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Improving the Care of Patients With Regard to Chemotherapy-Induced Nausea and Emesis: The Effect of Feedback to Clinicians on Adherence to Antiemetic Prescribing Guidelines

Wilson C. Mertens, Donald J. Higby, David Brown, Regina Parisi, Janice Fitzgerald, Evan M. Benjamin, Peter K. Lindenauer

From the Baystate Regional Cancer Program, Divisions of Hematology Oncology and Healthcare Quality, Baystate Medical Center, Springfield, MA, and Tufts University School of Medicine, Boston, MA.

Address reprint requests to Wilson C. Mertens, MD, Baystate Regional Cancer Program, 3400 Main St, Springfield, MA 01107; email: wilson.mertens{at}bhs.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 
Purpose: To evaluate the effect of performance and outcomes feedback on adherence to clinical practice guidelines regarding chemotherapy-induced nausea and emesis (CINE).

Methods: Institutional CINE clinical practice guidelines were developed based on American Society of Clinical Oncology guidelines. Consecutive administrations of moderately/highly emetogenic chemotherapy were assessed for errors. Baseline statistical process control (SPC) charts were created and mean errors per administration were calculated. Prospective SPC charts were used to measure the effect of guideline development and distribution, a visiting lecturer, and ongoing feedback regarding compliance with guidelines employing SPC charts. Patients were surveyed regarding the extent and severity of CINE for 5 days postadministration. These outcomes were then shared with physicians.

Results: Baseline compliance was poor (mean, 0.87 omissions per chemotherapy administration), largely because of inadequate adherence to recommendations for delayed CINE management. Most patients experienced delayed nausea, particularly on day 3 postchemotherapy. Physician prescribing performance did not undergo sustained improvement despite guideline development or distribution, a lecture by a visiting expert, or sharing of adherence data with clinicians. Once patient outcomes were shared, physicians accepted the need for compliance and instituted nurse practitioner antiemetic prescribing, with almost complete compliance and concurrent measurable reduction in day 3 nausea. SPC charts documented improvements in both outcomes.

Conclusions: SPC charts effectively monitor ongoing compliance and patient symptoms and represent appropriate outcome measurement and change facilitation tools. However, physician participation in guideline development and evidence of poor compliance alone did not improve prescribing performance. Only evidence of patient CINE experience coupled with noncompliance improved results.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 
CHEMOTHERAPY-INDUCED nausea and emesis (CINE) is often noted by patients as the most common and feared side-effect resulting from cytotoxic chemotherapy.^1–3 Substantial progress has been made in the control of acute CINE (occurring in the first 24 hours after chemotherapy administration), attributable to the use of 5-hydroxytryptamine-3 (5HT₃) receptor antagonists, whose effectiveness has been confirmed in multiple well-designed randomized clinical trials.⁴ The consequence of these studies and the impressive results experienced by clinicians and patients in practice is the relatively rapid adoption of prechemotherapy administration of 5HT₃ receptor antagonists into routine patient care.⁵ The prevention of delayed (greater than 24 hours postchemotherapy administration) CINE has proven more problematic. Although a substantial proportion of patients experience delayed CINE, this symptom is generally not as dramatic as the presentation of acute CINE.^5–7 In addition, current therapies do not reduce symptoms to the same degree that 5HT₃ antagonist and corticosteroids do in early onset CINE.^5–10 Finally, there is widespread concern regarding the toxicity and intolerance of oral dexamethasone, the primary corticosteroid used in the prophylactic treatment of delayed CINE. Recommendations for the use of oral metoclopramide or 5HT₃ receptor antagonists in conjunction with corticosteroids for high-dose cisplatin-based therapy have also been slowly and incompletely adopted.^5,9,10 Despite data from randomized clinical trials and the publication of evidence-based clinical practice guidelines by the American Society of Clinical Oncology (ASCO)⁴ and others,^11–14 drugs designed to prevent delayed CINE remain underemployed.^5,15

Little is known about the factors that encourage physicians to follow evidence-based clinical practice guidelines.^15–18 In a review of studies concerning this topic, Cabana et al¹⁹ found a variety of adherence barriers, such as lack of awareness and familiarity with the guideline and disagreement with the guideline, and physician-based factors, such as lack of belief in the effectiveness of guideline-driven management, lack of confidence in the ability to implement the guidelines, and inertia of previous practice. All of these factors seem to contribute to the reluctance of physicians to follow clinical practice guidelines. They noted that the results of studies on improving guideline adherence may not be generalizable from one clinical setting to another. We set out to determine whether collaborative institutional clinical practice guideline development, visiting lectures, feedback on group performance, and sharing of patient outcomes had any sustained effect on oncologist prescribing patterns, and whether such changes could be monitored by statistical process control (SPC) charting.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 
Patients were included in the study if they were age 18 or older and receiving highly emetogenic chemotherapy, including both cisplatin- and noncisplatin-containing regimens, as defined by the ASCO guidelines⁴ in an ambulatory hematology/oncology infusion suite. One of the authors (W.C.M.) undertook an extensive retrospective chart review, reviewing nursing notes regarding ambulatory prescriptions and pharmacy orders of medications delivered in the suite to evaluate compliance with CINE guidelines developed by ASCO.⁴ Chemotherapy administrations were coded consecutively based on date and time of administration; regimens administering chemotherapy over consecutive days were coded only once weekly. Compliance with recommendations for the prophylaxis of acute and delayed CINE was noted, both in terms of omission of recommended therapy as well as addition of prophylactic therapy that was not recommended. Omissions were defined as a failure to prescribe a recommended agent or a recommended agent prescribed at a dosage below those recommended in the ASCO clinical practice guideline.⁴ As the priority of our study was the institution of evidence-based recommendations, omission of recommended therapy was the emphasized prescribing error tracked in the follow-up of patients.

SPC charts were used to determine whether the system remained "in control" (ie, that no statistically significant change was found over time) or whether a statistically significant change in compliance could be related to a particular process change. These charts were also used to give ongoing, statistically valid feedback to the oncologists with respect to the compliance of the group.^20–22 The steps taken to create these charts and the rules for evaluating "out-of-control" conditions are contained in the Appendix (available online at www.jco.org), but in summary, an initial set of 25 samples of data (each consisting of five consecutive chemotherapy administrations per sample) was evaluated for the number of omissions of guideline recommendations. The results were charted in consecutive fashion in an SPC chart; in the case of omissions of recommended antiemetic prescriptions, a U chart (charting defects per unit, or sample) was used. If an in-control state was seen, with no sample results found to be out of control according to established rules (designed to determine significant changes at alpha = 0.01; see Appendix as well as Doty²¹), ongoing charting using the established chart mean and upper and lower control limits (effectively defining ± 3 sigma around the mean) was undertaken. Interventions were then evaluated to see whether a statistically significant effect on performance had been realized.²²

Initiation of prospective monitoring took place concurrently with the retrospective review and commenced in February 2001. Data on patient identification (by medical record number), date of administration, chemotherapy regimen and cycle, previous CINE, and pre- and postchemotherapy antiemetic orders were documented by infusion center nursing staff before chemotherapy completion. On discharge from the unit, patients were given a survey tool that recorded their medical record number, date of chemotherapy administration, and nausea measurement scales. These were based on tools (modified from the McGill Pain Survey) that were validated and published by Melzack et al²³ but altered to facilitate data collection. Two nausea scales were used. An overall nausea scale requested patients to describe their nausea in terms of descriptors (none, mild, discomforting, distressing, horrible, or excruciating); numerically, these were coded 0 to 5. A nausea rating scale was modified from the original linear analog scale to an interval (0 [no nausea] to 10 [extreme nausea]) scale for ease of coding. Episodes of emesis were also enumerated. Questions about emesis and nausea were requested in 24-hour periods for a total of 5 days, beginning with the first day postchemotherapy. Patients could return the form at their next clinic appointment or by return mail with a provided stamped and addressed envelope. The prospective SPC charts for the overall nausea scale and the nausea rating scale were constructed from the data derived from the surveys, which were ordered by date of chemotherapy administration.

The collaborative development of evidence-based institutional CINE clinical practice guidelines, based on those published by ASCO,⁴ was then undertaken according to the recommendations of Browman et al.²⁴ A task force including oncologists and pharmacists evaluated the literature and developed a draft that was then distributed widely for comment and input from relevant practitioners. Revisions were incorporated, and the final guideline was then distributed to the medical staff. In addition, pocket cards containing the recommendations were widely distributed to relevant physicians, nurses, and pharmacists. However, antiemetic ordering remained the choice of the attending oncologist; the content of any prescriptions written by nurse practitioners was determined by the patient’s attending oncologist.

Compliance with the guidelines was monitored by following omissions in antiemetic ordering and displayed through SPC charting on an ongoing basis. Interventions to improve compliance were undertaken, including repeated distribution of compliance results in control chart format with relevant explanations after guideline distribution and after a lecture from a noted expert in the field. Finally, control charts were distributed coupled with presentation of the results of the ongoing patient survey of postchemotherapy nausea and emesis (employing X [or mean of sample means] control charts, also known as Shewhart charts, for continuous data).

Data were collected on forms created by TELEform software (version 6.2, Cardiff Software, Vista, CA), permitting simplified form completion by infusion suite nurses and patients; data were entered into a computerized database by facsimile. Associations with delayed CINE and postchemotherapy dexamethasone use were explored with logistic and standard least squares regression models, as appropriate, using forward selection for variables selected from bivariate analysis (alpha = 0.20).²⁵ Fisher’s exact or ² test were used for categorical data; correlations of continuous data used the Spearman rank test. Analyses were performed by software programs (JMP4, SAS Institute, Cary, NC; MedCalc, Brussels, Belgium). Patients were identified on forms by both hospital medical record number and date of service to concatenate data from nursing assessments of compliance and patient outcome survey forms. Patient medical record numbers were then removed from the spreadsheets before analysis. This study was reviewed and approved by the institutional review board of Baystate Medical Center, Springfield, MA.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 
A baseline SPC U chart was created (Fig 1) from 125 initial chemotherapy administrations, retrospectively analyzed, that were administered between June and November 2000. Doxorubicin/cyclophosphamide was the most commonly administered regimen (34%) followed by paclitaxel/carboplatin (22%); only 16% of chemotherapy administrations consisted of or contained cisplatin at any dose. No outlier points were removed, and as a consequence, the mean and upper and lower limits were calculated on the entire sample. An average of 0.87 omissions per chemotherapy administration was found; 73% of chemotherapy administrations were not in compliance with ASCO or institutional clinical practice guidelines. Most recommendations to prevent acute CINE were complied with; 95% of administrations pretreated patients with a 5HT₃ receptor antagonist, and 93% contained prechemotherapy dexamethasone. The vast majority of compliance issues involved delayed CINE prevention and the absence of postchemotherapy corticosteroid administration; only 25% of chemotherapy administrations received postchemotherapy steroids, and 52% were treated with postchemotherapy 5HT₃ receptor antagonists. Postchemotherapy 5HT₃ receptor antagonists in combination with corticosteroids are an option under ASCO clinical practice guidelines for delayed CINE prevention only after high-dose cisplatin administration; 23% of patients receiving cisplatin were treated with these agents, and none of these patients were prescribed concurrent dexamethasone. Under ASCO guidelines, metoclopramide may be substituted for 5HT₃ agents in the setting of postcisplatin therapy. For cisplatin-containing regimens, metoclopramide was prescribed 50% of the time, again without concomitant corticosteroids. Almost half of the patients were prescribed agents not primarily recommended by ASCO guidelines for postinfusion management, predominantly trimethobenzamide and lorazepam. Overuse of established agents before chemotherapy was not seen. The initial prospective SPC was constructed using the same control limits that were determined from the baseline chart; no initial statistical shift from the centerline was determined, confirming an in-control state (Fig 2).

View larger version (18K): [in this window] [in a new window]   Fig 1. U Chart of omissions in antiemetic prescription: Baseline chart. X-axis lists chemotherapy samples; each sample consists of five consecutive chemotherapy administrations. Avg, average of sample defects; UCL, upper control limit (+3 sigma); LCL, lower control limit (-3 sigma).

View larger version (25K): [in this window] [in a new window]   Fig 2. Prospective U chart of omissions in antiemetic prescriptions. X-axis shows date of sampling; each sample consists of five consecutive chemotherapy administrations. A significant reduction in omission rate was seen after distribution of patient outcome.

Finally, a distribution of compliance SPC charts was undertaken in conjunction with summary statistics from the patient survey; data were also presented regarding associations with dexamethasone use and nausea experience. Seventy-four percent of patient surveys were returned. Although most chemotherapy administrations (81%) were not complicated by emesis during the 5 days of observation, only 37% were free of nausea. Nausea ratings for both scales used were highest on day 3 postchemotherapy, although these did not differ significantly from the other days. Nausea ratings were positively correlated between days; patients experiencing more day 1 nausea experienced more nausea on subsequent days (P < .0001 for pairwise correlations between day 1 nausea and nausea on other days, for both nausea scales). Anthracycline-containing regimens tended to have higher nausea rating scores (P = .071), and lower rates of postchemotherapy dexamethasone use (43% v 24% for nonanthracycline-containing regimens, P = .073). Ordering physician was associated with nausea (Kruskal-Wallis, P = .019 for day 3 overall nausea and P = .0099 for day 3 nausea rating scale).

Use of postchemotherapy dexamethasone was associated in a logistic regression model with chemotherapy regimen (P = .0021) and month of chemotherapy administration (P = .0004), but not with nausea. A logistic regression model of day 3 nausea using the overall nausea scale yielded chemotherapy regimens (P = .0009), day 1 overall nausea (P < .0001), ordering physician (P = .016), chemotherapy cycle (P = .017), and month of chemotherapy administration (P = .083) as independently associated variables. Chemotherapy cycles beyond four tended (P = .13 in bivariate analysis) to have less day 3 nausea (presumably because of reduced frequency of doxorubicin administration). Similar results were found for the nausea rating scale.

After distribution of these results, a general group discussion ensued. Initially, sentiments expressed by the physician staff concerned the validity of the data; specifically, that compliance was better than that demonstrated. Other comments included surprise regarding the extent of delayed CINE and the lack of acceptance of dexamethasone by patients and physicians with respect to the agent’s toxicity—predominantly insomnia and psychiatric symptomatology. Ultimately, consensus regarding the advisability of compliance developed among oncologists, nurses, and pharmacists, particularly with regard to the use of steroids after chemotherapy administration and the need to offer guideline-recommended care to patients without prejudging patients’ experience with the recommendations. Subsequent compliance was virtually complete; only physicians not present for the distribution continued to order antiemetic prophylaxis at variance with the guidelines. This compliance was sudden and sustained, as demonstrated by SPC charts (Fig 2). At the same meeting, the program oncologists adopted by consensus the antiemetic prescription writing by nurse practitioners performing chemotherapy toxicity teaching, with all prescriptions written in compliance with the institutional guidelines rather than by individual physician preference; this was instituted program-wide 2 weeks later. In line with other methods of prescription ordering designed to reduce variation,^14,26,27 this procedure likely encouraged more complete compliance, less variability, and sustained improvement.

Continued follow-up of patients using the patient survey demonstrated an improvement nausea experienced on day 3 (a significant improvement when measured by the overall nausea scale; Fig 3) whose timing coincided with the improvement in clinical practice guideline compliance after patient survey distribution.

View larger version (23K): [in this window] [in a new window]   Fig 3. X chart of day 3 overall nausea scale results. X-axis shows sample of patient survey; sample size 4 ordered consecutively based on date of chemotherapy administration. Decrease in mean was seen after sample 20, within 2 weeks of initiation of improved compliance.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

The methodologies of clinical research in CINE are complex and challenging,³² and blinding and random allocation are not practical for use in the clinic setting, particularly when evaluating compliance with therapy proven in randomized clinical trials to be effective. Although a number of investigators have evaluated antiemetic guideline outcomes with respect to cost containment,^26,27 few have evaluated the effect of guideline implementation on patient care from the symptom-control perspective. Given the relatively low intensity of delayed CINE and the modest reduction anticipated by full implementation of current best-evidenced therapy compared with acute CINE, increased guideline compliance might not translate into measurable improvement in patient experience.

Our study demonstrated substantial compliance with prechemotherapy prophylaxis recommendations and little overuse of established agents prechemotherapy, a probable consequence of this report’s focus on highly emetogenic regimens rather than on regimens of low emetogenic potential. However, poor compliance with delayed CINE therapy was seen. An association of delayed nausea symptoms with symptom extent experienced in the first 24 hours postchemotherapy was noted, a finding also identified by others,^5,8,9,33 and like others,⁹ we found that some patients suffered delayed nausea despite excellent initial control. Patients on anthracycline-containing regimens received postchemotherapy dexamethasone less frequently and experienced more delayed CINE. Chemotherapy regimens and ordering physician were associated with nausea on day 3 in univariate and multivariate analyses, but postchemotherapy antiemetic therapy was not, presumably because its use was not prophylactic.

Cabana et al¹⁹ have conceptually divided barriers to physician adherence to clinical practice guidelines into three categories: knowledge (lack of awareness of and familiarity with the guideline), attitudes (disagreement with evidence-based medicine and specific guideline, and lack of belief in guideline efficacy and ability to comply with guideline recommendations), and behavior (patient preferences and characteristics of practice relating to the guidelines). Most reports of guidelines evaluated in their review demonstrated multiple physician barriers to implementation. Davis et al³⁴ described the variable effectiveness of the practice audit, with improved performance if physician feedback included chart review, and noted that multiple (three or more) interventions yielded generally positive results. Our study supports the suggestion of others:^19,34,35 that development of and participation³⁶ in guideline development do not produce improved results. One-day continuing medical education interventions have been found to be ineffective in other clinical practice guideline settings^34,35; unlike De Angelis et al,¹⁵ we found that a lecture by a visiting professor was unhelpful in increasing compliance.

SPC charts were introduced in the 1920s as a statistically sound graphical method to evaluate processes occurring over time.^20–22 These charts permit analysis of significant changes in sample means (out-of-control situations) merely by recognizing chart patterns. Widely used in the manufacturing sector, this charting methodology is now being employed more frequently in the health care setting, and has been accepted by the Joint Commission on Accreditation of Healthcare Organizations.²⁰ In our study, these charts effectively measured the degree of compliance with guideline recommendations, but they were not effective in improving physician compliance or in sustaining the improvement in compliance seen during the weeks immediately after guideline development and distribution. Evidence of patient experience with delayed CINE in connection with poor compliance resulted not only in a general consensus to comply but also in a standardized approach to antiemetic prescription. These findings indicate that statistically valid charting, although useful in measuring compliance, will not achieve improved compliance as a physician feedback tool. However, enhanced compliance may be achieved when adverse patient outcomes are coupled with evidence of poor compliance with evidence-based guidelines. Using a standardized order set, either by nursing-driven prescription (as implemented in this report in response to the results of patient outcomes), by pharmacy-driven prescription, or by specific ordering software or similar tools^14,26,27 can further reduce variability and maintain gains in compliance, but physician consent and agreement are key to implementation.

Browman et al³⁶ emphasized the need to incorporate clinicians in the clinical practice guideline development process through consensus methods as a way to enhance acceptance and further enable implementation. Our experience, and that of others,^19,34,35 implies that this alone is inadequate. However, measuring the ultimate outcome of clinical practice guidelines—the patient experience—did strongly encourage compliance by addressing or overcoming some of the attitude barriers to guidelines^19,37 and can be additionally useful in measuring their clinical effectiveness and effect. In fact, as the purpose of clinical practice guidelines should be the improvement of the patient condition, measuring this patient outcome "report card" is likely to be far more effective in improving the quality of care through effective guideline development, implementation, and compliance than the intrainstitutional or public dissemination of descriptions of clinician or health system clinical practice guideline adherence.

	APPENDIX 1.

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 

Steps to Creating Statistical Process Control (SPC) Charts (after Doty²¹)

1. Select the quality characteristic • Number of omissions in implementation of guidelines • Severity of nausea on day 3 2. Develop the quality plan • Choose the tool to measure omissions • Choose the tool that will be used to measure nausea • Decide where and how frequently to measure 3. Choose the type of control chart • Omissions are "attributes" per sample of chemotherapy administrations and measured on U (defect per unit) charts • Nausea is measured as a continuous variable (Xbar charts) 4. Choose the sample size • Sample size of five for U charts and four for Xbar (mean of sample means) charts 5. Collect the data • Retrospective chart review (initial chart) • Automated collection (ongoing evaluation) • Serial, consecutive samples obtained and data entered in temporal order 6. Determine the trial chart control limits and chart centerline (average) • Initial charts consist of 25 samples (for chemotherapy administration U chart, 125 administrations) • Calculate upper control limit (UCL) and lower control limit (LCL) both at ± sigma, by standard methods • Centerline corresponds to the process average (the mean of all sample means) • "Out of control" values (see Appendix 2) evaluated and discarded if assignable special cause(s) are found 7. Determine revised control limits and chart centerline • Evaluate for "out of control" samples • If none are found, suggests that prescribing practice or nausea experience has not changed significantly • Use the chart prospectively using the revised control limits 8. Continue to use the charts • Use rules in Appendix 2 to evaluate potential "out of control" samples and effect of interventions

	APPENDIX 2.

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 

Description of Some Special Cause Tests at alpha = 0.01 level (Adapted from Doty²¹)

Test 1 One subsample mean beyond control limits Test 2 Seven subsample means in a row (above or below the chart centerline, going up, or going down) Test 3 Ten of 11 subsamples in a row Test 4 Twelve of 14 subsamples in a row Test 5 Patterns between +1 and -1 standard deviation above or below chart centerline (five subsamples in a row, or six of seven) Test 6 Patterns between +1 and +2, or -1 and -2, standard deviations from centerline (three subsamples in a row, or four or five) Test 7 Two values between +2 and +3, or -2 and -3, standard deviations from centerline NOTE. A number of statistical tests can be used to evaluate a statistically significant shift in the process mean (ie, sample means are significantly different than the centerline). These rules represent presentations of patterns on statistical process control charts that represent a significant change. Normally, three or four rules are applied to a single chart to avoid increasing the probability of detecting a change of shift in process mean beyond 1 in 100.

	NOTES

 
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 2002.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX 1. APPENDIX 2. REFERENCES

 
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Submitted August 16, 2002; accepted December 23, 2002.

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