Current guidelines have recommended intravenous narcotics (IVNs) for patients with ST-segment elevation acute coronary syndromes (STEACS) and patients with non-STEACS (NSTEACS), although the safety of IVNs has been challenged. We performed a retrospective analysis of the 30-day outcomes stratified by IVN use among patients enrolled in a national survey, using logistic regression and propensity score analysis. Of the 765 patients with STEACS and 993 patients with NSTEACS, 261 (34.1%) and 97 (9.8%) had received IVNs, respectively. The patients with STEACS who received IVNs were more likely to undergo reperfusion (79.7% vs 55.2%, p <0.0001), received it more rapidly (median 59 minutes vs 70 minutes, p = 0.02), and were more likely to undergo coronary angiography and revascularization. No difference was found in hemodynamic status. The patients with NSTEACS who received IVNs were more likely to present with Killip class II-IV (39.2% vs 10.0%, p <0.001) and to have left ventricular systolic dysfunction (39.0% vs 17.0%, p <0.001). No difference was found in the use of invasive procedures. Using propensity score analysis, of 249 matched STEACS pairs, the rate of 30-day death was lower in the group that had received IVNs (2.4% vs 6.2%, p = 0.04), and this trend persisted after logistic regression analysis (odds ratio 0.40, 95% confidence interval 0.14 to 1.14, p = 0.09). Using propensity score analysis, of 95 matched NSTEACS pairs, no difference was found in the 30-day death rate (2.2% for patients receiving IVNs vs 6.3%, p = 0.16), even after logistic regression analysis (odds ratio 0.56, 95% confidence interval 0.14 to 2.33, p = 0.43). In conclusion, IVNs were commonly used in different scenarios—patients with STEACS were more likely to receive IVNs in the context of prompt reperfusion, and patients with NSTEACS were more likely to receive IVNs in the context of heart failure. In both scenarios, IVN use did not adversely affect the outcomes.
The use of intravenous narcotics (IVNs), primarily morphine, is common in the initial treatment of patients with the various types of acute coronary syndromes (ACS). The approaches regarding the use of IVN among the different ACS guidelines are conflicting. The European Society of Cardiology practice guidelines for the management of non–ST-segment elevation ACS (NSTEACS) have no graded recommendation for IVN use but have recommended IVNs as one of the primary therapeutic measures. In contrast, the American College of Cardiology and American Heart Association 2007 NSTEACS guidelines have downgraded the recommendation for IVN use from I to IIa, because of a retrospective analysis of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC and AHA Guidelines (CRUSADE) Quality Improvement Initiative in the United States registry, which reported increased in-hospital mortality associated with IVN use. In addition, the updated 2007 American Heart Association/American College of Cardiology ST-segment elevation ACS (STEACS) guidelines, as well as the European Society of Cardiology STEACS guidelines, have recommended IVN use (class IC), although few data are available regarding its safety in this setting. Given the widespread use of IVNs for the various types of ACS, it is necessary to determine its safety in the “real world” scenario. Toward this end, we evaluated the effect of prehospital and in-hospital IVN use on the in-hospital and 30-day outcomes among consecutive patients with various types of ACS enrolled in a national survey.
Methods
No extramural funding was used to support the present study. The investigators are solely responsible for the design and conduct of the study, all study analyses, and the drafting and editing of the report.
Our cohort included patients recruited in the Acute Coronary Syndrome Israeli Survey (ACSIS) 2008 database, a prospective nationwide survey conducted from March 15 to May 15, 2008, in all 26 coronary cardiac units and cardiology wards in Israel. The study physicians recorded the demographic and clinical data on prespecified electronic forms for consecutive participants. The institutional review board of each institution approved participation in this survey. The data were collected only during the initial hospitalization in an anonymous fashion for all patients with a final diagnosis of an ACS. The final diagnosis of ACS, including the specific type of ACS, was made by the attending physician according to the clinical presentation and ancillary tests.
The patients were treated at the discretion of each center. The decisions regarding therapy and management, including referral for coronary angiography and revascularization, were at the discretion of the attending physician and were not protocol driven. On-site catheterization and bypass surgery facilities were available in 22 and 10 of the centers, respectively.
The data collected included the use of medications, use and timing of invasive cardiac procedures, laboratory results, clinical outcomes, and discharge therapies and interventions. In-hospital outcomes, including in-hospital death, recurrent myocardial infarction, congestive heart failure, and cardiogenic shock, and 30-day mortality were reported by all sites. We excluded patients who were transferred to another institution. The mortality rates at 7 and 30 days were determined for all participants from the hospital charts and by telephone interview.
We sought to compare patients with ACS who did or did not receive IVNs before or during their hospitalization. To address the respective guidelines pertaining to the specific type of ACS, we separately analyzed the subgroups with NSTEACS and STEACS. The end points were in-hospital and 30-day mortality and the combined 30-day end point of death, recurrent infarction, repeat ischemia, stent thrombosis, and cerebrovascular event.
Statistical Analysis Systems, version 8.2 (SAS Institute, Cary, North Carolina) was used for statistical analysis.
The patient characteristics, management, and in-hospital clinical outcomes were compared for both subgroups. The median value and twenty-fifth and seventy-fifth percentiles were reported for continuous variables and frequencies for categorical variables. The Kruskal-Wallis test (>2 comparison groups) and Wilcoxon rank-sum test (2 comparison groups only) were used for continuous variables, and chi-square tests were used for categorical variables. All tests were 2-sided, and p <0.05 was considered statistically significant.
The potential selection bias was accounted for by developing a propensity score for receiving IVNs. A propensity score was calculated by logistic regression analysis that included the following variables: age, gender, smoking status, previous myocardial infarction, previous angina, previous percutaneous coronary intervention, previous coronary bypass surgery, previous congestive heart failure, renal failure, peripheral vascular disease, previous stroke, hypercholesterolemia, hypertension, diabetes mellitus, heart rate, systolic blood pressure, Killip class, and chronic treatment with lipid-lowering drugs, diuretics, β-adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and hypoglycemic drugs.
Using a macro (available at www2.sas.com/proceedings/sugi26/p214-26.pdf ), we also used the propensity score to match patients with IVN use to control patients. We were able to match 249 pairs among the patients with STEACS and 95 pairs among the patients with NSTEACS. The categorical variables in the matched pairs were compared using McNemar’s test.
The multivariate adjusted odds ratio of 30-day mortality and the combined 30-day end point of death, recurrent infarction, reischemia, stent thrombosis, and cerebrovascular event in the IVN and non-IVN groups was estimated using the logistic regression model. Adjustment was done for age, gender, Killip class, previous myocardial infarction, previous angina, previous congestive heart failure, renal failure, peripheral vascular disease, previous stroke, hypercholesterolemia, hypertension, diabetes mellitus, heart rate, systolic blood pressure, and the propensity score for IVN use.
Results
Of the patients enrolled in the Acute Coronary Syndrome Israeli Survey 2008, 765 had STEACS and 993 had NSTEACS. In the STEACS subgroup, 261 patients (34.1%) had received IVN, compared to 97 (9.8%) in the NSTEACS subgroup. Overall, the patients who received IVNs were younger, more likely to be smokers, to have had previous angina pectoris, and to have received aspirin. They were less likely to have received lipid-lowering treatment, β-adrenergic blockers, angiotensin-receptor blockers, or angiotensin-converting enzyme inhibitors, or oral hypoglycemics on a chronic basis.
Among patients with STEACS, those receiving IVN were younger and fewer patients had had previous angina pectoris than their non-IVN counterparts ( Table 1 ). Patients receiving IVN sought medical assistance earlier with a median interval to first medical contact of 62.0 minutes (twenty-fifth to seventy-fifth percentile 30.0 to 150.0) compared to 93.0 minutes (twenty-fifth to seventy-fifth percentile 39.0 to 254.0; p <0.001). Those who received IVNs were more commonly treated more promptly, as reflected by the shortest arrival-to-first electrocardiogram interval (median 7.0 minutes, twenty-fifth to seventy-fifth percentile 5.0 to 11.0; compared to 10.0 minutes, twenty-fifth to seventy-fifth percentile 4.0 to 18.0; p = 0.04). They were also more commonly directed to the cardiac care unit (23.0% vs 13.2%, p <0.001) or the catheterization laboratory (12.3% vs 5.0%, p <0.001), bypassing the emergency room. The IVN patients more frequently presented with typical angina (93.5% vs 88.6%, p = 0.04), but no differences were found in the hemodynamic status on admission between the IVN and non-IVN groups (89.1% of IVN patients presented with Killip class I vs 86.6% of non-IVN patients, p = 0.37). The initial heart rate and blood pressure measurements recorded were also not significantly different (data not shown). Patients receiving IVN, however, tended to more often have anterior wall involvement (49.0% vs 41.7%, p = 0.05).
| IVN Use | |||
|---|---|---|---|
| Baseline Characteristic | Yes (n = 261) | No (n = 504) | p Value |
| Age (years) | 57.0 (50.0–66.0) | 61.0 (53.0–71.0) | <0.001 |
| Men | 82.8% | 80.2% | 0.38 |
| Hypertension | 50.2% | 49.2% | 0.80 |
| Diabetes mellitus | 26.8% | 30.7% | 0.27 |
| Smoking | 68.8% | 64.4% | 0.26 |
| Dyslipidemia ⁎ | 69.4% | 66.2% | 0.38 |
| Previous angina pectoris | 14.2% | 28.2% | <0.001 |
| Previous myocardial infarction | 23.8% | 22.2% | 0.63 |
| Previous percutaneous coronary intervention | 24.2% | 23.8% | 0.92 |
| Previous coronary artery bypass surgery | 2.3% | 3.8% | 0.28 |
| Previous heart failure | 3.8% | 5.0% | 0.48 |
| Renal failure † | 6.5% | 7.7% | 0.54 |
⁎ Defined as total cholesterol >200 mg/dl or low-density lipoprotein cholesterol >160 mg/dl or high-density lipoprotein cholesterol <40 mg/dl or triglycerides >150 mg/dl.
Also, no significant difference was found in the rate of antecedent use of cardiovascular, antidiabetic, or lipid-lowering medications (data not shown). Before admission to the first ward, the IVN patients more frequently received acute treatment with aspirin (93.9% vs 82.1%, p <0.001), nitrates (57.1% vs 36.1%, p <0.001), and heparins (80.8% vs 67.9%, p <0.001).
The IVN patients underwent more primary reperfusion with a shorter door-to-needle time and door-to-balloon time ( Figure 1 ). Of the patients referred for percutaneous reperfusion, IVN patients had an initial Thrombolysis In Myocardial Infarction class 3 flow less often (9.8% vs 19.4%, p = 0.011), but after the intervention, no difference was found in Thrombolysis In Myocardial Infarction class 3 flow (87.1% vs 87.7%, p = 0.98). No difference was found in the distribution or patency of the infarct-related artery or in adjunctive pharmacologic and device use during the primary percutaneous coronary interventions (data not shown). The IVN patients were more likely to have one-vessel coronary artery disease (42.5% vs 32.2%, p = 0.006), and non-IVN patients tended to have more multivessel or left main coronary artery disease (55.1% vs 62.1%, p = 0.07). Approximately 1 of 5 patients had a left ventricular ejection fraction of <40% in both groups (20.5% vs 22.4%, p = 0.57).
While in-hospital, the IVN patients were more likely to undergo cardiac catheterization and percutaneous coronary revascularization but were less likely to undergo resuscitation ( Table 2 ). During hospitalization and at discharge (among the survivors), no difference was found between the 2 groups in the use of evidence-based and guideline-recommended treatments (data not shown).
| IVN Use | |||
|---|---|---|---|
| Variable | Yes | No | p Value |
| Any catheterization | 96.6% | 91.1% | 0.01 |
| Any percutaneous coronary intervention | 90.0% | 78.4% | <0.001 |
| Any coronary bypass surgery | 3.4% | 6.2% | 0.11 |
| Resuscitation | 2.3% | 6.2% | 0.02 |
| Mechanical ventilation | 5.4% | 7.3% | 0.30 |
| Intra-aortic balloon pump | 7.7% | 8.1% | 0.82 |
| Any pacemaker | 2.7% | 6.7% | 0.03 |
In-hospital mortality tended to be lower among patients receiving IVNs ( Figure 2 ). Cardiogenic shock also tended to occur less often in IVN patients. The 30-day mortality rate was lower for IVN patients, as was the combined 30-day end point.
Propensity score analysis was performed to further evaluate the effects of IVN use on in-hospital mortality. The characteristics most strongly associated with receiving IVN included younger age and absence of history of angina pectoris or previous β-blocker treatment. Using propensity score analysis of 249 matched pairs, the 30-day death rate was lower (2.4% vs 6.2%, p = 0.04) but not the combined 30-day end point (10.8% vs 13.3%, p = 0.46). After logistic regression analysis, the differences in the 30-day death and the combined 30-day end points were not significant ( Table 3 ), although they tended to favor the IVN group.
| Predictor | Odds Ratio | 95% Confidence Interval | p Value |
|---|---|---|---|
| 30-Day death ⁎ | |||
| Use of intravenous narcotics | 0.40 | 0.14–1.14 | 0.08 |
| Age (years) | 1.14 | 1.08–1.21 | <0.001 |
| Previous angina pectoris | 4.90 | 1.08–23.51 | 0.04 |
| Combined 30-day end point † | |||
| Use of intravenous narcotics | 0.69 | 0.42–1.16 | 0.16 |
| Age (years) | 1.03 | 1.003–1.06 | 0.03 |
| Admission heart rate (beat/min) | 1.01 | 1.001–1.02 | 0.03 |
| Admission systolic blood pressure (mm Hg) | 0.98 | 0.98–0.99 | <0.001 |
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