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(Chest. 2007;131:20-28.)
© 2007 American College of Chest Physicians

Risk Indexes for Exacerbations and Hospitalizations Due to COPD*

Dennis E. Niewoehner, MD, FCCP; Yuliya Lokhnygina, PhD; Kathryn Rice, MD, FCCP; Ware G. Kuschner, MD, FCCP; Amir Sharafkhaneh, MD, FCCP; George A. Sarosi, MD, FCCP; Peter Krumpe, MD, FCCP; Karen Pieper, MSc and Steven Kesten, MD, FCCP

* From the Departments of Medicine at Veterans Affairs Medical Centers in Minneapolis, MN (Drs. Niewoehner and Rice), Palo Alto, CA (Dr. Kuschner), Houston, TX (Dr. Sharafkhaneh), Indianapolis, IN (Dr. Sarosi), and Reno, NV (Dr. Krumpe); the Duke Clinical Research Institute (Dr. Lokhnygina and Ms. Pieper), Durham, NC; and Boehringer-Ingelheim Pharmaceuticals (Dr. Kesten), Ridgefield, CT.

Correspondence to: Dennis E. Niewoehner, MD, FCCP, Veterans Affairs Medical Center, One Veterans Dr, Minneapolis, MN 55417; e-mail: niewo001{at}umn.edu

Abstract

Objective: The ability to predict exacerbations in patients with COPD might permit more rational use of preventive interventions. Our objective was to develop risk indexes for exacerbations and hospitalizations due to exacerbations that might be applied to the individual patient.

Methods: Spirometry, demographics, and medical history were obtained at baseline in 1,829 patients with moderate-to-very severe COPD who entered a trial of inhaled tiotropium. Information about exacerbations and hospitalizations due to exacerbation was collected during the 6-month follow-up period. Analyses of first outcomes were modeled using univariable and multivariable Cox proportional hazards regressions.

Results: During follow-up, 551 patients had at least one exacerbation and 151 patients had at least one hospitalization due to exacerbation. In the multivariable model for exacerbation, older age, percentage of predicted FEV1, duration of COPD, a productive cough, antibiotic or systemic corticosteroid use for COPD in the prior year, hospitalization for COPD in the prior year, and theophylline use at baseline predicted a higher risk. In the multivariable model for hospitalization, older age, percentage of predicted FEV1, unscheduled clinic/emergency department visits for COPD in the prior year, any cardiovascular comorbidity, and prednisone use at baseline were associated with greater risk. Both the exacerbation and the hospitalization models provided moderately good discrimination, the validated concordance indexes being 0.66 and 0.73, respectively. Methods for calculating risk in individual patients are provided.

Conclusions: Spirometry along with a few questions directed to the patient are strongly predictive of exacerbations and related hospitalizations over the ensuing 6 months.

Key Words: COPD • exacerbations • risk models

Exacerbations of COPD are morbid and costly events. Exacerbations seriously impair quality of life and may also cause permanent loss of lung function.12 Hospitalizations due to COPD exacerbations account for a major portion of the economic costs for this disease.3 Hence, the prevention of COPD exacerbations is recognized as an important management goal.45 A number of inhaled respiratory drugs, as well as certain other interventions, appear capable of preventing or ameliorating the severity of exacerbations.6 A method for reliably assessing exacerbation risk in individual COPD patients might allow these interventions to be used in a more rational and cost-effective manner. There is ample precedent for using risk models as clinical management tools, cardiovascular events and community-acquired pneumonia being two examples.78910 A reliable method for estimating exacerbation risk might also be useful for designing trials and other types of research studies.

Observational studies with various designs have evaluated risk factors for hospitalization due to COPD. Independent risk factors reported in these studies include low levels of lung function1112131415; the number of respiratory medications15; advancing age16; abnormal blood gas levels1117; pulmonary hypertension17; low body mass index17; low levels of physical activity11; prior hospital admissions11131516; impaired quality of life12161819; current smoking status1320; lack of influenza vaccination21; and air pollution.22 While hospitalization is an important event, most patients with medically important exacerbations do not require hospital admission. No previous study has attempted to identify risk factors for exacerbations using prospective data collection and a clearly stated definition of exacerbation.

We previously reported that tiotropium, a once-daily inhaled anticholinergic bronchodilator, reduces the frequencies of COPD exacerbations and hospitalizations due to exacerbations.23 In this report, we used clinical and patient-centered information collected at baseline from that large, multicenter trial to develop and validate risk indexes for these same two outcomes. We present our findings so as to allow assignment of an overall risk score to individual patients.

Materials and Methods

The trial was performed in accordance with the recommendations in the Helsinki Declaration of 1975.24 The institutional review board of all participating medical centers approved this study. All subjects gave written informed consent.

Details of the study protocol were previously described.23 Briefly, all men and women receiving medical care at participating Veterans Affairs medical centers were potential study subjects. Major inclusion criteria were a clinical diagnosis of COPD, age ≥ 40 years, smoking history ≥ 10 pack-years, and FEV1 ≤ 60% of predicted and ≤ 70% of FVC. Principal exclusion criteria were a clinical diagnosis of asthma; myocardial infarction within the prior 6 months; a serious cardiac arrhythmia or hospitalization for heart failure within the prior year; known moderate-to-severe renal impairment; moderate-to-severe symptomatic prostatic hypertrophy or bladder-neck obstruction; narrow-angle glaucoma; current radiation or chemotherapy for a malignancy; and inability to give informed consent. We also excluded patients who took systemic corticosteroids at unstable doses, or in regular daily doses ≥ 20 mg of prednisone (or equivalent), or who had not fully recovered from an exacerbation for at least 30 days prior to the first study visit.

We collected baseline data relating to demographics, respiratory disease history, current respiratory medications, and comorbidities by questionnaire. Comorbidities were classified by organ system according to the Medical Dictionary for Regulatory Activities.25 For purposes of analysis, we preselected those organ systems that we thought were most likely to be important and further collapsed them into seven categories as follows: (1) cardiovascular, (2) endocrine/metabolic, (3) infectious, (4) GI/hepatobiliary, (5) musculoskeletal, (6) neuropsychiatric, and (7) genitourinary. We measured weight and height to compute body mass index. We performed spirometry using a common predictive nomogram and with equipment and methods that conformed to American Thoracic Society recommendations.2627

Each morning randomized patients inhaled the contents of one capsule of tiotropium (18 µg) or of identical placebo (HandiHaler; Boehringer Ingelheim Pharma GmbH; Ingelheim, Germany) dry powder inhalation device.28 The patients continued their usual medications, except that they were not allowed to use any open-label anticholinergic bronchodilator. The follow-up period was 6 months. Information about exacerbations and hospitalizations was gathered during site visits at 3-month intervals and by telephone calls at 1-month intervals between visits. We defined an exacerbation as a complex of respiratory symptoms (increase or new onset) of more than one of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics and/or systemic corticosteroids and/or hospital admission. We identified hospitalizations due to COPD exacerbations from those events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event resulted in a hospitalization. Admissions to nursing homes or other extended-care facilities were not considered to be hospitalizations.

We performed univariable and multivariable Cox regression analyses to evaluate the association between baseline characteristics, concomitant medications and the study drug and the time to first COPD exacerbation and the time to first hospitalizations due to exacerbation.29 For each continuous potential predictor, the shape of the relationship with the outcomes was examined by a model-fitting technique using restricted cubic spline functions. When the relationship appeared to be nonlinear, the cubic spline was approximated by a linear spline to allow a better clinical interpretation. The final models were constructed using a stepwise selection method. The predictive accuracy of the models was quantified by calculating the concordance index (c-index). The impact of the possible overfitting during stepwise regression was further evaluated by bootstrapping techniques. One hundred bootstrap samples were drawn, with replacement, and c-indexes were calculated adjusting for possible overoptimism in fitting the models. Finally, risk nomograms were constructed based on the selected multivariable models.30

Results

We randomized 1,829 subjects from among 2,498 candidates who were screened at 26 Veterans Affairs medical centers, of whom 915 were allocated to placebo and 914 to tiotropium. Study subjects were predominately white (91%) and male (99%), reflecting the composition of patients who receive medical care in Veterans Affairs medical facilities. As shown in Table 1 , the average subject was elderly (mean age, 68 ± 9 years), had relatively severe COPD (FEV1, 36% predicted), received multiple respiratory medications, and had numerous comorbidities. We strongly encouraged continued follow-up even among those patients who stopped study drug. Ninety percent of the randomized patients completed all study visits, and only approximately 6% of the data relating to exacerbations and hospitalizations was missing. Discharge summaries were available for review in 94% of all hospitalizations. During the 6-month follow-up period, 551 patients had at least one exacerbation and 151 patients were hospitalized at least once for a COPD exacerbation.


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  		Table 1. Univariable Relationships of Baseline Characteristics to First COPD Exacerbation and to First Hospitalization According to a Cox Proportional Hazards Model

 
We subjected baseline characteristics to univariable Cox analyses with survival to the first COPD exacerbation and survival to the first hospitalization attributable to COPD exacerbation as separate dependent outcomes (Table 1). As might be anticipated from the large sample size and frequency of the outcomes, numerous baseline characteristics were associated with both COPD exacerbations and hospitalizations due to exacerbation. Statistically significantly greater risks for both outcomes were associated with older age; with being a current nonsmoker; with poorer lung function; with home oxygen use; with more frequent scheduled clinic visits; unscheduled clinic or emergency department (ED) visits and hospitalizations for COPD in the prior year; with more frequent use of either antibiotics or systemic steroids for COPD in the prior year; and with use of a short-acting ß agonist, an inhaled corticosteroid, or an oral corticosteroid at baseline. Allocation to placebo, being of white race, presence of a productive cough, longer duration of COPD, use of a long-acting ß-agonist or theophylline at baseline, and presence of any GI or hepatobiliary comorbidities were associated with a statistically significantly greater risk for a COPD exacerbation but not for a hospitalization. Conversely, a lower body mass index and the presence of any cardiovascular comorbidity were associated with a statistically significantly larger risk for hospitalization but not for exacerbation.

The variables included in the final multivariable Cox regression models for exacerbation and hospitalization for exacerbation appear in Tables 2, 3 . A lower percentage of predicted FEV1, older age, and hospitalization for COPD in the prior year pose higher risks in both models. Other variables associated with greater risk in the exacerbation model are duration of COPD, presence of productive cough, more frequent use of antibiotics or systemic corticosteroids for COPD in the past year, and use of theophylline at baseline. Other variables associated with higher risk in the hospitalization model include more frequent unscheduled clinic/ED visits for COPD in the prior year, any cardiovascular condition, and use of oral corticosteroids at baseline. We evaluated discrimination of the multivariable models to observations by calculating c-indexes. Both models discriminated moderately well, the c-indexes being 0.67 for the exacerbation model and 0.75 for the hospitalization model. We also ran bootstrap analyses to evaluate internal validity of the models, and these results demonstrated excellent consistency for both the exacerbation model (validated c-index = 0.66) and for the hospitalization model (validated c-index = 0.73).


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  		Table 2. Multivariable Relationships of Baseline Characteristics to First COPD Exacerbation According to a Cox Proportional Hazards Model

 

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  		Table 3. Multivariable Relationships of Baseline Characteristics to First COPD Hospitalization According to a Cox Proportional Hazards Model

 
The probability of an individual patient having either an exacerbation or a hospitalization due to exacerbation can be computed from the information provided in Tables 4, 5 , and Figures 1, 2 . For example, a 60-year-old patient (40 points) with an FEV1 of 40% of predicted (47 points), no sputum-producing cough (0 points), COPD duration of 2 years (5 points), no COPD hospital admission in the prior year (0 points), one course of systemic corticosteroids for COPD in the prior year (39 points), antibiotic use for COPD in the prior year (63 points), and no current theophylline use (0 points) would have a total score of 194. From Figure 1, a risk score of 194 corresponds to a probability of 0.25 for having an exacerbation in the next 6 months. Table 5 and Figure 2 can be used similarly to compute probability of hospitalization due to exacerbation over a 6-month period. Reliability plots, shown as insets in both Figures 1and 2, indicate that predictions correlate closely with observed data over a wide range of scores in both models.


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  		Table 4. Calculation of Exacerbation Risk Score for Individual Patients

 

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  		Table 5. Calculation of COPD Hospitalization Risk Score for Individual Patients*

 

Figure 1
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  		Figure 1. Plot of total risk score, as calculated from Table 4, to probability of having a COPD exacerbation in the ensuing 6 months. The inset is a reliability plot comparing predicted vs actual probabilities over a wide range.

 

Figure 2
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  		Figure 2. Plot of total risk score, as calculated from Table 5, to probability of being hospitalized for a COPD exacerbation in the ensuing 6 months. The inset is a reliability plot comparing predicted vs actual probabilities over a wide range.

 
Discussion

Using a database from a large trial, we identified advancing age and low levels of lung function as major independent risk factors for both exacerbations and hospitalizations due to exacerbations. Other important independent risk factors in both models are medical events (frequencies of antibiotic and systemic corticosteroid use, unscheduled clinic/ED visits, and hospitalization, all for COPD in the prior year) that as a group might be viewed as reflecting an intrinsic susceptibility to exacerbations not explained by advancing age or poor lung function. We internally validated both models with a bootstrapping procedure. and we present the results in a form that permits assessments of risk in individual patients.

This is the first study to gather information about predictors of exacerbations in a prospective fashion using a clear definition of exacerbation. Save for one, previous studies111213151617181920 on this subject utilized hospitalization for COPD as a surrogate for exacerbation and did not provide sufficient information to allow calculation of individual patient risk. The sole exception was a cross-sectional study in which information about exacerbations was collected retrospectively through patient report.14

We confirmed one previous suggestion that chronic productive cough is an independent predictor for exacerbation.14 A unique finding in this study is the strong and independent association of any cardiovascular comorbidity with hospitalizations that were attributed to COPD exacerbations. Indeed, we may have underestimated the strength of this relationship because we excluded certain patients with a recent history of unstable heart disease. Whether cardiovascular disease truly predisposes to COPD-related hospitalizations or whether it merely represents misdiagnosis is unclear, as the clinical presentation of acute heart failure may mimic that seen with a COPD exacerbation.

All baseline respiratory medications were significant univariable predictors of exacerbation or of hospitalization or of both. However, only oral corticosteroid use was retained in the multivariable hospitalization model and only theophylline use was retained in the multivariable exacerbation model. Oral corticosteroid use as a predictor of hospitalization had been previously noted.16 This finding is not particularly surprising because the so-called "steroid-dependent" COPD patient is widely recognized as a challenging clinical problem, in no small part because of frequent exacerbations and hospitalizations. Indeed, there is reason to suspect that chronic oral corticosteroids may be prescribed to many of these patients specifically for that reason, even though the effectiveness of this practice remains uncertain.31 Similarly, theophylline is no longer widely used for COPD, and one might suspect that many physicians reserve its use for difficult patients who are prone to exacerbations.

In the univariable models, we identified current smokers as being at substantially lower risk for both exacerbations and hospitalizations. This finding appears on first impression to be counterintuitive, but similar findings have been noted in previous studies.1314 Since this variable was not retained in either of the multivariable models, we infer co-linearity with other characteristics that are more strongly predictive of exacerbations, such as lower levels of lung function and a history of frequent exacerbations. Poor lung function and/or frequent exacerbations could well be factors in a patient’s decision to quit smoking. This type of "healthy smoker" effect has been described previously in patients with severe COPD.32 In contrast, current smoking is associated with substantially higher hospitalization rates among subjects who have less severe disease.20

The risk indexes developed in this study have a number of strengths. The large size of the trial and the overall severity of COPD among the trial subjects provided adequate numbers of outcomes to ensure a reasonable level of statistical precision. The baseline and outcome data are of very high quality because we collected information in a prospective, systematic manner. We think it unlikely that we missed very many exacerbations or hospitalizations because we contacted patients monthly. We used an "event-based" definition of exacerbation that combined a characteristic symptom complex with a discrete medical intervention (antibiotics, systemic corticosteroids, or hospitalization).33 This definition excluded milder illnesses, defined solely by symptoms or by changes in rescue medication use, that are medically less important and probably more difficult to identify in a reproducible manner. To ensure accuracy of hospitalization diagnosis, we reviewed discharge summaries and all available medical records to determine primary cause. Finally, risk assessments of the individual patient utilizing our models can be simply performed, as they require only that the clinician obtain spirometry and ask a few questions of the patient.

There are also a number of important limitations. Most importantly, we do not know how generalizable our risk models might be, because they were developed from the database of a trial that utilized certain eligibility criteria, that was conducted within a single health-care system, and that included very few women. These concerns are mitigated to some extent because the trial was conducted at 26 widely dispersed study sites and with eligibility criteria that were broad by the standard of most COPD trials. Of potentially useful data that we did not collect, quality of life might be the most important because several studies showed that it is a strong independent predictor of hospitalization.12161819 However, administering a validated quality of life instrument requires significant time and is not likely to be done except in a research setting.

In summary, we have developed models to assess the risk from COPD exacerbations and from hospitalizations due to exacerbation in patients with moderate-to-very severe COPD. The models are robust and can be easily applied to individual patients. We suggest that risk models might find a role for decision making in the clinical management of COPD. For example, risk assessment might be used to justify the added cost of prescribing inhaled corticosteroids or long-acting bronchodilators, agents that reduce exacerbation rates when given singly or in combination.34 Our risk models might also have research applications. They may allow more accurate predictions of event rates, which are critically important in determining sample sizes for trials and other clinical research studies where COPD exacerbation or hospital admission is the primary outcome. Validation studies in other study populations would have obvious value.

Appendix

Participating Investigators and Study Staff
Other investigators and study staff at individual Veterans Affairs medical centers are as follows: Bay Pines: Dr. C. Cote, K. Wilson; Birmingham: Dr. A. Cooper, Jr., J. Bowden, R. Culbreth, J. Cooper; Boston: Dr. D. Gottlieb, K. Hickson; Bronx: Dr. M. Lesser, Dr. G. Schilero; Buffalo: Dr. S. Sethi, K. Eschberger; Dallas: Dr. M. Hasan, C. Lusk; Durham: Dr. S. Young, J. Smith; Gainesville: Dr. R. Gonzalez-Rothi, L. Thompson; Hampton: Dr. B. Rossheim, G. Troupe; Hines: Dr. N. Gross, A. Burns; Houston: Dr. B. Dickey, P. Smithwick, A. Bernardo; Indianapolis: Dr. M. Farber, C. Magnes; Kansas City: Dr. M. Plautz, C. Perkins; Lexington: Dr. J. McCormick, Dr. D. Doherty, S. Shariaty, A. Surface; Long Beach: Dr. C.K. Mahutte, G. Orakcilar; Minneapolis: F. Lebahn, C. Bagne; New Orleans: Dr. M. Friedman, S. Ditta; North Chicago: Dr. A. Fulambarker, J. Nyland; Omaha: Dr. C. Piquette, H. Despiegelaere, K. Stanley; Palo Alto: Guvenc-Tuncturk; Phoenix: Dr. L. Wesselius, P. Jacobs; Reno: M. Wing; Richmond: Dr. D. Paulson, D. Kennedy; Salt Lake City: Dr. J. Shigeoka, JA. Pell, K. Barlow; San Antonio: Dr. A. Anzueto, Dr. S. Kucera; Tucson: Dr. M. Habib, G. Blackwell, T. Vincent.

Footnotes

Abbreviations: c-index = concordance index; ED = emergency department

The Duke Clinical Research Institute managed data for the trial.

Administrative support for all study centers was provided by the Minnesota Veterans Research Institute.

Financial support was provided by Boehringer Ingelheim and Pfizer.

Dr. Niewoehner has received grants, honoraria, or advisory fees from Boehringer-Ingelheim, Pfizer, AstraZeneca, GlaxoSmithKline, Adams Respiratory Therapeutics, and Sanofi Pasteur within the past 3 years. Dr. Rice has received honoraria from Boehringer-Ingelheim and Pfizer within the past 3 years. Dr. Sharafkhaneh has received honoraria from Boehringer-Ingelheim, Pfizer, and GlaxoSmith-Kline. Dr. Krumpe has received grants, honoraria, or advisory fees from Altana, Astra-Zeneca, Boehringer-Ingelheim, Chiron, and Pulmonix. Dr. Kesten is an employee of Boehringer-Ingelheim. Dr. Lokhnygina, Dr. Kuschner, Dr. Sarosi, and Ms. Pieper report no potential conflicts of interest.

Received for publication May 24, 2006. Accepted for publication September 8, 2006.

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