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CHMP says ponatinib’s benefits outweigh risks
Credit: CDC
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted its final opinion on ponatinib (Iclusig), saying the drug’s benefits outweigh its risks.
The CHMP recommends that ponatinib continue to be used in accordance with its approved indications.
However, the drug’s product information should be updated with strengthened warnings, particularly about the risk of arterial and venous thrombotic events.
Ponatinib is approved in the European Union (EU) to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
Roughly a year ago, follow-up data revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Then, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events. The EMA also revised its recommendations for ponatinib but kept the drug on the market.
PRAC review and recommendations
Because of these risks, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) conducted an 11-month review of the available data on ponatinib and consulted with a scientific advisory group.
The PRAC assessed the available data on the nature, frequency, and severity of arterial and venous thrombotic events. And the committee concluded that the benefits of ponatinib outweigh its risks.
The PRAC said the risk of thrombotic events is likely dose-related, but there are insufficient data to formally recommend using lower doses of ponatinib. And there is a risk that lower doses might not be as effective in all patients and in long-term treatment.
The PRAC therefore concluded that the recommended starting dose of ponatinib should remain 45 mg once a day.
However, the committee also recommended updates to the product information to provide healthcare professionals with the latest evidence, in case they want to consider reducing the dose in patients with chronic phase CML who are responding well to treatment and who might be at particular risk of thrombotic events.
In addition, PRAC recommended that healthcare professionals stop ponatinib if there has been no response after 3 months of treatment and monitor patients for high blood pressure or signs of heart problems.
The CHMP concurred with these recommendations and is forwarding them to the European Commission. The commission is expected to issue a final, legally binding decision on ponatinib in December 2014, which will be valid throughout the EU.
A new study on the safety and benefits of ponatinib is in the works to help clarify if lower doses of the drug carry a lower risk of thrombotic events while still having a beneficial effect in patients with chronic phase CML. 
Credit: CDC
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted its final opinion on ponatinib (Iclusig), saying the drug’s benefits outweigh its risks.
The CHMP recommends that ponatinib continue to be used in accordance with its approved indications.
However, the drug’s product information should be updated with strengthened warnings, particularly about the risk of arterial and venous thrombotic events.
Ponatinib is approved in the European Union (EU) to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
Roughly a year ago, follow-up data revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Then, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events. The EMA also revised its recommendations for ponatinib but kept the drug on the market.
PRAC review and recommendations
Because of these risks, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) conducted an 11-month review of the available data on ponatinib and consulted with a scientific advisory group.
The PRAC assessed the available data on the nature, frequency, and severity of arterial and venous thrombotic events. And the committee concluded that the benefits of ponatinib outweigh its risks.
The PRAC said the risk of thrombotic events is likely dose-related, but there are insufficient data to formally recommend using lower doses of ponatinib. And there is a risk that lower doses might not be as effective in all patients and in long-term treatment.
The PRAC therefore concluded that the recommended starting dose of ponatinib should remain 45 mg once a day.
However, the committee also recommended updates to the product information to provide healthcare professionals with the latest evidence, in case they want to consider reducing the dose in patients with chronic phase CML who are responding well to treatment and who might be at particular risk of thrombotic events.
In addition, PRAC recommended that healthcare professionals stop ponatinib if there has been no response after 3 months of treatment and monitor patients for high blood pressure or signs of heart problems.
The CHMP concurred with these recommendations and is forwarding them to the European Commission. The commission is expected to issue a final, legally binding decision on ponatinib in December 2014, which will be valid throughout the EU.
A new study on the safety and benefits of ponatinib is in the works to help clarify if lower doses of the drug carry a lower risk of thrombotic events while still having a beneficial effect in patients with chronic phase CML.
Credit: CDC
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted its final opinion on ponatinib (Iclusig), saying the drug’s benefits outweigh its risks.
The CHMP recommends that ponatinib continue to be used in accordance with its approved indications.
However, the drug’s product information should be updated with strengthened warnings, particularly about the risk of arterial and venous thrombotic events.
Ponatinib is approved in the European Union (EU) to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
Roughly a year ago, follow-up data revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Then, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events. The EMA also revised its recommendations for ponatinib but kept the drug on the market.
PRAC review and recommendations
Because of these risks, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) conducted an 11-month review of the available data on ponatinib and consulted with a scientific advisory group.
The PRAC assessed the available data on the nature, frequency, and severity of arterial and venous thrombotic events. And the committee concluded that the benefits of ponatinib outweigh its risks.
The PRAC said the risk of thrombotic events is likely dose-related, but there are insufficient data to formally recommend using lower doses of ponatinib. And there is a risk that lower doses might not be as effective in all patients and in long-term treatment.
The PRAC therefore concluded that the recommended starting dose of ponatinib should remain 45 mg once a day.
However, the committee also recommended updates to the product information to provide healthcare professionals with the latest evidence, in case they want to consider reducing the dose in patients with chronic phase CML who are responding well to treatment and who might be at particular risk of thrombotic events.
In addition, PRAC recommended that healthcare professionals stop ponatinib if there has been no response after 3 months of treatment and monitor patients for high blood pressure or signs of heart problems.
The CHMP concurred with these recommendations and is forwarding them to the European Commission. The commission is expected to issue a final, legally binding decision on ponatinib in December 2014, which will be valid throughout the EU.
A new study on the safety and benefits of ponatinib is in the works to help clarify if lower doses of the drug carry a lower risk of thrombotic events while still having a beneficial effect in patients with chronic phase CML.
FDA approves treatment for acquired hemophilia A
The US Food and Drug Administration (FDA) has approved a recombinant porcine factor VIII (FVIII) product known as Obizur to treat bleeding episodes in adults with acquired hemophilia A.
Obizur replaces the inhibited human FVIII with a recombinant porcine sequence FVIII based on the rationale that porcine FVIII is less susceptible to inactivation by circulating human FVIII antibodies.
Physicians can manage Obizur’s efficacy and safety by measuring FVIII activity levels.
The ability to measure FVIII levels gives physicians an objective marker of hemostasis that can guide dosing and prevent overdosing, said Rebecca Kruse-Jarres, MD, Director of the Hemophilia Care Program at Puget Sound Blood Center in Seattle and principal investigator of a phase 2/3 trial of Obizur.
Trial results
The FDA approved Obizur based on results of a prospective, multicenter, phase 2/3 trial in which adults with acquired hemophilia A received the product to treat serious bleeding episodes.
Twenty-nine patients were enrolled and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or greater.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse reaction most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur. Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
About acquired hemophilia A and Obizur
Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder caused by the development of antibodies directed against the body’s own FVIII.
Acquired hemophilia A development has been related to other medical conditions or health states, such as pregnancy, cancer, or the use of certain medications. However, in about half of acquired hemophilia A cases, no underlying cause can be found.
Diagnosis of this condition can be difficult, and the severity of bleeding can make treatment challenging.
“The approval of [Obizur] provides an important therapeutic option for use in the care of patients with this rare disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA previously granted Obizur orphan drug designation because it is intended for use in the treatment of a rare disease or condition. The product is manufactured by Baxter Healthcare Corporation.
Baxter said Obizur will be commercially available in the US in the coming months and is currently under regulatory review in Europe and Canada.
For more details on Obizur, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved a recombinant porcine factor VIII (FVIII) product known as Obizur to treat bleeding episodes in adults with acquired hemophilia A.
Obizur replaces the inhibited human FVIII with a recombinant porcine sequence FVIII based on the rationale that porcine FVIII is less susceptible to inactivation by circulating human FVIII antibodies.
Physicians can manage Obizur’s efficacy and safety by measuring FVIII activity levels.
The ability to measure FVIII levels gives physicians an objective marker of hemostasis that can guide dosing and prevent overdosing, said Rebecca Kruse-Jarres, MD, Director of the Hemophilia Care Program at Puget Sound Blood Center in Seattle and principal investigator of a phase 2/3 trial of Obizur.
Trial results
The FDA approved Obizur based on results of a prospective, multicenter, phase 2/3 trial in which adults with acquired hemophilia A received the product to treat serious bleeding episodes.
Twenty-nine patients were enrolled and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or greater.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse reaction most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur. Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
About acquired hemophilia A and Obizur
Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder caused by the development of antibodies directed against the body’s own FVIII.
Acquired hemophilia A development has been related to other medical conditions or health states, such as pregnancy, cancer, or the use of certain medications. However, in about half of acquired hemophilia A cases, no underlying cause can be found.
Diagnosis of this condition can be difficult, and the severity of bleeding can make treatment challenging.
“The approval of [Obizur] provides an important therapeutic option for use in the care of patients with this rare disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA previously granted Obizur orphan drug designation because it is intended for use in the treatment of a rare disease or condition. The product is manufactured by Baxter Healthcare Corporation.
Baxter said Obizur will be commercially available in the US in the coming months and is currently under regulatory review in Europe and Canada.
For more details on Obizur, see the full prescribing information.
The US Food and Drug Administration (FDA) has approved a recombinant porcine factor VIII (FVIII) product known as Obizur to treat bleeding episodes in adults with acquired hemophilia A.
Obizur replaces the inhibited human FVIII with a recombinant porcine sequence FVIII based on the rationale that porcine FVIII is less susceptible to inactivation by circulating human FVIII antibodies.
Physicians can manage Obizur’s efficacy and safety by measuring FVIII activity levels.
The ability to measure FVIII levels gives physicians an objective marker of hemostasis that can guide dosing and prevent overdosing, said Rebecca Kruse-Jarres, MD, Director of the Hemophilia Care Program at Puget Sound Blood Center in Seattle and principal investigator of a phase 2/3 trial of Obizur.
Trial results
The FDA approved Obizur based on results of a prospective, multicenter, phase 2/3 trial in which adults with acquired hemophilia A received the product to treat serious bleeding episodes.
Twenty-nine patients were enrolled and evaluated for safety. Researchers determined that one of the patients did not actually have acquired hemophilia A, so this patient could not be evaluated for efficacy.
At 24 hours after the initial infusion, all 28 patients in the efficacy analysis had a positive response to Obizur. This meant that bleeding stopped or decreased, the patients experienced clinical stabilization or improvement, and FVIII levels were 20% or greater.
Eighty-six percent of patients (24/28) had successful treatment of their initial bleeding episode. The overall treatment success was determined by the investigator based on the ability to discontinue or reduce the dose and/or dosing frequency of Obizur.
The adverse reaction most frequently reported in the 29 patients in the safety analysis was the development of inhibitors to porcine FVIII.
Nineteen patients were negative for anti-porcine FVIII antibodies at baseline, and 5 of these patients (26%) developed anti-porcine FVIII antibodies following exposure to Obizur. Of the 10 patients with detectable anti-porcine FVIII antibodies at baseline, 2 (20%) experienced an increase in titer, and 8 (80%) decreased to a non-detectable titer.
About acquired hemophilia A and Obizur
Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder caused by the development of antibodies directed against the body’s own FVIII.
Acquired hemophilia A development has been related to other medical conditions or health states, such as pregnancy, cancer, or the use of certain medications. However, in about half of acquired hemophilia A cases, no underlying cause can be found.
Diagnosis of this condition can be difficult, and the severity of bleeding can make treatment challenging.
“The approval of [Obizur] provides an important therapeutic option for use in the care of patients with this rare disease,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA previously granted Obizur orphan drug designation because it is intended for use in the treatment of a rare disease or condition. The product is manufactured by Baxter Healthcare Corporation.
Baxter said Obizur will be commercially available in the US in the coming months and is currently under regulatory review in Europe and Canada.
For more details on Obizur, see the full prescribing information.
An Antiemetic for Irritable Bowel Syndrome?
PRACTICE CHANGER
Consider prescribing ondansetron (up to 24 mg/d) for patients who have irritable bowel syndrome with diarrhea (IBS-D).1
STRENGTH OF RECOMMENDATION
B: Based on a well-done double-blind, placebo-controlled randomized controlled trial (RCT).1
ILLUSTRATIVE CASE
A 23-year-old woman who was diagnosed with irritable bowel syndrome (IBS) comes to your clinic with complaints of increased frequency of defecation with watery stools and generalized, cramping abdominal pain. She also notes increased passage of mucus and a sensation of incomplete evacuation.
She says the only thing that relieves her pain is defecation. She has tried loperamide, acetaminophen, and ibuprofen without relief. She does not have Crohn disease or ulcerative colitis. What else can you offer her that is safe and effective?
IBS is a chronic, episodic functional gastrointestinal disorder characterized by abdominal pain or discomfort and altered bowel habits: constipation (IBS-C), diarrhea (IBS-D), or alternating periods of both—mixed (IBS-M).2 The diagnosis is based on Rome III criteria, which include recurrent abdominal pain or discomfort on at least three days per month in the past three months associated with two or more of the following: improvement with defecation, onset associated with a change in frequency of stool, and onset associated with a change in form (appearance) of stool.3 IBS often is unrecognized or untreated, and as few as 25% of patients with IBS seek care.4
IBS-D affects approximately 5% of the general population in North America.5,6 IBS-D is associated with a considerably decreased quality of life and is a common cause of work absenteeism.7,8 Because many conditions can cause diarrhea, patients typically undergo numerous tests before receiving an accurate diagnosis, which creates a financial burden.9
For many patients, current IBS treatments—including fiber supplements, laxatives, antidiarrheal medications, antispasmodics, and antidepressants such as tricyclics and selective serotonin reuptake inhibitors—are unsatisfactory.10 Alosetron, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has been used to treat IBS-D,11 but this medication was voluntarily withdrawn from the US market in 2000 due to concerns about ischemic colitis and severe constipation.12 It was reintroduced in 2002 but can be prescribed only by clinicians who enroll in a prescribing program provided by the manufacturer, and there are restrictions on its use.
Ondansetron—another 5-HT3 receptor antagonist used to treat nausea and vomiting caused by chemotherapy—may be another option for treating IBS-D. Garsed et al1 recently conducted an RCT to evaluate the efficacy of ondansetron for patients with IBS-D.
Study summary >>
STUDY SUMMARY
Ondansetron improves stool consistency, severity of IBS symptoms
In a five-week, double-blind crossover RCT, Garsed et al1 compared ondansetron with placebo for symptom relief in 120 patients who met Rome III criteria for IBS-D. All patients were ages 18 to 75 and had no evidence of inflammatory bowel disease. Exclusion criteria included pregnancy or breastfeeding, unwillingness to stop antidiarrheal medication, prior abdominal surgery other than appendectomy or cholecystectomy, or enrollment in another trial.
Patients were started on ondansetron 4 mg/d with dose titration up to 24 mg/d based on response; no dose adjustments were allowed during the last two weeks of the study. There was a two- to three-week washout between treatment periods.
The primary endpoint was average stool consistency in the last two weeks of treatment, as measured by the Bristol Stool Form (BSF) scale.13 The BSF is a visual scale that depicts stool as hard (type 1) to watery (type 7); types 3 and 4 describe normal stools. The study also looked at urgency and frequency of defecation, bowel transit time, and pain scores.
Treatment with ondansetron resulted in a small but statistically significant improvement in stool consistency. The mean difference in BSF score between ondansetron and placebo was –0.9, indicating slightly more formed stool with use of ondansetron. Scores for IBS severity—mild (a score of 75 to 175 out of 500), moderate (175 to 300), or severe (> 300)—were reduced by more points with ondansetron than with placebo (83 ± 9.8 vs 37 ± 9.7, respectively). Although this mean difference of 46 points fell just short of the 50-point threshold that is considered clinically significant, many patients exceeded this threshold.
Compared to those who received placebo, patients who took ondansetron also had less frequent defecation and lower urgency scores. Gut transit time was lengthened in the ondansetron group by 10 hours more than in the placebo group.
Pain scores did not change significantly for patients taking ondansetron, although they experienced significantly fewer days of urgency and bloating. Symptoms typically improved in as little as seven days but returned after ondansetron use stopped (typically within two weeks). Sixty-five percent of patients reported adequate relief with ondansetron, compared to 14% with placebo.
Patients whose diarrhea was more severe at baseline didn’t respond as well to ondansetron as did those whose diarrhea was less severe. The only frequent adverse effect was constipation, which occurred in 9% of patients receiving ondansetron and 2% of those on placebo.
WHAT’S NEW
Another option for IBS-D
A prior, smaller study of ondansetron that used a lower dosage (12 mg/d) suggested benefit in IBS-D.14 In that study, ondansetron decreased diarrhea and functional dyspepsia. The study by Garsed et al1 is the first large RCT to show significantly improved stool consistency, less frequent defecation, and less urgency and bloating from using ondansetron to treat IBS-D.
CAVEATS
Ondansetron doesn’t appear to reduce pain
In Garsed et al,1 patients who received ondansetron did not experience relief from pain, which is one of the main complaints of IBS. However, this study did find slight improvement in formed stools, symptom relief that approached—but did not quite reach—clinical significance, fewer days with urgency and bloating, and less frequent defecation.
This study did not evaluate the long-term effects of ondansetron use. However, ondansetron has been used for other indications for more than 25 years and has been reported to have a low risk for adverse effects.15
CHALLENGES TO IMPLEMENTATION
Remember ondansetron is not for IBS patients with constipation
Proper use of this drug among patients with IBS is key. The primary benefits of ondansetron are limited to IBS patients who have diarrhea, and not constipation. Ondansetron should not be prescribed to IBS patients who experience constipation or those with mixed symptoms.
REFERENCES
1. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625.
2. Hahn BA, Yan S, Strassels S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion. 1999;60:77-81.
3. Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006;15:237-241.
4. Luscombe FA. Health-related quality of life and associated psychosocial factors in irritable bowel syndrome: a review. Qual Life Res. 2000;9:161-176.
5. Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol. 2000;95:2816-2824.
6. Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut. 2000;46:78-82.
7. Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:896-904.
8. Schuster MM. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am. 1991;20:269-278.
9. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511.
10. Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:750-758.
11. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545-555.
12. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006;101:1069-1079.
13. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol. 1994;19:28-30.
14. Maxton DG, Morris J, Whorwell PJ. Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther. 1996;10:595-599.
15. Gill SK, Einarson A. The safety of drugs for the treatment of nausea and vomiting of pregnancy. Expert Opin Drug Saf. 2007;6:685-694.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(10):600-602.
PRACTICE CHANGER
Consider prescribing ondansetron (up to 24 mg/d) for patients who have irritable bowel syndrome with diarrhea (IBS-D).1
STRENGTH OF RECOMMENDATION
B: Based on a well-done double-blind, placebo-controlled randomized controlled trial (RCT).1
ILLUSTRATIVE CASE
A 23-year-old woman who was diagnosed with irritable bowel syndrome (IBS) comes to your clinic with complaints of increased frequency of defecation with watery stools and generalized, cramping abdominal pain. She also notes increased passage of mucus and a sensation of incomplete evacuation.
She says the only thing that relieves her pain is defecation. She has tried loperamide, acetaminophen, and ibuprofen without relief. She does not have Crohn disease or ulcerative colitis. What else can you offer her that is safe and effective?
IBS is a chronic, episodic functional gastrointestinal disorder characterized by abdominal pain or discomfort and altered bowel habits: constipation (IBS-C), diarrhea (IBS-D), or alternating periods of both—mixed (IBS-M).2 The diagnosis is based on Rome III criteria, which include recurrent abdominal pain or discomfort on at least three days per month in the past three months associated with two or more of the following: improvement with defecation, onset associated with a change in frequency of stool, and onset associated with a change in form (appearance) of stool.3 IBS often is unrecognized or untreated, and as few as 25% of patients with IBS seek care.4
IBS-D affects approximately 5% of the general population in North America.5,6 IBS-D is associated with a considerably decreased quality of life and is a common cause of work absenteeism.7,8 Because many conditions can cause diarrhea, patients typically undergo numerous tests before receiving an accurate diagnosis, which creates a financial burden.9
For many patients, current IBS treatments—including fiber supplements, laxatives, antidiarrheal medications, antispasmodics, and antidepressants such as tricyclics and selective serotonin reuptake inhibitors—are unsatisfactory.10 Alosetron, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has been used to treat IBS-D,11 but this medication was voluntarily withdrawn from the US market in 2000 due to concerns about ischemic colitis and severe constipation.12 It was reintroduced in 2002 but can be prescribed only by clinicians who enroll in a prescribing program provided by the manufacturer, and there are restrictions on its use.
Ondansetron—another 5-HT3 receptor antagonist used to treat nausea and vomiting caused by chemotherapy—may be another option for treating IBS-D. Garsed et al1 recently conducted an RCT to evaluate the efficacy of ondansetron for patients with IBS-D.
Study summary >>
STUDY SUMMARY
Ondansetron improves stool consistency, severity of IBS symptoms
In a five-week, double-blind crossover RCT, Garsed et al1 compared ondansetron with placebo for symptom relief in 120 patients who met Rome III criteria for IBS-D. All patients were ages 18 to 75 and had no evidence of inflammatory bowel disease. Exclusion criteria included pregnancy or breastfeeding, unwillingness to stop antidiarrheal medication, prior abdominal surgery other than appendectomy or cholecystectomy, or enrollment in another trial.
Patients were started on ondansetron 4 mg/d with dose titration up to 24 mg/d based on response; no dose adjustments were allowed during the last two weeks of the study. There was a two- to three-week washout between treatment periods.
The primary endpoint was average stool consistency in the last two weeks of treatment, as measured by the Bristol Stool Form (BSF) scale.13 The BSF is a visual scale that depicts stool as hard (type 1) to watery (type 7); types 3 and 4 describe normal stools. The study also looked at urgency and frequency of defecation, bowel transit time, and pain scores.
Treatment with ondansetron resulted in a small but statistically significant improvement in stool consistency. The mean difference in BSF score between ondansetron and placebo was –0.9, indicating slightly more formed stool with use of ondansetron. Scores for IBS severity—mild (a score of 75 to 175 out of 500), moderate (175 to 300), or severe (> 300)—were reduced by more points with ondansetron than with placebo (83 ± 9.8 vs 37 ± 9.7, respectively). Although this mean difference of 46 points fell just short of the 50-point threshold that is considered clinically significant, many patients exceeded this threshold.
Compared to those who received placebo, patients who took ondansetron also had less frequent defecation and lower urgency scores. Gut transit time was lengthened in the ondansetron group by 10 hours more than in the placebo group.
Pain scores did not change significantly for patients taking ondansetron, although they experienced significantly fewer days of urgency and bloating. Symptoms typically improved in as little as seven days but returned after ondansetron use stopped (typically within two weeks). Sixty-five percent of patients reported adequate relief with ondansetron, compared to 14% with placebo.
Patients whose diarrhea was more severe at baseline didn’t respond as well to ondansetron as did those whose diarrhea was less severe. The only frequent adverse effect was constipation, which occurred in 9% of patients receiving ondansetron and 2% of those on placebo.
WHAT’S NEW
Another option for IBS-D
A prior, smaller study of ondansetron that used a lower dosage (12 mg/d) suggested benefit in IBS-D.14 In that study, ondansetron decreased diarrhea and functional dyspepsia. The study by Garsed et al1 is the first large RCT to show significantly improved stool consistency, less frequent defecation, and less urgency and bloating from using ondansetron to treat IBS-D.
CAVEATS
Ondansetron doesn’t appear to reduce pain
In Garsed et al,1 patients who received ondansetron did not experience relief from pain, which is one of the main complaints of IBS. However, this study did find slight improvement in formed stools, symptom relief that approached—but did not quite reach—clinical significance, fewer days with urgency and bloating, and less frequent defecation.
This study did not evaluate the long-term effects of ondansetron use. However, ondansetron has been used for other indications for more than 25 years and has been reported to have a low risk for adverse effects.15
CHALLENGES TO IMPLEMENTATION
Remember ondansetron is not for IBS patients with constipation
Proper use of this drug among patients with IBS is key. The primary benefits of ondansetron are limited to IBS patients who have diarrhea, and not constipation. Ondansetron should not be prescribed to IBS patients who experience constipation or those with mixed symptoms.
REFERENCES
1. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625.
2. Hahn BA, Yan S, Strassels S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion. 1999;60:77-81.
3. Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006;15:237-241.
4. Luscombe FA. Health-related quality of life and associated psychosocial factors in irritable bowel syndrome: a review. Qual Life Res. 2000;9:161-176.
5. Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol. 2000;95:2816-2824.
6. Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut. 2000;46:78-82.
7. Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:896-904.
8. Schuster MM. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am. 1991;20:269-278.
9. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511.
10. Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:750-758.
11. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545-555.
12. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006;101:1069-1079.
13. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol. 1994;19:28-30.
14. Maxton DG, Morris J, Whorwell PJ. Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther. 1996;10:595-599.
15. Gill SK, Einarson A. The safety of drugs for the treatment of nausea and vomiting of pregnancy. Expert Opin Drug Saf. 2007;6:685-694.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(10):600-602.
PRACTICE CHANGER
Consider prescribing ondansetron (up to 24 mg/d) for patients who have irritable bowel syndrome with diarrhea (IBS-D).1
STRENGTH OF RECOMMENDATION
B: Based on a well-done double-blind, placebo-controlled randomized controlled trial (RCT).1
ILLUSTRATIVE CASE
A 23-year-old woman who was diagnosed with irritable bowel syndrome (IBS) comes to your clinic with complaints of increased frequency of defecation with watery stools and generalized, cramping abdominal pain. She also notes increased passage of mucus and a sensation of incomplete evacuation.
She says the only thing that relieves her pain is defecation. She has tried loperamide, acetaminophen, and ibuprofen without relief. She does not have Crohn disease or ulcerative colitis. What else can you offer her that is safe and effective?
IBS is a chronic, episodic functional gastrointestinal disorder characterized by abdominal pain or discomfort and altered bowel habits: constipation (IBS-C), diarrhea (IBS-D), or alternating periods of both—mixed (IBS-M).2 The diagnosis is based on Rome III criteria, which include recurrent abdominal pain or discomfort on at least three days per month in the past three months associated with two or more of the following: improvement with defecation, onset associated with a change in frequency of stool, and onset associated with a change in form (appearance) of stool.3 IBS often is unrecognized or untreated, and as few as 25% of patients with IBS seek care.4
IBS-D affects approximately 5% of the general population in North America.5,6 IBS-D is associated with a considerably decreased quality of life and is a common cause of work absenteeism.7,8 Because many conditions can cause diarrhea, patients typically undergo numerous tests before receiving an accurate diagnosis, which creates a financial burden.9
For many patients, current IBS treatments—including fiber supplements, laxatives, antidiarrheal medications, antispasmodics, and antidepressants such as tricyclics and selective serotonin reuptake inhibitors—are unsatisfactory.10 Alosetron, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, has been used to treat IBS-D,11 but this medication was voluntarily withdrawn from the US market in 2000 due to concerns about ischemic colitis and severe constipation.12 It was reintroduced in 2002 but can be prescribed only by clinicians who enroll in a prescribing program provided by the manufacturer, and there are restrictions on its use.
Ondansetron—another 5-HT3 receptor antagonist used to treat nausea and vomiting caused by chemotherapy—may be another option for treating IBS-D. Garsed et al1 recently conducted an RCT to evaluate the efficacy of ondansetron for patients with IBS-D.
Study summary >>
STUDY SUMMARY
Ondansetron improves stool consistency, severity of IBS symptoms
In a five-week, double-blind crossover RCT, Garsed et al1 compared ondansetron with placebo for symptom relief in 120 patients who met Rome III criteria for IBS-D. All patients were ages 18 to 75 and had no evidence of inflammatory bowel disease. Exclusion criteria included pregnancy or breastfeeding, unwillingness to stop antidiarrheal medication, prior abdominal surgery other than appendectomy or cholecystectomy, or enrollment in another trial.
Patients were started on ondansetron 4 mg/d with dose titration up to 24 mg/d based on response; no dose adjustments were allowed during the last two weeks of the study. There was a two- to three-week washout between treatment periods.
The primary endpoint was average stool consistency in the last two weeks of treatment, as measured by the Bristol Stool Form (BSF) scale.13 The BSF is a visual scale that depicts stool as hard (type 1) to watery (type 7); types 3 and 4 describe normal stools. The study also looked at urgency and frequency of defecation, bowel transit time, and pain scores.
Treatment with ondansetron resulted in a small but statistically significant improvement in stool consistency. The mean difference in BSF score between ondansetron and placebo was –0.9, indicating slightly more formed stool with use of ondansetron. Scores for IBS severity—mild (a score of 75 to 175 out of 500), moderate (175 to 300), or severe (> 300)—were reduced by more points with ondansetron than with placebo (83 ± 9.8 vs 37 ± 9.7, respectively). Although this mean difference of 46 points fell just short of the 50-point threshold that is considered clinically significant, many patients exceeded this threshold.
Compared to those who received placebo, patients who took ondansetron also had less frequent defecation and lower urgency scores. Gut transit time was lengthened in the ondansetron group by 10 hours more than in the placebo group.
Pain scores did not change significantly for patients taking ondansetron, although they experienced significantly fewer days of urgency and bloating. Symptoms typically improved in as little as seven days but returned after ondansetron use stopped (typically within two weeks). Sixty-five percent of patients reported adequate relief with ondansetron, compared to 14% with placebo.
Patients whose diarrhea was more severe at baseline didn’t respond as well to ondansetron as did those whose diarrhea was less severe. The only frequent adverse effect was constipation, which occurred in 9% of patients receiving ondansetron and 2% of those on placebo.
WHAT’S NEW
Another option for IBS-D
A prior, smaller study of ondansetron that used a lower dosage (12 mg/d) suggested benefit in IBS-D.14 In that study, ondansetron decreased diarrhea and functional dyspepsia. The study by Garsed et al1 is the first large RCT to show significantly improved stool consistency, less frequent defecation, and less urgency and bloating from using ondansetron to treat IBS-D.
CAVEATS
Ondansetron doesn’t appear to reduce pain
In Garsed et al,1 patients who received ondansetron did not experience relief from pain, which is one of the main complaints of IBS. However, this study did find slight improvement in formed stools, symptom relief that approached—but did not quite reach—clinical significance, fewer days with urgency and bloating, and less frequent defecation.
This study did not evaluate the long-term effects of ondansetron use. However, ondansetron has been used for other indications for more than 25 years and has been reported to have a low risk for adverse effects.15
CHALLENGES TO IMPLEMENTATION
Remember ondansetron is not for IBS patients with constipation
Proper use of this drug among patients with IBS is key. The primary benefits of ondansetron are limited to IBS patients who have diarrhea, and not constipation. Ondansetron should not be prescribed to IBS patients who experience constipation or those with mixed symptoms.
REFERENCES
1. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617-1625.
2. Hahn BA, Yan S, Strassels S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion. 1999;60:77-81.
3. Drossman DA, Dumitrascu DL. Rome III: new standard for functional gastrointestinal disorders. J Gastrointestin Liver Dis. 2006;15:237-241.
4. Luscombe FA. Health-related quality of life and associated psychosocial factors in irritable bowel syndrome: a review. Qual Life Res. 2000;9:161-176.
5. Saito YA, Locke GR, Talley NJ, et al. A comparison of the Rome and Manning criteria for case identification in epidemiological investigations of irritable bowel syndrome. Am J Gastroenterol. 2000;95:2816-2824.
6. Thompson WG, Heaton KW, Smyth GT, et al. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut. 2000;46:78-82.
7. Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:896-904.
8. Schuster MM. Diagnostic evaluation of the irritable bowel syndrome. Gastroenterol Clin North Am. 1991;20:269-278.
9. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500-1511.
10. Talley NJ. Pharmacologic therapy for the irritable bowel syndrome. Am J Gastroenterol. 2003;98:750-758.
11. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545-555.
12. Chang L, Chey WD, Harris L, et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am J Gastroenterol. 2006;101:1069-1079.
13. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol. 1994;19:28-30.
14. Maxton DG, Morris J, Whorwell PJ. Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther. 1996;10:595-599.
15. Gill SK, Einarson A. The safety of drugs for the treatment of nausea and vomiting of pregnancy. Expert Opin Drug Saf. 2007;6:685-694.
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(10):600-602.
When the Biggest Mistake Yields the Smallest Impact
In February 2007, a 65-year-old man consulted an internist. A blood test showed an infection. Antibiotics were administered successfully, and the patient was declared free of infection. He was noted to have a heart murmur, however, prompting the internist to refer him to a cardiologist, Dr K., for an echocardiogram.
But the internist’s nurse practitioner provided the wrong clinical indication for the referral. As a result, Dr K., unaware of what to look for, read the echocardiogram as negative. The internist and NP did not realize the mistake, because they never requested a copy of the results.
The internist later sent the patient to an infectious disease (ID) specialist, Dr G., to rule out endocarditis. Dr G.’s opinion was that there was no infection.
The patient’s condition deteriorated, however, and he was admitted to a hospital in early May 2007. Two day later, he was diagnosed with endocarditis. He subsequently underwent open-heart surgery and received antibiotics. He died later that month.
Continue for the outcome and David Lang's comments >>
OUTCOME
A $1.2 million settlement was reached, with Dr K. paying $500,000, the internist and NP paying another $500,000, and Dr G. responsible for $200,000.
COMMENT
Here, the causal problem was a communication breakdown between the primary care provider and the cardiologist.
When ordering a test, the indication may be as important as the choice of modality. Be mindful to include the indication and patient history wherever relevant—particularly when you as the referring clinician do not directly speak to the specialist. This holds true for all diagnostic studies, but particularly for laboratory analysis and imaging studies, when the clinician and the appropriate department do not communicate verbally.
We think of studies as automated—and some are. But many more involve human decision making and interpretation.
Imaging always involves the selection of modality, which may not be chosen correctly if the technician does not know or understand what the clinician is looking for.
The same is true with laboratory analysis: While a complete blood count and electrolyte measurements are automated, other tests aren’t. When a lab technician performs a manual differential or reviews a stool specimen for ova and parasites, a human is selecting a technique and interpreting the results. When a pathologist analyzes a specimen, a human process of evaluation and interpretation is rendered based on an understanding of the issue.
Don’t order tests in a vacuum. Give your human interpreters—technicians, pathologists, radiologists—as much information about the clinical case as you reasonably can. Any unusual cases involving zebra hunting are ripe candidates for misunderstanding and require a phone call.
Clearly communicating the patient history and indication also may be helpful when the clinician has ordered an incorrect or suboptimal study. If you order a standard forearm radiograph, you will get imaging of the bones. However, if you are looking for soft-tissue foreign bodies, a soft-tissue technique is better. When the indication is communicated, it gives the technician a chance to call the unknowing clinician to discuss the better option. Keeping diagnostic staff in the dark helps no one.
Finally, when you are the evaluator, protect yourself and the patient. When asked to review a study, in your report echo back the indication for the study and what you’ve been asked to address. This ensures the ordering clinician knows how the study was undertaken and what you were looking for, and it provides an opportunity to restudy if needed. Make sure to discuss limitations in the test modality and what follow-up or repeat studies would be required to properly address the indication. Make sure the report is forwarded to the ordering clinician. If the indication is unclear or the wrong test was chosen—call the ordering clinician.
Here, the internist’s NP ordered an echocardiogram to evaluate a heart murmur. We don’t know what the stated indication for the echocardiogram was, but it was not endocarditis. The cardiologist interpreted the echocardiogram as normal. Would he have detected valvular vegetations if he knew the ordering clinician was concerned about endocarditis?
The jury was persuaded that the cardiologist’s negative interpretation of the echocardiogram breached the standard of care—even given the fact he was given the wrong indication for the study. The jury also faulted the primary care clinicians, likely in part for providing the wrong indication and in part for failing to review the report.
Interestingly, the ID specialist was held least culpable (in payment terms), despite being explicitly requested to rule out endocarditis—and failing to do so. This is probably due to a short interval between the ID physician’s evaluation and the patient’s final admission. Even given the massive breach of the standard of care in failure to diagnose endocarditis, a short delay would have a relatively modest causal role in the patient’s deterioration.
Thus, even though the ID physician arguably made the biggest mistake, it may have had the least impact on the patient’s overall condition—leaving the ID physician less legally culpable in terms of damages. —DML
In February 2007, a 65-year-old man consulted an internist. A blood test showed an infection. Antibiotics were administered successfully, and the patient was declared free of infection. He was noted to have a heart murmur, however, prompting the internist to refer him to a cardiologist, Dr K., for an echocardiogram.
But the internist’s nurse practitioner provided the wrong clinical indication for the referral. As a result, Dr K., unaware of what to look for, read the echocardiogram as negative. The internist and NP did not realize the mistake, because they never requested a copy of the results.
The internist later sent the patient to an infectious disease (ID) specialist, Dr G., to rule out endocarditis. Dr G.’s opinion was that there was no infection.
The patient’s condition deteriorated, however, and he was admitted to a hospital in early May 2007. Two day later, he was diagnosed with endocarditis. He subsequently underwent open-heart surgery and received antibiotics. He died later that month.
Continue for the outcome and David Lang's comments >>
OUTCOME
A $1.2 million settlement was reached, with Dr K. paying $500,000, the internist and NP paying another $500,000, and Dr G. responsible for $200,000.
COMMENT
Here, the causal problem was a communication breakdown between the primary care provider and the cardiologist.
When ordering a test, the indication may be as important as the choice of modality. Be mindful to include the indication and patient history wherever relevant—particularly when you as the referring clinician do not directly speak to the specialist. This holds true for all diagnostic studies, but particularly for laboratory analysis and imaging studies, when the clinician and the appropriate department do not communicate verbally.
We think of studies as automated—and some are. But many more involve human decision making and interpretation.
Imaging always involves the selection of modality, which may not be chosen correctly if the technician does not know or understand what the clinician is looking for.
The same is true with laboratory analysis: While a complete blood count and electrolyte measurements are automated, other tests aren’t. When a lab technician performs a manual differential or reviews a stool specimen for ova and parasites, a human is selecting a technique and interpreting the results. When a pathologist analyzes a specimen, a human process of evaluation and interpretation is rendered based on an understanding of the issue.
Don’t order tests in a vacuum. Give your human interpreters—technicians, pathologists, radiologists—as much information about the clinical case as you reasonably can. Any unusual cases involving zebra hunting are ripe candidates for misunderstanding and require a phone call.
Clearly communicating the patient history and indication also may be helpful when the clinician has ordered an incorrect or suboptimal study. If you order a standard forearm radiograph, you will get imaging of the bones. However, if you are looking for soft-tissue foreign bodies, a soft-tissue technique is better. When the indication is communicated, it gives the technician a chance to call the unknowing clinician to discuss the better option. Keeping diagnostic staff in the dark helps no one.
Finally, when you are the evaluator, protect yourself and the patient. When asked to review a study, in your report echo back the indication for the study and what you’ve been asked to address. This ensures the ordering clinician knows how the study was undertaken and what you were looking for, and it provides an opportunity to restudy if needed. Make sure to discuss limitations in the test modality and what follow-up or repeat studies would be required to properly address the indication. Make sure the report is forwarded to the ordering clinician. If the indication is unclear or the wrong test was chosen—call the ordering clinician.
Here, the internist’s NP ordered an echocardiogram to evaluate a heart murmur. We don’t know what the stated indication for the echocardiogram was, but it was not endocarditis. The cardiologist interpreted the echocardiogram as normal. Would he have detected valvular vegetations if he knew the ordering clinician was concerned about endocarditis?
The jury was persuaded that the cardiologist’s negative interpretation of the echocardiogram breached the standard of care—even given the fact he was given the wrong indication for the study. The jury also faulted the primary care clinicians, likely in part for providing the wrong indication and in part for failing to review the report.
Interestingly, the ID specialist was held least culpable (in payment terms), despite being explicitly requested to rule out endocarditis—and failing to do so. This is probably due to a short interval between the ID physician’s evaluation and the patient’s final admission. Even given the massive breach of the standard of care in failure to diagnose endocarditis, a short delay would have a relatively modest causal role in the patient’s deterioration.
Thus, even though the ID physician arguably made the biggest mistake, it may have had the least impact on the patient’s overall condition—leaving the ID physician less legally culpable in terms of damages. —DML
In February 2007, a 65-year-old man consulted an internist. A blood test showed an infection. Antibiotics were administered successfully, and the patient was declared free of infection. He was noted to have a heart murmur, however, prompting the internist to refer him to a cardiologist, Dr K., for an echocardiogram.
But the internist’s nurse practitioner provided the wrong clinical indication for the referral. As a result, Dr K., unaware of what to look for, read the echocardiogram as negative. The internist and NP did not realize the mistake, because they never requested a copy of the results.
The internist later sent the patient to an infectious disease (ID) specialist, Dr G., to rule out endocarditis. Dr G.’s opinion was that there was no infection.
The patient’s condition deteriorated, however, and he was admitted to a hospital in early May 2007. Two day later, he was diagnosed with endocarditis. He subsequently underwent open-heart surgery and received antibiotics. He died later that month.
Continue for the outcome and David Lang's comments >>
OUTCOME
A $1.2 million settlement was reached, with Dr K. paying $500,000, the internist and NP paying another $500,000, and Dr G. responsible for $200,000.
COMMENT
Here, the causal problem was a communication breakdown between the primary care provider and the cardiologist.
When ordering a test, the indication may be as important as the choice of modality. Be mindful to include the indication and patient history wherever relevant—particularly when you as the referring clinician do not directly speak to the specialist. This holds true for all diagnostic studies, but particularly for laboratory analysis and imaging studies, when the clinician and the appropriate department do not communicate verbally.
We think of studies as automated—and some are. But many more involve human decision making and interpretation.
Imaging always involves the selection of modality, which may not be chosen correctly if the technician does not know or understand what the clinician is looking for.
The same is true with laboratory analysis: While a complete blood count and electrolyte measurements are automated, other tests aren’t. When a lab technician performs a manual differential or reviews a stool specimen for ova and parasites, a human is selecting a technique and interpreting the results. When a pathologist analyzes a specimen, a human process of evaluation and interpretation is rendered based on an understanding of the issue.
Don’t order tests in a vacuum. Give your human interpreters—technicians, pathologists, radiologists—as much information about the clinical case as you reasonably can. Any unusual cases involving zebra hunting are ripe candidates for misunderstanding and require a phone call.
Clearly communicating the patient history and indication also may be helpful when the clinician has ordered an incorrect or suboptimal study. If you order a standard forearm radiograph, you will get imaging of the bones. However, if you are looking for soft-tissue foreign bodies, a soft-tissue technique is better. When the indication is communicated, it gives the technician a chance to call the unknowing clinician to discuss the better option. Keeping diagnostic staff in the dark helps no one.
Finally, when you are the evaluator, protect yourself and the patient. When asked to review a study, in your report echo back the indication for the study and what you’ve been asked to address. This ensures the ordering clinician knows how the study was undertaken and what you were looking for, and it provides an opportunity to restudy if needed. Make sure to discuss limitations in the test modality and what follow-up or repeat studies would be required to properly address the indication. Make sure the report is forwarded to the ordering clinician. If the indication is unclear or the wrong test was chosen—call the ordering clinician.
Here, the internist’s NP ordered an echocardiogram to evaluate a heart murmur. We don’t know what the stated indication for the echocardiogram was, but it was not endocarditis. The cardiologist interpreted the echocardiogram as normal. Would he have detected valvular vegetations if he knew the ordering clinician was concerned about endocarditis?
The jury was persuaded that the cardiologist’s negative interpretation of the echocardiogram breached the standard of care—even given the fact he was given the wrong indication for the study. The jury also faulted the primary care clinicians, likely in part for providing the wrong indication and in part for failing to review the report.
Interestingly, the ID specialist was held least culpable (in payment terms), despite being explicitly requested to rule out endocarditis—and failing to do so. This is probably due to a short interval between the ID physician’s evaluation and the patient’s final admission. Even given the massive breach of the standard of care in failure to diagnose endocarditis, a short delay would have a relatively modest causal role in the patient’s deterioration.
Thus, even though the ID physician arguably made the biggest mistake, it may have had the least impact on the patient’s overall condition—leaving the ID physician less legally culpable in terms of damages. —DML
Baystate Medical Center's Unit-Based, Multidisciplinary Rounding Enhances Inpatient Care
The hospitalist-led Broder Service empowers all care-team members to focus on patient quality, satisfaction. Get an up-close look at the service with our 6-minute feature video:
The hospitalist-led Broder Service empowers all care-team members to focus on patient quality, satisfaction. Get an up-close look at the service with our 6-minute feature video:
The hospitalist-led Broder Service empowers all care-team members to focus on patient quality, satisfaction. Get an up-close look at the service with our 6-minute feature video:
Practical Considerations for Infant Formula Recommendations
This educational supplement to Pediatric News was sponsored by Perrigo Nutritionals.
Topics
- Introduction
- Switching Infant Formula
- Conclusion
Faculty/Faculty Disclosures
Jenifer R. Lightdale, MD, MPH
Division Chief, Pediatric Gastroenterology,
Hepatology and Nutrition
UMass Memorial Children’s Medical Center
Professor of Pediatrics
University of Massachusetts Medical School
Worcester, MA
Dr. Lightdale reports that she is on the medical advisory board for Perrigo Company plc, and is an invited speaker for Mead Johnson & Company, LLC.
This educational supplement to Pediatric News was sponsored by Perrigo Nutritionals.
Topics
- Introduction
- Switching Infant Formula
- Conclusion
Faculty/Faculty Disclosures
Jenifer R. Lightdale, MD, MPH
Division Chief, Pediatric Gastroenterology,
Hepatology and Nutrition
UMass Memorial Children’s Medical Center
Professor of Pediatrics
University of Massachusetts Medical School
Worcester, MA
Dr. Lightdale reports that she is on the medical advisory board for Perrigo Company plc, and is an invited speaker for Mead Johnson & Company, LLC.
This educational supplement to Pediatric News was sponsored by Perrigo Nutritionals.
Topics
- Introduction
- Switching Infant Formula
- Conclusion
Faculty/Faculty Disclosures
Jenifer R. Lightdale, MD, MPH
Division Chief, Pediatric Gastroenterology,
Hepatology and Nutrition
UMass Memorial Children’s Medical Center
Professor of Pediatrics
University of Massachusetts Medical School
Worcester, MA
Dr. Lightdale reports that she is on the medical advisory board for Perrigo Company plc, and is an invited speaker for Mead Johnson & Company, LLC.
Insured cancer patients forgo care, scrimp to get by
cancer patient and her father
Credit: Rhoda Baer
Despite having insurance, many US cancer patients may forgo medical care and change their lifestyles due to treatment-related financial burdens, a new survey suggests.
Nearly 40% of the 174 patients surveyed adopted medical care-altering strategies, such as skipping recommended testing and treatment.
And nearly 9 out of 10 patients made at least one lifestyle change, such as spending less money on food and clothing or selling their possessions.
Prior research has suggested that about 13% of patients suffer from high out-of-pocket financial burden after they are diagnosed with cancer. According to the American Cancer Society, as many as 20% of Americans with cancer spend their life savings to pay for their care.
“We need a better, more open dialogue between patients and providers about the financial burden associated with cancer care costs,” said lead study author Ryan Nipp, MD, of Dana-Farber Cancer Institute in Boston.
“We found that people use a range of different cost-coping strategies, and we need to engage with patients on their choices and develop screening tools to identify patients who are likely to make potentially harmful decisions about their treatment.”
Dr Nipp presented these findings (abstract 161*) in a presscast in advance of the 2014 Palliative Care in Oncology Symposium, which is taking place October 24-25 at the Westin Boston Waterfront in Boston.
The researchers surveyed 174 patients (median age 67, 96% female, 83% white) undergoing treatment for cancer (85% breast, 4% colorectal, 11% other solid tumors). All patients were insured and had requested financial assistance through a national copay assistance program.
Overall, 89% of participants used at least one lifestyle-altering strategy, and 39% used at least one medical care-altering strategy.
The most common medical care-altering strategies were not filling a prescription (28%) and taking less medication than prescribed (22%). Patients also reported skipping tests (10%), forgoing procedures (8%), and missing doctor’s appointments (6%).
Lifestyle-altering strategies included spending less on leisure activities (78%), spending less on basics like food and clothing (57%), borrowing money (54%), spending savings (50%), selling possessions (18%), and having family members work more (15%).
Younger age, higher education, and shorter time on chemotherapy were all associated with a greater likelihood of adopting lifestyle coping strategies compared to older age, lower education, and longer time on chemotherapy.
Younger patients were also more likely to use care-altering strategies compared to older patients. And lower-income patients used more care-altering strategies than higher-income patients.
*Data in the abstract differ from data presented.
cancer patient and her father
Credit: Rhoda Baer
Despite having insurance, many US cancer patients may forgo medical care and change their lifestyles due to treatment-related financial burdens, a new survey suggests.
Nearly 40% of the 174 patients surveyed adopted medical care-altering strategies, such as skipping recommended testing and treatment.
And nearly 9 out of 10 patients made at least one lifestyle change, such as spending less money on food and clothing or selling their possessions.
Prior research has suggested that about 13% of patients suffer from high out-of-pocket financial burden after they are diagnosed with cancer. According to the American Cancer Society, as many as 20% of Americans with cancer spend their life savings to pay for their care.
“We need a better, more open dialogue between patients and providers about the financial burden associated with cancer care costs,” said lead study author Ryan Nipp, MD, of Dana-Farber Cancer Institute in Boston.
“We found that people use a range of different cost-coping strategies, and we need to engage with patients on their choices and develop screening tools to identify patients who are likely to make potentially harmful decisions about their treatment.”
Dr Nipp presented these findings (abstract 161*) in a presscast in advance of the 2014 Palliative Care in Oncology Symposium, which is taking place October 24-25 at the Westin Boston Waterfront in Boston.
The researchers surveyed 174 patients (median age 67, 96% female, 83% white) undergoing treatment for cancer (85% breast, 4% colorectal, 11% other solid tumors). All patients were insured and had requested financial assistance through a national copay assistance program.
Overall, 89% of participants used at least one lifestyle-altering strategy, and 39% used at least one medical care-altering strategy.
The most common medical care-altering strategies were not filling a prescription (28%) and taking less medication than prescribed (22%). Patients also reported skipping tests (10%), forgoing procedures (8%), and missing doctor’s appointments (6%).
Lifestyle-altering strategies included spending less on leisure activities (78%), spending less on basics like food and clothing (57%), borrowing money (54%), spending savings (50%), selling possessions (18%), and having family members work more (15%).
Younger age, higher education, and shorter time on chemotherapy were all associated with a greater likelihood of adopting lifestyle coping strategies compared to older age, lower education, and longer time on chemotherapy.
Younger patients were also more likely to use care-altering strategies compared to older patients. And lower-income patients used more care-altering strategies than higher-income patients.
*Data in the abstract differ from data presented.
cancer patient and her father
Credit: Rhoda Baer
Despite having insurance, many US cancer patients may forgo medical care and change their lifestyles due to treatment-related financial burdens, a new survey suggests.
Nearly 40% of the 174 patients surveyed adopted medical care-altering strategies, such as skipping recommended testing and treatment.
And nearly 9 out of 10 patients made at least one lifestyle change, such as spending less money on food and clothing or selling their possessions.
Prior research has suggested that about 13% of patients suffer from high out-of-pocket financial burden after they are diagnosed with cancer. According to the American Cancer Society, as many as 20% of Americans with cancer spend their life savings to pay for their care.
“We need a better, more open dialogue between patients and providers about the financial burden associated with cancer care costs,” said lead study author Ryan Nipp, MD, of Dana-Farber Cancer Institute in Boston.
“We found that people use a range of different cost-coping strategies, and we need to engage with patients on their choices and develop screening tools to identify patients who are likely to make potentially harmful decisions about their treatment.”
Dr Nipp presented these findings (abstract 161*) in a presscast in advance of the 2014 Palliative Care in Oncology Symposium, which is taking place October 24-25 at the Westin Boston Waterfront in Boston.
The researchers surveyed 174 patients (median age 67, 96% female, 83% white) undergoing treatment for cancer (85% breast, 4% colorectal, 11% other solid tumors). All patients were insured and had requested financial assistance through a national copay assistance program.
Overall, 89% of participants used at least one lifestyle-altering strategy, and 39% used at least one medical care-altering strategy.
The most common medical care-altering strategies were not filling a prescription (28%) and taking less medication than prescribed (22%). Patients also reported skipping tests (10%), forgoing procedures (8%), and missing doctor’s appointments (6%).
Lifestyle-altering strategies included spending less on leisure activities (78%), spending less on basics like food and clothing (57%), borrowing money (54%), spending savings (50%), selling possessions (18%), and having family members work more (15%).
Younger age, higher education, and shorter time on chemotherapy were all associated with a greater likelihood of adopting lifestyle coping strategies compared to older age, lower education, and longer time on chemotherapy.
Younger patients were also more likely to use care-altering strategies compared to older patients. And lower-income patients used more care-altering strategies than higher-income patients.
*Data in the abstract differ from data presented.
NICE supports use of rivaroxaban in ACS
Credit: Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending rivaroxaban (Xarelto) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).
The agency is recommending rivaroxaban in combination with aspirin plus clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the draft guidance.
Because rivaroxaban increases the risk of bleeding, NICE recommends that clinicians undertake a careful assessment of a patient’s bleeding risk prior to treatment and ensure patients understand the benefits and risks associated with rivaroxaban.
Furthermore, clinicians should reassess the relative benefits and risks of continuing rivaroxaban treatment no later than 12 months after starting treatment.
Clinical and cost-effectiveness
An independent appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
“The committee therefore recommended rivaroxaban as a cost-effective use of [National Health Service] resources,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
The committee noted that, according to Bayer Healthcare (makers of rivaroxaban), the base case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base case estimate was £5622 per QALY gained.
The committee acknowledged that there is uncertainty about the validity of the results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
The draft guidance for rivaroxaban in ACS can be found on the NICE website. The closing date for comments is November 13, 2014.
Credit: Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending rivaroxaban (Xarelto) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).
The agency is recommending rivaroxaban in combination with aspirin plus clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the draft guidance.
Because rivaroxaban increases the risk of bleeding, NICE recommends that clinicians undertake a careful assessment of a patient’s bleeding risk prior to treatment and ensure patients understand the benefits and risks associated with rivaroxaban.
Furthermore, clinicians should reassess the relative benefits and risks of continuing rivaroxaban treatment no later than 12 months after starting treatment.
Clinical and cost-effectiveness
An independent appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
“The committee therefore recommended rivaroxaban as a cost-effective use of [National Health Service] resources,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
The committee noted that, according to Bayer Healthcare (makers of rivaroxaban), the base case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base case estimate was £5622 per QALY gained.
The committee acknowledged that there is uncertainty about the validity of the results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
The draft guidance for rivaroxaban in ACS can be found on the NICE website. The closing date for comments is November 13, 2014.
Credit: Andre E.X. Brown
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending rivaroxaban (Xarelto) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).
The agency is recommending rivaroxaban in combination with aspirin plus clopidogrel or aspirin alone to prevent atherothrombotic events in ACS patients with elevated cardiac biomarkers.
This includes patients who have had ST-segment-elevation myocardial infarctions (STEMIs) or non-ST-segment myocardial infarctions (NSTEMIs) but not unstable angina. In unstable angina, damage to the heart is not severe enough to result in the release of biomarkers into the blood, so this condition is not included in the draft guidance.
Because rivaroxaban increases the risk of bleeding, NICE recommends that clinicians undertake a careful assessment of a patient’s bleeding risk prior to treatment and ensure patients understand the benefits and risks associated with rivaroxaban.
Furthermore, clinicians should reassess the relative benefits and risks of continuing rivaroxaban treatment no later than 12 months after starting treatment.
Clinical and cost-effectiveness
An independent appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.
“The committee therefore recommended rivaroxaban as a cost-effective use of [National Health Service] resources,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
The committee noted that, according to Bayer Healthcare (makers of rivaroxaban), the base case incremental cost-effectiveness ratio (ICER) was £6203 per quality-adjusted life-year (QALY) gained. The evidence review group’s preferred base case estimate was £5622 per QALY gained.
The committee acknowledged that there is uncertainty about the validity of the results, which were based on the ATLAS-ACS 2-TIMI 51 trial, because of the risk of bias resulting from missing trial data and informative censoring.
However, the committee considered that the ICERs presented were all within the range that could be considered cost-effective, and adjusting for the various types of bias that might have occurred was unlikely to increase the ICER to the extent that it would become unacceptable.
The list price of rivaroxaban is £58.88 per 2.5 mg, 56-capsule pack (excluding value-added tax). The license dose is 2.5 mg twice daily, which equates to a price of £2.10 per day.
Assuming a treatment duration of 12 months, total acquisition costs are £766.50. Costs may vary in different settings because of negotiated procurement discounts.
The draft guidance for rivaroxaban in ACS can be found on the NICE website. The closing date for comments is November 13, 2014.
Managing CNS relapse in cardiac lymphoma
Two cases of central nervous system (CNS) relapse in patients with primary cardiac lymphoma underline the importance of CNS evaluation in these patients, according to researchers.
Cardiac lymphoma is a rare condition, and doctors often overlook the potential of metastasis to the CNS, said study author Niccolò Frungillo, MD, of the European Institute of Oncology in Milan, Italy.
“In my opinion, it is very important to identify prognostic factors that predict the brain relapse of lymphoma,” he said. “It’s a rare—but often fatal—complication.”
In ecancermedicalscience, Dr Frungillo and his colleagues described the diagnosis and treatment of two women with cardiac lymphoma who achieved remission and later presented with isolated CNS relapse.
Doctors diagnosed the patients via endomyocardial biopsy, and results were consistent with diffuse large B-cell lymphoma in both cases. Immunochemotherapy produced complete remissions (CRs) in both women.
The patients then experienced isolated CNS relapses, one 8 weeks after achieving a CR, and one 5 weeks after CR.
In the first patient, MRI and cerebrospinal fluid confirmed her relapse, after she presented with a 3-day history of headache and vomiting.
The patient then received high-dose methotrexate and high-dose cytarabine, which prompted a second CR. She went on to receive an autologous stem cell transplant but died before engraftment due to a pulmonary infection.
The second patient received systemic CNS prophylaxis with high-dose methotrexate prior to her relapse. Nevertheless, one week after she was declared lymphoma-free, she presented with headache and a deterioration of motor skills.
MRI and lumbar puncture confirmed her relapse, and she received induction chemotherapy with high-dose methotrexate. Her disease progressed after two courses of treatment, so she was placed on salvage therapy with cytarabine and high-dose methotrexate.
Whole-brain radiotherapy prompted a CR, and the patient went on to receive an autologous stem cell transplant.
The researchers noted that isolated CNS relapse is very uncommon in cardiac lymphoma, but CNS evaluation should be considered. Additional studies are needed to determine the appropriate management of CNS relapse in cardiac lymphoma.
Two cases of central nervous system (CNS) relapse in patients with primary cardiac lymphoma underline the importance of CNS evaluation in these patients, according to researchers.
Cardiac lymphoma is a rare condition, and doctors often overlook the potential of metastasis to the CNS, said study author Niccolò Frungillo, MD, of the European Institute of Oncology in Milan, Italy.
“In my opinion, it is very important to identify prognostic factors that predict the brain relapse of lymphoma,” he said. “It’s a rare—but often fatal—complication.”
In ecancermedicalscience, Dr Frungillo and his colleagues described the diagnosis and treatment of two women with cardiac lymphoma who achieved remission and later presented with isolated CNS relapse.
Doctors diagnosed the patients via endomyocardial biopsy, and results were consistent with diffuse large B-cell lymphoma in both cases. Immunochemotherapy produced complete remissions (CRs) in both women.
The patients then experienced isolated CNS relapses, one 8 weeks after achieving a CR, and one 5 weeks after CR.
In the first patient, MRI and cerebrospinal fluid confirmed her relapse, after she presented with a 3-day history of headache and vomiting.
The patient then received high-dose methotrexate and high-dose cytarabine, which prompted a second CR. She went on to receive an autologous stem cell transplant but died before engraftment due to a pulmonary infection.
The second patient received systemic CNS prophylaxis with high-dose methotrexate prior to her relapse. Nevertheless, one week after she was declared lymphoma-free, she presented with headache and a deterioration of motor skills.
MRI and lumbar puncture confirmed her relapse, and she received induction chemotherapy with high-dose methotrexate. Her disease progressed after two courses of treatment, so she was placed on salvage therapy with cytarabine and high-dose methotrexate.
Whole-brain radiotherapy prompted a CR, and the patient went on to receive an autologous stem cell transplant.
The researchers noted that isolated CNS relapse is very uncommon in cardiac lymphoma, but CNS evaluation should be considered. Additional studies are needed to determine the appropriate management of CNS relapse in cardiac lymphoma.
Two cases of central nervous system (CNS) relapse in patients with primary cardiac lymphoma underline the importance of CNS evaluation in these patients, according to researchers.
Cardiac lymphoma is a rare condition, and doctors often overlook the potential of metastasis to the CNS, said study author Niccolò Frungillo, MD, of the European Institute of Oncology in Milan, Italy.
“In my opinion, it is very important to identify prognostic factors that predict the brain relapse of lymphoma,” he said. “It’s a rare—but often fatal—complication.”
In ecancermedicalscience, Dr Frungillo and his colleagues described the diagnosis and treatment of two women with cardiac lymphoma who achieved remission and later presented with isolated CNS relapse.
Doctors diagnosed the patients via endomyocardial biopsy, and results were consistent with diffuse large B-cell lymphoma in both cases. Immunochemotherapy produced complete remissions (CRs) in both women.
The patients then experienced isolated CNS relapses, one 8 weeks after achieving a CR, and one 5 weeks after CR.
In the first patient, MRI and cerebrospinal fluid confirmed her relapse, after she presented with a 3-day history of headache and vomiting.
The patient then received high-dose methotrexate and high-dose cytarabine, which prompted a second CR. She went on to receive an autologous stem cell transplant but died before engraftment due to a pulmonary infection.
The second patient received systemic CNS prophylaxis with high-dose methotrexate prior to her relapse. Nevertheless, one week after she was declared lymphoma-free, she presented with headache and a deterioration of motor skills.
MRI and lumbar puncture confirmed her relapse, and she received induction chemotherapy with high-dose methotrexate. Her disease progressed after two courses of treatment, so she was placed on salvage therapy with cytarabine and high-dose methotrexate.
Whole-brain radiotherapy prompted a CR, and the patient went on to receive an autologous stem cell transplant.
The researchers noted that isolated CNS relapse is very uncommon in cardiac lymphoma, but CNS evaluation should be considered. Additional studies are needed to determine the appropriate management of CNS relapse in cardiac lymphoma.
Patients in GDR trials were not properly informed
Credit: Esther Dyson
New research has shown that clinical trials carried out in the German Democratic Republic (GDR) in the second half of the 20th century were not always conducted with the full knowledge or understanding of participants.
A review of documents from that time suggests that, although questionable practices took place, the GDR attempted to conduct trials according to international ethical standards.
And there was no evidence to suggest that trial investigators intentionally hurt patients.
Nevertheless, these trials were hidden from the public, there was no record of patient consent, and some documents suggest patients did not receive adequate information.
Dr Rainer Erices, of Friedrich-Alexander-Universität Erlangen-Nuernberg in Germany, and his colleagues detailed these findings in the Journal of Medical Ethics.
The GDR, also known as East Germany, was a state within the Eastern Bloc during the Cold War period and between 1949 and 1990. Since the 1990s, the media has reported that unofficial clinical trials were conducted by Western pharmaceutical companies in East Germany from the 1960s onward.
Reports have suggested the GDR “sold” its patients as “guinea pigs” for experiments in exchange for hard currency; for example, for tests on doping effects in premature babies and on treating seriously ill patients with placebo instead of actual medicine.
However, there is still a lack of reliable data about the extent of studies taking place then, the contracts, the amount of money paid, and more moral issues, such as patient education and informed consent.
Dr Erices and his colleagues set out to uncover more information by evaluating the clinical trials based on archival material from the health system and the secret service.
The team found documents related to 220 trials carried out between 1983 and 1990, which involved more than 14,000 patients and 68 Western pharmaceutical companies.
However, there was no record of patient information forms or systematic documentation regarding the provision of patient consent.
A range of drugs were tested in these studies, including chemotherapeutic agents, heparin, insulin, anti-depressants, anti-allergy drugs, contrast agents, and toothpastes.
Between 1983 and 1990, the GDR’s health system received approximately DM 16.5 million for the trials, which were cost-effective for the drug firms, according to the researchers. The team also noted that the GDR agreed to these trials due to its desperate need for hard currency (impending bankruptcy).
Overall, the files the researchers studied suggested that the GDR attempted to conduct trials according to international ethical standards.
However, the trials were concealed from the public. And state legislation stipulated that patients had to consent to the trials, but no evidence was found to suggest that patients were systematically informed.
Some documents suggested that at least some of the trials were carried out without patients having a comprehensive understanding of what the trial involved. And it was unclear whether the patients themselves knew that they were participating in trials and were aware of all the risks.
The researchers concluded that further investigation of these trials is needed, and specific trials should be studied separately.
Credit: Esther Dyson
New research has shown that clinical trials carried out in the German Democratic Republic (GDR) in the second half of the 20th century were not always conducted with the full knowledge or understanding of participants.
A review of documents from that time suggests that, although questionable practices took place, the GDR attempted to conduct trials according to international ethical standards.
And there was no evidence to suggest that trial investigators intentionally hurt patients.
Nevertheless, these trials were hidden from the public, there was no record of patient consent, and some documents suggest patients did not receive adequate information.
Dr Rainer Erices, of Friedrich-Alexander-Universität Erlangen-Nuernberg in Germany, and his colleagues detailed these findings in the Journal of Medical Ethics.
The GDR, also known as East Germany, was a state within the Eastern Bloc during the Cold War period and between 1949 and 1990. Since the 1990s, the media has reported that unofficial clinical trials were conducted by Western pharmaceutical companies in East Germany from the 1960s onward.
Reports have suggested the GDR “sold” its patients as “guinea pigs” for experiments in exchange for hard currency; for example, for tests on doping effects in premature babies and on treating seriously ill patients with placebo instead of actual medicine.
However, there is still a lack of reliable data about the extent of studies taking place then, the contracts, the amount of money paid, and more moral issues, such as patient education and informed consent.
Dr Erices and his colleagues set out to uncover more information by evaluating the clinical trials based on archival material from the health system and the secret service.
The team found documents related to 220 trials carried out between 1983 and 1990, which involved more than 14,000 patients and 68 Western pharmaceutical companies.
However, there was no record of patient information forms or systematic documentation regarding the provision of patient consent.
A range of drugs were tested in these studies, including chemotherapeutic agents, heparin, insulin, anti-depressants, anti-allergy drugs, contrast agents, and toothpastes.
Between 1983 and 1990, the GDR’s health system received approximately DM 16.5 million for the trials, which were cost-effective for the drug firms, according to the researchers. The team also noted that the GDR agreed to these trials due to its desperate need for hard currency (impending bankruptcy).
Overall, the files the researchers studied suggested that the GDR attempted to conduct trials according to international ethical standards.
However, the trials were concealed from the public. And state legislation stipulated that patients had to consent to the trials, but no evidence was found to suggest that patients were systematically informed.
Some documents suggested that at least some of the trials were carried out without patients having a comprehensive understanding of what the trial involved. And it was unclear whether the patients themselves knew that they were participating in trials and were aware of all the risks.
The researchers concluded that further investigation of these trials is needed, and specific trials should be studied separately.
Credit: Esther Dyson
New research has shown that clinical trials carried out in the German Democratic Republic (GDR) in the second half of the 20th century were not always conducted with the full knowledge or understanding of participants.
A review of documents from that time suggests that, although questionable practices took place, the GDR attempted to conduct trials according to international ethical standards.
And there was no evidence to suggest that trial investigators intentionally hurt patients.
Nevertheless, these trials were hidden from the public, there was no record of patient consent, and some documents suggest patients did not receive adequate information.
Dr Rainer Erices, of Friedrich-Alexander-Universität Erlangen-Nuernberg in Germany, and his colleagues detailed these findings in the Journal of Medical Ethics.
The GDR, also known as East Germany, was a state within the Eastern Bloc during the Cold War period and between 1949 and 1990. Since the 1990s, the media has reported that unofficial clinical trials were conducted by Western pharmaceutical companies in East Germany from the 1960s onward.
Reports have suggested the GDR “sold” its patients as “guinea pigs” for experiments in exchange for hard currency; for example, for tests on doping effects in premature babies and on treating seriously ill patients with placebo instead of actual medicine.
However, there is still a lack of reliable data about the extent of studies taking place then, the contracts, the amount of money paid, and more moral issues, such as patient education and informed consent.
Dr Erices and his colleagues set out to uncover more information by evaluating the clinical trials based on archival material from the health system and the secret service.
The team found documents related to 220 trials carried out between 1983 and 1990, which involved more than 14,000 patients and 68 Western pharmaceutical companies.
However, there was no record of patient information forms or systematic documentation regarding the provision of patient consent.
A range of drugs were tested in these studies, including chemotherapeutic agents, heparin, insulin, anti-depressants, anti-allergy drugs, contrast agents, and toothpastes.
Between 1983 and 1990, the GDR’s health system received approximately DM 16.5 million for the trials, which were cost-effective for the drug firms, according to the researchers. The team also noted that the GDR agreed to these trials due to its desperate need for hard currency (impending bankruptcy).
Overall, the files the researchers studied suggested that the GDR attempted to conduct trials according to international ethical standards.
However, the trials were concealed from the public. And state legislation stipulated that patients had to consent to the trials, but no evidence was found to suggest that patients were systematically informed.
Some documents suggested that at least some of the trials were carried out without patients having a comprehensive understanding of what the trial involved. And it was unclear whether the patients themselves knew that they were participating in trials and were aware of all the risks.
The researchers concluded that further investigation of these trials is needed, and specific trials should be studied separately.