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How might acknowledging a medical error promote patient safety?
Examination
- Patient looks well and is in no distress
- Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
- Normal heart, lung, and abdominal exam. No cervical or other adenopathy.
Medical history
- Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
- Married, with 1 grown son who is healthy
- Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
- Walks 40 minutes 4 times a week
- Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
- Review of systems negative for cough, fever, weight loss, or swollen glands
A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.
The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.1 The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.1
A:
Interpreting TB test results
The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.1 Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).
An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.2
Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).3 It was unavailable in the county where the patient was tested.
TABLE
TST results regarded as positive for tuberculosis, given a patient’s specific risk factors
| 5 MM | INDURATION 10 MM | 15 MM |
|---|---|---|
| HIV infection Close contact of person with TB Previous TB on chest x-ray Intravenous drug use, or unknown HIV status | Native of country with endemic TB HIV-negative intravenous drug user Low income, inadequate healthcare Resident of long-term care facility Medical condition with increased TB risk Ages less than 4 years Likely exposure to TB | Patient has no risk factors |
The patient’s return 48 hours later
A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“
A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.4
The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.
The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.
A:
Dealing responsibly with medical errors
A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.
A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.5 In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.
Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.6
To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.
Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:
- Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
- Report these facts to risk management or to the professional liability carrier, according to internal policies
- Apologize to the patient.
A:
Important features of an apology
- Make the apology promptly
- Be sincere
- Apologize in person
- Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.
The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.
After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.
Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.
A:
Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.7 These include:
- Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
- Avoid blame—search for root causes.
- Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
- Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.
Openly acknowledging a mistake and apologizing to a patient, as the authors suggest, is sound advice increasingly followed in the United States and internationally. Disclosure of mistakes is a cornerstone of the safety work, as is being carried out in the United Kingdom by the National Patient Safety Agency (NPSA). They have prepared excellent online interactive educational materials to support health care professionals as they participate in the disclosure process.8
A second step the authors took was to learn about the inherent risks and potential failure points that are often deeply embedded in our care delivery processes. Mistakes are windows into the clinical work environment. If we peer through these windows regularly and systematically, we can learn a good deal about protecting our patients from harm. The mistake reported here—though of little or no harm to the patient (ie, possibly a near miss)—has potential as a rich information source about how care is delivered in the family practice clinic.9 In addition, because there was a recovery by the patient’s family physician, we have the added benefit of learning from that part of the narrative.
Learning from mistakes an intentional process, not an automatic one
First, an organization or setting must have a just culture to enable learning.10 Tools for assessing safety culture are available from the Agency for Healthcare Research and Quality (AHRQ)11 and from the Institute for Healthcare Improvement (IHI).12 A just culture is an essential attribute of a learning organization.13
Second, a systematic process must be available for inquiring about the root causes and contributing factors of events. Examples of such systems are those used by Veterans Health Administration (VHA)14 and the UK’s NPSA.15 The Medical Events Reporting System for transfusion medicine (MERS-TM) is a model reporting system in the US and is developed as a learning system.16,17
Third, we have learned that simply gathering information about the causes of events is not sufficient to prevent future events. Those involved in mistakes must be given an opportunity to come together to make sense of the causal information before they can make changes.
Fourth, a system-change method is needed to correct underlying causes. Such a method is the Plan-Do-Study Act (PDSA), which translates knowledge about causes into actions that can be implemented in the health care work environment.18
How might these processes apply to the case at hand
Two aspects of this case in particular bear scrutiny.
The clinic protocol. Protocols standardize care as well as complement the cognitive work required in clinical care. Understanding the contents and use of this protocol would shed light on this event. To what extent did the protocol support the interpretation of the TB test; how informative was it? Did it require obtaining a history from the patient as a component of the test interpretation? Did it detail the skills of the test interpreter? Did it spell out a contingency plan in the event those administering and reading the tests are unclear about the findings? Who had access to the protocol?
Handoffs, when things can get dropped. Another focus of this case is the 3 handoffs: the nurse reading the test handed the interpretation off to a physician; the physician handed the patient off to the public health clinic; and the clinic then handed the patient back to her primary care physician. Handoffs often lead to mistakes because they involve interpersonal communication and transfer of information, both of which are fraught with opportunities for errors.19
In the first handoff, we might well ask what information the nurse had about the patient’s history and what information she communicated to the physician? A full understanding of this handoff helps to make explicit hierarchical relationships in the clinic as well as information flow.
With the second handoff, we might ask what information regarding the uncertainty of the patient’s TB test interpretation and history were passed along to the TB clinic? How was the information communicated—on paper, electronically, by telephone? Each of these methods has unique constraints.
Finally, the fortunate third handoff—follow-up with the patient’s family practice physician that resulted in the discovery of the mistake and therefore recovery. It is particularly important to note that the recovery came because of an apparent system of feedback of information to the patient’s family physician. Such feedback loops contribute to safety. The family physician noticed something that did not make sense and investigated it. That is, the family physician was mindful.20 This attitude of mindfulness is a critical component in safe or reliable systems. Hubris is the enemy of safety.
Shirley Kellie, MD, MSc
Physician epidemiologist, American Medical Association
A:
In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:
- Create specific written instructions for office procedures
- Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
- Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
- Have regular updates or ”recertification,” particularly for procedures that are done infrequently
- A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
- Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”
1. Tuberculosis control. North Carolina Tuberculosis Policy Manual (2nd rev, 2005). Available at: www.epi.state.nc.us/epi/gcdc/tb/manual.html. Accessed on July 27, 2006.
2. Pouchot J, Grassland A, et al. Reliability of tubercelin skin test measurement. Ann Int Med 1997;126:210-214.
3. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep 2003;52(RR-02):15-18.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5202a2.htm. Accessed on July 27, 2006
4. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Accessed on July 27, 2006.
5. Gallagher TH, Levinsen W. Disclosing harmful medical errors to patients: a time for professional action. Arch Int Med 2005;165:1819-1824.
6. Kraman SS, Ham G. Risk management: extreme honesty maybe the best policy. Ann Int Med 1999;131:963-967.
7. Vincent C. Patient safety: understanding and responding to adverse events. N Engl J Med 2003;348:1051-1056.
8. National Patient Safety Agency. Being open: Communicating patient safety incidents with patients and their carers [website]. Available at: www.npsa.nhs.uk/health/resources/beingopen. Accessed on July 27, 2006.
9. Kaplan HS. Benefiting from the “gift of failure”: essentials for an event reporting system. J Leg Med 2003;24:29-35.
10. Marx D. Patient safety and the “just culture”: a primer for health care executives. Available at: www.merstm.net/support/Marx_Primer.pdf. Accessed on July 27, 2006.
11. Agency for Healthcare Research and Quality. Hospital Survey on Patient Safety Culture [online database]. Available at: www.ahrq.gov/qual/hospculture. Accessed on July 27, 2006.
12. Institute for Healthcare Improvement. Safety climate survey 2005. Available at: www.ihi.org/IHI/Topics/PatientSafety/MedicationSystems/Tools/SafetyClimateSurvey2005IHITool.htm. Accessed on July 27, 2006.
13. Department of Health. An organisation with a memory: Report of an expert group on learning from adverse events in the NHS. London, 2000. Available at: www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4065083&chk=PARoiF. Accessed on July 27, 2006.
14. Veterans Administration National Center for Patient Safety. Root cause analysis. Available at: www.va.gov/ncps/rca.html. Accessed on July 27, 2006.
15. National Patient Safety Agency. National Health Service, United Kingdom. Root cause analysis toolkit and e-learning. Available at: www.npsa.nhs.uk/health/resources/root_cause_analysis/conditions. Accessed on July 27, 2006.
16. Battles JB, Kaplan HS, Van der Schaaf TW, Shea CE. The attributes of medical event reporting systems: Experience with a prototype medical event reporting system for transfusion medicine. Arch Pathol Lab Med 1998;122:231-238.
17. Medical Event Reporting System (MERS)—transfusion medicine [website]. Available at: www.mers-tm.net. Accessed on July 27, 2006.
18. Institute for Healthcare Improvement. Improvement methods. Available at: www.ihi.org/IHI/Topics/Improvement/ImprovementMethods/Changes. Accessed on July 27, 2006.
19. Sutcliffe KM, Lewton E, Rosenthal MM. Communication failures: an insidious contributor to medical mishaps. Acad Med 2004;79:186-194.
20. Sutcliffe KM. A mindful infrastructure for increasing reliability. Ambul Outreach 2000;30-34.
CORRESPONDENCE: Wail Malaty, MD, Hendersonville Family Health Center & Residency Program, 741 6th Ave W, Hendersonville, NC 28739. E-mail: [email protected]
Examination
- Patient looks well and is in no distress
- Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
- Normal heart, lung, and abdominal exam. No cervical or other adenopathy.
Medical history
- Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
- Married, with 1 grown son who is healthy
- Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
- Walks 40 minutes 4 times a week
- Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
- Review of systems negative for cough, fever, weight loss, or swollen glands
A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.
The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.1 The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.1
A:
Interpreting TB test results
The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.1 Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).
An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.2
Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).3 It was unavailable in the county where the patient was tested.
TABLE
TST results regarded as positive for tuberculosis, given a patient’s specific risk factors
| 5 MM | INDURATION 10 MM | 15 MM |
|---|---|---|
| HIV infection Close contact of person with TB Previous TB on chest x-ray Intravenous drug use, or unknown HIV status | Native of country with endemic TB HIV-negative intravenous drug user Low income, inadequate healthcare Resident of long-term care facility Medical condition with increased TB risk Ages less than 4 years Likely exposure to TB | Patient has no risk factors |
The patient’s return 48 hours later
A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“
A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.4
The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.
The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.
A:
Dealing responsibly with medical errors
A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.
A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.5 In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.
Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.6
To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.
Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:
- Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
- Report these facts to risk management or to the professional liability carrier, according to internal policies
- Apologize to the patient.
A:
Important features of an apology
- Make the apology promptly
- Be sincere
- Apologize in person
- Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.
The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.
After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.
Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.
A:
Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.7 These include:
- Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
- Avoid blame—search for root causes.
- Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
- Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.
Openly acknowledging a mistake and apologizing to a patient, as the authors suggest, is sound advice increasingly followed in the United States and internationally. Disclosure of mistakes is a cornerstone of the safety work, as is being carried out in the United Kingdom by the National Patient Safety Agency (NPSA). They have prepared excellent online interactive educational materials to support health care professionals as they participate in the disclosure process.8
A second step the authors took was to learn about the inherent risks and potential failure points that are often deeply embedded in our care delivery processes. Mistakes are windows into the clinical work environment. If we peer through these windows regularly and systematically, we can learn a good deal about protecting our patients from harm. The mistake reported here—though of little or no harm to the patient (ie, possibly a near miss)—has potential as a rich information source about how care is delivered in the family practice clinic.9 In addition, because there was a recovery by the patient’s family physician, we have the added benefit of learning from that part of the narrative.
Learning from mistakes an intentional process, not an automatic one
First, an organization or setting must have a just culture to enable learning.10 Tools for assessing safety culture are available from the Agency for Healthcare Research and Quality (AHRQ)11 and from the Institute for Healthcare Improvement (IHI).12 A just culture is an essential attribute of a learning organization.13
Second, a systematic process must be available for inquiring about the root causes and contributing factors of events. Examples of such systems are those used by Veterans Health Administration (VHA)14 and the UK’s NPSA.15 The Medical Events Reporting System for transfusion medicine (MERS-TM) is a model reporting system in the US and is developed as a learning system.16,17
Third, we have learned that simply gathering information about the causes of events is not sufficient to prevent future events. Those involved in mistakes must be given an opportunity to come together to make sense of the causal information before they can make changes.
Fourth, a system-change method is needed to correct underlying causes. Such a method is the Plan-Do-Study Act (PDSA), which translates knowledge about causes into actions that can be implemented in the health care work environment.18
How might these processes apply to the case at hand
Two aspects of this case in particular bear scrutiny.
The clinic protocol. Protocols standardize care as well as complement the cognitive work required in clinical care. Understanding the contents and use of this protocol would shed light on this event. To what extent did the protocol support the interpretation of the TB test; how informative was it? Did it require obtaining a history from the patient as a component of the test interpretation? Did it detail the skills of the test interpreter? Did it spell out a contingency plan in the event those administering and reading the tests are unclear about the findings? Who had access to the protocol?
Handoffs, when things can get dropped. Another focus of this case is the 3 handoffs: the nurse reading the test handed the interpretation off to a physician; the physician handed the patient off to the public health clinic; and the clinic then handed the patient back to her primary care physician. Handoffs often lead to mistakes because they involve interpersonal communication and transfer of information, both of which are fraught with opportunities for errors.19
In the first handoff, we might well ask what information the nurse had about the patient’s history and what information she communicated to the physician? A full understanding of this handoff helps to make explicit hierarchical relationships in the clinic as well as information flow.
With the second handoff, we might ask what information regarding the uncertainty of the patient’s TB test interpretation and history were passed along to the TB clinic? How was the information communicated—on paper, electronically, by telephone? Each of these methods has unique constraints.
Finally, the fortunate third handoff—follow-up with the patient’s family practice physician that resulted in the discovery of the mistake and therefore recovery. It is particularly important to note that the recovery came because of an apparent system of feedback of information to the patient’s family physician. Such feedback loops contribute to safety. The family physician noticed something that did not make sense and investigated it. That is, the family physician was mindful.20 This attitude of mindfulness is a critical component in safe or reliable systems. Hubris is the enemy of safety.
Shirley Kellie, MD, MSc
Physician epidemiologist, American Medical Association
A:
In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:
- Create specific written instructions for office procedures
- Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
- Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
- Have regular updates or ”recertification,” particularly for procedures that are done infrequently
- A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
- Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”
Examination
- Patient looks well and is in no distress
- Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
- Normal heart, lung, and abdominal exam. No cervical or other adenopathy.
Medical history
- Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
- Married, with 1 grown son who is healthy
- Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
- Walks 40 minutes 4 times a week
- Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
- Review of systems negative for cough, fever, weight loss, or swollen glands
A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.
The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.1 The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.1
A:
Interpreting TB test results
The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.1 Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).
An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.2
Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).3 It was unavailable in the county where the patient was tested.
TABLE
TST results regarded as positive for tuberculosis, given a patient’s specific risk factors
| 5 MM | INDURATION 10 MM | 15 MM |
|---|---|---|
| HIV infection Close contact of person with TB Previous TB on chest x-ray Intravenous drug use, or unknown HIV status | Native of country with endemic TB HIV-negative intravenous drug user Low income, inadequate healthcare Resident of long-term care facility Medical condition with increased TB risk Ages less than 4 years Likely exposure to TB | Patient has no risk factors |
The patient’s return 48 hours later
A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“
A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.4
The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.
The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.
A:
Dealing responsibly with medical errors
A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.
A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.5 In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.
Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.6
To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.
Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:
- Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
- Report these facts to risk management or to the professional liability carrier, according to internal policies
- Apologize to the patient.
A:
Important features of an apology
- Make the apology promptly
- Be sincere
- Apologize in person
- Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.
The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.
After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.
Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.
A:
Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.7 These include:
- Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
- Avoid blame—search for root causes.
- Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
- Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.
Openly acknowledging a mistake and apologizing to a patient, as the authors suggest, is sound advice increasingly followed in the United States and internationally. Disclosure of mistakes is a cornerstone of the safety work, as is being carried out in the United Kingdom by the National Patient Safety Agency (NPSA). They have prepared excellent online interactive educational materials to support health care professionals as they participate in the disclosure process.8
A second step the authors took was to learn about the inherent risks and potential failure points that are often deeply embedded in our care delivery processes. Mistakes are windows into the clinical work environment. If we peer through these windows regularly and systematically, we can learn a good deal about protecting our patients from harm. The mistake reported here—though of little or no harm to the patient (ie, possibly a near miss)—has potential as a rich information source about how care is delivered in the family practice clinic.9 In addition, because there was a recovery by the patient’s family physician, we have the added benefit of learning from that part of the narrative.
Learning from mistakes an intentional process, not an automatic one
First, an organization or setting must have a just culture to enable learning.10 Tools for assessing safety culture are available from the Agency for Healthcare Research and Quality (AHRQ)11 and from the Institute for Healthcare Improvement (IHI).12 A just culture is an essential attribute of a learning organization.13
Second, a systematic process must be available for inquiring about the root causes and contributing factors of events. Examples of such systems are those used by Veterans Health Administration (VHA)14 and the UK’s NPSA.15 The Medical Events Reporting System for transfusion medicine (MERS-TM) is a model reporting system in the US and is developed as a learning system.16,17
Third, we have learned that simply gathering information about the causes of events is not sufficient to prevent future events. Those involved in mistakes must be given an opportunity to come together to make sense of the causal information before they can make changes.
Fourth, a system-change method is needed to correct underlying causes. Such a method is the Plan-Do-Study Act (PDSA), which translates knowledge about causes into actions that can be implemented in the health care work environment.18
How might these processes apply to the case at hand
Two aspects of this case in particular bear scrutiny.
The clinic protocol. Protocols standardize care as well as complement the cognitive work required in clinical care. Understanding the contents and use of this protocol would shed light on this event. To what extent did the protocol support the interpretation of the TB test; how informative was it? Did it require obtaining a history from the patient as a component of the test interpretation? Did it detail the skills of the test interpreter? Did it spell out a contingency plan in the event those administering and reading the tests are unclear about the findings? Who had access to the protocol?
Handoffs, when things can get dropped. Another focus of this case is the 3 handoffs: the nurse reading the test handed the interpretation off to a physician; the physician handed the patient off to the public health clinic; and the clinic then handed the patient back to her primary care physician. Handoffs often lead to mistakes because they involve interpersonal communication and transfer of information, both of which are fraught with opportunities for errors.19
In the first handoff, we might well ask what information the nurse had about the patient’s history and what information she communicated to the physician? A full understanding of this handoff helps to make explicit hierarchical relationships in the clinic as well as information flow.
With the second handoff, we might ask what information regarding the uncertainty of the patient’s TB test interpretation and history were passed along to the TB clinic? How was the information communicated—on paper, electronically, by telephone? Each of these methods has unique constraints.
Finally, the fortunate third handoff—follow-up with the patient’s family practice physician that resulted in the discovery of the mistake and therefore recovery. It is particularly important to note that the recovery came because of an apparent system of feedback of information to the patient’s family physician. Such feedback loops contribute to safety. The family physician noticed something that did not make sense and investigated it. That is, the family physician was mindful.20 This attitude of mindfulness is a critical component in safe or reliable systems. Hubris is the enemy of safety.
Shirley Kellie, MD, MSc
Physician epidemiologist, American Medical Association
A:
In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:
- Create specific written instructions for office procedures
- Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
- Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
- Have regular updates or ”recertification,” particularly for procedures that are done infrequently
- A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
- Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”
1. Tuberculosis control. North Carolina Tuberculosis Policy Manual (2nd rev, 2005). Available at: www.epi.state.nc.us/epi/gcdc/tb/manual.html. Accessed on July 27, 2006.
2. Pouchot J, Grassland A, et al. Reliability of tubercelin skin test measurement. Ann Int Med 1997;126:210-214.
3. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep 2003;52(RR-02):15-18.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5202a2.htm. Accessed on July 27, 2006
4. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Accessed on July 27, 2006.
5. Gallagher TH, Levinsen W. Disclosing harmful medical errors to patients: a time for professional action. Arch Int Med 2005;165:1819-1824.
6. Kraman SS, Ham G. Risk management: extreme honesty maybe the best policy. Ann Int Med 1999;131:963-967.
7. Vincent C. Patient safety: understanding and responding to adverse events. N Engl J Med 2003;348:1051-1056.
8. National Patient Safety Agency. Being open: Communicating patient safety incidents with patients and their carers [website]. Available at: www.npsa.nhs.uk/health/resources/beingopen. Accessed on July 27, 2006.
9. Kaplan HS. Benefiting from the “gift of failure”: essentials for an event reporting system. J Leg Med 2003;24:29-35.
10. Marx D. Patient safety and the “just culture”: a primer for health care executives. Available at: www.merstm.net/support/Marx_Primer.pdf. Accessed on July 27, 2006.
11. Agency for Healthcare Research and Quality. Hospital Survey on Patient Safety Culture [online database]. Available at: www.ahrq.gov/qual/hospculture. Accessed on July 27, 2006.
12. Institute for Healthcare Improvement. Safety climate survey 2005. Available at: www.ihi.org/IHI/Topics/PatientSafety/MedicationSystems/Tools/SafetyClimateSurvey2005IHITool.htm. Accessed on July 27, 2006.
13. Department of Health. An organisation with a memory: Report of an expert group on learning from adverse events in the NHS. London, 2000. Available at: www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4065083&chk=PARoiF. Accessed on July 27, 2006.
14. Veterans Administration National Center for Patient Safety. Root cause analysis. Available at: www.va.gov/ncps/rca.html. Accessed on July 27, 2006.
15. National Patient Safety Agency. National Health Service, United Kingdom. Root cause analysis toolkit and e-learning. Available at: www.npsa.nhs.uk/health/resources/root_cause_analysis/conditions. Accessed on July 27, 2006.
16. Battles JB, Kaplan HS, Van der Schaaf TW, Shea CE. The attributes of medical event reporting systems: Experience with a prototype medical event reporting system for transfusion medicine. Arch Pathol Lab Med 1998;122:231-238.
17. Medical Event Reporting System (MERS)—transfusion medicine [website]. Available at: www.mers-tm.net. Accessed on July 27, 2006.
18. Institute for Healthcare Improvement. Improvement methods. Available at: www.ihi.org/IHI/Topics/Improvement/ImprovementMethods/Changes. Accessed on July 27, 2006.
19. Sutcliffe KM, Lewton E, Rosenthal MM. Communication failures: an insidious contributor to medical mishaps. Acad Med 2004;79:186-194.
20. Sutcliffe KM. A mindful infrastructure for increasing reliability. Ambul Outreach 2000;30-34.
CORRESPONDENCE: Wail Malaty, MD, Hendersonville Family Health Center & Residency Program, 741 6th Ave W, Hendersonville, NC 28739. E-mail: [email protected]
1. Tuberculosis control. North Carolina Tuberculosis Policy Manual (2nd rev, 2005). Available at: www.epi.state.nc.us/epi/gcdc/tb/manual.html. Accessed on July 27, 2006.
2. Pouchot J, Grassland A, et al. Reliability of tubercelin skin test measurement. Ann Int Med 1997;126:210-214.
3. Mazurek GH, Villarino ME. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep 2003;52(RR-02):15-18.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5202a2.htm. Accessed on July 27, 2006
4. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1-77.Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Accessed on July 27, 2006.
5. Gallagher TH, Levinsen W. Disclosing harmful medical errors to patients: a time for professional action. Arch Int Med 2005;165:1819-1824.
6. Kraman SS, Ham G. Risk management: extreme honesty maybe the best policy. Ann Int Med 1999;131:963-967.
7. Vincent C. Patient safety: understanding and responding to adverse events. N Engl J Med 2003;348:1051-1056.
8. National Patient Safety Agency. Being open: Communicating patient safety incidents with patients and their carers [website]. Available at: www.npsa.nhs.uk/health/resources/beingopen. Accessed on July 27, 2006.
9. Kaplan HS. Benefiting from the “gift of failure”: essentials for an event reporting system. J Leg Med 2003;24:29-35.
10. Marx D. Patient safety and the “just culture”: a primer for health care executives. Available at: www.merstm.net/support/Marx_Primer.pdf. Accessed on July 27, 2006.
11. Agency for Healthcare Research and Quality. Hospital Survey on Patient Safety Culture [online database]. Available at: www.ahrq.gov/qual/hospculture. Accessed on July 27, 2006.
12. Institute for Healthcare Improvement. Safety climate survey 2005. Available at: www.ihi.org/IHI/Topics/PatientSafety/MedicationSystems/Tools/SafetyClimateSurvey2005IHITool.htm. Accessed on July 27, 2006.
13. Department of Health. An organisation with a memory: Report of an expert group on learning from adverse events in the NHS. London, 2000. Available at: www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4065083&chk=PARoiF. Accessed on July 27, 2006.
14. Veterans Administration National Center for Patient Safety. Root cause analysis. Available at: www.va.gov/ncps/rca.html. Accessed on July 27, 2006.
15. National Patient Safety Agency. National Health Service, United Kingdom. Root cause analysis toolkit and e-learning. Available at: www.npsa.nhs.uk/health/resources/root_cause_analysis/conditions. Accessed on July 27, 2006.
16. Battles JB, Kaplan HS, Van der Schaaf TW, Shea CE. The attributes of medical event reporting systems: Experience with a prototype medical event reporting system for transfusion medicine. Arch Pathol Lab Med 1998;122:231-238.
17. Medical Event Reporting System (MERS)—transfusion medicine [website]. Available at: www.mers-tm.net. Accessed on July 27, 2006.
18. Institute for Healthcare Improvement. Improvement methods. Available at: www.ihi.org/IHI/Topics/Improvement/ImprovementMethods/Changes. Accessed on July 27, 2006.
19. Sutcliffe KM, Lewton E, Rosenthal MM. Communication failures: an insidious contributor to medical mishaps. Acad Med 2004;79:186-194.
20. Sutcliffe KM. A mindful infrastructure for increasing reliability. Ambul Outreach 2000;30-34.
CORRESPONDENCE: Wail Malaty, MD, Hendersonville Family Health Center & Residency Program, 741 6th Ave W, Hendersonville, NC 28739. E-mail: [email protected]
Is the long-term use of proton pump inhibitors safe?
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
Evidence-based answers from the Family Physicians Inquiries Network
What regimens eradicate Heliobacter pylori?
Fourteen-day triple therapy with a proton pump inhibitor (PPI) plus clarithromycin and either amoxicillin or metronidazole is superior to 7-day therapy in eradicating Heliobacter pylori (strength of recommendation [SOR]: A, high-quality meta-analysis).
Seven-day triple therapy with a PPI or ranitidine bismuth citrate plus clarithromycin and either amoxicillin or metronidazole is also effective (SOR: A, high-quality systematic review).
Three-day quadruple therapy with a combination of PPI, clarithromycin, bismuth subcitrate, and metronidazole or a combination of PPI, clarithromycin, amoxicillin, and metronidazole also appears to be effective (SOR: B, unblinded randomized controlled trial).
Evidence summary
The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).1 Effective regimens are:
Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).2 Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.
Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).3
Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.4
Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).6
Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.7
The problems of emerging clarithromycin and metronidazole resistance have not been
extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).4 When an infection is resistant to metronidazole, amoxicillin should be used instead.4 In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.7
TABLE
Effective therapies for Heliobacter pylorieradication
| Regimen | Dosage | Duration (days) | Cost ($)b | SOR |
|---|---|---|---|---|
| PPIa | 14 | 210 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily or | |||
| amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 85 | A |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 82 | A |
| Clarithromycin | 250 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| PPI | 3 | 46 | B | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| Bismuth subcitrate | 240 mg twice daily | |||
| PPI (5 days) | 3 | 60 | B | |
| Clarithromycin | 250 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| a. PPI: standard twice-daily dosing—eg, lansoprazole 30 mg or omeprazole 20 mg | ||||
| b. Approximate cost of entire course of therapy from www.drugstore.com, August 2003. | ||||
| PPI, proton pump inhibitor; SOR, strength of recommendation (for an explanation of evidence ratings, see page 779) | ||||
Recommendations from others
The Maastricht Consensus of the European Heliobacter Study Group1 recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.
The American College of Gastroenterology recommends 14-day therapy of one of the following options:8
- PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
- PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
- Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).
The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.9
Patients beginning complex regimens require counseling
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver, Colorado
The most effective regimens (>80% eradication) for H pylori include a 10- to 14-day course of at least 2 antibiotics and an antisecretory agent. However, even optimal treatment regimens can fail in approximately 10% of patients. Poor compliance is among the most common reasons for treatment failure. Medication side effects can affect up to 50% of patients taking triple-agent regimens.
Treatment regimens with multiple medications administered several times daily can be difficult to follow. Convenient packaging containing all daily medications are available to optimize adherence.
Counseling points for patients should include how to take the medicine correctly, expected side effects, the importance of completing the entire therapy regimen, and warnings of specific interactions (eg, alcohol and metronidazole). Lastly, the patient should be made aware of the cost of the entire regimen, which ranges from $50 to $250.
1. Current European concepts in the management of Heliobacter pylori infection. The Maastricht Consensus Report. European Heliobacter Pylori Study Group. Gut 1997;41:8-13.
2. Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Heliobacter pylori infection. Aliment Pharmacol Ther 2000;14:603-609.
3. Huang J, Hunt RH. The importance of clarithromycin dose in the management of Heliobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. Aliment Pharmacol Ther 1999;13:719-729.
4. Janssen MJ, Van Oijen AH, Verbeek AL, Jansen JB, De Boer WA. A systematic comparison of triple therapies for treatment of Heliobacter pylori infection with proton pump inhibitor/ranitidine bismuth citrate plus clarithromycin and either amoxicillin or a nitroimidazole. Aliment Pharmacol Ther 2001;15:613-624.
5. Delaney B, Moayyedi P, Forman D. Heliobacter pylori. Clin Evid [online], Issue 8. London: BMJ Publishing Group, Last updated 2003 March. Available at www.ovid.com. Accessed on March 4, 2003.
6. Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ, Klotz U. Clinical outcome and influencing factors for a new short-term quadruple therapy for Heliobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med. 2002;162:153-160.
7. Wong BC, Wang WH, Wong WM, et al. Three-day lansoprazole quadruple therapy for Heliobacter pylori-positive duodenal ulcers: a randomized controlled study. Aliment PharmacTher 2001;15:843-849.
8. Howden CW, Hunt RH. Guidelines for the management of Heliobacter pylori infection. Ad Hoc Committee on the Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 1998;93:2330-2338.
9. Institute for Clinical Systems Improvement (ICSI). Dyspepsia. Bloomington, Minn: ICSI; last updated January 2003. Available at: http://www.icsi.org/ knowledge/detail.asp?catID=29&itemID=171. Accessed on September 8, 2003.
Fourteen-day triple therapy with a proton pump inhibitor (PPI) plus clarithromycin and either amoxicillin or metronidazole is superior to 7-day therapy in eradicating Heliobacter pylori (strength of recommendation [SOR]: A, high-quality meta-analysis).
Seven-day triple therapy with a PPI or ranitidine bismuth citrate plus clarithromycin and either amoxicillin or metronidazole is also effective (SOR: A, high-quality systematic review).
Three-day quadruple therapy with a combination of PPI, clarithromycin, bismuth subcitrate, and metronidazole or a combination of PPI, clarithromycin, amoxicillin, and metronidazole also appears to be effective (SOR: B, unblinded randomized controlled trial).
Evidence summary
The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).1 Effective regimens are:
Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).2 Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.
Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).3
Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.4
Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).6
Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.7
The problems of emerging clarithromycin and metronidazole resistance have not been
extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).4 When an infection is resistant to metronidazole, amoxicillin should be used instead.4 In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.7
TABLE
Effective therapies for Heliobacter pylorieradication
| Regimen | Dosage | Duration (days) | Cost ($)b | SOR |
|---|---|---|---|---|
| PPIa | 14 | 210 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily or | |||
| amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 85 | A |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 82 | A |
| Clarithromycin | 250 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| PPI | 3 | 46 | B | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| Bismuth subcitrate | 240 mg twice daily | |||
| PPI (5 days) | 3 | 60 | B | |
| Clarithromycin | 250 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| a. PPI: standard twice-daily dosing—eg, lansoprazole 30 mg or omeprazole 20 mg | ||||
| b. Approximate cost of entire course of therapy from www.drugstore.com, August 2003. | ||||
| PPI, proton pump inhibitor; SOR, strength of recommendation (for an explanation of evidence ratings, see page 779) | ||||
Recommendations from others
The Maastricht Consensus of the European Heliobacter Study Group1 recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.
The American College of Gastroenterology recommends 14-day therapy of one of the following options:8
- PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
- PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
- Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).
The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.9
Patients beginning complex regimens require counseling
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver, Colorado
The most effective regimens (>80% eradication) for H pylori include a 10- to 14-day course of at least 2 antibiotics and an antisecretory agent. However, even optimal treatment regimens can fail in approximately 10% of patients. Poor compliance is among the most common reasons for treatment failure. Medication side effects can affect up to 50% of patients taking triple-agent regimens.
Treatment regimens with multiple medications administered several times daily can be difficult to follow. Convenient packaging containing all daily medications are available to optimize adherence.
Counseling points for patients should include how to take the medicine correctly, expected side effects, the importance of completing the entire therapy regimen, and warnings of specific interactions (eg, alcohol and metronidazole). Lastly, the patient should be made aware of the cost of the entire regimen, which ranges from $50 to $250.
Fourteen-day triple therapy with a proton pump inhibitor (PPI) plus clarithromycin and either amoxicillin or metronidazole is superior to 7-day therapy in eradicating Heliobacter pylori (strength of recommendation [SOR]: A, high-quality meta-analysis).
Seven-day triple therapy with a PPI or ranitidine bismuth citrate plus clarithromycin and either amoxicillin or metronidazole is also effective (SOR: A, high-quality systematic review).
Three-day quadruple therapy with a combination of PPI, clarithromycin, bismuth subcitrate, and metronidazole or a combination of PPI, clarithromycin, amoxicillin, and metronidazole also appears to be effective (SOR: B, unblinded randomized controlled trial).
Evidence summary
The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).1 Effective regimens are:
Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).2 Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.
Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).3
Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.4
Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).6
Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.7
The problems of emerging clarithromycin and metronidazole resistance have not been
extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).4 When an infection is resistant to metronidazole, amoxicillin should be used instead.4 In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.7
TABLE
Effective therapies for Heliobacter pylorieradication
| Regimen | Dosage | Duration (days) | Cost ($)b | SOR |
|---|---|---|---|---|
| PPIa | 14 | 210 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily or | |||
| amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| PPI | 7 | 105 | A | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 85 | A |
| Clarithromycin | 500 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Ranitidine bismuth citrate | 400 mg twice daily | 7 | 82 | A |
| Clarithromycin | 250 mg twice daily | |||
| Metronidazole | 500 mg twice daily | |||
| PPI | 3 | 46 | B | |
| Clarithromycin | 500 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| Bismuth subcitrate | 240 mg twice daily | |||
| PPI (5 days) | 3 | 60 | B | |
| Clarithromycin | 250 mg twice daily | |||
| Amoxicillin | 1000 mg twice daily | |||
| Metronidazole | 400 mg twice daily | |||
| a. PPI: standard twice-daily dosing—eg, lansoprazole 30 mg or omeprazole 20 mg | ||||
| b. Approximate cost of entire course of therapy from www.drugstore.com, August 2003. | ||||
| PPI, proton pump inhibitor; SOR, strength of recommendation (for an explanation of evidence ratings, see page 779) | ||||
Recommendations from others
The Maastricht Consensus of the European Heliobacter Study Group1 recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.
The American College of Gastroenterology recommends 14-day therapy of one of the following options:8
- PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
- PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
- Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).
The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.9
Patients beginning complex regimens require counseling
Laura B. Hansen, PharmD, BCPS
University of Colorado Health Sciences Center, Denver, Colorado
The most effective regimens (>80% eradication) for H pylori include a 10- to 14-day course of at least 2 antibiotics and an antisecretory agent. However, even optimal treatment regimens can fail in approximately 10% of patients. Poor compliance is among the most common reasons for treatment failure. Medication side effects can affect up to 50% of patients taking triple-agent regimens.
Treatment regimens with multiple medications administered several times daily can be difficult to follow. Convenient packaging containing all daily medications are available to optimize adherence.
Counseling points for patients should include how to take the medicine correctly, expected side effects, the importance of completing the entire therapy regimen, and warnings of specific interactions (eg, alcohol and metronidazole). Lastly, the patient should be made aware of the cost of the entire regimen, which ranges from $50 to $250.
1. Current European concepts in the management of Heliobacter pylori infection. The Maastricht Consensus Report. European Heliobacter Pylori Study Group. Gut 1997;41:8-13.
2. Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Heliobacter pylori infection. Aliment Pharmacol Ther 2000;14:603-609.
3. Huang J, Hunt RH. The importance of clarithromycin dose in the management of Heliobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. Aliment Pharmacol Ther 1999;13:719-729.
4. Janssen MJ, Van Oijen AH, Verbeek AL, Jansen JB, De Boer WA. A systematic comparison of triple therapies for treatment of Heliobacter pylori infection with proton pump inhibitor/ranitidine bismuth citrate plus clarithromycin and either amoxicillin or a nitroimidazole. Aliment Pharmacol Ther 2001;15:613-624.
5. Delaney B, Moayyedi P, Forman D. Heliobacter pylori. Clin Evid [online], Issue 8. London: BMJ Publishing Group, Last updated 2003 March. Available at www.ovid.com. Accessed on March 4, 2003.
6. Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ, Klotz U. Clinical outcome and influencing factors for a new short-term quadruple therapy for Heliobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med. 2002;162:153-160.
7. Wong BC, Wang WH, Wong WM, et al. Three-day lansoprazole quadruple therapy for Heliobacter pylori-positive duodenal ulcers: a randomized controlled study. Aliment PharmacTher 2001;15:843-849.
8. Howden CW, Hunt RH. Guidelines for the management of Heliobacter pylori infection. Ad Hoc Committee on the Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 1998;93:2330-2338.
9. Institute for Clinical Systems Improvement (ICSI). Dyspepsia. Bloomington, Minn: ICSI; last updated January 2003. Available at: http://www.icsi.org/ knowledge/detail.asp?catID=29&itemID=171. Accessed on September 8, 2003.
1. Current European concepts in the management of Heliobacter pylori infection. The Maastricht Consensus Report. European Heliobacter Pylori Study Group. Gut 1997;41:8-13.
2. Calvet X, Garcia N, Lopez T, Gisbert JP, Gene E, Roque M. A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Heliobacter pylori infection. Aliment Pharmacol Ther 2000;14:603-609.
3. Huang J, Hunt RH. The importance of clarithromycin dose in the management of Heliobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. Aliment Pharmacol Ther 1999;13:719-729.
4. Janssen MJ, Van Oijen AH, Verbeek AL, Jansen JB, De Boer WA. A systematic comparison of triple therapies for treatment of Heliobacter pylori infection with proton pump inhibitor/ranitidine bismuth citrate plus clarithromycin and either amoxicillin or a nitroimidazole. Aliment Pharmacol Ther 2001;15:613-624.
5. Delaney B, Moayyedi P, Forman D. Heliobacter pylori. Clin Evid [online], Issue 8. London: BMJ Publishing Group, Last updated 2003 March. Available at www.ovid.com. Accessed on March 4, 2003.
6. Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ, Klotz U. Clinical outcome and influencing factors for a new short-term quadruple therapy for Heliobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med. 2002;162:153-160.
7. Wong BC, Wang WH, Wong WM, et al. Three-day lansoprazole quadruple therapy for Heliobacter pylori-positive duodenal ulcers: a randomized controlled study. Aliment PharmacTher 2001;15:843-849.
8. Howden CW, Hunt RH. Guidelines for the management of Heliobacter pylori infection. Ad Hoc Committee on the Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 1998;93:2330-2338.
9. Institute for Clinical Systems Improvement (ICSI). Dyspepsia. Bloomington, Minn: ICSI; last updated January 2003. Available at: http://www.icsi.org/ knowledge/detail.asp?catID=29&itemID=171. Accessed on September 8, 2003.
Evidence-based answers from the Family Physicians Inquiries Network