Effect of Implementing Routine Early Invasive Strategy on One-Year Mortality in Patients With Acute Myocardial Infarction

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Acknowledgment
• References
• Copyright

The aim of the present study was to investigate whether the implementation of an early invasive strategy for unselected patients with acute myocardial infarction (AMI) would be associated with reduced long-term mortality compared to a conservative approach. In this prospective observational cohort study of consecutive patients admitted for AMI in 2003 (conservative cohort, n = 311) and 2006 (invasive cohort [IC], n = 307), an 11% absolute and 41% relative reduction in 1-year mortality was found for patients with AMI in the IC compared to the conservative cohort (p = 0.001). These findings were consistent after adjustment for age, gender, previous AMI, previous stroke, diabetes, smoking status, previous left ventricular systolic dysfunction, and serum creatinine at admission (hazard ratio 0.54, 95% confidence interval 0.38 to 0.78) and Global Registry of Acute Coronary Events risk score (hazard ratio 0.67, 95% confidence interval 0.46 to 0.97). More patients with ST-segment elevation myocardial infarction received primary percutaneous coronary intervention in the IC (57% vs 3%, p <0.001), and a sixfold (25% vs 4%, p <0.001) increase in early percutaneous coronary intervention (<72 hours) for patients with non–ST-segment elevation myocardial infarction was observed. A greater proportion of patients in the IC received clopidogrel, aspirin, and statins during follow-up; otherwise, the secondary prevention measures were similar in the 2 cohorts. In conclusion, the introduction of a strategy for routine transfer to a high-volume percutaneous coronary intervention center for early invasive therapy was accompanied by a substantial reduction in mortality among unselected patients with AMI. Differences in unmeasured confounders might have accounted for a part of the difference in outcome.

In a study of unselected patients with acute myocardial infarction (AMI) treated in 2003 with a conservative regimen in our department,¹ the 1-year mortality rates were greater than those reported in clinical trials and registries.², ³, ⁴, ⁵, ⁶ In September 2005, we implemented new guidelines,⁷ including transportation of patients with ST-segment elevation myocardial infarction (STEMI) to a high-volume invasive center located 100 km (63 miles) from our hospital for primary percutaneous coronary intervention. Patients with non–STEMI (NSTEMI) underwent invasive procedures within 48 to 72 hours, regardless of evidence of ongoing myocardial ischemia. The aim of the present study was to investigate whether the introduction of an early invasive management strategy for unselected patients with AMI was associated with reduced long-term mortality compared to a conservative strategy.

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Methods 

During 2 1-year periods, all patients referred to our hospital with a suspected AMI were prospectively registered. The diagnosis of AMI was made in accordance with the European Society of Cardiology/American College of Cardiology criteria from 2000.⁸ The conservative strategy cohort (CC) included patients admitted from February 1, 2003 through January 31, 2004.¹ The invasive strategy cohort (IC) included patients admitted from February 15, 2006 through February 14, 2007. In 2003, the catchment population totaled 126,000 inhabitants. In September 2006, it was increased to 165,000 but from an area of similar risk and socioeconomic status. The baseline characteristics included an estimation of the Global Registry of Acute Coronary Events risk score for 6-month mortality in both cohorts.⁹ All patients were offered participation in a 6-week cardiac rehabilitation program.¹⁰

A diagnosis of AMI was made in the presence of typical symptoms and elevated troponin T to greater than a cutoff level of ≥0.1 μg/L in both cohorts. The subtype of AMI was classified according to the electrocardiographic findings. STEMI was considered present if persistent ST-segment elevation occurred in 2 adjacent leads (>0.1 mV in limb leads, >0.2 mV in V₁ to V₃, and >0.1 mV in V₄ to V₆). Patients qualifying for AMI but presenting without persistent ST-segment elevation were classified as having NSTEMI. In the presence of left bundle branch block, patients were categorized as having STEMI if left bundle branch block was presumed to be of recent onset and otherwise as having NSTEMI.

A 12-lead electrocardiogram was recorded by paramedics for all patients with a suspected AMI and sent by telemetry to our coronary care unit for analysis by the physician on duty. Prehospital activation of the invasive center was done by this physician.

Reperfusion therapy for patients with STEMI in the CC was determined by fibrinolysis, preferably administered in the ambulance. Patients in the IC with a symptom duration of <12 hours and a transfer time to the invasive center <90 minutes were scheduled for primary percutaneous coronary intervention. Otherwise, eligible patients were treated with fibrinolysis. In both cohorts, patients treated with fibrinolytic therapy with <50% ST-segment recovery and/or recurrent symptoms after 60 minutes were transferred for rescue-percutaneous coronary intervention. Patients with successful fibrinolysis in the CC underwent ischemia-driven diagnostics and were referred for coronary angiography in the presence of symptoms and/or objective evidence of ischemia. Patients in the IC routinely underwent coronary angiography within 24 to 48 hours after fibrinolysis.

For patients with NSTEMI in the CC a “cool-down” policy was applied according to the guidelines.¹¹, ¹² Only those with ongoing ischemic symptoms accompanied by ST-segment depression and/or negative T waves were transferred for invasive management within the first 48 to 72 hours. Patients in the CC underwent a submaximal exercise electrocardiogram at discharge and a maximal test after 6 weeks and were referred for coronary angiography in the case of positive findings and/or ischemic symptoms. The patients in the IC were referred for coronary angiography within 48 to 72 hours, regardless of symptoms or evidence of ongoing ischemia, provided dementia or severe co-morbidities were absent.

The diagnostic and therapeutic procedures were performed using standard techniques, mainly through radial access. In patients with STEMI, only the culprit lesion was treated in the acute setting, unless cardiogenic shock was present. Other lesions were treated after some weeks if clinically indicated. For patients with NSTEMI, all lesions were (in principle) treated with stenting whenever technically possible. In patients with advanced age or severe co-morbidities, complete revascularization procedures were not always performed. Patients with extensive triple vessel disease, including left main or proximal left anterior descending artery stenosis, were referred for surgery, which was performed within 1 to 7 days if not contraindicated.

In the CC, 147 patients (47%) and in the IC, 154 patients (50%) refused or were not considered capable of follow-up visits owing to dementia and/or severe co-morbidity. We confirmed the vital status for all patients included in the present study, regardless of their follow-up status. Because of regulatory restrictions, the causes of death were not available. Data were collected from the invasive center for all patients, including patients bypassing our hospital en route for primary percutaneous coronary intervention.

The regional ethics committee for South-East Norway Regional Health Authority and the Norwegian Social Science Data Services approved the study.

The Mann-Whitney U test was used for the comparison of continuous data between different groups of patients. Proportions were analyzed using the chi-square test or Fisher's exact test. Two-tailed p values <0.05 were considered statistically significant. Kaplan-Meier plots and log-rank tests were used for comparison of survival between different subsets of patients. Cox proportional hazards regression models were used for additional survival analyses. In these analyses, the cohort was used as a surrogate variable for the treatment strategy. The assumption of proportional hazards was explored with partial residual plots. Interaction terms between cohort/age, cohort/smoking, and previous AMI/previous left ventricular systolic dysfunction were included and tested. An a priori power analysis was performed before the inclusion of patients in the second cohort (IC). The study had a power >80% (α = 0.05) to demonstrate a reduced mortality of 40% for NSTEMI and 35% for NSTEMI and STEMI combined. The analyses were implemented using the Statistical Package for Social Sciences, version 16.0 (SPSS, Chicago, Illinois).

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Results 

In 2003 (the CC period), a total of 755 patients were admitted to our hospital with a clinical suspicion of AMI, of whom 126 (17%) had STEMI and 185 (25%) had NSTEMI. The corresponding numbers in 2006 (the IC period) were 934, 107 (11%), and 200 (21%). Accordingly, the incidence of AMI in our catchment area was 247/100,000 inhabitants in 2003 and 220/100,000 inhabitants in 2006. The baseline characteristics of the patients with AMI in both cohorts are presented in Table 1. A nonsignificant tendency was seen for older patients with STEMI in the CC, but no such difference was observed for NSTEMI or for all patients with AMI (median age 74 years, interquartile range 23, vs 72 years, interquartile range 24, p = 0.61). Creatinine was slightly greater in the CC, for both STEMI and NSTEMI. Otherwise, the baseline characteristics were comparable in the 2 cohorts, including the Global Registry of Acute Coronary Events risk score,⁹ which could be obtained for 94% of participants in both cohorts (median 133 in the CC vs 125 in the IC, p = 0.054).

Table 1. Baseline characteristics

Variable	STEMI			NSTEMI
	CC (n=126)	IC (n=107)	p Value	CC (n=185)	IC (n=200)	p Value
Age (years)	69(25)	62(23)	0.13	76(20)	76(23)	0.91
Male gender	81(64%)	75(70%)	0.42	115(62%)	121(61%)	0.82
Current smoker⁎	47%	45%	0.87	30%	25%	0.29
Diabetes mellitus	12(10%)	14(13%)	0.52	27(15%)	35(18%)	0.53
Previous acute myocardial infarction	14(11%)	18(17%)	0.28	57(31%)	65(33%)	0.81
Previous left ventricular systolic dysfunction†	3(2%)	2(2%)	1.00	17(9%)	22(11%)	0.70
Hypertension	34(27%)	21(20%)	0.22	64(35%)	58(29%)	0.29
Stroke	4(3%)	6(6%)	0.56	12(7%)	19(10%)	0.40
Coronary bypass	5(4%)	1(1%)	0.30	17(9%)	23(12%)	0.57
Coronary angioplasty	4(3%)	6(6%)	0.56	9(5%)	20(10%)	0.086
S-creatinine (μmol/L‡)	87(28)	78(37)	0.021	95(51)	87(34)	0.028

Categorical data presented as n (%) and continuous data as median (interquartile range).

CC = conservative cohort; IC = invasive cohort.

The Kaplan-Meier estimates of patient survival are shown in Figure 1. For all patients with AMI, the 1-year mortality rate was 16% in the IC and 27% in the CC, with a 41% relative and 11% absolute risk reduction for the IC (p = 0.001). The corresponding risk reductions were 41% and 13% for patients with NSTEMI (p = 0.003) and 45% and 9% for those with STEMI (p = 0.09). One patient with STEMI in the IC who died during transfer for primary percutaneous coronary intervention was also included in the analysis. The influence of variables predicting 1-year mortality according to univariate and multiple Cox proportional hazards regression analyses is presented in Table 2. The IC had a 46% lower relative risk of death (hazard ratio 0.54, 95% confidence interval 0.38 to 0.78, p <0.001) after 1 year, after adjustment for age, gender, previous AMI, previous stroke, diabetes, smoking status, previous left ventricular systolic dysfunction, and serum creatinine at admission, and a 33% lower relative risk (hazard ratio 0.67, 95% confidence interval 0.46 to 0.97, p = 0.033) when adjusted for the Global Registry of Acute Coronary Events risk score. The interaction terms tested were not statistically significant.

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• Figure 1. 

  Kaplan-Meier plots demonstrating 1-year survival in all patients with AMI (A), patients with NSTEMI (B), and patients with STEMI (C).

Table 2. Hazard ratios of death in patients with acute myocardial infarction (AMI) (n = 618) during 1 year of follow-up using Cox proportional hazards regression

CI = confidence interval; HR = hazard ratio.

The in-hospital mortality for patients with NSTEMI not treated with early reperfusion was lower in the IC than in the CC (Table 3). A nonsignificant tendency was seen for reduced postdischarge survival in the IC versus the CC. The postdischarge mortality for patients with STEMI was significantly greater in the CC (14% [16 of 117] vs 4% [4 of 99], p = 0.015). For the patients with NSTEMI, the corresponding data were 21% (34 of 159) versus 15% (29 of 191; p = 0.14).

Table 3. In-hospital and total deaths for total cohort and subgroups not treated with early reperfusion

Variable	STEMI			NSTEMI
	CC	IC	p Value	CC	IC	p Value
In-hospital deaths
Total cohort	9/126(7%)	8/107(7%)	0.92	26/185(14%)	9/200(5%)	0.001
No early reperfusion⁎	4/49(8%)	6/37(16%)	0.26	26/177(15%)	8/150(5%)	0.006
Total deaths
Total cohort	25/126(20%)	12/107(11%)	0.086	60/185(32%)	38/200(19%)	0.002
No early reperfusion⁎	14/49(29%)	8/37(22%)	0.54	60/177(34%)	37/150(25%)	0.052

Abbreviations as in Table 1.

The median time from the telephone call to the emergency medical systems to arrival of an ambulance was 9 minutes and the door-to-balloon time was 20 to 30 minutes for patients with STEMI in both cohorts. Primary percutaneous coronary intervention was performed in 61 patients (57%) in the IC and 4 patients (3%) in the CC (p <0.001; Figure 2). The corresponding numbers for fibrinolytic therapy were 9 (8%) and 73 (58%; p <0.001). Facilitated percutaneous coronary intervention was performed in 1 patient in the CC. Rescue percutaneous coronary intervention was performed in 4 of 9 patients in the IC and 9 of 73 patients in the CC. During follow-up, another 18 patients (17%) in the IC were treated with percutaneous coronary intervention and 3 (3%) with coronary artery bypass grafting. In the CC, another 43 patients (34%) underwent percutaneous coronary intervention and 9 (8%) underwent coronary artery bypass grafting. The total revascularization rate in the IC and CC was 81% and 54%, respectively (p <0.001). Repeated percutaneous coronary intervention was performed in 10 patients in the IC and in 1 patient in the CC.

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• Figure 2. 

  Invasive procedures during 1 year of follow-up for STEMI patients.

For the patients with NSTEMI, early percutaneous coronary intervention (<72 hours) was performed in 49 patients (25%) in the IC and 8 patients (4%) in the CC (p <0.001; Figure 3). Only 1 patient (in the IC) underwent early coronary artery bypass grafting. Late percutaneous coronary intervention was performed in another 16 patients (8%) in the IC and 32 (17%) in the CC (p = 0.009). The corresponding data for late bypass surgery were 22 (11%) and 12 (6%) patients (p = 0.17). The total revascularization rate was 45% in the IC and 29% in the CC (p = 0.001). Patients not treated with revascularization procedures were significantly older than those who underwent such procedures (median age 82 years, interquartile range 19, vs 66 years, interquartile range 18, in the IC; and 80 years, interquartile range 15, vs 65 years, interquartile range 19, in the CC; p <0.001 for both).

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• Figure 3. 

  Early (<72 hours) and late invasive procedures during 1 year of follow-up for NSTEMI patients.

Complete angiographic data were available from all patients in the IC. In the CC, such data were obtained for 51 of 76 patients with STEMI and 54 of 74 of patients with NSTEMI who had undergone angiography. No statistically significant difference was found between the numbers of diseased epicardial vessels in the 2 cohorts. More patients with STEMI had 1-vessel disease (p <0.001) compared to the patients with NSTEMI, who had more 3-vessel disease (p <0.001; Table 4).

Table 4. Angiographic findings

Variable	STEMI		NSTEMI
	CC (n=51)	IC (n=93)	CC (n=54)	IC (n=127)
Left main stenosis	2(4%)	3(3%)	3(6%)	15(12%)
Number of diseased coronary arteries⁎
3	10(20%)	6(7%)	16(30%)	34(27%)
2	12(24%)	25(27%)	18(33%)	27(21%)
1	26(51%)	57(61%)	13(24%)	37(29%)
0	3(6%)	5(5%)	7(13%)	29(23%)

Categorical data presented as n (%).

Abbreviations as in Table 1.

Data on medical treatment during index hospitalization and follow-up were obtained from survivors who had given their informed consent to attend follow-up visits (53% of the CC and 50% of the IC). Significantly more patients with STEMI had received clopidogrel (92% vs 29%, p <0.001) during the index hospitalization. A greater proportion of patients in the IC had received clopidogrel at 6 months compared to those in the CC (80% vs 52%, p <0.001). At 12 months, the opposite pattern was observed. More patients in the IC had been prescribed aspirin at both 6 and 12 months than in the CC. In addition, a tendency was seen toward more statin use in the IC for patients with NSTEMI.

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Discussion 

In the present comparison of 1-year mortality among consecutive patients with AMI treated conservatively in 2003 with more aggressive, early invasive management in 2006, a 41% relative reduction and an 11% absolute reduction was found. The study was prospectively designed for both cohorts, with identical inclusion criteria, no exclusion criteria, the same enrollment time, and follow-up without seasonal variation. In the IC, significantly more patients with AMI underwent early invasive management. A nonsignificant trend was seen for a greater Global Registry of Acute Coronary Events risk score in the CC, among whom the serum creatinine level was slightly greater at baseline. During follow-up, the IC patients had a greater use of clopidogrel, aspirin, and statins. Otherwise, the distribution of baseline risk factors and secondary prevention measures were similar in the 2 cohorts.

Although a survival benefit from early invasive treatment has been demonstrated in a meta-analysis of patients with STEMI,¹³ single randomized trials of STEMI¹⁴, ¹⁵ and NSTEMI³, ¹⁶, ¹⁷ have failed to show a statistically significant effect on total mortality, possibly because such studies might have been hampered by selection bias (e.g., the most severely ill and oldest patients were excluded). In the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS)¹⁸ and the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18)¹⁹ trials, the patients were 14 years younger than the patients with NSTEMI in our study. The revascularization rates in the conservatively treated groups were comparable to those in our invasive cohort. The long-term mortality rates were 1/10 that for our conservative cohort. An early invasive strategy is most likely to be beneficial in the highest risk patients, and this could account for some of the findings in our study.

In an analogous period to that of the present study, a decrease in 6-month mortality from 13.3% to 9.1% after an acute coronary syndrome was observed in a multinational observational registry.⁶ We observed even more marked changes in long-term mortality. This might have been in part because the event rates were greater in our first cohort; however, these were similar to those reported from another noninvasive hospital at that time.²⁰

The difference in postdischarge mortality among patients with STEMI might have been related to the favorable long-term effects of primary percutaneous coronary intervention; however, the effect of improved secondary prevention in the IC could not be excluded. The effect on outcome in NSTEMI was mainly driven by the early mortality reduction. Such an observation might contradict the substantially improved secondary prevention during follow-up in the IC but could also indicate that a part of the influence resulted from factors other than the intervention itself. The better outcome in the IC among those without early reperfusion strongly suggests that additional management measures beyond reperfusion were important.

A possible explanation for our findings could be differences in the rate of smoking cessation in the 2 cohorts. The study design did not include the recording of smoking cessation; however, the rehabilitation program with comprehensive information on the importance of stopping smoking was identical in both cohorts. In previous studies of smoking cessation in patients after myocardial infarction²¹ and coronary artery disease,²² the benefit in survival did not appear in the acute phase, but rather after several months. Another possible confounder might be the introduction of a smoking ban in public places and restaurants in Norway since June 2004. Recent reports on the introduction of such regulations from Italy,²³ the United States,²⁴ and Scotland²⁵ have demonstrated a reduction in hospitalization rates for AMI. In Norway, the coronary heart disease death rate was reduced by 21% in the period 2003 to 2006.²⁶ In our catchment area, the incidence of AMI decreased by 11% during the same period. The lower coronary mortality in the general population could therefore partly be explained by the lower incidence of AMI, in addition to the improved outcome after an acute cardiovascular event. We assessed the case fatality rather than the incidence. Provided that the baseline risk in the 2 cohorts was similar, the decrease in coronary mortality in the general population should not have had an effect on our findings.

An additional possible confounding effect might have been the greater prevalence of extensive coronary artery disease in the CC. Although the angiographic data from the CC were incomplete, those patients were carefully selected for coronary angiograms because of evidence of angina or ischemia. Despite this, the number of diseased epicardial vessels did not differ from that in the IC patients who routinely underwent coronary angiography. The earlier prescription of clopidogrel might also have had some effect. Owing to the modest mortality effect in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,²⁷ however, the additive effect of clopidogrel compared to aspirin in this preventative setting seems insufficient to explain our results.

This was a nonrandomized observational study comparing the mortality rates between 2 cohorts of patients with AMI, with the possibility of influence by unidentified confounders. Owing to the modest group sizes, the differences between the groups might not have been statistically significant because of a type 2 error. Data on medical treatment after hospital discharge was only available for patients who visited the clinic in the follow-up program. As such, the data might not be representative of the whole study population. The confounding effect of medical secondary prophylaxis on our results was, therefore, difficult to estimate. The interval from the onset of symptoms to revascularization was not properly recorded for the patients with STEMI.

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Acknowledgment 

We are grateful to the 2 projects secretaries, Hege Bjørndahl and Merethe Bellsund, for their contribution to this study. We thank Frank Brosstad, MD, PhD, and Dan Atar, MD, PhD, for their valuable input to the manuscript.

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