Association Between Timeliness of Reperfusion Therapy and Clinical Outcomes in ST-Elevation Myocardial Infarction FREE

Both primary percutaneous coronary intervention (PPCI) and fibrinolysis are well-recognized treatments for ST-segment elevation myocardial infarction (STEMI) in international guidelines, and benefits are maximized when treatment occurs early.^1- 2 Although meta-analyses of randomized clinical trials support the superiority of PPCI over fibrinolysis,³ the generalizability of these results to everyday clinical practice may be compromised by the highly selective recruitment of both patients and centers in these trials and the inability to assess the effect of timeliness of treatment on outcomes because of the generally rapid performance of PPCI.^3- 4 In STEMI registries, the observed delays for PPCI often largely exceed those realized in clinical trials,^5- 7 and a substantial proportion of patients do not receive either PPCI or fibrinolysis within maximum delays recommended in international guidelines (90 minutes for PPCI and 30 minutes for fibrinolysis).^1- 2 In these registries, shorter treatment delays are associated with better outcomes^5,8- 10 and results of the 2 treatments tend to be similar.^11- 12

However, registry data also have limitations, including selection bias, information bias (noninclusion of patients referred for PPCI but not receiving it), incomplete and inappropriately short follow-up, frequent exclusion of patients transferred for PPCI, and residual confounding (lack of detailed measurements of important covariates).^{7- 8,10,13- 14} An assessment of bias within a large patient registry found that a substantial proportion of eligible patients were not enrolled and that these patients received poorer-quality care and had 3-fold higher in-hospital mortality than enrolled patients.^13- 14 Finally, registries based on voluntary participation of institutions usually provide information from well-performing, motivated academic and research-oriented centers but tend to miss an important proportion of patients in the larger real-world setting.

To address these issues, the Agence d’évaluation des techniques et modes d’interventions en santé, a government-supported but independent health care evaluation agency in Quebec, Canada, recently undertook a systematic province-wide evaluation of STEMI care in Quebec (population, 7.8 million). The objectives were to obtain a contemporary portrait of reperfusion treatments and their delays across Quebec and to determine whether STEMI reperfusion treatment outside of the guideline-recommended delays is associated with poorer outcomes than treatment within recommended delays.

The evaluation covered a 6-month period (October 1, 2006, to March 31, 2007) and included all acute care Quebec hospitals (n=80) that treated at least 30 acute myocardial infarctions (AMIs) in the preceding year. These 80 hospitals treat more than 95% of all AMIs occurring in Quebec and are distributed across 15 of Quebec's 18 administrative health care regions. Some regions with small populations and similar systems of care were combined in our analyses (n=12 regions).

Ethics approval was obtained from each of the 80 hospitals as well as by the provincial ethics board (Quebec Commission for Access to Information), which waived the need for patient consent because this evaluation involved no intervention or patient contact and anonymity was ensured.

In each hospital, a certified medical record librarian was designated, received an individualized on-site training session, and followed a standardized data collection process to abstract all information directly from medical charts and enter data onto a secure, centralized Web site with automatic encryption. At the completion of data entry, date-time values were independently validated by senior medical librarians in a representative 10% sample and concordance was very high (median difference for door to reperfusion therapy = 0 min [interquartile range {IQR}, 0-0]).¹⁵

Study eligibility was assessed via an algorithm in all patients with appropriate presenting symptoms, a final diagnosis of AMI (International Classification of Diseases, Ninth Revision code 410), and a hospital discharge date between October 1, 2006, and March 31, 2007. Patients whose AMI occurred after their initial emergency department presentation were excluded. For each potential STEMI patient, the first electrocardiogram (ECG) taken after arrival at the emergency department was sent to the coordinating center, where it was interpreted by 2 cardiologists and an emergency physician. Patients included in the evaluation had to have 1 of the following features: (1) received fibrinolysis in the 4 hours following triage at the first emergency department; (2) were sent to a catheterization laboratory in the 4 hours following triage at the first emergency department and had mention of STEMI in the medical chart or, if not, evidence of STEMI on the first ECG validated at the coordinating center; or (3) did not receive fibrinolysis and were not sent to a catheterization laboratory in the 4 hours after triage at the first emergency department but had mention of STEMI in the medical chart and evidence of STEMI on the first ECG validated at the coordinating center.

In data analyses, all patients who satisfied criteria 1 and 2 as described were considered to have received reperfusion treatment (intention to treat). However, patients fulfilling criteria 2 who were sent for PPCI but who did not undergo PPCI were not evaluated in analyses of timeliness of treatment. Patients fulfilling criteria 3 were considered as not having received reperfusion treatment (no intention to treat). For patients included more than once during the observation period, only the first event was retained in the analysis.

Clinical factors included age, sex, earliest in-hospital measure of systolic blood pressure, heart rate at first in-hospital ECG, and symptom duration. A TIMI index was calculated for each patient: (heart rate × [age/10]²)/systolic blood pressure.¹⁶ The TIMI index was used in statistical analyses rather than the 3 factors individually because it has been validated as a powerful predictor of mortality in STEMI patients and improved the statistical power of the multivariate model.¹⁶ Anterior STEMI and left bundle branch block were centrally identified based on the admission ECG.

Treatment time was calculated from patient arrival at the first hospital (door) to either start of fibrinolysis (needle) or first dilation (balloon). To ascertain patient comorbidities, the recorded principal diagnosis as well as the 15 secondary diagnoses of all hospital admissions in the 5 years preceding the date of admission for the index STEMI were identified in Quebec's administrative hospital discharge database. We included diagnoses in the index STEMI admission only for comorbidities considered to be chronic to avoid confusing an index admission complication with a comorbidity.

The primary end points were death at 30 days, death at 1 year, and the combined end point of death or hospital readmission for congestive heart failure or AMI at 1 year. Other end points included PCI at 1 year (excluding the index admission) and coronary artery bypass graft surgery at 1 year. All end points were determined by linkage with provincial medicoadministrative databases whose reliability has been shown.^17- 18

Mortality at 30 days and at 1 year was ascertained according to type of treatment (fibrinolysis or PPCI), treatment delay and timeliness (≤30 minutes for fibrinolysis and ≤90 minutes for PPCI), clinical factors, and comorbidities. After adjustment for age, no significant interaction was observed between any clinical risk factor or comorbidity and type of treatment. Thus, the odds ratio (OR) and 95% confidence interval (CI) for the association between each variable and mortality were calculated with the 2 treatment groups combined. Statistical significance was based on 2-sided testing with P<.05.

To measure the association between timeliness of reperfusion (fibrinolysis and PPCI combined) and mortality, we used a multivariate logistic regression model that included timeliness of treatment, 3 clinical factors (TIMI index, sex, and anterior MI), 4 comorbidities (congestive heart failure, renal failure, peripheral vascular disease, and cancer), and 2 confounding factors (arrival by ambulance and transfer status) that have been shown to be associated with both timeliness of treatment and mortality.^8,19- 20 The number of variables in the model was limited to have a reasonable ratio of factors to outcome events. The choice of variables was made a priori on the basis of consensual clinical judgment, established associations with mortality,^6,10- 11 and sufficient prevalence within the study population (>5%). All 10 variables were included in each multivariate model. Given the number of STEMI patients identified during the observation period, we had 80% power to detect an OR of 2.0 for the effect of timeliness on 30-day mortality and an OR of 1.8 for 1-year mortality. We had 80% power to detect an OR of 1.6 for the combined outcome.

To address concerns that low-risk patients might be preferentially selected for reperfusion treatment, an analysis of 30-day mortality at the regional level was performed that included all STEMI patients (with and without intention to treat). Overall regional 30-day mortality was plotted as a function of the regional proportion of patients treated within maximum recommended delays as well as a function of the proportion of patients treated with PPCI. An unadjusted inverse-variance weighted least squares regression was performed to ascertain the slope of each association. A multilevel logistic regression analysis was conducted that included the 10 variables as fixed effects and the intercept term as a region-level random effect.²¹ Of the 10 variables, those referring to process of care were included as region-level variables (percentage of patients receiving timely reperfusion, who used an ambulance, or who were transferred for PPCI) while the remaining 7 risk factors were included at the individual patient level. Because of the inclusion of patients without intention to treat in this model, an additional region-level variable was added to the model representing the percentage of patients who received reperfusion treatment. The model estimated the region-level intercepts and their overall variance.

Due to the possibility of biased multivariate effect estimates in nonexperimental studies when the ratio of outcomes to potential confounders is low, a matched propensity score analysis was used as a sensitivity analysis of the effect of treatment timeliness.^21- 22 The propensity score was calculated by using 18 variables (age, female sex, systolic blood pressure <100 mm Hg, heart rate >100/min, transfer status, mode of patient arrival, previous MI, previous chronic heart failure, cardiac dysrhythmia, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, hypertension, cerebrovascular disease, cancer, renal failure, previous hospital admission, and presence of ≥2 comorbidities) in a multivariate logistic regression for timeliness of treatment. Patients receiving timely treatment were matched 1:1 with patients receiving late treatment if they had a propensity score within 0.1 of each other and in such a way that minimized total absolute differences in propensity scores.²³ Match balance was assessed by standardized and absolute differences on each covariate.²⁴ Conditional logistic regression was used to assess the OR and 95% CI of death (at 30 days and at 1 year) and the combined outcome for the matched pairs.

In another sensitivity analysis, we examined timeliness and mortality by type of treatment for patients who, on the basis of the first ECG, were unanimously considered by the emergency physician and the 2 cardiologists at the coordinating center to have an unequivocal STEMI.

In a third sensitivity analysis, we compared mortality by type of treatment for patients who were treated in study hospitals where there was an exclusive treatment practice (hospitals treating ≥95% of STEMI patients with either fibrinolysis or PPCI). In these hospitals, the choice of reperfusion treatment is unlikely to have any association with patient characteristics. Statistical analyses were performed using SAS software²⁵ and R software²⁶ as well as the R add-ons lme4²⁷ and Matching.²⁸

We identified 6734 patients who presented to an emergency department with both characteristic symptoms and a final diagnosis of AMI, of whom 2361 (35%) had STEMI. Five (0.2%) were excluded because no link could be established with the other medicoadministrative databases, leaving 2356 patients.

The majority of STEMI patients were treated with PPCI (1440/2356 [61.1%]); 16.6% (392/2356 patients) were treated with fibrinolysis (tenecteplase in 99%) and 22.2% (524/2356 patients) neither had fibrinolysis nor were sent for PPCI within 4 hours of emergency department arrival. Thus, of the patients treated with acute reperfusion (n = 1832), 78.6% (n = 1440) were sent for PPCI and 21.4% (n = 392) received fibrinolytic therapy. Of the patients sent for PPCI, 34.7% (n = 499) were direct admissions to a PPCI center while 65.3% (n = 941) were transferred from a non-PCI center. Of patients treated with fibrinolysis, 79.1% (n = 310) were eventually sent for cardiac catheterization, the majority (53%) more than 12 hours later.

Among patients referred for PPCI, 10.6% (n = 153) did not undergo the procedure for various reasons, such as resolution of symptoms, a nonsignificantly narrowed culprit lesion, uncertainty about the culprit lesion, inability to pass the guide wire, or a decision to perform coronary artery bypass graft surgery instead.

Patient characteristics and comorbidities by type of treatment are shown in Table 1. The median age was 58 years in patients who received fibrinolysis and 60 years in PPCI patients (P = .01). The median TIMI index was 2 points higher in PPCI patients than in patients who received fibrinolysis (P = .003). Compared with patients sent for PPCI, more fibrinolytic-treated patients presented to the emergency department within 3 hours of the start of symptoms while fewer of them arrived by ambulance. They were less likely than patients sent for PPCI to have a history of arterial hypertension or diabetes but more likely to have a history of congestive heart failure.

Among patients who underwent PPCI, the median door-to-balloon time was 110 minutes (IQR, 82-149 minutes); 32% had a delay within the maximum recommended limit of 90 minutes. Among patients who were directly admitted to a PPCI center, the median door-to-balloon time was 83 minutes (IQR, 61-117 minutes); 57% were treated within 90 minutes. For transferred patients, the median door-to-balloon time was 123 minutes (IQR, 98-160 minutes), and only 19% were treated within 90 minutes. For patients who received fibrinolysis, the median delay was 33 minutes (IQR, 20-52 minutes); 46% had a door-to-needle time within the maximum recommended delay of 30 minutes.

We examined timeliness of treatment in patients who had an admission ECG that was considered unequivocal for STEMI. These patients constituted 52% (669/1287) of PPCI patients and 62% (242/392) of fibrinolysis patients. Timeliness of treatment of PPCI-treated patients directly admitted to a PPCI center increased to 70% (from 57%); for patients transferred for PPCI, it increased to 25% (from 19%); and for patients treated with fibrinolysis, timeliness of treatment increased from 46% to 55%.

The 2 other factors most strongly associated with untimely reperfusion treatment in univariate analyses were transfer from a non-PCI center to a PPCI center (OR, 4.63; 95% CI, 3.73-5.78) and arrival without use of an ambulance (OR, 1.92; 95% CI, 1.56-2.38).

Among patients who neither received fibrinolysis nor were sent for PPCI within 4 hours of triage, all-cause mortality was 18% at 30 days and 29% at 1 year. Table 2 shows that all-cause mortality in the 2 treatment groups was similar. At 30 days, 6.1% of patients who received fibrinolysis and 5.6% of patients sent for PPCI had died (OR, 0.91; 95% CI, 0.57-1.46). At 1 year, 7.4% who received fibrinolysis and 8.3% of patients sent for PPCI had died (OR, 1.13; 95% CI, 0.75-1.73). When only patients with an admission ECG unequivocal for STEMI were considered, mortality at 30 days was 4.5% for those receiving fibrinolysis and 4.7% in those sent for PPCI (OR, 1.06; 95% CI, 0.52-2.12). At 1 year, mortality was 5.4% for those receiving fibrinolysis and 7.3% in those sent for PPCI (OR, 1.51; 95% CI; 0.81-2.81). In patients who actually underwent PPCI, mortality was 5.2% at 30 days and 7.9% at 1 year compared with 9.2% and 11.7%, respectively, in those who did not undergo the procedure.

About two-thirds of patients received reperfusion therapy in hospitals where choice of reperfusion treatment was exclusive or nearly so (≥95% either PPCI or fibrinolysis). In exclusive treatment hospitals, 30-day mortality in patients who received fibrinolysis was 5.8% compared with 5.0% in patients sent for PPCI (OR, 0.85; 95% CI, 0.45-1.63). At 1 year, mortality was 6.8% for patients who received fibrinolysis and 7.3% for patients sent for PPCI (OR, 1.08; 95% CI, 0.60-1.96).

Incidence of the combined end point (death or readmission for heart failure or AMI) at 1 year was 13.5% for fibrinolysis patients and 13.6% for PPCI patients (OR, 1.01; 95% CI, 0.73-1.40) (Table 2). Occurrence at 1 year of coronary artery bypass graft surgery was lower in the PPCI group than in the fibrinolysis group (7.9% vs 11.7%, respectively; OR, 0.65; 95% CI, 0.45-0.93), while occurrence of PCI (after the index hospitalization) was similar in the 2 groups (5.4% vs 6.4%, respectively; OR, 0.84; 95% CI, 0.53-1.34).

In an unadjusted analysis, for each treatment type, mortality was significantly higher in patients treated outside of recommended times than in patients treated within recommended times (Table 3). At 30 days, patients treated with PPCI outside of recommended times had higher mortality (OR, 1.87; 95% CI, 1.02-3.41) as did patients treated outside of recommended times with fibrinolysis (OR, 2.75; 95% CI, 1.07-7.08). The increase in mortality of untimely treatment was sustained at 1 year for both untimely PPCI (OR, 1.71; 95% CI, 1.06-2.76) and untimely fibrinolysis (OR, 2.41; 95% CI, 1.04-6.00).

Within each treatment group, there was nonsignificantly less readmission for congestive heart failure with timely compared with untimely treatment (Table 3). Overall, the composite end point of death or readmission for congestive heart failure or AMI at 1 year occurred significantly more frequently when treatment was untimely among both patients who received fibrinolysis and those who underwent PPCI (Table 3). Untimely fibrinolysis was associated with a worse prognosis than timely PPCI, just as untimely PPCI was associated with a worse prognosis than timely fibrinolysis. When the 2 treatment groups were combined, the risk of adverse events at 1 year was higher (OR, 1.75; 95% CI, 1.26-2.41) in patients who were not treated within maximum recommended delays.

When treatment delay beyond maximum recommended guidelines was examined in 30-minute intervals in patients who underwent PPCI, there was an increasing risk of 30-day mortality with increasing treatment delay for both patients admitted directly to a PPCI center (P=.003) and patients transferred for PPCI (P<.001).

Univariate associations with 30-day mortality are shown in Table 4. Clinical factors significantly associated with increased 30-day mortality were female sex and higher TIMI index. Each comorbidity was associated with a statistically significant increase in risk of death. Arrival by ambulance was associated with an increased risk of death, while being transferred for PPCI was associated with a lower risk of death that was not statistically significant.

After multivariate adjustment, estimates of the association between timeliness of treatment and adverse events remained largely unchanged from unadjusted estimates (Table 3). For mortality in the 2 treatment groups combined, the adjusted relative risk associated with untimely treatment was 2.14 (95% CI, 1.21-3.93) at 30 days and 1.61 (95% CI, 1.00-2.66) at 1 year. For the combined outcome of death or readmission for heart failure or AMI at 1 year, the adjusted relative risk for untimely treatment was 1.57 (95% CI, 1.08-2.30).

In the propensity analysis, of the 599 patients receiving timely treatment (Table 3), a matched patient receiving late treatment was found for 504 patients (84%; difference of <5% of standard deviation for all variables). The resultant ORs from the matched propensity analysis for 30-day mortality (OR, 2.00; 95% CI, 1.12-3.58), for 1-year mortality (OR, 1.59; 95% CI, 0.98-2.58), and for the combined outcome (OR, 1.57; 95% CI, 1.07-2.29) were not substantially different than those yielded by the multivariate logistic regression models.

Across Quebec health care regions, overall timeliness of treatment (PPCI and fibrinolysis combined) ranged from 19% to 76% and use of fibrinolysis and PPCI each varied from 0% to 100% (Figure). In the unadjusted least squares regression analysis, each 10% increase in patients treated within recommended time was associated with a 1.09% decrease (95% CI, −1.76% to −0.42%) in region-level mortality at 30 days (Figure, A). However, there was no relationship between regional use of PPCI and region-level overall mortality at 30 days (slope, 0.0117; 95% CI, −0.046 to 0.070) (Figure, B).

After adjustment for patient and regional characteristics, the proportion of patients treated within recommended time at the region level was significantly associated with the region's odds of death for all STEMI patients. Each 10% increase in regional timeliness was associated with a region-level odds of overall 30-day mortality of 0.80 (95% CI, 0.65-0.98). The other region-level variables in the multilevel model were not significant. Regional mortality in patients who did not receive reperfusion treatment was not higher in regions where mortality for patients receiving reperfusion treatment was low (slope, 0.54; 95% CI, −1.39 to 2.46). This suggests that the relationship between timeliness of reperfusion and mortality was not due to selective treatment of healthier patients.

In this evaluation, we sought to obtain a complete contemporary portrait of STEMI reperfusion treatment in Quebec and to ascertain the effect of untimely treatment on patient outcomes. The principal findings are that (1) PPCI is the predominant reperfusion strategy in the province of Quebec, with most PPCI patients transferred from non-PCI hospitals; (2) delays to reperfusion treatment exceeded maximum recommended delays in a substantial proportion of patients treated with fibrinolysis and PPCI, particularly in patients transferred for PPCI; (3) risk of adverse events was similar in patients treated with PPCI and fibrinolysis but was higher in those treated outside of the maximum recommended delays, regardless of the reperfusion strategy; and (4) timeliness of treatment with either reperfusion mode was a strong predictor of overall regional mortality but no association was observed with choice of reperfusion treatment within health care regions.

Our study, while consistent with registry and clinical data associating longer treatment delays with poorer outcomes,^8- 10 is novel and robust in several ways. Above all, it represents not a sampling but more than 95% of all STEMI patients within a large and complex system of care and provides very recent information that transcends the relative selectivity of randomized clinical trials and most registries. Importantly, patients transferred for PPCI, patients in whom there was no initial intention to treat with reperfusion, and patients who were sent for reperfusion treatment but who did not receive it for various reasons were all included. Patients with STEMI were systematically identified on the basis of an algorithm and central interpretation of the admission ECG. Linkage with medicoadministrative databases permitted assessment of comorbidities and ensured completeness of follow-up beyond the short term not only of mortality but also of the important end points of readmission for AMI or heart failure and revascularization procedures. Sensitivity analyses, notably restricted to patients with an ECG unequivocal for STEMI and centers performing exclusive reperfusion treatments, as well as propensity analysis and region-level analysis, strengthen confidence in the observed associations.

Moreover, since this study was performed in a single-payer, universal access system, observed associations are unlikely to be confounded by patient differences in insurance and socioeconomic status. Thus, we believe this evaluation represents a needed contribution to the evidence base for deriving clinical practice guidelines²⁹ and an important advance in knowledge of the outcomes associated with contemporary processes of STEMI care. This “real-world” information is relevant both clinically and from a perspective of evidence-based health care policy and planning,¹⁴ pointing to the lifesaving potential for approaches that focus on offering the most timely reperfusion treatment to patients with STEMI.

Time, rather than mode of reperfusion, emerges as a critical determinant of outcome in this systematic evaluation of STEMI care. Regardless of reperfusion strategy, patients treated beyond maximum recommended delays had increased mortality. Occurrence of congestive heart failure, an important determinant of poor prognosis, was also increased and is consistent with the notion that longer treatment times lead to less myocardial salvage, making subsequent heart failure more likely. In contrast, longer treatment delay was not associated with an increased risk of readmission for AMI, which may not be unexpected since there is no plausible pathophysiological link between longer treatment delay and risk of new MI.

The association between longer delay to reperfusion treatment and poorer outcome may be confounded because patients who are “sicker” may be treated later rather than earlier. For example, hemodynamically unstable patients could require more time to be stabilized before being able to undergo reperfusion treatment. Also, patients unlikely to survive a long delay to reperfusion may be less likely to be transferred for PPCI and might receive no reperfusion treatment.

However, after multivariate-adjusted analyses that included adjustment for clinical risk factors (TIMI index, female sex) and comorbidities (history of heart failure, peripheral vascular disease, renal failure, or cancer) as well as factors known to be associated with both timeliness and mortality (presentation by ambulance and transfer status),^8,19- 20 an increase in adverse outcomes in patients with longer delays to reperfusion was observed for mortality in the short term and for a combined measure of morbidity and mortality in the long term. Moreover, a propensity analysis that matched an array of variables in patients with untimely treatment to patients with timely treatment resulted in similar observations of increased risk. Thus, this province-wide evaluation provides up-to-date, real-world evidence for the emphasis expressed in international guidelines on the importance of considering timeliness of treatment when choosing the mode of reperfusion.^1- 2 Faced with a choice between a timely reperfusion option and an untimely one, the former option appears associated with better patient outcomes.

Consistent with results in treated patients only, we found an important and statistically significant relation between regions' timeliness of treatment and survival in an analysis of all patients with STEMI. Regions that delivered reperfusion treatment beyond maximum recommended delays had higher mortality than regions that delivered reperfusion treatment within recommended delays while mode of reperfusion within the region was not associated with mortality. This regional analysis of all STEMI patients suggests that the observed benefits of timely treatment are not due to a selection bias of treating healthier patients or treating them more quickly. These results may reassure clinicians and health care policy planners in regions where PPCI is not an option that timely fibrinolysis is a very acceptable standard of STEMI care.

Although retrospective collection of data has limitations, it has the important advantage of allowing a more complete and systematic process for STEMI patient identification, thus minimizing some biases.^13- 14 The accuracy of data entry concerning the process of STEMI care was also found to be high¹⁵ but this observational study has limitations. Nonrecorded data might have led to residual confounding that could have influenced our findings. However, adjustment for available confounding variables, including important clinical factors, did not materially change observed results. Although medicoadministrative databases ensured completeness of follow-up for the primary end points, they did not contain appropriate information to assess hemorrhagic events.

Among patients in Quebec with STEMI, reperfusion delivered outside of guideline-recommended treatment delays was associated with significantly increased 30-day mortality, a statistically nonsignificant increase in 1-year mortality, and significantly increased risk of the composite outcome of mortality or readmission for AMI or heart failure at 1 year. The study findings suggest that time to reperfusion rather than treatment strategy may be more important in terms of outcomes and can help inform clinical decision making to optimize care for patients with AMI presenting to hospitals in Quebec.