Abstract
Background
Since 2007, clinical practice guidelines have recommended beta-blocker therapy early in the course of acute myocardial infarction (AMI) for patients who are not at high risk for complications. Our objective was to perform a national quality assessment of early beta-blocker use during hospitalization for AMI over the past decade in China.
Methods
We conducted medical record review of a nationally representative sample of patients admitted to Chinese hospitals with AMI and studied those without absolute contraindications to beta-blocker therapy during 2001, 2006, and 2011. We evaluated the use, type, and dose of beta-blockers within the first 24 hours of admission over time and identified predictors of not using this treatment both in ideal candidates and in those with risk factors for cardiogenic shock.
Results
Among 14,241 patients with AMI (representing 43,165 patients in 2001, 106,167 patients in 2006, and 221,874 patients in 2011 in China, respectively), 45.1% had no contraindications to early beta-blocker therapy; 21.1% had risk factors for cardiogenic shock but no absolute contraindication. Beta-blocker use in ideal patients was 54.3% in 2001, 67.8% in 2006, and 61.8% in 2011 (P=0.28 for trend). Predictors of non-treatment were older age, lower systolic blood pressure, lower heart rate, absence of chest discomfort and admission to a non-teaching hospital. Use in patients with risk factors for cardiogenic shock was 42.6% in 2001, 59.5% in 2006, and 52.9% in 2011 (P=0.31 for trend). Metoprolol was used most frequently (91.5%), but dosages were often below those recommended in guidelines.
Conclusions
The use of early beta-blocker therapy for patients with AMI in China is suboptimal, with underuse in patients who could benefit and substantial use among those who might be harmed. Patterns of use have not changed over time, thus creating an important target of efforts to improve quality of care for AMI.
Keywords: beta-blocker therapy, acute myocardial infarction, trends, dose
INTRODUCTION
Early administration of beta-blockers in patients with acute myocardial infarction (AMI) has the potential to reduce mortality,(1–3) but indiscriminate use, especially in patients at high risk for cardiogenic shock could be harmful.(4) The COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial), published in 2005, showed that early beta-blocker therapy for patients with AMI significantly reduced the risk of re-infarction and ventricular fibrillation, but this benefit was counterbalanced by an increased risk of cardiogenic shock among patients with risk factors such as advanced age or evidence of hemodynamic instability.(4) In 2007, the American College of Cardiology and the American Heart Association tempered their broad endorsement of early beta-blocker use for patients with AMI, retaining a recommendation for early beta-blocker therapy in those patients without risk factors for shock and suggesting avoidance among those with risk factors (including age greater than 70 years, systolic blood pressure less than 120 mmHg, or heart rate greater than 110 or less than 60).(5–6) The 2010 Chinese guideline includes a similar recommendation to avoid beta-blockers in patients with these risk factors.(7)
For countries such as China, challenged by limited health care resources and a growing burden of AMI, there is a particular need to optimize the use of effective and inexpensive medications such as beta-blockers. Implementing the guideline recommendations for beta-blockers could be challenging because it involves the identification of patients who are ideal candidates for therapy as well as those who, despite the absence of absolute contraindications, are at high risk for adverse outcomes from therapy. However, it is unclear how these nuanced guideline recommendations for early beta-blocker treatment have been translated into clinical practice.
The China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) study identified significant underutilization of beta-blocker therapy among eligible patients with ST-segment elevation myocardial infarction (STEMI), with no increase in use over the past decade.(8) To improve the utilization requires an understanding of current practice patterns among patients in whom there is an expected benefit (where the goal is maximal use) and among patients who may be harmed (where the goal is minimal use). There is also a question about whether practice changed with the evidence obtained in Chinese and the introduction of the new guidelines, and whether the response varied by type of hospital and geographic region.
Accordingly, we sought to evaluate patterns of early beta-blocker use among patients with AMI across China in 2001, 2006 and 2011, a period before, contemporaneous with, and after the publication of COMMIT. Our specific objectives were to describe: (1) trends of overall use of early beta-blocker therapy in patients with AMI without contraindications; (2) trends of use in both patients with high risk for cardiogenic shock and those without this high risk (i.e., ideal candidates); (3) characteristics among ideal candidates independently associated with not being treated; and (4) type and dosage of beta-blockers used. This government-sponsored study was specifically designed to generate evidence that could promote improvements in practices and policies in China.
METHODS
Study design
The design of the China PEACE-Retrospective AMI Study has been published previously.(9) In brief, we created a nationally representative sample of hospitalizations for AMI during 2001, 2006, and 2011 using two-stage random sampling. In the first stage, we identified hospitals using a simple random sampling procedure within each of the 5 study strata: Eastern-rural, Central-rural, Western-rural, Eastern-urban, and Central/Western-urban regions, since hospital volumes and clinical capacities differ between urban and rural areas as well among the three official economic-geographic regions (Eastern, Central, and Western) of Mainland China. We considered Central and Western urban regions together given their similar per capita income and health services capacity. In the 3 rural strata, the sampling framework consisted of the central hospital in each of the predefined rural regions (2010 central hospitals in 2010 rural regions). In the 2 urban strata, the sampling framework consisted of the highest-level hospitals (i.e. tertiary referral hospitals with advanced facilities) in each of the predefined urban regions (833 hospitals in 287 urban regions). Since the majority of hospitals in China are publicly owned and administered, hospital closure is rare. We selected representative hospitals from 2011 to reflect current practices and traced this cohort backward to 2006 and 2001 to provide a perspective on temporal trends. In the second stage, we identified cases based on the local hospital database for patients with AMI in each year at each hospital in the study sample using systematic random sampling procedures. Patients with AMI were identified using International Classification of Diseases - Clinical Modification codes, including versions 9 (410.××, 5.3% of AMI cases) and 10 (I21. ××, 47.7% of AMI cases) when available or through principal discharge diagnosis terms (47.0% of AMI cases). Site coordinators reviewed the original medical records in cases where the diagnosis of AMI was uncertain.
Clinical data from medical records were collected via medical record abstraction using an explicit abstraction protocol and standardized data definitions. The records were copied at each of the sites and sent to a central data abstraction center in Beijing. Our research team employed rigorous monitoring at each stage to ensure data quality. Data abstraction quality was monitored by randomly auditing 5% of the medical records, with overall variable accuracy exceeding 98%.(9) All of the variables were abstracted from medical records except hospital teaching status, which was derived from a national hospital survey.
The central ethics committee at the China National Center for Cardiovascular Diseases approved the China PEACE-Retrospective AMI Study. All collaborating hospitals accepted the central ethics approval except for five hospitals, which obtained local approval by internal ethics committees. The study is registered at www.clinicaltrials.gov (NCT01624883).
The Chinese government, which provided financial support for the study, had no role in the design or conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation or approval of the manuscript.
Study Sample
Only those patients with a definite discharge diagnosis of AMI were included in the study sample. The diagnosis of AMI was determined by the clinical discharge diagnosis terms. Among available medical records sampled, we excluded cases that were not appropriate for study analysis (including uninterpretable medical charts, duplicate cases, non-AMI diagnoses, cases not within study periods, and AMI that occurred during hospitalization). We further excluded patients who were transferred in because these patients may have received acute treatments at their presenting hospital. We also excluded patients who were transferred out, were discharged, or died during the first 24 hours of admission because these patients might not have had the opportunity to receive beta-blockers before death or transfer. We also excluded patients who participated in the COMMIT study because beta-blocker use for these patients was blinded (Figure 1). In addition, we excluded patients with an absolute contraindication to beta-blocker therapy: systolic blood pressure <100 mm Hg, bradycardia (heart rate <60 beat/min), second and third degree atrio-ventricular block with no pacemaker implanted; cardiogenic shock or heart failure on admission; or any other documented reasons for not using beta-blockers (Figure 1). Heart failure on admission was defined as documentation of heart failure, Killip classification equal or greater than II, or documentation of any of the symptoms or signs of heart failure (dyspnea on light exertion, recurrent dyspnea occurring in the supine position, fluid retention; the description of rales, jugular venous distension, pulmonary edema on physical exam, or pulmonary edema on chest X-ray presumed to be due to cardiac dysfunction).
Figure 1.
Flowchart of the random sampling and study cohorts.
To evaluate the use of beta-blocker therapy early in the course of AMI (defined as within 24 hours of admission), we divided the study cohort into a group without any risk factors for cardiogenic shock (defined as “ideal” candidates, those for whom maximal benefit may be derived if beta-blocker is given within the early stages of AMI) and a group with at least one risk factor for cardiogenic shock according to the COMMIT trial and the guidelines (defined as “high-risk” patients, those who have an increased risk for adverse events if beta-blockers are administered in the early stages of AMI) including: age >70 years, systolic blood pressure (on admission) <120 mm Hg, or heart rate (on admission) >110 beats/min(4–7) (Figure 1). High-risk patients were further categorized according to the number of risk factors (one vs. two or more risk factors).
Factors Associated with Early Beta-blocker Use Among Ideal Candidates and High-risk patients
To identify factors independently associated with beta-blocker use, we examined demographic characteristics, AMI type, cardiovascular risk factors, medical history, clinical conditions on admission, year of hospitalization, economic-geographic region, and rural/urban region. In addition, hospital characteristics, such as teaching status and PCI capability were included in the analysis. Details of these variables are shown in Table 1.
Table 1.
Characteristics of patients ideal for beta-blockers and patients with at least one risk factor for shock
| Characteristics | Patients ideal for early BB | Patients with at least one risk factor for shock | ||||
|---|---|---|---|---|---|---|
|
| ||||||
| No. (%) in patients receiving early BB | No. (%) in patients not receiving early BB | P value | No. (%) in patients receiving early BB | No. (%) in patients not receiving early BB | P value | |
| All patients | 2161 (63.2) | 1258 (36.8) | 1638 (54.5) | 1369 (45.5) | ||
| Demographic | <0.001 | 0.09 | ||||
| Age <60 yr | 1301 (60.2) | 672 (53.4) | 427 (26.1) | 318 (23.2) | ||
| Age 60–70 yr | 860 (39.8) | 586 (46.6) | 254 (15.5) | 244 (17.8) | ||
| Age >70 yr | - | - | 957 (58.4) | 807 (58.9) | ||
| Male | 1712 (79.2) | 961 (76.4) | 0.05 | 1126 (68.7) | 904 (66.0) | 0.11 |
| Cardiovascluar risk factors | ||||||
| Prior hypertension | 1198 (55.4) | 593 (47.1) | <0.001 | 751 (45.8) | 561 (41.0) | 0.007 |
| Prior diabetes | 337 (15.6) | 198 (15.7) | 0.91 | 277 (16.9) | 177 (12.9) | 0.002 |
| Current smoker | 960 (44.4) | 530 (42.1) | 0.19 | 539 (32.9) | 407 (29.7) | 0.06 |
| Medical histories | ||||||
| Ischemic stroke | 157 (7.3) | 88 (7.0) | 0.77 | 162 (9.9) | 136 (9.9) | 0.97 |
| Chronic lung diseases | 23 (1.1) | 21 (1.7) | 0.13 | 42 (2.6) | 58 (4.2) | 0.01 |
| Myocardial infarction | 168 (7.8) | 91 (7.2) | 0.56 | 188 (11.5) | 119 (8.7) | 0.01 |
| Clinical characteristics at admission | ||||||
| Chest discomfort | 2084 (96.4) | 1172 (93.2) | <0.001 | 1545 (94.3) | 1203 (87.9) | <0.001 |
| Heart rate, beat/min | <0.001 | <0.001 | ||||
| 60–79 | 1081 (50.0) | 773 (61.4) | 791 (48.3) | 817 (59.7) | ||
| 80–99 | 901 (41.7) | 404 (32.1) | 617 (37.7) | 411 (30.0) | ||
| 100–110 | 179 (8.3) | 81 (6.4) | 125 (7.6) | 82 (6.0) | ||
| >110 | 105 (6.4) | 59 (4.3) | ||||
| Systolic blood pressure, mm Hg | <0.001 | <0.001 | ||||
| 100–119 | 818 (49.9) | 765 (55.9) | ||||
| 120–139 | 970 (44.9) | 642 (51.0) | 318 (19.4) | 283 (20.7) | ||
| ≥140 | 1191 (55.1) | 616 (49.0) | 502 (30.6) | 321 (23.4) | ||
| MI type | 0.15 | 0.009 | ||||
| STEMI | 1868 (86.4) | 1109 (88.2) | 1437 (87.7) | 1156 (84.4) | ||
| NSTEMI | 293 (13.6) | 149 (11.8) | 201 (12.3) | 213 (15.6) | ||
| Hospital characteristics | ||||||
| Teaching hospital | 1775 (82.1) | 958 (76.2) | <0.001 | 1292 (78.9) | 1066 (77.9) | 0.50 |
| PCI-capable hospital | 1410 (65.2) | 725 (57.6) | <0.001 | 1023 (62.5) | 832 (60.8) | 0.35 |
| Economic-geographic Region | 0.13 | 0.13 | ||||
| Eastern | 1267 (58.6) | 775 (61.6) | 937 (57.2) | 816 (59.6) | ||
| Central | 447 (20.7) | 256 (20.3) | 354 (21.6) | 255 (18.6) | ||
| Western | 447 (20.7) | 227 (18.0) | 347 (21.2) | 298 (21.8) | ||
| Rural/Urban | 0.03 | 0.81 | ||||
| Rural | 802 (37.1) | 513 (40.8) | 650 (39.7) | 549 (40.1) | ||
| Urban | 1359 (62.9) | 745 (59.2) | 988 (60.3) | 820 (59.9) | ||
| Year | <0.001 | <0.001 | ||||
| 2001 | 288 (13.3) | 253 (20.1) | 154 (9.4) | 215 (15.7) | ||
| 2006 | 634 (29.3) | 304 (24.2) | 520 (31.7) | 343 (25.1) | ||
| 2011 | 1239 (57.3) | 701 (55.7) | 964 (58.9) | 811 (59.2) | ||
BB: beta-blocker, PCI: percutaneous coronary intervention, STEMI: ST-elevation myocardial infarction, NSTEMI: non-ST-elevation myocardial infarction.
Because early use of intravenous beta-blockers is not a Class I guideline recommendation, we performed the analyses with further exclusion of patients receiving intravenous beta-blockers as a secondary analysis. We also identified the factors associated with early beta-blocker use among high-risk candidates.
Type and Dosage of Early Beta-blocker Therapy
The type and route of early beta-blocker therapy was determined from physician orders. We only included patients receiving oral early beta-blockers in the analysis of type and dosage. For metoprolol, we also described the cumulative oral dose administered within the first 24 hours of admission.
Statistical Analysis
We described the use of early beta-blocker therapy in the whole study cohort and in both the ideal and high-risk cohorts. To make national estimates each study year, we applied weights proportional to the inverse sampling fraction of hospitals within each stratum and the sampling fraction of patients within each hospital, to account for differences in the sampling fraction for each time period in all analyses. We calculated the number of patients hospitalized for AMI based on the corresponding weights. We employed standard techniques for observational data, including the Chi-square tests and Wilcoxon rank sum tests. Factors independently associated with the early beta-blocker therapy were identified with a logistic regression model using generalized estimating equation (GEE) model to account for clustering by hospital. We selected explanatory variables based on clinical judgment and review of the literature, including patient demographics, clinical factors, region, and year (Table 1). We transformed continuous variables (e.g. age and heart rate) into categorical variables according to clinically meaningful cut-off values, and then created dummy variables. All selected variables were included in the multivariable model to identify predictors of not receiving early beta-blocker therapy. Odds ratios (OR) and 95% confidence intervals (CI) are reported.
All comparisons were 2-sided, with a P-value <0.05 considered statistically significant. P values for trends refer to differences in the rate of early beta-blocker use from 2001 to 2011. Statistical analysis was performed using SAS software (version 9.2, SAS Institute, Cary, NC) and R software (version 3.0.2).
RESULTS
Study Sample
We sampled 175 hospitals, 7 of which had no admissions for AMI during the study years and 6 of which declined to participate. Among the 162 remaining hospitals, there were 31,601 hospitalizations for AMI in 2001, 2006 and 2011, from which we sampled 18,631 cases and acquired medical records for 18,110 cases (97.2%). After the application of the study exclusion criteria, 14,241 cases with AMI remained in the cohort. Of these patients, those with potential absolute contraindications (N=7815, 54.9%) were excluded, about two-thirds of whom were excluded because of heart failure on admission. The final study cohort included 6426 patients (representing 43,165 patients in 2001, 106,167 patients in 2006, and 221,874 patients in 2011 in China, respectively) based upon the corresponding weights.(9) Of these, over half (53.2%) were ideal patients and nearly half (46.8%) were patients with at least one risk factor for cardiogenic shock (Figure 1). Among these high-risk patients, 83.9% had only one risk factor, 16.1% had two or more risk factors.
Use of Early Beta-blocker Therapy
In the overall study cohort in all three time periods, 59.1% received early beta-blocker therapy (weighted use was 49.6% in 2001, 63.9% in 2006 and 57.7% in 2011, P=0.046 for trend). Among ideal patients, overall use was 63.2% (weighted proportions was 54.3% in 2001, 67.8% in 2006 and 61.8% in 2011, P=0.28 for trend). Among the 46.8% of patients with at least one risk factor for cardiogenic shock, the overall use was 54.5% (weighted use was 42.6% in 2001, 59.5% in 2006 and 52.9% in 2011, P=0.31 for trend) (Figure 2).
Figure 2.
Temporal trends in early beta-blocker use (weighted) in overall patients with AMI (n=6426), ideal patients (n=3419) and high-risk patients (n=3007), 2001–2011.
Among the ideal patients, early beta-blocker use in rural hospitals increased during the 3 study years (P<0.001 for trend), however, use in urban hospitals did not increase significantly during this period (P=0.85 for trend, Figure 3-A). Among the patients with risk factors for shock, early beta-blocker use increased significantly in rural hospitals (P<0.001 for trend), while there was no significant change in urban hospitals (P= 0.35 for trend) from 2001 to 2011 (Figure 3-B). Patients with two or more risk factors were less likely to be treated than those with one risk factor (47.5% vs. 55.8%, P<0.001).
Figure 3.
Temporal trends in early beta-blocker use (unweighted) in ideal patients (A) and high-risk patients (B) in strata of rural and urban hospitals, 2001–2011.
Factors Associated with Early Beta-blocker Use in Ideal Candidates and High-risk Patients
Among ideal patients, those treated with beta-blockers were younger and had a higher prevalence of hypertension, more often presented with chest discomfort, had relatively higher systolic blood pressures (SBP) and higher heart rates (HR), and were more often treated in teaching or PCI-capable hospitals (Table 1).
In multivariable analysis, characteristics of ideal candidates that were independently associated with the use of early beta-blocker therapy are shown in Figure 4. Specifically, older patients were less likely to be treated than younger patients (OR 0.75, 95% Confidence Interval [CI]: 0.63–0.89). Patients with symptoms of chest discomfort (OR 2.02, 95% CI: 1.39–2.92) or history of hypertension (OR 1.30, 95% CI: 1.10–1.54) were more likely to be treated. Patients with SBP ≥140 mm Hg were more likely to receive early beta-blocker therapy than patients with SBP 120–139 mm Hg (OR 1.18, 95% CI: 1.01–1.37). Patients with HR 80–99 beat/min (OR 1.62, 95% CI: 1.38–1.91) and HR 100–110 beat/min (OR 1.61, 95% CI: 1.23–2.11) were more likely to be treated compared with patients with HR 60–79 beats per minute. Patients from teaching hospitals (OR 1.44, 95% CI: 1.02–2.03) were more likely to receive early beta-blocker therapy. There were no significant interactions between any of these factors and year.
Figure 4. Factors associated with early beta-blocker use in the ideal cohort (n=3419).
Variables having significant association with early beta-blocker use are shown along the vertical axis. The strength of effect is shown along the horizontal axis with the vertical line demarking an odds ratio of 1 (that is, no association); estimates to the right (that is, > 1) are associated with greater likelihood of early beta-blocker use, while those to the left (that is, < 1) indicate association with reduced likelihood of early beta-blocker use. Each square represents the point estimate of the effect of that variable in the model, while the line shows the 95% confidence interval.
To evaluate only oral beta-blockers use, we excluded patients receiving intravenous beta-blockers (59 patients), and found that no significant change in both groups compared with the original cohorts. In multivariable analysis for characteristics in ideal candidates, the results were similar, except that teaching hospital was no longer significantly associated with early beta-blocker use.
Among high-risk patients, factors associated with the use of early beta-blocker therapy were similar to those among ideal patients with a few notable exceptions (Table 1 and Supplementary Figure S): patients with prior diabetes and myocardial infarction were more likely to be treated, and patients with NSTEMI were less likely to be treated. After excluding patients receiving intravenous beta-blockers, there were no significant differences in the results compared with the original analytic cohorts.
Type and Dosage
Among the patients treated with early beta-blockers, 59 (1.6%) patients received intravenous therapy, of whom 9 did not receive any oral beta-blockers and were thus excluded from the analysis of type and dosage. Metoprolol was the predominant oral beta-blocker used (3468, 91.5% across all study years). Few patients received atenolol (2.5%), bisoprolol (5.5%), or other beta-blockers including propranolol, carvedilol and arotinolol (0.5%). Among the 3468 patients treated with oral metoprolol, 73.6% received cumulative dosage of no more than 25 mg in the first 24 hours of admission, and only 4.0% received more than 50 mg (Figure 5).
Figure 5. Type and dosage of oral beta-blockers.
Dosage distribution of metoprolol in each year is shown as the cumulative oral dose administered within the first 24 hours of admission. The numbers of patients using atenolol, bisoprolol or other beta-blockers was small and thus only the proportions of total use are shown. Others including propranolol, carvedilol and arotinolol.
DISCUSSION
This is the first study, to our knowledge, to evaluate early beta-blocker therapy for AMI in a cohort representing estimated 40,000, 100,000 and 220,000 patients with AMI across China in 2001, 2006 and 2011 respectively and one of the few studies that has systematically examined this issue in contemporary practice.(10–15) We found substantial underuse of early beta-blocker therapy in ideal candidates with AMI over the past decade with lower utilization in 2011 as compared with 2006. Simultaneously, many patients with risk factors for cardiogenic shock were treated despite the evidence that such therapy may be harmful.(4) The most widely used beta-blocker across the three study years was metoprolol, and dosing varied markedly, often falling short of guideline recommendations.(6–7,16) We identified patient and health system factors that were associated with greater responsiveness to guideline recommendations, but gaps in quality of care with respect to early use of beta-blocker therapy is pervasive and has not changed over the recent past.
Patterns of underuse of beta-blockers for AMI in China identified in this study have also been documented in other areas, including the US,(10–12) the Middle East,(15) and Brazil.(17) The benefits of beta-blockers, when appropriately employed in the early stages of AMI, are supported by substantial evidence(1–2,4) and strong guideline recommendations.(5–7,16,18–20). The reasons for the failure to employ this therapy among patients who are likely to benefit presumably reflect many factors, including inadequacies of practitioner knowledge and deficiencies in the structure of healthcare systems that create barriers, or fail, to facilitate the best practice.
The promise of early beta-blocker therapy in the Chinese population with AMI may be further undermined by frequent use in patients at high risk for cardiogenic shock. Few studies have addressed this issue,(13–14) which was highlighted in COMMIT. This trial, conducted entirely in China, found that beta-blockers that were administered in the early phase of AMI were associated with a higher risk of cardiogenic shock, particularly among the elderly or those with relative hypotension or tachycardia. Although the trial employed a relatively high beta-blocker dose, the publication resulted in substantial changes in the United States and Chinese AMI guidelines, which subsequently discouraged use of early beta-blockers in patients with risk factors for shock.(5–7) Despite these recommendations, which were generated after the publication of COMMIT in 2005, our study shows that the use of beta-blockers in high-risk patients commonly occurred in China throughout the period 2001 through 2011, especially in rural hospitals, and has not changed appreciably. This practice pattern mirrors findings in Canada in 2007, where overuse was also common.(13) Our study cannot explain the reasons for this pervasive and potentially unsafe practice pattern, which, as with underuse, may stem from inadequate knowledge or the failure of systems to facilitate optimal care. Alternatively, clinicians may have interpreted the finding of increased cardiogenic shock from the COMMIT trial to be isolated to intravenous beta-blockers and the dose used in that study. Two recent observational studies evaluating the effects of any early beta-blocker therapy on AMI outcomes suggest that there may be increased risk of adverse events, especially if used in the very early phase of AMI care.(14,21) More data may be required to better understand how best to risk stratify patients for beta-blocker therapy in the first 24 hours of presentation.
This study also provides a perspective on the favored approaches to beta-blocker therapy in patients with AMI in China. Metoprolol, typically in modest doses, was predominantly employed. Although the guidelines are relatively flexible regarding dosage, the general recommendations for metoprolol dosing are between 50–200 mg total daily when administered orally.(6–7,16) In contrast, most patients in China receive a daily dosage of less than or equal to 25 mg. These lower dosages may not provide equivalent benefits to those identified in the randomized trials. On the other hand, the lower dosages may also not generate a similar risk of adverse consequences in patients at higher risk for shock.
The findings of this study have important implications for efforts to optimize the use of beta-blockers early in the course of AMI in China and other countries around the world, especially those with limited resources given the low cost and demonstrated efficacy of this therapy in the appropriate population. Traditionally, quality improvement initiatives have focused predominantly, if not exclusively, on correcting underuse. Although practice in China suggests that beta-blocker underuse is a worthy target, addressing this issue alone will be inadequate. Effective quality improvement programs should also act to minimize beta-blocker administration to those who might be harmed and to promote optimal beta-blocker dosage. Thus, by identifying issues with underuse, overuse, and inadequate dosing of beta-blockers, this study provides a rational roadmap for the planning of programs to address several deficiencies in the application of this evidence-based and cost-effective therapy for patients with AMI.
Limitations
Certain factors should be considered in the interpretation of our results. First, our study was based on information abstracted from medical records; as such, documentation of clinical and nonclinical factors to explain the low usage of beta-blockers may be imprecise or lacking. Moreover, medical charts in China do not routinely contain data on patients’ prior use of and experience with beta-blocker therapy, so we were unable to collect this information. Although it is possible that the 6 hospitals identified through our sampling procedure that declined participation in the study may have been less focused on quality improvement, it is likely that our findings are generalizable because these hospitals accounted only for a small proportion of the sample. In the ideal cohort, we excluded patients with potential contraindications to treatment, although in some cases beta-blocker therapy may have been reasonable in those not considered ideal. Our objective with the ideal cohort was to ensure a subgroup of patients for whom beta-blocker therapy was clearly warranted. On the other hand, the risk factors for cardiogenic shock delineated in the guidelines are also relatively broad, thus some of the patients in our “high-risk” group may have been reasonable candidates for therapy. However, even among those with two or more risk factors for cardiogenic shock, beta-blocker use was quite high, ranging from a third to over a half of patients across years, indicating that some physicians may not pay attention to risk when prescribing this medication. Finally, we did not have longer-term follow-up to determine if the patterns of beta-blocker use and dosing were associated with health outcomes, and we were underpowered to determine the early benefits and harms of beta-blocker therapy in this population. Nevertheless, despite these limitations, this study is the most representative and comprehensive assessment, based on central abstraction of medical records, of the health system responsiveness to guidelines regarding early beta-blocker use.
Conclusions
Our study found that over the last decade in China, beta-blocker therapy within the first 24 hours of admission for AMI was significantly underused and under-dosed among ideal patients and commonly used in patients at high risk for cardiogenic shock. Our findings highlight the need for better translation of complex evidence into clinical practice and the need to improve care for patients with AMI.
Supplementary Material
Variables having significant association with early beta-blocker use are shown along the vertical axis. The strength of effect is shown along the horizontal axis with the vertical line demarking an odds ratio of 1 (that is, no association); estimates to the right (that is, > 1) are associated with greater likelihood of early beta-blocker use, while those to the left (that is, < 1) indicate association with reduced likelihood of early beta-blocker use. Each square represents the point estimate of the effect of that variable in the model, while the line shows the 95% confidence interval.
Acknowledgments
Funding sources: This project was partly supported by the Research Special Fund for Public Welfare Industry of Health (201202025) from National Health and Family Planning Commission of China. Dr. Ross is supported by the National Institute on Aging (K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. Dr. Krumholz is supported by grant U01 HL105270-05 (Center for Cardiovascular Outcomes Research at Yale University) from the National Heart, Lung, and Blood Institute. Dr. Masoudi reports a contract with the American College of Cardiology as the Senior Medical Officer of the National Cardiovascular Data Registries. The funders had no role in the conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation or approval of the manuscript.
We appreciate the multiple contributions made by study teams at the China Oxford Centre for International Health Research and the Yale-New Haven Hospital Center for Outcomes Research and Evaluation in the realms of study design and operations, particularly the data collection, by Yi Pi, Jiamin Liu, Wuhanbilige Hundei, Lihua Zhang, Xue Du, Wenchi Guan, Xin Zheng, and Yuanlin Guo. We appreciate the advice of analysis by Zhenqiu Lin, Xiao Xu, and Haiqun Lin. We appreciate the editing by Sisi Wang, Erica Spatz, Tasce Bongiovanni, and Sudhakar V. Nuti. We are grateful for the funding support provided by the Chinese government. We are particularly grateful for all the collaborators listed in the appendix.
Footnotes
Disclosures: There are no relevant conflicts of interest.
Study registration: www.clinicaltrials.gov (NCT01624883)
CONTRIBUTOR STATEMENT
HMK and LJ conceived the China PEACE study and take responsibility for all aspects of it. JL, XL, FAM, JAS, HMK and LJ designed the study. HZ, JL, XL, FAM, HMK and LJ conceived this article. HZ wrote the first draft of the article, with further contributions from FAM, JL, JAS, JSR, NRD, HMK, and LJ. QW did statistical analysis, with support from XL. All authors interpreted data and approved the final version of the article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Variables having significant association with early beta-blocker use are shown along the vertical axis. The strength of effect is shown along the horizontal axis with the vertical line demarking an odds ratio of 1 (that is, no association); estimates to the right (that is, > 1) are associated with greater likelihood of early beta-blocker use, while those to the left (that is, < 1) indicate association with reduced likelihood of early beta-blocker use. Each square represents the point estimate of the effect of that variable in the model, while the line shows the 95% confidence interval.