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J Am Coll Cardiol, 2003; 42:1438-1445, doi:10.1016/S0735-1097(03)01058-1
© 2003 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

Beta-blockers and angiotensin-converting enzyme inhibitors/receptor blockers prescriptions after hospital discharge for heart failure are associated with decreased mortality in Alberta, Canada

David Johnson, MD*, Yan Jin, MA{dagger}, Hude Quan, MD, PhD{ddagger} and Bibiana Cujec, MD§,*

* Division of Critical Care Medicine, University of Alberta, Alberta, Canada
{dagger} Research and Evidence, Alberta Health and Wellness, Alberta, Canada
{ddagger} Department of Community Health Sciences, University of Calgary, Calgary, Canada
§ Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

Manuscript received January 8, 2003; revised manuscript received June 18, 2003, accepted June 25, 2003.

* Reprint requests and correspondence: Dr. Bibiana Cujec, Division of Cardiology, University of Alberta, 2C2.39 WMC, Edmonton, Alberta, Canada T6G 2B7.
Bibiana.Cujec{at}ualberta.ca


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to evaluate the common utilization of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors or receptor blockers (RBs) in congestive heart failure (CHF).

BACKGROUND: We assessed the association between prescriptions of beta-blockers and ACE inhibitors or RBs within three months after hospitalization and mortality for newly diagnosed CHF in Alberta, Canada seniors (age 65 years and older).

METHODS: Administrative hospital discharge abstracts and drug data during October 1, 1994, to December 31, 1999, were analyzed.

RESULTS: There were 11,854 hospitalizations for newly diagnosed CHF. The use of beta-blockers within three months after hospitalization increased from 7.3% in 1994–1995 to 20.9% in 1999–2000. The use of ACE inhibitor or RBs within three months after hospitalization increased from 31.0% in 1994–1995 to 44.3% in 1999–2000. Adjusted one-year mortality was lower in seniors with prescriptions for beta-blockers (18.2%; 95% confidence interval [CI] 14.2 to 22.2), ACE inhibitors/RBs (22.3%; 95% CI 20.9 to 23.7), or both (16.6%; 95% CI 13.3 to 20.0), compared with those with no prescriptions (29.9%; 95% CI 28.8 to 31.0). Absolute adjusted risk reduction comparing no prescription with prescription of both beta-blockers or ACE inhibitors/RBs was 13.3% for a relative adjusted risk reduction of 44%.

CONCLUSIONS: This study of incident CHF hospitalizations among seniors demonstrates an association between decreased mortality and the use of beta-blockers, ACE inhibitors/RBs, or combination of both. The effectiveness of beta-blockers and ACE inhibitors/RBs for CHF should be more broadly tested in clinical trials that recruit older patients and those with diastolic dysfunction.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  CHF = congestive heart failure
  CPX = Canadian Classification of Procedures
  ICD-9-CM = International Classification of Disease- Ninth Revision-Clinical Modification
  RB = receptor blocker

Congestive heart failure (CHF) is the most common diagnosis for hospital admission in the U.S. (1) and other industrialized countries (2–6). Despite the increased incidence, mortality has declined, suggesting that recent therapy may have improved outcomes (7,8). In randomized clinical trials, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors or receptor blockers (RBs) reduced mortality (9). Despite proven efficacy in clinical trials, physician prescription practices vary depending on system supports (10–15), which, if not present, may result in suboptimal utilization of these pharmaceuticals (16,17). Physicians may also be reluctant to extrapolate results from clinical trials that excluded patients older than 75 years and only enrolled patients with low ejection fractions (9). These older patients constituted up to 50% of hospitalizations for newly diagnosed CHF, and a low ejection fraction was not present in up to 50% of patients with the hospital admission diagnosis of CHF (14,18,19).

Using administrative data, we analyzed the prescription pattern in seniors taking beta-blockers and ACE inhibitors/RBs within three months after hospitalization for newly diagnosed CHF during October 1, 1994, to December 31, 1999. To better understand prescription practices, we assessed patient, geographic, and physician factors that may have influenced the utilization of therapy. Finally, after adjusting for comorbidity and CHF severity, we assessed the association between the utilization of therapy and one-year mortality. We hypothesized that the efficacy demonstrated in clinical trials would extrapolate into efficacious therapy for the population of one Canadian province.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
The following administrative data sources were used for this study: 1) the Canadian Institute for Health Information's Inpatient Discharge Abstract Database for the province of Alberta for fiscal years 1992–1993 to 1999–2000; and 2) the Alberta Health Insurance Plan Registry File for fiscal years 1994–1995 to 2000–2001, the Alberta Physician Claims Assessment System Database for 1992–1993 to 1999–2000, and the Alberta Blue Cross Insurance plan for fiscal years 1994–1995 to 1999–2000.

Study population.   The in-hospital discharge abstract data for the province of Alberta, Canada, during the fiscal years 1994–1995 to 1999–2000 were used to define the study population. The in-hospital discharge abstract data capture sociodemographic and clinical information of inpatients admitted to all hospitals in Alberta. All hospitals in Alberta are administered by an autonomous regional board in each of the 17 health regions. Nearly all of three million residents of Alberta are enrolled in the public health care insurance plan. Firstly, we identified heart failure patients by searching the validated and widely used International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes (428.x, 398.91, 402.x1, 404.1– 404.9, 514.x, 518.4, 425.9) in the most responsible diagnosis field (20,21). Secondly, we excluded patients who met the following criteria:

  1. not an Alberta resident;
  2. age <20 years or >105 years; and
  3. admission to an Alberta non–acute care facility. Thirdly, to identify "incidence" cases;
  4. we linked patients thus defined with the inpatient discharge abstract from 1992–1993 to 1999–2000 and excluded patients hospitalized for heart failure (as the most responsible diagnosis) during the two fiscal years before the index encounter;
  5. we excluded admissions if the same patient had an later hospital discharge within the five study years; and
  6. we excluded patients with an outpatient internal medicine specialist/subspecialist consultation claim (22) for heart failure (defined as for hospitalizations) during the two years before the index encounter.

Study variables.   Sociodemographic variables and transfers
Patient characteristics
The patients' sociodemographic and geographic characteristics were defined during the index admission, including: 1) age (65–74, 75–84, and 85+ years); 2) gender; 3) year of heart failure hospital discharge; 4) region of residence (the 17 health regions in Alberta were grouped into two metropolitan regions [Calgary and Edmonton] and one nonmetropolitan region); and 5) exported patient (patient admission to a hospital located in a health region not within the health region of residence). We also defined residents of a nursing home, long-term care facility, or senior's lodge before the hospital admission.

Transfers to another acute care hospital where the receiving hospital also identified heart failure as the primary reason for admission were identified through linking the study population and the inpatient discharge abstract during 1994–1995 to 1999–2000. Cases with a one-day difference between the discharge date of the index admission and the second admission date were assigned as transfers. Discharges and admissions for heart failure to the same hospital within 24 h were counted as separate admissions.

Case-mix and severity of disease
Case-mix and severity of disease were defined using diagnoses coded in the index and transferred admission. For case-mix, we defined the 17 comorbidities that constitute the Charlson index (23,24), using Deyo's coding algorithm by searching the 15 supplemental diagnosis fields in the hospital abstract. The Charlson comorbidities were aggregated into none, one, two, or more of the individual conditions. To define severity of comorbidities, we employed Polanczyk's weight scale (25). We defined: 1) anemia (ICD-9-CM 280.xx to 285.xx); 2) hyponatremia and other electrolyte disturbance (ICD-9-CM 276.x); 3) coronary artery disease (ICD-9-CM 411.xx, 413.xx, 414.xx); 4) hypertension (ICD-9-CM 401.xx to 405.xx); 5) valvular heart disease (ICD-9-CM 394.xx to 398.xx, 424.xx); 6) ventricular arrhythmia (ICD-9-CM 427.4x, 427.5x, 427.6x); and 7) hypotension and shock (ICD-9-CM 458.xx, 758.5x). Then we assigned a severity score (25) for each patient by using the following weighting method: 1 point for age ≤40 years; increasing 1 point per decade of age >40 years; 2 points for each of the comorbidities of transferred admission, cerebral vascular disease, chronic obstructive lung disease, hyponatremia, other electrolyte disturbance, and metastatic disease; 4 points for the comorbidity of moderate to severe renal disease; 6 points for each of the comorbidities of ventricular arrhythmia, mild liver disease, and malignancy; and 13 points for each of the comorbidities of hypotension, shock.

Revascularization
Revascularization within one year after admission was determined using both the hospital discharge data and physician claims data. For the hospital discharge data, data were extracted in any of the 10 procedural diagnosis fields, which were coded by ICD-9-CM. Procedures for the physician claims were coded with the Alberta Health and Wellness Health Services Codes based on the Canadian Classification of Procedures (CPX) (22). We defined three variables for the procedure of care, including coronary angiography (found in physician claims and coded as CPX 48.92A, 48.98A, 48.98B, 49.96A, and 49.96B), percutaneous transluminal coronary angioplasty/stenting (found in physician claims and coded as CPX 51.59C), and coronary artery bypass graft surgery (found in physician claims and coded as CPX 48.0A, 48.12, 48.12A, 48.13, 48.13A, 48.14, 48.14A, 48.15A, 48.15B, 48.15C, 48.15D, 48.15E, 48.15F, 48.15G, 48.15H, and 48.19A).

Physician and hospital characteristics
The specialty of the most responsible physician at the index admission was grouped into two categories: nonspecialist (general or family practitioners) or other internal medicine specialist/subspecialist for the index admission. Cardiology specialist/subspecialist was also identified among internal medicine specialists/subspecialists. All hospitalizations for heart failure (newly diagnosed or previously diagnosed) during the period 1994–1995 to 1999–2000 were used to estimate the most responsible physicians' annual volume, crediting any listing as the most responsible physician or consultation during hospitalization. The volume was classified into quartiles.

Hospital factors
We noted the following hospital environment factors: 1) hospital type (see subsequently); 2) remote distance to hospital (see subsequently); 3) hospital beds per capita in each health region (all active hospitals' acute care beds in each year per health region were recorded in the provincial data bases); 4) hospital bed turnover ratio (number of hospital admissions divided by the number of hospital beds in the specific hospital on the date of the heart failure admission; 5) occupancy rate (total monthly length of stay per hospital divided by the total number of beds in each hospital on the date of the CHF admission); 6) transfer to hospital by ambulance, as defined in hospital chart abstract; 7) weekend/holiday admission date; 8) admission time between 6:00 PM to 8:00 AM; 10) emergent admission; and 11) special care (intensive care) unit admission.

Hospital type
The hospital location was classified into rural, regional, and metropolitan, considering the service population size for each hospital and whether the hospital had angiography capability. Rural hospitals admitting heart failure patients were categorized into two groups based on the 50th percentile of heart failure hospital discharges between April 1, 1994, and March 31, 2000. The hospital types included: 1) rural hospitals with a low volume (n = 77; <200 cases); 2) rural hospitals with a high volume (n = 25; 204 to 646 cases); 3) regional hospitals (n = 5; 238 to 646 cases) located in one of the five nonmetropolitan regional health care cities; 4) metropolitan hospitals (n = 6; 327 to 2,199 cases) located in the metropolitan health region of Calgary and Edmonton without angiography capability; and 5) metropolitan hospitals (n = 3; 1,793 to 2,700 cases) located in the metropolitan health regions of Calgary and Edmonton with angiography capability.

Remote distance to hospital
The residence of each hospital and patient was mapped to the center of a postal code, and "crow flies" distances between centroids were calculated. The nearest hospital distance (one each for rural, regional, and metropolitan hospitals) to the patient's residence location was obtained for rural residents. Urban resident to hospital distances were designated as zero. Distances >50 km were defined as remote.

Prescription characteristics
All seniors registered with the Alberta Health Care Insurance received subsidized prescriptions with Alberta Blue Cross. The anonymous patient identifier for each prescription was merged with the prescription data base identifying each drug identification number in order to classify all prescriptions for either beta-blockers or ACE inhibitors/RBs. Any prescription within three months before hospital admission or after hospital discharge was identified. Use of either drug was assumed if any prescription was linked before or after the study period after the initial diagnosis of CHF was made. Relative contraindications to the use of secondary prevention therapy are outlined: 1) for asthma/chronic obstructive pulmonary disease/other chronic respiratory conditions (coded as ICD-9 CM 490- 496, 500-505, 506.4), beta-blockers were contraindicated; 2) for moderate to severe renal disease (coded as ICD-9-CM 582, 583–583.7, 585, 586, 588), ACE inhibitors/RBs were contraindicated.

Due to the limitations of Blue Cross data and the time lag between prescription and hospitalization (i.e., 3 months before admission and after discharge), we only included patients discharged from October 1, 1994, to March 31, 1995 (last two quarters), for year 1994–1995 and patients discharged from April 1, 1999, to December 31, 1999 (first three quarters), for year 1999–2000.

Heart failure outcomes.   The length of stay was calculated as the days between discharge and admission dates. Transfers between different hospitals were attributed to the index admission and cumulative hospital length of stay calculated for an episode of care. In-hospital mortality was obtained from the hospital chart abstract. One-year mortality was obtained from vital statistics declaration of death certificates.

Statistics for outcomes
Adjusted one-year mortality was calculated using logistic regression. We averaged the predicted probabilities of mortality for each prescription (E). The observed mortality (O) divided by the expected rate (E) generated an O/E ratio for each prescription. The adjusted mortality was calculated by multiplying each prescription O/E ratio by the overall mortality. Covariates used for regression adjustment included patient characteristics (year of diagnosis, age group, gender, export to another region, transfer to another acute hospital), severity of illness (anemia, coronary artery disease, hypertension, valvular heart disease, special care unit admission, overall severity score, ambulance transfer, cardiac catheterization within one year from admission), number of comorbidities (i.e., 0, 1, 2, or >2 and transfer from a continuing care institution), and hospital volumes. All covariates added were significant by univariate analysis. To verify the logistic regression model for mortality, we performed a secondary analysis by constructing a propensity score using the covariates described earlier (26). Scores were matched by quintiles and compared using the Fisher exact test. Modeling used SAS (version 6.12, 2000, SAS Institute Inc., Cary, North Carolina), and significance was defined as p < 0.05.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
During October 1, 1994, to December 31, 1999, there were 11,854 senior hospital admissions for newly diagnosed CHF (incidence cases), representing ~50% of the total senior hospitalizations (n = 23,697) for CHF during this period. Over the six study years, the use of beta-blockers both before and after hospitalization increased (Table 1). Over the six study years, the use of ACE inhibitors or RBs both before and after hospitalization increased, reaching a peak during 1997–1998. The one-year mortality rate was similar over the six study years. A statistical comparison of overall mortality over time was not attempted, as the first and last years' acquisition of cases was not for the entire 12-month period. Excluding the first and last years of incomplete data, mortality tended to decrease, consistent with the increased use of either beta-blockers or ACE inhibitors/RBs.


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  		Table 1 Temporal Changes in Seniors (Age ≥65 Years) Hospitalized With Newly Diagnosed Congestive Heart Failure in Alberta, Canada During 1994–1995 to 1999–2000

 
Compared with those receiving either beta-blockers or ACE inhibitors/RBs, or both, those not receiving either prescription were older, fewer resided in a metropolitan region, and more had greater comorbidity and severity of illness (Table 2). Compared with those receiving either beta-blockers or ACE inhibitors/RBs, or both, those not receiving either prescription were more likely to be admitted into a small rural hospital, less likely to be admitted into a metropolitan hospital with angiography capability, more likely to have a general practice physician as the most responsible physician, less likely to have an internal medicine or cardiology consultation, less likely to have a most responsible physician with a high volume of similar cases, and less likely to receive cardiac catheterization or admission to a special care unit (Table 3). One-year crude mortality was higher in those not receiving either beta-blockers or ACE inhibitors/RBs than in those receiving either drug or both.


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  		Table 2 Severity of Illness and Comorbidity in Seniors (Age ≥65 Years) Hospitalized With CHF in Alberta, Canada During 1994–1995 to 1999–2000

 

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  		Table 3 Physician and Hospital Factors for Seniors (Age ≥65 Years) Hospitalized With Newly Diagnosed CHF in Alberta, Canada, During April 1, 1994, to March 31, 2000

 
Adjusted one-year mortality (Table 4) was lower in seniors with prescriptions for beta-blockers or ACE inhibitors/RBs, or both. The comparison of patients with and without relative contraindications for either beta-blockers or ACE inhibitors/RBs did not alter the benefit toward decreased mortality. Propensity analysis results were analogous to those for logistic regression. For each quintile of propensity score, patients who did not take either beta-blockers or ACE inhibitors/RBs had higher one-year mortality than those who took at least one. For each quintile of propensity score, patients who used only beta-blockers did not have a statistically different one-year mortality than those who used ACE inhibitors/RBs only. In one quintile group, the one-year mortality was higher for patients who used beta-blockers only, compared with patients who used both beta-blockers and ACE inhibitors/RBs. For the other four quintile groups, the mortality was not statistically different. For one quintile group, the one-year mortality was higher for patients who used ACE inhibitors/RBs only, compared with patients who used both beta-blockers and ACE inhibitors/RBs. For the other four quintile groups, the mortality was not statistically different.


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  		Table 4 Adjusted Mortality in Seniors (Age ≥65 Years) Hospitalized With Newly Diagnosed CHF in Alberta, Canada During 1995–1996 to 1999–2000

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We believe that this is the first population-based study to demonstrate an association between the use beta-blockers, ACE inhibitors/RBs, or combination of both, and decreased mortality after CHF hospitalization. The absolute adjusted risk reduction comparing no prescription with both beta-blockers and ACE inhibitors/RBs was 13.3% (i.e., 29.9% to 16.6%), for a relative adjusted risk reduction of 44%. The absolute risk reduction in this population cohort was greater than that noted in clinical trials (9,27–29), likely as a result of the higher mortality in our study, which enrolled unselected patients (30,31). Our population cohort was not stratified by left ventricular systolic or diastolic function, and the majority was in an age group (≥75 years old) that has been traditionally excluded in clinical trials. The benefits of ACE inhibitors have been noted in another study, irrespective of left ventricular ejection fraction (32). The critical message of this study for the clinician is that the mortality reduction with the use of beta-blockers and ACE inhibitors/RBs found in clinical trials may be generalizable to all patients hospitalized with CHF. If true, future clinical trials of beta-blockers and ACE inhibitors/RBs in CHF (33) should not be restricted to only those with a documented low ejection fraction, as these patients constitute only a proportion of the at-risk population (34,35).

Both ACE inhibitors and RBs are underutilized in patients with CHF (36,37). Familiarity with medications may increase utilization, which would be an explanation for the greater use in specialists/subspecialists and high-practice-volume physicians noted in this study and others (38). Passive and active dissemination of practice guidelines are not always successful strategies in increasing utilization (33,36). Some programs have been more successful at including a local provincial program, which was associated with the peak use of ACE inhibitors/RBs in 1997–1998 (39). There exists a paradox of need where those most likely to benefit from practice guidelines (low volume practice, smaller rural hospitals) are least likely to receive them (40).

Relative contraindications to ACE inhibitors/RBs, such as renal failure, or beta-blockers, such as asthma and chronic obstructive pulmonary disease, may decrease utilization, even though a benefit persists (41,42). We found that the association with decreased mortality persisted even in those patients with relative contraindications, unlike in a previous study (43). The poorer prognosis for CHF in population-based cohorts (44–47), as well as the fact that many deaths are not related to CHF in the general population composed of older patients, may make physicians even more reluctant to adopt clinical recommendations concerning the use of these therapeutic agents (9,48,49). Our data do not support the exclusion of all patients with contraindications, as defined by hospital abstracts.

Study limitations.   This study has several limitations. Population-based administrative data base research is highly generalizable, although limited in clinical details. We attempted to adjust for case severity and comorbidity, although these data may not have captured all important variations. The diagnosis of CHF from hospital discharge data may underestimate the true prevalence of this disease (50,51). We constructed an episode of care by attributing re-admissions within the first day of discharge back to the original index admission. Our length of stay was attributed to the presenting hospital rather than all hospitals in which care could have been rendered. We potentially missed incident cases if a contact with the health system was never made. We also may have similarly misclassified some prevalent cases as incident cases; however, this was likely infrequent, as hospitalized patients were excluded if a previous ambulatory diagnosis of CHF had been made. Another potential bias in this study is that patients who died soon after hospital discharge were given a prescription but never had the opportunity to fill this prescription. These patients would have been misclassified into the no prescription group. We do not believe that this effect was large, as only 4.9% of deaths were within the first week of hospital discharge. The large relative risk reduction was influenced by the asymmetry in the severity of illness and comorbidity in those not receiving prescriptions, as well as their higher mortality rate. We attempted to account for these differences by adjustment and propensity score; however, residual confounding because of unmeasured or unaccounted differences between those patients who did and did not receive prescription may still have existed.

Conclusions.   We believe that this is the first population-based study to demonstrate an association between decreased mortality and beta-blockers, ACE inhibitors/RBs, or a combination of both, after CHF hospitalization. This study did not exclude those without documented left ventricular systolic or diastolic function or those in the age group ≥75 years. As such, the effectiveness of beta-blockers and ACE inhibitors/RBs should be tested in clinical trials enrolling the entire population of hospitalized patients with CHF.


   Footnotes
 
This work was partially supported by the Alberta Center for Health Service Utilization Research. The opinions and conclusions expressed in this paper are those of the authors, and no endorsement by the Alberta Ministry of Health and Wellness is implied.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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