Apiaceae), licorice root (Glycyrrhiza glabra L., Fabaceae), lemon balm leaves (Melissa officinalis L., Lamiaceae), celandine herb (i.e., aerial parts of Chelidonium majus L., Papaveraceae), angelica root and rhizome (Angelica archangelica L., Apiaceae), and milk thistle fruit (Silybum marianum [L.] Gaertn. Asteraceae) Antispasmodics (e.g. anticholinergics) Dicyclomine, Hyoscyamine Anti diarrheals Imodium (loperamide), Lomotil (diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025mg) Gas X, Mylicon (simethicone) Tricyclic Antidepressants, (TCAs) e.g. Nortriptyline (e.g., Pamelor), Desipramine (e.g., Norpramin), Amitriptyline (e.g., Elavil), Doxepin (e.g., Sinequan) Caution is advised when using TCAs in IBS patients w/ constipation Range to SSRIs (selective serotonin reuptake inhibitors) e.g. Fluoxetine (e.g., Prozac), Paroxetine (e.g., Paxil) Serotonin Receptor Antagonists for Diarrhea Lotronex (alosetron) (urgency) Behavioral Health Interventions Grade B for certain individual symptoms Information & Decision Aid Page 5

6 Question What is IBS? What causes IBS? Do I need blood or stool tests or an examination of my intestines? III. Information About IBS Answer IBS is a medical condition of the intestinal tract. Frequent symptoms of IBS include abdominal discomfort or pain, urgency to go to the bathroom, altered bowel habits, gas, bloating, diarrhea and/or constipation. These symptoms can be in combination. The cause of IBS is unknown. Many experts believe that contraction patterns in the intestinal tract become altered ( out of sync ) in many patients with IBS, and the abnormal contractions lead to cramping, pain, diarrhea and constipation. Not all patients with IBS have abnormal contractions, however. o o o There is no evidence that IBS does any damage to the intestinal tract or other parts of the body. Worry, stress, anxiety and depression may make the symptoms of IBS worse, but studies have not shown that stress causes IBS. Certain foods appear to make the symptoms of IBS worse and eliminating certain items from your diet may be helpful (see For You & Your Doctor: Information About Treating IBS ). However, diet does not appear to be the cause of IBS. Screening for colon cancer is a separate issue, and you should discuss it with your physician. There is no evidence that patients with IBS have a higher chance of getting colon cancer. If any of the following are true for you, or if your doctor wishes to test for any alarm symptoms, he or she will probably order blood and/or stool tests and may possibly arrange for an examination of your intestinal tract: o Age: Onset age 50 or older o Any change in progression or in expected pattern of symptoms o Unintended weight loss >5 10 lbs. o Anorexia o Vomiting o GI bleeding o Nocturnal symptoms o Fever o Any signs of infection o Other diseases of the colon (e.g., colitis) o Anemia o Any abnormal findings upon exam Information Quality Grade B Fair evidence and consensus of medical experts Grade B Fair evidence and consensus of medical experts Grade B Fair evidence and consensus of medical experts Information & Decision Aid Page 6

7 Question Can I treat this condition myself? Are there medications my doctor can prescribe for IBS? Where can I get more information about IBS? Answer Information Quality Self care can play a role in IBS. See below in Self care Options. Grade U to B See below in Selfcare Options. Yes. If you are suffering from the symptoms of IBS and self care is not working, your physician can prescribe medications. It is important for you to know the benefits, risks and uncertainties about these medications. See below in Physician directed Care. The goal of the following websites is to provide useful information about IBS and other medical conditions, but be aware that there is great variability in the accuracy, balance and completeness of the medical information even when it comes from respected associations and governmental agencies. Sometimes even poorly done research studies do get published, even in high quality medical journals or on websites, and using them can result in wrong information which may mislead you and your doctor about your chances of being helped or harmed or to know the right thing to do. Grade U to A Evidence varies from drug to drug: Uncertain Usefulness to Useful depending upon the problem. All sites are ungradable Accuracy, quality and usefulness of information may vary. It is best that all medical information first be evaluated by persons who have expertise both in medicine and in scientific methods before it is used. National Library of Medicine s Medline Plus The American Gastroenterological Association The American College of Gastroenterology International Foundation for Functional Gastrointestinal Disorders Information & Decision Aid Page 7

8 Self Care Options IV. For You & Your Doctor: Information About Treating IBS Self care Options and Physician Directed Care Information About Options Information Quality Dietary Changes: Eliminating foods for gas, abdominal cramping and diarrhea The following dietary changes do not have good evidence of benefit, but carry little known risk, there are reports of benefit and you may wish to try them for abdominal discomfort or diarrhea in case they work for you: Quit smoking, reduce or stop use of alcohol, coffee and/or tobacco. Avoid dairy products. Problems with dairy products are common in adults, and the symptoms can be very similar to those of IBS. Eliminating dairy products or adding lactase enzyme (Lactaid) may be helpful for improving the digestion of dairy products. Avoid fats. Fats may increase contractions in your intestines. For decreasing gas, avoid legumes (e.g. beans) and cruciferous vegetables (e.g., broccoli, cabbage, Brussels sprouts, cauliflower) as well as corn, cucumbers, garlic, onions, turnips, peppers, radishes, raw apples, carbonated beverages and chocolate. Keeping a food diary may help reveal how foods affect your symptoms. Uncertain Usefulness There is insufficient scientific information to conclude that eliminating foods will improve IBS symptoms. However there are many reports of benefit, and many experts recommend a trial period of eliminating certain foods. Information & Decision Aid Page 8

9 Self Care Options Dietary Changes: Increasing dietary fiber (foods and fiber in the form of bulking agents) for constipation NOTE: IBS symptoms may initially worsen Information About Options There are some reports that fiber might improve the consistency of stools and help patients with constipation. Treatment must be individualized, but grams of high fiber food per day is recommended. Fiber can be soluble or insoluble. Insoluble fiber is found in fruits, vegetables and cereal and is used for treatment of constipation. Fiber does not benefit everyone with IBS. It can increase gas and bloating especially if fiber is added to the diet too rapidly, and it can make diarrhea worse. If you choose to add dietary fiber to your diet Start by slowly adding fruits and vegetables that you like to your diet; and, Increase whole grain breads and cereals. Soluble fiber (bulking agents) is used to treat constipation Psyllium (Metamucil) or polycarbophil (Citrucel, FiberCon) compounds can be used as follows: Take 1 teaspoon by mouth daily (up to three times daily) or 1 packet daily dissolved in a full glass of water or juice; and, Drink enough fluids (~ 6 glasses/day). Soluble fiber absorbs water and has been reported to cause constipation or bowel obstruction. Polycarbophil compounds (e.g., Citrucel, FiberCon) have been reported to cause less gas than psyllium compounds (e.g., Metamucil). Information Quality Uncertain Usefulness All the research studies that have been done have some significant problems which make us uncertain about the results. Although there are reports of benefit from increased fiber in the treatment of IBS, there is insufficient evidence that bulking agents improve overall symptoms in IBS. Although adverse effects (bloating, constipation, bowel obstruction) have been reported in patients taking increased fiber, the risks do not appear to outweigh possible benefits for patients with constipation. Information & Decision Aid Page 9

10 Physician Directed Care: For Your Doctor See Delfini Evidence and Usability Scale at the end of this guide for our choices about weight of the scientific evidence. Class Medications Actions Benefits Harms Dosing Scientific Evidence Herbal Preparations STW 5 (9 herbs sold under the name IberogastAA, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany; distributed in the United States by Enzymatic Therapy, Green Bay, WI [independent health food stores] and PhytoPharmica, Green Bay, WI [pharmacies and healthcare professionals]). STW 5 contains bitter candytuft plant (a.k.a. clown s mustard; Iberis amara L., Brassicaceae), German chamomile flower (Matricaria recutita L., Asteraceae), peppermint leaves (Mentha x piperita L., Lamiaceae), caraway fruit (Carum carvi L., Apiaceae), licorice root (Glycyrrhiza glabra L., Fabaceae), lemon balm leaves (Melissa officinalis L., Lamiaceae), celandine herb (i.e., aerial parts of Chelidonium majus L., Papaveraceae), angelica root and rhizome (Angelica archangelica L., Apiaceae), and milk thistle fruit (Silybum marianum [L.] Gaertn. Asteraceae) There is one well done randomized controlled trial of STW men and women with persistent IBS participated in this randomized, placebo controlled, double blind, multicenter, 4 week study based in Germany. The patients were assigned to 1 of 4 treatment groups: (1) STW 5; (2) a special research preparation called STW 5 II containing bitter candytuft, German chamomile flower, peppermint leaves, caraway fruit, licorice root, and lemon balm leaves; (3) bitter candytuft monoextract (BCT); and (4) a placebo. The trial medications were taken 3 times daily (20 drops) for 4 weeks. The quantity of each component and the manufacturer were not mentioned in the article. Note: There are 3 subtypes of IBS: constipation predominant (IBS C), diarrhea predominant (IBS D), and alternating (IBS Mixed). The authors of this study do not provide information on how many of each subtype were included in each of the 4 treatment groups. It should not be assumed that the mechanism of action for all 3 subtypes of IBS is the same. This is a major limitation of this study. Note: If you use STW 5, you should inform your physician that this is part of your self directed care. Possibly Useful Although this is the only RCT of STW 5, the study was conducted and no serious adverse events were reported. STW 5 may be a reasonable therapeutic option for short term treatment of abdominal pain. Study duration was only 4 weeks and therefore there is no evidence regarding efficacy or safety beyond 4 weeks. Information & Decision Aid Page 10

11 Physician Directed Care: For Your Doctor See Delfini Evidence and Usability Scale at the end of this guide for our choices about weight of the scientific evidence. Class Medications Actions Benefits Harms Dosing Scientific Evidence Bulking Agents (IBS symptoms may initially worsen) Psyllium Wheat bran Corn fiber Calcium polycarbophil Ispaghula husk Antispasmodics (e.g., anticholinergics) Bentyl, D Spaz (dicyclomine) Anaspaz, Cytospaz, Levsin (hyoscyamine) Anti diarrheals Imodium (loperamide) Lomotil (diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025mg) Used to treat diarrhea and constipation Fiber can be soluble or insoluble. Insoluble fiber (see Self Care above) is found in fruits, vegetables and cereals and is used in the treatment of constipation. It can make diarrhea worse. Soluble fiber (bulking agents) is used for treating constipation. Adverse effects of bulking agents include increased gas, bloating, cramping and diarrhea. Dosage: Psyllium (e.g., Metamucil, Citrucel, PerDiem, Fiberall and Konsyl) 1 tsp orally daily to 3 times daily, or 1 packet orally daily (dissolve in full glass of water or juice) Used to treat intestinal spasms and abdominal discomfort or pain Adverse effects include constipation and atropine like side effects at higher doses. Dosage: Bentyl, Di Spaz (dicyclomine): 20mg 40mg four times daily. Anaspaz, Cystospaz, Levsin (hyoscyamine): 0.125mg 0.25mg orally or sublingual four times daily. Used to treat diarrhea does not appear to improve abdominal pain Mechanism of action is peripheral opiod antagonist and slowing of intestinal transit. Adverse effects include worsening of pre existing liver dysfunction. Dosage: Imodium (loperamide): Start with 4 mg orally once, then 2mg orally after each loose stool Max: 16mg/d Used to treat diarrhea Mechanism of action: decreases intestinal motility. Adverse effects: constipation; should not be used in patients with liver disease or glaucoma. Dosage: Start with 1 tab four times daily. Uncertain Usefulness Reports of benefit, but RCTs are small, weak and contradictory. There is insufficient evidence to conclude benefit. Uncertain Usefulness Reports of benefit, but RCTs are small, methodologically weak and contradictory. Possibly Useful Several small RCTs have shown benefit (f/u ~ 5 weeks) for stool consistency, frequency and incidence of urgency. Uncertain Usefulness Reports of benefit, but only two RCTs with some threats to validity. Information & Decision Aid Page 11

12 Physician Directed Care: For Your Doctor See Delfini Evidence and Usability Scale at the end of this guide for our choices about weight of the scientific evidence. Class/ Medications Gas X, Mylicon (simethicone) Actions/Benefits/Harms/Dosing Used to treat bloating or gas Mechanism of action: unknown. Dosing: mg orally four times daily as needed. Scientific Evidence Uncertain Usefulness Reports of benefit, but only one RCT with methodological flaws. Tricyclic Antidepressants, e.g. Nortriptyline (e.g., Pamelor) Desipramine (e.g., Norpramin) Amitriptyline (e.g., Elavil) Doxepin (e.g., Sinequan) SSRIs (selective serotonin reupdate inhibitors) e.g. Fluoxetine (e.g., Prozac) Paroxetine (e.g., Paxil) Used to treat abdominal discomfort/pain Mechanism of action is thought to be similar to that in chronic pain decreased distress and increased well being. SSRIs have not been studied as a treatment for IBS. Adverse effects: the usual adverse effects of tricyclics. TCAs should be used with caution in patients with constipation. Increased constipation has been reported. Dosing: Dosages vary with drug 30mg 300mg per day depending upon the drug. May be taken in divided doses or in a single daily dose. Please check dosing for each drug. Used to treat abdominal discomfort/pain Mechanism of action is thought to be similar to that in chronic pain decreased distress and increased well being. Adverse effects: the usual adverse effects of SSRIs. SSRIs should be used with caution in numerous situations e.g., recent MAO use, seizure disorders, impaired liver or renal function, narrow angle glaucoma. Dosing: Dosages vary with drug Please check dosing for each drug Possibly Useful Reports of benefit, but RCTs are small with some threats to validity. There is weak evidence to conclude benefit. Uncertain Usefulness Reports of benefit, but only RCTs have methodological flaws. Information & Decision Aid Page 12

13 Physician Directed Care: For Your Doctor See Delfini Evidence and Usability Scale at the end of this guide for our choices about weight of the scientific evidence. Class/ Medications Serotonin Receptor Antagonists for Diarrhea Lotronex (alosetron) Actions/Benefits/Harms/Dosing Used to treat IBS patients whose primary bowel symptom is diarrhea. It is indicated only for women with IBS whose primary symptom is severe diarrhea and who have failed to respond to conventional therapy. The indication has been narrowed to this group of severely affected patients because serious gastrointestinal adverse events, some fatal, have been reported with the use of alosetron. Less than 5 percent of IBS is considered severe. Before receiving the initial prescription for alosetron, the patient must read and sign the Patient Physician Agreement. Scientific Evidence Useful Well designed and conducted RCTs (12 weeks) have shown alosetron to be effective in treating diarrhea and urgency (abdominal pain). The studies included only women. Mechanism of action is thought to be through blockade of serotonin (5 hydroxytryptamine) receptors in the gastrointestinal tract. This results in decreased peristasis and intestinal secretion and may result in decreased abdominal discomfort. Benefits: It is estimated that 1 woman in 7.35 will have overall improvement in IBS symptoms (abdominal pain or fecal urgency) during a 12 week course of treatment. The improvement varied in the 3 studies from 1 in 3.7 to 1 in 8.33 women. Adverse effects: 1 woman in 500 will develop ischemic colitis during a 3 month course of treatment; 1 woman in 333 will develop ischemic colitis during a 6 month course of treatment. Alosetron should be discontinued immediately in patients with signs of ischemic colitis such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Because ischemic colitis can be life threatening, patients with signs or symptoms of ischemic colitis should be evaluated promptly and have appropriate diagnostic testing performed. Treatment with alosetron should not be resumed in patients who develop ischemic colitis. See the next page for Dosing information. Information & Decision Aid Page 13

14 Physician Directed Care: For Your Doctor See Delfini Evidence and Usability Scale at the end of this guide for our choices about weight of the scientific evidence. Class/ Medications Continuation Serotonin Receptor Antagonists for Diarrhea Lotronex (alosetron) Actions/Benefits/Harms/Dosing Dosage: Lotronex (alosetron) should be started at a dosage of 1 mg orally once a day for 4 weeks. This dosage may be less constipating than a regimen of 1 mg twice a day. If, after 4 weeks, the 1 mg once a day dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to 1 mg twice a day, the dose used in controlled clinical trials. Although the efficacy of the 1 mg once a day dosage in treating women with IBS whose primary symptom is diarrhea has not been evaluated in clinical trials, for safety reasons, consideration may be given to continuing this dosage if well tolerated and IBS symptoms in the individual patient are adequately controlled. Lotronex (alosetron) should be discontinued in patients: Who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. Who develop constipation or signs of ischemic colitis. Lotronex (alosetron) should not be restarted in patients who develop ischemic colitis. Clinical trial and postmarketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow up should be exercised if alosetron is prescribed for these patients. Scientific Evidence Information & Decision Aid Page 14

15 Behavioral Health Interventions Psychological, Psychiatric Interventions Information About Options In addition to understanding IBS, self care options and prescription/nonprescription drug options, various supportive, psychological and psychiatric interventions are further choices for patients who choose to pursue them. Psychotherapy, cognitive therapy, biofeedback, relaxation therapy and hypnotherapy are reasonable options to try. Primary care physicians play a critical role in managing the behavioral health options in IBS through the physician patient relationship and by utilizing the components of behavioral therapy such as o Providing information; o Assisting patients with problem solving; and/or, o Supporting patients through cognitive restructuring (when appropriate) and improved coping strategies. Information Quality Possibly Useful Multiple RCTs have reported benefits in various IBS symptoms from psychotherapy, cognitive therapy, biofeedback, relaxation therapy and hypnotherapy. All studies have some threats to validity. Information & Decision Aid Page 15

16 V. Benefits, Risks and Uncertainties of the Newest Drugs: Serotonin Antagonists Lotronex (alosetron) Benefits, harms and uncertainties should always be considered before deciding to take a medication. Caution is urged especially with new drugs. There is always the chance that unknown risks could be discovered with longer use. About Lotronex (alosetron) Lotronex (alosetron) is a drug for treating IBS with diarrhea. Alosetron has been shown in good scientific studies to be an effective drug. In some people, alosetron has been shown to result in significant harms. High quality scientific studies have shown that a serious medical condition called ischemic colitis has been reported to occur in approximately 1 in 500 women taking the drug over a 3 month period and 1 in 333 women taking alosetron over a six month period. The effects in men have not been studied. Symptoms of ischemic colitis may include new or increasing abdominal pain, rectal bleeding or bloody diarrhea. If these symptoms develop while taking alosetron, the drug should be immediately stopped, not restarted, and a physician should be consulted immediately. See Physician directed Care above for more specific information about risks. Alosetron should be discontinued in patients who have not had adequate control of IBS symptoms (diarrhea) after 4 weeks of treatment with 1 mg twice a day; or who develop constipation or signs of ischemic colitis. How the Known Benefits and Risks of Lotronex (alosetron) Stack Up The boxes below give you numeric information from high quality scientific studies to let you know the likelihood of known risks and benefits of taking a certain medication. There is no way to know which one person might benefit or be at risk. Each person making a decision about which medication to take will have different feelings about whether the benefits of the medications are important to her. The information below shows you the known benefits and risks a healthy woman could expect from taking alosetron to treat her diarrhea, based on high quality scientific studies. Benefits of taking alosetron for a 12 week period compared to placebo are: Overall Improvement* X 1 woman in 7.35 will have overall improvement in IBS symptoms. The improvement varied in the 2 studies from 1 in 3.7 to 1 in 8.33 women. Risks of taking alosetron for 6 months** compared to placebo are: Ischemic Colitis** 1 woman in 333 will develop ischemic colitis which is an extremely serious condition.*** X * Overall improvement includes well being and symptoms of abdominal discomfort, pain and altered bowel habits. ** Symptoms of ischemic colitis, a serious medical condition, include new or increasing abdominal pain, rectal bleeding or bloody diarrhea. *** Note that approximately 1 in 500 women taking the drug for 3 months will have this risk. Information & Decision Aid Page 16

17 VII. For You & Your Doctor: Scientific Information About the principles and processes we used to analyze this information We used a process called Evidence based Medicine (EBM) to tell you the best information we have about these different choices. About Evidence based Medicine Evidence based medicine (EBM) is a new and improved way of using science to help doctors understand the best way to practice medicine. In medical publications, there are good research studies and not so good research studies. There are also instances where the studies are of high quality but the results are weak or contradictory. This can be confusing even to the best of doctors. EBM helps make science easier to understand for both doctors and patients. In EBM, research studies are evaluated by experts to find the best available evidence. This helps doctors and patients more accurately predict the health benefits and health risks that patients might expect from using specific drugs or undergoing certain procedures. About Medications People react differently to the same medication a medication that works well for someone else might not be the best choice for you. Often there is no way to know ahead of time which drug will work best for a specific person. Frequently, the best that science can tell us are the chances of known benefit or risk by examining health results in a group of people who may be similar to you or different from you in important ways. This is similar to what happens in a lottery. Each person has so many chances to win or lose, based on estimates of the odds of winning or losing. Many drugs are so similar that they are considered to be in the same family or drug class. Drugs in the same class are often substituted for each other even if research has not been done for each of the specific drugs. About Drug Families If one type of medication has not worked for you, there may be another drug in the same medication family or drug class which may work very well. You do not always have to change to a newer, more expensive drug to find a solution. However, sometimes this may be the best solution for you. Information & Decision Aid Page 17

18 About New Drugs Many of us become hopeful when we learn about a new drug on the market. But new does not always mean improved. We need good science, through evidence based medicine, to learn if a new drug really is better or even as good as the older drug. And sometimes this takes time before we know. Many patients begin treatment with lifestyle changes and older drugs that are frequently over the counter. Many of these patients do well without ever needing the newer and usually more expensive medications. There are some definite advantages to taking this more conservative approach: Advantages of a Conservative Approach to Drug Use Safety Older medications may be safer. Newer medications are sometimes found after a year or more to have unsuspected side effects or health risks. Most long term risks of newly approved medications are not known until physicians discover unsuspected side effects in their patients over time. (For example, it took several years before it was discovered that certain drugs used by millions of people to treat heart attacks actually increased heart problems.) Effectiveness Many newer medications provide little improvement for patients. Even when effective advertising and marketing make it appear that the newer medications are breakthroughs, often they are not. Cost Cost is a real issue. Older drugs are frequently less expensive than newer medications. However, many new drugs are significant advances in health care. You need to make a decision based on what you feel may be most right for you. Information & Decision Aid Page 18

19 Delfini Validity & Usability Grading Scale for Summarizing the Evidence for Interventions (In case of split decision use an in between designation e.g., A B or B U, etc.) Grade of Usability Grade A: Useful Grade B: Possibly Useful Grade B U: Possible to uncertain usefulness Grade U: Uncertain Validity and/or Usefulness Grade UA: Uncertainty of Author Strength of Evidence The evidence is strong and appears sufficient to use in making health care decisions it is both valid and useful (e.g., clinical significance, of sufficient magnitude, physician and patient acceptability, etc.) Evidence from well designed and conducted systematic reviews might fall into this category or they might be considered Grade B. Suggestion is to do a careful analysis of the review and the studies included. Several well designed and conducted studies that consistently show similar results o For therapy, screening, prevention and diagnostic studies: RCTs. In some cases a single, large well designed and conducted RCT may be sufficient. o For natural history and prognosis: Cohort studies The evidence is potentially strong and might be sufficient to use in making health care decisions. The evidence is strong enough to conclude that the results are probably valid and useful (see above); however, study results from multiple studies are inconsistent or the studies may have some (but not lethal) threats to validity. Evidence from well designed and conducted systematic reviews might fall into this category or they might be considered Grade A. Suggestion is to do a careful analysis of the review and the studies included. Evidence from at least one well designed and conducted RCT (cohort studies for natural history and prognosis; for diagnosis, valid studies assessing test accuracy for detecting a condition when there is evidence of effectiveness from valid, applicable RCTs.) The evidence might be sufficient to use in making health care decisions; however, there remains sufficient uncertainty that the evidence cannot fully reach a Grade B and the uncertainty is not great enough to fully warrant a Grade U. There is sufficient uncertainty so that caution is urged regarding its use in making health care decisions. Uncertain Validity: This may be due to uncertain validity due to methodology (enough threats to validity to raise concern our suggestion would be to not use such a study in most circumstances) or may be due to conflicting results. Uncertain Usefulness: Or this may be due to uncertain applicability due to results (good methodology, but questions due to effect size, applicability of results when relating to biologic markers, or other issues). These latter studies may be useful and should be viewed in the context of the weight of the evidence. Uncertain Validity and Usefulness: This is a combination of the above. Uncertainty of Author: If the author has reached a conclusion that the findings are uncertain, doing a critical appraisal is unlikely to result in a different conclusion. The evidence leaves us uncertain regardless of whether the study is valid or not. Critical appraisal is at the discretion of the reviewer. Information & Decision Aid Page 19

20 Evidence Grading Recommendations for Primary Studies Grade of Usability Grade A: Useful Grade B: Possibly Useful Grade B U: Possible to uncertain usefulness Strength of Evidence The evidence is strong and appears sufficient to use in making health care decisions it is both valid and useful (e.g., clinical significance, of sufficient magnitude, physician and patient acceptability, etc.) Study should be outstanding in design, execution and reporting with useful information to aid clinical decision making, enabling reasonable certitude in drawing conclusions. The evidence is potentially strong and might be sufficient to use in making health care decisions. Study should be of sufficient quality in design, execution and reporting with few enough threats to validity and with sufficiently useful information to aid clinical decision making, enabling reasonable certitude in drawing conclusions. The evidence might be sufficient to use in making health care decisions; however, there remains sufficient uncertainty that the evidence cannot fully reach a Grade B and the uncertainty is not great enough to fully warrant a Grade U. Grade U: Uncertain Validity and/or Usefulness Grade UA: Uncertainty of Author There is sufficient uncertainty so that caution is urged regarding its use in making health care decisions. Uncertain Validity: This may be due to uncertain validity due to methodology (enough threats to validity to raise concern our suggestion would be to not use such a study in most circumstances) or may be due to conflicting results. Uncertain Usefulness: Or this may be due to uncertain applicability due to results (good methodology, but questions due to effect size, applicability of results when relating to biologic markers, or other issues). These latter studies may be useful and should be viewed in the context of the weight of the evidence. Uncertain Validity and Usefulness: This is a combination of the above. Uncertainty of Author: If the author has reached a conclusion that the findings are uncertain, doing a critical appraisal is unlikely to result in a different conclusion. The evidence leaves us uncertain regardless of whether the study is valid or not. Critical appraisal is at the discretion of the reviewer. Information & Decision Aid Page 20