Sunday, May 10, 2009

Cardiac Circulation Video

Even slight BP elevations linked to increased AF incidence among women

April 2009

MedWire News: Blood pressure (BP) is strongly associated with incident atrial fibrillation (AF) among initially healthy women, with the systolic a better predictor than the diastolic measure, findings from the Women’s Health Study show.

Furthermore, the study indicates that BP values below the current threshold for the diagnosis of arterial hypertension are significantly associated with the risk for incident AF.

“Even slightly elevated BP levels at baseline imposed some degree of increased risk,” write study authors David Conen (University Hospital Basel, Switzerland) and colleagues in the journal Circulation.

Because treatment of established AF has limited long-term success and is associated with significant risks, characterizing treatable risk factors for AF has “substantial clinical relevance” the team notes.

The researchers prospectively followed up 34,211 women for incident AF over 12.4 years, and then compared the incidence of AF across systolic and diastolic BP categories.

The women were aged 55 years on average at baseline; during follow-up, 644 had at least one confirmed episode of AF.

Analysis showed that both systolic and diastolic BP components were significantly and strongly associated with incident AF, after multivariable adjustment.

Even women with high-normal systolic (130 to 139 mm Hg) or diastolic (85 to 89 mm Hg) BP at baseline had 28% and 53% increased risks for incident AF compared with women with systolic BP <120 mm Hg or diastolic BP <65 mm Hg, respectively.

In further continuous and combined hazard modeling, systolic BP remained significantly and strongly positively associated with AF incidence, whereas diastolic BP did not.

Of note, say Conen and co-workers, models incorporating BP measures updated over time showed that women with systolic BP values between 130 and 139 mm Hg during follow-up also had a significantly increased risk for subsequent AF.

The team concludes: “Taken together, our findings indicate that tight BP control may help to reduce the growing burden of AF in the community.”

Circulation 2009; 119: 2146–2152

Noncompliance ‘major cause of aspirin resistance’ in stented patients

May 2009

MedWire News: Aspirin resistance is rare in compliant patients receiving the drug for secondary cardiovascular disease prevention after coronary stenting, being mostly found in noncompliant patients who respond when therapy is controlled, reports a French team.

Thomas Cuisset (CHU Timone, Marseille, France) and colleagues prospectively followed-up 136 consecutive patients undergoing coronary stenting for compliance and aspirin response during hospitalization and at 1 month after hospital discharge. The patients’ aspirin responses were determined using the arachidonic acid-induced platelet aggregation (AA-Ag) assay performed on peripheral blood samples.

The researchers contend that, while several mechanisms have been put forward for the wide variability in antiplatelet therapy response, “the first reason to have inadequate platelet inhibition in patients treated with aspirin is noncompliance.” Thus they hypothesized that aspirin resistance would be rare when assessed by methods that directly measure inhibition of platelet cyclo-oxygenase (COX)-1 activity.

Their results showed that AA-Ag ranged from 0 to 34% during the inhospital phase, at a mean of 7.5%. Four (3%) patients were classed as nonresponders, defined as having AA-Ag >30%, although Cuisset and team note all four had post-treatment AA-Ag lower than 35%.

At 1 month postdischarge, however, AA-Ag ranged from 0 to 94%, with a significantly higher mean compared with the hospital phase, at 15.3% (p=0.004), and 19 (14%) patients were identified as nonresponders.

The 19 nonresponders received controlled intake of oral 75 mg aspirin and their response was reassessed. Only one patient remained a nonresponder.

The authors say a similar pattern was seen using the most common definition of aspirin nonresponse of AA-Ag >20%, with 12 nonresponders in hospital and 32 at 1 month, suggesting a further 18 noncompliant patients who were clearly identified as such following further investigation with the patients, families, and general practitioners. Nine claimed they simply forgot to take their medication, while the other nine stopped because of side effects, mainly gastrointestinal (seven patients) or minor bleeding (two patients).

“Noncompliance should be eliminated before treating with alternative and/or additional antiplatelet medications,” the team concludes in the American Heart Journal.

MedWire is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Am Heart J 2009; 157: 889-893

Sustained VT/VF linked to increased mortality after PCI in STEMI patients

6 May 2009

MedWire News: Patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who develop sustained ventricular fibrillation or tachycardia before or after the procedure have significantly increased 90-day mortality, a study reveals.

Rajendra Mehta (Duke Clinical Research Institute, Durham, North Carolina, USA) and team evaluated the association of ventricular fibrillation (VF) or ventricular tachycardia (VT) and its timing with risk for death at 30 and 90 days in 5745 patients with STEMI undergoing PCI at 296 hospitals in 17 countries.

They report in the Journal of the American Medical Association that VT/VF occurred in 329 (5.7%) patients. The majority of these occurred early (before the end of catheterization, n=205; 64%), and 90% occurred within 48 hours of presentation with STEMI symptoms.

The 90-day mortality rate was significantly higher among patients with any VT/VF compared with those without, at 23.2% versus 3.6%, and an adjusted hazard ratio (HR) of 3.63. Outcomes were particularly worsened among patients with late (after the end of catheterization) VT/VF, with a 90-day mortality of 33.3% (HR=5.59), although still significantly worse for those with early VT/VF,at 90-day mortality of 17.2% (HR=2.34).

Factors associated with late VT/VF were low systolic blood pressure, increased heart rate (>70 beats per minute) and body weight, ST resolution less than 70%, post-PCI Thrombolysis in MI (TIMI) flow below grade 3 and pre-PCI TIMI flow grade 0, and beta-blocker treatment for less than 24 hours.

“Our analysis identified patients who may benefit from closer surveillance int eh intensive care or telemetry unit after the PCI procedure because of the risk for late VT/VF,” the authors write.

“In contrast, because of very low risk for late VT/VF in patients with complete reperfusion, our findings suggest that close monitoring for late VT.VF may not be necessary and these patients may be candidates for early discharge.”

They add that, as most patients with STEMI worldwide are routinely moitored for longer than 72 hours, these findings have the potential to decrease resource use without compromising patient safety when a risk-based strategy of monitoring or early discharge is followed.

JAMA 2009; 301: 1779-1789

Saturday, May 9, 2009

Prediction of Early Complications in Patients With Acute Myocardial Infarction by Calculation of the ST Score

Prediction of Early Complications in Patients With Acute Myocardial Infarction by Calculation of the ST Score

Marianne Gwechenberger MD
Wolfgang Schreiber MD
Harald Kittler MD
Michael Binder MD
Bernhard Hohenberger
Anton N Laggner MD
Michael M Hirschl MD


Clinic of Internal Medicine II, Department of Cardiology Department of Emergency Medicine, University of Vienna, Vienna, Austria.


47/1/85428

Study objective:

To assess the relationship between the sum of ST-segment elevations (ST score) in the admission ECG and the occurrence of early complications in patients with acute myocardial infarction (MI).
Methods:

We conducted an observational study of patients who presented with acute anterior or inferior MI to the ED of a 2,000-bed inner-city hospital. Age, sex, time from onset of pain and the start of thrombolysis, and ST score were evaluated by the emergency physician. "Early complications" were defined as acute congestive heart failure or severe rhythm disturbances in the 24 hours after the start of thrombolysis. The outcome measures were the relationship between ST score and the occurrence of early complications; the influence of age, sex, or time between onset of pain and thrombolysis; and identification of a cutoff value with the highest sensitivity and specificity for prediction of complications.
Results:

We included 243 patients (194 men, 49 women; mean age, 56.6 years) with acute MI (anterior, 119; inferior, 124) who underwent thrombolysis in our analysis. ST score was significantly greater in patients with early complications, compared with patients without complications (anterior, 10.3 versus 19.4 mm [ P<.001]; inferior, 6.9 versus 10.4 mm [ P<.001]). Receiver-operator curve analysis revealed an ST score of 13 mm in patients with anterior MI and 9 mm in patients with inferior MI as the cutoff value with the greatest sensitivity and specificity for predicting early complications of MI. (For anterior MI, sensitivity was .79, specificity .73; for inferior MI, sensitivity was .64 and specificity .68.). On multivariate regression analysis, ST score was an independent predictor of the occurrence of at least one complication. (For anterior MI, the odds ratio [OR] was 9.7 and the 95% confidence interval [CI] 3.9 to 25.1; for inferior MI the OR was 5.0 and the 95% CI 2.0 to 12.8). Age, sex, and interval from onset of pain to treatment had no significant effect on the occurrence of early complications.
Conclusion:

The absolute ST score is useful in estimating the probability of early complications in patients with acute MI receiving
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thrombolytic therapy. A cutoff value of 13 mm for anterior MI and 9 mm for inferior MI stratifies patients into high- and low-risk subgroups for the development of acute congestive heart failure and severe rhythm disturbances during the first 24 hours of hospitalization.

[Gwechenberger M, Schreiber W, Kittler H, Binder M, Hohenberger B, Laggner A, Hirschl MM: Prediction of early complications in patients with acute myocardial infarction by calculation of the ST score. Ann Emerg Med November 1997;30:563-570.]


Received for publication February 28, 1997.
Revision received June 20, 1997.
Accepted for publication July 3, 1997.

Copyright © by the American College of Emergency Physicians.

Address for reprints:
Michael M Hirschl, MD
Department of Emergency Medicine
Wahringer Gurtel 18-20
A-1090 Vienna
Austria
43-1-40400-1964
Fax 43-1-40400-1965
E-mail michael.hirschl@akh-wien.ac.at
INTRODUCTION

The initial ECGs of patients admitted to the ED or CCU have been used to stratify patients into groups at low and high risk for the development of in-hospital life-threatening complications and death. [1] [2] [3] [4] [5] Whereas signs of myocardial infarction (MI), left bundle-branch block, and left ventricular hypertrophy on the initial ECG are associated with a high frequency of adverse events or the need for procedures, [6] normal ECG findings or an ECG with minimal changes indicate a low risk of further complications in patients with suspected MI. [7] In addition, it has been demonstrated that the presence of ST-segment elevation in lead V4R in patients with acute inferior MI is a strong and independent predictor of major complications. [8] [9]

In the last 10 years, thrombolytic therapy has become an important therapeutic tool in patients with acute MI, as survival of patients with acute MI has markedly improved as a result of thrombolysis. [10] [11] However, especially in the early phase after acute MI (within 24 hours of the onset of pain), acute complications including congestive heart failure or rhythm disturbances are commonly observed. Easily available markers for the prediction of these complications would be helpful in stratifying patients with acute MI undergoing thrombolysis into high- and low-risk groups at the time of admission to the ED or CCU. Birnbaum et al [12] demonstrated that different patterns of ST-segment changes in the initial ECG are associated with different prognoses in patients who have sustained acute MI. In contrast to the assessment of the initial ECG pattern, the amount of ST-segment elevation (ST score) seems a more easily available parameter for the treating physician in the ED or CCU. [13] The predictive value of the ST score for early complications in patients with acute MI undergoing thrombolytic therapy has not been investigated until now. We therefore designed a study to assess (1) the relationship between ST score on the admission ECG and occurrence of early complications and (2) the influence of other factors (eg, interval from onset of pain to treatment, age, sex) on this relationship in patients with acute MI undergoing thrombolytic therapy.
MATERIALS AND METHODS

We conducted this study in the ED of the General Hospital (Vienna, Austria) between January 1, 1994, and December 31, 1996. Data from all patients who were admitted to the ED with evidence of an acute MI and given thrombolytic therapy were prospectively collected.

The study protocol was renewed by the local institutional review board and found to be in accordance with the ethical standards of the review board and with the Helsinki Declaration of 1975, as revised in 1983.

In this study we sought to evaluate the relationship between ST score on the admission ECG and the occurrence of early complications and the influence of other factors (eg, interval between the onset of pain and treatment, age, and sex) on this relationship in patients with acute MI who were undergoing thrombolytic therapy.

All patients with suspected MI (eg, chest pain of >30 minutes' duration, persistent ST-segment elevation in two or more anterior or inferior leads on the admission ECG) who were undergoing thrombolytic therapy were eligible for study. Consecutive ECGs and serial creatine kinase-MB (CK-MB) determinations were performed to confirm the diagnosis of acute MI (ie, evidence of new Q waves in serial ECGs, a typical increase and decrease (or both) of the CK-MB concentration in the first 24 hours after ED admission).

Patients in whom Q waves did not develop (.04 seconds or longer) and those in whom the typical increase and decrease in CK-MB concentration did not appear were excluded from further analysis. Patients with evidence of early complications on admission (eg, acute congestive heart failure on the initial chest radiograph or severe rhythm disturbances on the initial ECG) were also dismissed from analysis.

In summary, the inclusion criteria for the study were evidence of acute MI, treatment with a thrombolytic agent, and no signs of early complications at the time of ED admission.

After admission, each patient received thrombolytic treatment with 100 mg recombinant tissue plasminogen activator (rtPA) in accordance with an accelerated front-loading scheme published by Neuhaus et al. [11] Treatment was preceded with an intravenous bolus of 5,000 IU conventional heparin and an oral 100-mg dose of aspirin. beta-Blockers and nitrates were given as deemed clinically appropriate.

Standard 12-lead electrocardiographic tracings were performed immediately after admission. The records were made at a paper speed of 25 mm/second and standardization at 1.0 mV to 1.0 cm. Infarct location was determined
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on admission, and patients were classified a priori as having anterior MI (ST-segment elevation in leads V1 through V6) or inferior MI (ST segment elevation in leads II, III, and aVF). A small proportion of patients exhibited ST-segment elevation in both anterior (V1 through V6, I, aVL) and inferior leads (II, III, aVF, V5, V6). These patients were classified as having anterior or inferior MI depending on whether the anterior or the inferior site had the greatest ST score. [14] ST-segment elevation was measured to the nearest .5 mm at the J point and summed for all leads but aVR. [14] [15] ST-segment elevation was considered significant if it was more than .1 mm from the baseline. ST-segment depression as observed in patients with posterior AMI as well as elevations in the right ventricular leads were not included in the analysis. Evaluation of the ECG also included the assessment of the number of leads involved and the extent of ST-segment elevation divided by the number of leads involved (ST score/ number of leads with ST-segment elevation).

The ECGs were generally analyzed by the emergency physician on duty. Reevaluation was conducted by two experienced emergency physicians (MMH, WS), blinded to all clinical data. The ST scores measured by all three physicians were averaged and used for analysis. In the case of a marked difference between the physician (ie, >2 mm difference), the ECG was reanalyzed by all three emergency physicians together in an attempt to reach a consensus. The interobserver variability was 96%.

Patients with evidence of acute congestive heart failure on admission or severe rhythm disturbances at the time of the initial ECG were excluded from analysis.

Acute congestive heart failure was defined as evidence of bibasilar rales over the lungs that did not clear with coughing, a third-sound gallop over the heart and signs of congestion in one of the subsequent chest radiographs routinely performed 12 and 24 hours after ED admission. Radiographic signs of acute congestive heart failure were central or perihilar infiltrates, increased size of vessels serving the upper portions of the lungs in the upright position, and increased prominence of interlobular septa (usually bilateral and symmetric).

Severe rhythm disturbances included bradyarrhythmias (asystole, type 2 second-degree or third-degree atrioventricular block, bradycardia associated with hypotension [systolic blood pressure <90 mm Hg] requiring atropine or insertion of a temporary pacemaker), and tachyarrhythmias (ventricular fibrillation, ventricular tachycardia requiring electrical or chemical cardioversion, rapid atrial fibrillation associated with hypotension [systolic blood pressure <90 mm Hg] requiring digitalis or amiodarone).

All patients who died during the 24 hours after admission to the ED were noted.

We retrieved the following data from the ED charts: age, sex, duration of chest pain, peak creatine kinase (CK) and CK-MB, and complications noted during the 24 hours after ED admission. ST score was calculated according to the previously noted criteria. On the basis of these data, we established a model to predict the appearance of early complications according to the extent of the ST score in the admission ECG.

The following parameters were classified as independent variables in the model: age, sex, interval between onset of pain and the start of thrombolytic therapy, and the calculated sum of ST-segment elevation in the admission ECG.

Evidence of acute congestive heart failure or severe rhythm disturbances in the 24 hours after ED admission were the dependent or outcome variables in this model. Cutoff points were identified for the greatest sensitivity or specificity for the prediction of early complications. The influence of time from onset of pain to treatment, age, and sex was evaluated with the use of a multivariate regression analysis.

Diagnostic performance was described in terms of areas under the receiver-operator curves (ROCs) in accordance with the methods described previously. [16] [17] [18] The ROC analysis software of Centor and Keightley (Blue Ridge Express) was used to obtain area calculations.

We described continuous data with the mean and SD or median and interquartile range (IQR) as appropriate. We used the unpaired Student t test or the nonparametric Mann-Whitney U test for the comparison of groups and the chi2 test for comparisons of proportions. Logistic-regression analysis was used for the estimation of odds ratios (ORs). Numeric values were rounded to the nearest integer. Two-tailed P values less than .05 were considered statistically significant.
TABLE 1 -- General data. Features Anterior MI Inferior MI P
No. of patients 119 124
Age (yr) [mean±SD] 57.1±12.2 56.2±11.5 NS
Sex (M/F) 98/21 96/28 NS
Median peak CK
value (U/L) [IQR] 1,221 (502-1,980) 724 (399-1,115) .006
Median peak CK-MB
value (U/L) [IQR] 120 (72-194) 85 (45-130) .004
ST score (mm)
[mean±SD] 14.4±9.9 8.3±4.6 <.001
Median time to therapy
(min) [IQR] 110 (75-175) 110 (85-218) NS

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RESULTS

We included 243 patients (194 men, 49 women) with a mean±SD age of 56.6±11.8 years in the study (Table 1) . On the basis of electrocardiographic data, MI was located in the anterior wall in 119 patients and in the inferior wall in 124. Peak CK and CK-MB values were significantly greater in patients with anterior-wall infarction compared with those who had sustained inferior-wall infarctions (CK: 1,221 versus 724 U/L, P=.006; CK-MB: 120 versus 85 U/L, P=.004). Overall, in 103 patients (anterior MI: n=53; inferior MI: n=50; NS) either acute congestive heart failure (anterior MI: n=30; inferior MI: n=16; P=.03) or a rhythm disturbance (anterior MI: n=23; inferior MI: n=34; NS) was observed. The median interval from onset of pain to start of thrombolytic therapy was equal in patients with anterior and inferior MI (anterior MI: 110 minutes, IQR=75 to 175; inferior MI: 110 minutes, IQR=85 to 218; NS). Three patients died in the 24 hours after ED admission (anterior MI: n=2; inferior MI: n=1). Causes of death were cardiogenic shock (n=2) and left ventricular rupture (n=1).

In patients with evidence of complications, the sum of ST-segment elevation was significantly higher compared with


Figure 1. ROC curve showing the performance of ST score with regard to the prediction of early complications in patients with anterior MI.
that of patients without complications. This difference was observed in patients with anterior and inferior myocardial infarction (anterior MI: 10.3 versus 19.4 mm, P<.001; inferior MI: 6.9 versus 10.4 mm; P<.001). No significant differences were observed between patients with congestive heart failure and those with rhythm disturbances (anterior MI: 18.7 versus 15.9 mm, P=.42; inferior MI: 10.1 versus 9.5 mm; NS). The mean±SD ST score for the patients who died during the first 24 hours was 21.3±4.6 mm.

The number of leads with ST-segment elevation was significantly higher in patients with anterior MI and early complications than in those without serious events (4.2±1.2 versus 5.7±1.8, P<.05). In patients with inferior MI no significant difference was observed (3.3±.9 versus 3.4±.9, NS). The ST score divided by the number of leads with ST-segment elevation revealed a significantly higher score in patients with early complications compared with those without complications (anterior MI: 2.3±1.3 versus 3.6±1.9 mm/lead, P<.001; inferior MI: 1.9±.9 versus 3.0±1.4 mm/lead, P<.001). ROC curves show the performance of admission ST score in predicting early complications in anterior MI (Figure 1) . The mean±SD area under the curve is .80±.04. The optimal cutoff point maximizing sensitivity and specificity was found


Figure 2. ROC curve showing the performance of ST score with regard to the prediction of early complications in patients with inferior MI.
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at 13 mm, for a sensitivity of 79% and a specificity of 73%. The relative risk (RR) was significantly greater in patients above the cutoff value than in those below the cutoff (RR, 2.98; 95% confidence interval [CI], 1.9 to 4.8).

ROC curves show the performance of ST score on admission by early complications in inferior MI (Figure 2) . The mean±SD area under the curve was .72±.05. The optimal cutoff point was found at 9 mm, for a sensitivity of 64% and specificity of 68%. The RR is significantly greater in patients above the cutoff value compared with those below the cutoff value (RR, 2.1; IQR, 1.4 to 3.2).

With the cutoff values derived from ROC analysis, logistic-regression analysis showed that the admission ST score on admission was an independent predictor of the occurrence of early complications in patients with anterior MI (OR, 9.7; 95% CI, 3.9 to 25.1; P<.0001) and in patients with inferior MI (OR, 5.0; 95% CI, 2.0 to 12.8; P=.0002) (Table 2 , Figure 3) . An increase of 1.0 mm in ST score increases the odds of complications by 1.1 (95% CI, 1.1 to 1.2) for anterior MI and by 1.2 (95% CI, 1.1 to 1.4) for inferior MI. No other clinical variables available at the time of ED presentation were significantly associated with the occurrence of early complications in patients with anterior or inferior MI.
DISCUSSION

The initial ECG is frequently used to predict acute MI, serious complications and in-hospital mortality. [1] [2] [3] These studies were designed mainly to identify patients at high risk for a subsequent MI. [1] [2] [3] [4] [5] [6] Therefore patients with suspected acute MI were classified into high- and low-risk groups on the
TABLE 2 -- Multivariate analysis for the occurrence of early complications.
Anterior MI (n=119) Inferior MI (n=124)
Features OR (95% CI) P OR (95% CI) P
Age (yr)



70 1.0 NS 1.0 NS
>70 1.36 (.24-7.45)
.53 (.14-1.8)
Sex .84 (.22-3.29) NS .52 (.18-1.45) NS
Time to therapy
(min)



120 1.0 NS 1.0 NS
>120 1.46 (.55-3.99)
1.45 (.6-3.55)
ST score (mm)



13 1.0 <.0001

>13 9.73 (3.94-25.1)


9

1.0 .0002
>9

4.98 (2.04-12.84)

basis of evidence or absence of specific electrocardiographic patterns (eg, ST-segment elevation, left bundle-branch block, left ventricular hypertrophy, ST-segment depression). [1] Brush et al [1] demonstrated that patients with such "positive" admission-ECG findings had a significantly greater risk of a subsequent acute MI, serious complications or death than those with "negative" ECG findings. Also, patients with minimally abnormal admission ECG findings had a low risk of subsequent MI. [7]

In contrast, our study included patients with evidence of acute MI and was initiated to separate MI patients into those at high and low risk for subsequent complications in the 24 hours after admission on the basis of the ST score. In our series of 243 patients, the ST score was a good predictor of early complications during the 24 hours after acute MI; the ST score was significantly higher in patients with evidence of early complications compared with those without any events. This difference was observed in patients with anterior and inferior Mis, indicating that the ST score can be used independent of the infarct location. We also identified cutoff values of the ST score to calculate the risk for the occurrence of early complications. If the sum of the ST-segment elevations was greater than these cutoff values, the odds of early complications were 10 times greater in patients with anterior MI and five times greater in patients with inferior MI (Figure 3) . Other factors--age, sex, and time between onset of pain and thrombolysis--had no effect on the occurrence of early complications. Therefore ST


Figure 3. Schematic representation of the frequency of early complications in patients with anterior or inferior myocardial infarction according to the magnitude of the ST score on the admission ECG.
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score remains the only predictor of the occurrence of early complications in patients with acute MI.

The extent of the ST score is determined by the total number of leads and by the extent of ST-segment elevation in each lead with ST-segment changes. A higher ST score, therefore, can be due to an increase in the total number of leads with ST-segment elevation, an increase in the extent of ST-segment elevation in each lead, or both.

In patients with anterior MI and early complications increased ST score is caused not only by greater ST-segment elevation in each lead but by a higher total number of leads with ST-segment elevations. Therefore ST score may reflect the area of endangered myocardium in patients with anterior MI. Our data are in line with the findings of previously published reports demonstrating a relationship between ST score and infarct size. [19] [20] These reports also showed a correlation between the amount of ST-segment elevation and serious complications or death. [4] [21] [22] Figueras [4] et al reported a significant relationship between high ST-segment elevation and left ventricular rupture in patients with acute inferior MI. [4] Nielsen et al [21] demonstrated that "major ST elevations" were associated with a higher risk of fatal events compared with the patients with "minor ST elevations." These data are confirmed by our findings; the three patients who died in the first 24 hours were characterized by above-average ST scores (mean, 21.3 mm).

In contrast, the higher ST score in patients with inferior MI and early complications is caused by a greater ST-segment elevation in each affected lead; the total number of leads involved was similar in patients with and without early complications. Therefore, in patients with inferior MI, ST score only partially reflects the area of endangered myocardium.

Because ST-segment depressions are frequently observed in patients with inferior MI, [23] the exclusion of ST-segment depressions from ST-score calculation seems to be responsible for the lack of correlation between the area of endangered myocardium and ST score in patients with inferior MI. The calculation of the ST score without ST-segment depressions also contributes to the significant difference in the cutoff values between patients with anterior and inferior MI (9 mm versus 13 mm). However, ST-segment depression may be due to many nonischemic and chronic conditions (eg, left ventricular hypertrophy, treatment with digoxin or digitoxin, bundle-branch block) that may interfere with the acute ST-segment depressions caused by myocardial ischemia. Therefore inclusion of ST-segment depressions in such patients may lead to an increased ST score, resulting in decreased specificity. Currently the ST-scoring system is not suitable for patients with posterior infarction; these patients mainly exhibit ST-segment depressions. Further studies are required to evaluate the effect of the inclusion of ST-segment depressions in the ST score on sensitivity and specificity of our cutoff values in patients with inferior MI.

It must be emphasized that the results of our study are restricted to patients undergoing thrombolysis. The interval between onset of pain and treatment ranged from a minimum of 30 minutes to a maximum of 6 hours. It must also be emphasized that this interval may be too small to have any influence on the relationship between ST score and early complications. Whether longer intervals (eg, 6 to 12 hours between the onset of pain and the start of treatment) have any influence on the occurrence of early complications cannot be answered with our data. Also, the association between the area of endangered myocardium and the extent of ST score may be weak, especially in patients with inferior MI. Other methods such as echocardiography, scintigraphy or even biochemical markers may provide more accurate data about the area of endangered myocardium or infarct size. [24] [25] [26] [27] [28] Therefore these methods may be used to predict early complications more precisely than may the ST score. However, these methods require technical or laboratory skills, which may not be available in all EDs on a 24-hour basis. Additionally, none of these parameters is as easily available at the time of admission as the ST score.

Despite these limitations, our data have important clinical implications in the treatment of patients with acute MI. First, evaluation of the ST score on the initial ECG provides a simple method with which to identify patients at high risk for early complications. It follows that the patient at risk for complications may be transferred to an intermediate care unit with telemetric monitoring and trained nursing personnel. This procedure may save costs without compromising patient care. Second, patients at high risk of complications may be considered for a more aggressive therapeutic approach (eg, angioplasty or coronary artery bypass grafting) to reduce the risk of severe early complications.

In conclusion, the absolute ST score is useful in estimating the probability of early complications in patients with acute MI receiving thrombolytic therapy. A cutoff value of 13 mm for anterior MI and 9 mm for inferior MI risk-stratifies patients into high- and low-risk subgroups for development of acute congestive heart failure and severe rhythm disturbances during the first 24 hours of hospitalization. We therefore assume that the calculation of ST-segment elevation score on the admission ECG is clinically relevant because patients with acute MI may be classified as being at high or low risk shortly after ED admission. This stratification may have an important effect on the further treatment of the patient.
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13. Wellens HJJ, Conover MB: The ECG in Emergency Decision Making, ed 1. Philadelphia: WB Saunders, 1992:1-26.

14. Clemmensen P, Grande P, Saunamaki K, et al: Effect of intravenous streptokinase on the relation between initial ST-predicted size and final QRS-estimated size of acute myocardial infarcts. J Am Coll Cardiol 1990;5:1252-1257.

15. Aldrich HR, Wagner NB, Boswick J, et al: Use of initial ST segment deviation for prediction of final electrocardiographic size of acute myocardial infarcts. Am J Cardiol 1988;61:749-753.

16. Swets JA: Measuring the accuracy of diagnostic systems. Science 1988;240:1285-1293.

17. Centor RM: Signal detectability: The use of ROC curves and their analyses. Med Decis Making 1991;11:102-106.

18. Metz CE: ROC methodology in radiologic imaging. Invest Radiol 1986;21:720-733.

19. Mamko PR, Libby P, Covell JW, et al: Precordial ST segment elevation mapping: An atraumatic method for assessing alterations in the extent of myocardial injury: The effect of pharmacologic and hemodynamic interventions. Am J Cardiol 1972;29:223-230.

20. Muller JE, Maroko PR, Braunwald E: Evaluation of precordial mapping as a means of assessing changes in myocardial ischemic injury. Circulation 1975:52:16-27.

21. Nielsen BL: ST segment elevation in acute myocardial infarction: Prognostic importance. Circulation 1973;48:338-345.

22. Mauri F, Gasparini M, Barbonaglia L, et al: Prognostic significance of the extent of myocardial injury in acute myocardial infarction treated by streptokinase (the GISSI trial). Am J Cardiol 1989; 63:1291-1295.

23. Bates ER, Clemmensen PM, Califf RM, et al: Precordial ST-segment depression predicts a worse prognosis in inferior infarction despite reperfusion therapy. J Am Coll Cardiol 1990;16: 1538-1544.

24. Bonow RO, Dilsizian V, Cuocolo A, et al: Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction: Comparison of thallium scintigraphy with reinjection and PET imaging with 18 F-fluorodeoxyglucose. Circulation 1991;83:26-37.

25. Schiller N, Shah P, Crawford M, et al: American Society of Echocardiography Committee on Standards, Subcommittee on Quantification of Two-Dimensional Echocardiograms. J Am Soc Echo 1989;2:358-367.

26. Iliceto S, Marangelli V, Marchese A, et al: Myocardial contrast echocardiography in acute myocardial infarction: Pathophysiological background and clinical applications. Eur Heart J 1996;17:344-353.

27. Hamm CW, Katus HA: New biochemical markers for myocardial cell injury. Curr Opin Cardiol 1995;10:355-360.

28. Hirschl MM, Gwechenberger M, Binder T, et al: Assessment of myocardial injury by serum tumour necrosis factor alpha measurements in acute myocardial infarction. Eur Heart J 1996;17:1852-1859.
APPENDIX

TABLE 3 -- Sensitivity and specificity of different cutoff values in patients with anterior MI Cutoff Value
(ST Score [mm]) Sensitivity Specificity
51 .00 .98
50 .02 .98
42 .04 .97
38 .06 .97
31 .08 .97
30 .13 .97
29 .17 .97
28 .19 .97
27 .23 .97
26 .25 .97
25 .26 .95
24 .32 .95
23 .38 .95
22 .40 .95
21 .45 .95
20 .45 .92
19 .51 .91
18 .53 .89
17 .55 .86
16 .55 .83
15 .60 .82
14 .72 .79
13 .79 .73
12 .79 .68
11 .85 .65
10 .87 .56
9 .87 .50
8 .89 .35
7 .94 .32
6 .96 .27
5 1.00 .23
4 1.00 .15
3 1.00 .08
2 1.00 .02
0 1.00 .00


TABLE 4 -- Sensitivity and specificity of different cutoff values in patients with inferior MI Cutoff Value
(ST Score [mm]) Sensitivity Specificity
30 .02 1.00
21 .02 .99
18 .06 .97
17 .06 .96
16 .08 .96
15 .16 .95
14 .24 .93
13 .30 .93
12 .40 .93
11 .54 .86
10 .56 .80
9 .64 .68
8 .70 .58
7 .78 .53
6 .86 .41
5 .90 .32
4 .96 .22
3 .96 .07
2 .98 .00
1 1.00 .00

Em

Thursday, May 7, 2009

Full list of ESC Clinical Practice Guidelines & ATP III At-A-Glance

http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/GuidelinesList.aspx


What is an acute myocardial infarction?

Russell V. Luepker
School of Public Health, University of Minnesota, Minneapolis, MN, USA

The accurate diagnosis of acute myocardial infarction (AMI) is crucial for many reasons. For the practicing physician, the diagnosis has clear and directive therapeutic implications. For the hospital administrator, it has important influences on resource allocation and quality assurance. For the clinical trialist, it defines outcomes in studies of new therapies. For the epidemiologist, case definitions are essential for understanding incidence and prevalence and for monitoring disease trends in the population. However, despite its importance, the definition of AMI is in flux, leading to ambiguity and confusion for clinicians, administrators, trialists and epidemiologists.

Common case-criteria for AMI developed in the 1960s from a need to establish heart disease registries. Most of these efforts focused on discharge diagnoses and retrospective surveillance. The criteria became the widely used 'World Health Organization (WHO) criteria' [1,2], and included a triad of elements: classical symptoms, enzyme elevation and electrocardiographic (ECG) changes, particularly the newly developed Q-waves. But these were ambiguous ‘criteria’, enabling clinicians and investigators to use them as they saw fit, and yet still claim to be using the WHO standard. This ambiguity meant that comparisons of AMI between centers and over time were difficult and often invalid.

The field advanced in the 1980s with the advent of large surveillance projects that developed explicit definitions for symptoms, enzyme levels and ECG patterns. The WHO MONICA (multinational MONItoring of trends and determinants in CArdiovascular disease) study and parallel efforts in the United States exemplified this advance [3,4].

Unfortunately, the discharge diagnoses approach and retrospective chart abstraction used in these trials did not allow for an immediate diagnosis, which is needed for acute therapy, where clinicians must make decisions with limited information. Furthermore, the changing presentation of AMI was not taken into account, and the various new biomarkers were not used.

Changing treatments
The emergence of acute reperfusion therapies implied a need for rapid diagnosis. Thrombolysis and percutaneous angioplasty, early treatment interventions designed to restore blood flow, were highly effective but only when performed within hours of the onset of symptoms.

New biomarkers
The advent of new biomarkers, specifically troponins, also dramatically altered the field. Troponins are highly sensitive and specific blood markers of cardiac myocyte damage [5-7]. In comparison with older enzyme markers such as lactate dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), creatine kinase (CK) and CK isoenzyme MB, they represent a ‘sea change’ in diagnosis, because they allow smaller infarcts to be detected - and to be detected more quickly.

Changing presentation
Finally, the presentation of the disease began to change as traditional Q-wave infarctions diminished and a more subtle form of ECG-based AMI became prevalent [8].

This combination of clinical needs, improved diagnostic technology and changes in the presentation led to widespread interest in revising the diagnostic criteria for AMI, resulting in a series of new and widely endorsed AMI definitions.

In 2000, a joint working group of the European Society of Cardiology and American College of Cardiology developed a statement on the redefinition of myocardial infarction [9]. It addressed both the need for a more rapid diagnosis and the advent of new biomarker technologies. It also suggested that diagnostic imaging would play a role in case definitions.

Later on, in 2003, an American Heart Association (AHA), WHO and US National Institutes of Health (NIH) group put forward definitions necessary for population surveillance of cardiovascular disease [10]. These epidemiological criteria focused on longer-term surveillance issues, in which consistency of case definition is crucial. The group also considered comparisons between modern and earlier enzyme-defined cases.

Most recently, in 2007, a combined group of all these organizations discussed a universal definition of myocardial infarction. It refined and better described a number of clinical situations in which myocardial infarction might be considered, including inadequate oxygen supply, trauma, and myocardial infarction associated with cardiac procedures [11].

The results of the technological advances and the new definitions are dramatic. A number of studies have demonstrated that the use of troponins can lead to substantial increases in the number of patients hospitalized with AMI. In one study, using troponin as a biomarker instead of CK or CK-MB resulted, respectively, in a 0-320% or 3.9-195% increase in AMI hospitalizations [12].

These differences are debated in the literature, but most investigators suggest that using troponin as a biomarker results in the detection of milder myocardial infarctions [13-15]. These ’small‘ AMIs nonetheless carry prognostic significance, because long-term follow-up demonstrates that even minor perturbations are associated with increased long-term mortality [16].

This trend will be enhanced by the advent of ultrasensitive cardiac troponin markers, which enable clinicians to reliably detect even lower levels of troponin [17]. One result of more sensitive markers is the revelation that a mild elevation in troponins is associated with other cardiac and non-cardiac diseases. These include a variety of pathologies, from heart failure to pulmonary embolisms and renal failure. In addition, extreme exertion is associated with a mild elevation in troponins [11]. These observations add confusion to the field.

Given these recent changes, what are reasonable recommendations? It is apparent that the contemporary diagnosis of AMI is driven by biomarkers, specifically troponins. Using these markers in combination with symptoms will result in the diagnosis of AMI even in the setting of negative cardiograms. For the emergency reperfusion situation, a single biomarker and/or cardiographic changes might be all that is available and adequate to make a diagnosis for reperfusion treatment. For monitoring disease trends and for trials, multiple markers - at least 2 - in an ascending or descending pattern in association with symptoms are essential for making the diagnosis.

Conclusions
In the future, we will see a continuing evolution of the definition of AMI as more sensitive measures of myocardial damage emerge. Disease rates will rise in the setting of milder cases, as a result of more-sensitive measures. These changes should provide direction for clinicians to implement the most effective therapies for their patients, based on an improved understanding of the underlying pathophysiology. For those interested in disease outcomes, a continuing evolution of data-based criteria is needed.

References

1. Weinstein BJ, Epstein FH. Comparability of criteria and methods in the epidemiology of cardiovascular disease. Report of a survey. Circulation 1964;30:643-653.
2. World Health Organization. Working group on the establishment of ischaemic heart disease registers: Report of the fifth working group. 1971; WHO Report No. Eur 8201(5); Copenhagen.
3. Gillum RF, Folsom A, Luepker RV, et al. Sudden death and acute myocardial infarction in a metropolitan area, 1970-1980. The Minnesota Heart Survey. N Engl J Med 1983;309:1353-1358.
4. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994;90:583-612.
5. Apple FS. Cardiac troponin monitoring for detection of myocardial infarction: Newer generation assays are here to stay. Clinica Chimica Acta 2007;380:1-3.
6. Apple FS, Jesse RL, Newby LK, et al. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical issues for biochemical markers of acute coronary syndromes. Clin Chem 2007;53:547-551.
7. Saenger AK, Jaffe AS. Requiem for a heavyweight: the demise of creatine kinase-MB. Circulation 2008;118:2200-2206.
8. Crow RS, Hannan PJ, Jacobs DR Jr, et al. Eliminating diagnostic drift in the validation of acute in-hospital myocardial infarction - implication for documenting trends across 25 years: the Minnesota Heart Survey. Am J Epidemiol 2005;161:377-388.
9. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined - a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36:959-969.
10. Luepker RV, Apple FS, Christenson RH, et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation 2003;108:2543-2549.
11. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007;28:2525-2538.
12. White HD. Evolution of the definition of myocardial infarction: What are the implications of a new universal definition? Heart 2008;94:679-684.
13. Polanczyk CA, Schneid S, Imhof BV, et al. Impact of redefining acute myocardial infarction on incidence, management and reimbursement rate of acute coronary syndromes. Int J Cardiol 2006;107:180-187.
14. Salomaa V, Ketonen M, Koukkunen H, et al. The effect of correcting for troponins on trends in coronary heart disease events in Finland during 1993-2002: the FINAMI study. Eur Heart J 2006;27:2394-2399.
15. Salomaa V, Koukkunen H, Ketonen M, et al. A new definition for myocardial infarction: what difference does it make? Eur Heart J 2005;26:1719-1725.
16. Hochholzer W, Buettner HJ, Trenk D, et al. New definition of myocardial infarction: impact on long-term mortality. Am J Med 2008;121:399-405.
17. Casals G, Filella X, Auge JM, Bedini JL. Impact of ultrasensitive cardiac troponin I dynamic changes in the new universal definition of myocardial infarction. Am J Clin Pathol 2008;130:964-968.

Long-Term Safety and Efficacy of Drug-Eluting versus Bare-Metal Stents in Sweden

Long-Term Safety and Efficacy of Drug-Eluting versus Bare-Metal Stents in Sweden
Stefan K. James, M.D., Ph.D., Ulf Stenestrand, M.D., Ph.D., Johan Lindbäck, M.Sc., Jörg Carlsson, M.D., Ph.D., Fredrik Scherstén, M.D., Ph.D., Tage Nilsson, M.D., Ph.D., Lars Wallentin, M.D., Ph.D., Bo Lagerqvist, M.D., Ph.D., for the SCAAR Study Group



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ABSTRACT

Background The long-term safety and efficacy of drug-eluting coronary stents have been questioned.

Methods We evaluated 47,967 patients in Sweden who received a coronary stent and were entered into the Swedish Coronary Angiography and Angioplasty Registry between 2003 and 2006 and for whom complete follow-up data were available for 1 to 5 years (mean, 2.7). In the primary analysis, we compared patients who received one drug-eluting coronary stent (10,294 patients) with those who received one bare-metal stent (18,659), after adjustment for differences in clinical characteristics of the patients and characteristics of the vessels and lesions.

Results Analyses of outcome were based on 2380 deaths and 3198 myocardial infarctions. There was no overall difference between the group that received drug-eluting stents and the group that received bare-metal stents in the combined end point of death or myocardial infarction (relative risk with drug-eluting stents, 0.96; 95% confidence interval [CI], 0.89 to 1.03) or the individual end points of death (relative risk, 0.94; 95% CI, 0.85 to 1.05) and myocardial infarction (relative risk, 0.97; 95% CI, 0.88 to 1.06), and there was no significant difference in outcome among subgroups stratified according to the indication for stent implantation. Patients who received drug-eluting stents in 2003 had a significantly higher rate of late events than patients who received bare-metal stents in the same year, but we did not observe any difference in outcome among patients treated in later years. The average rate of restenosis during the first year was 3.0 events per 100 patient-years with drug-eluting stents versus 4.7 with bare-metal stents (adjusted relative risk, 0.43; 95% CI, 0.36 to 0.52); 39 patients would need to be treated with drug-eluting stents to prevent one case of restenosis. Among high-risk patients, the adjusted risk of restenosis was 74% lower with drug-eluting stents than with bare-metal stents, and only 10 lesions would need to be treated to prevent one case of restenosis.

Conclusions As compared with bare-metal stents, drug-eluting stents are associated with a similar long-term incidence of death or myocardial infarction and provide a clinically important decrease in the rate of restenosis among high-risk patients.

Prospective, randomized clinical trials and meta-analyses have shown that rates of target-lesion revascularization are unequivocally lower with drug-eluting coronary stents than with bare-metal stents and that rates of death and myocardial infarction are similar.1,2,3,4 However, no randomized trials have been prospectively designed and powered for the evaluation of rare outcome events during very-long-term follow-up. Drug-eluting stents are also widely used in broader populations than those specified by the Food and Drug Administration (FDA) and for indications that are not approved by the FDA on the basis of prospective, randomized trials. Registry studies have also suggested that rates of death and myocardial infarction with drug-eluting stents are similar to or lower than those with bare-metal stents,5,6,7 but these studies have shown trends toward increased rates of late events with drug-eluting stents after discontinuation of clopidogrel therapy.8 Although the risk of stent thrombosis is highest early after stent implantation, incomplete neointimal coverage and hypersensitivity reactions from the polymers may increase the risk of late stent thrombosis.9 Therefore, very-long-term follow-up after cessation of dual antiplatelet therapy in large patient cohorts is important.

We have previously reported the outcomes among all patients who received coronary stents in Sweden during the 2003–2004 period, as recorded in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Our results indicated that there was an increase in late mortality among patients who received a drug-eluting stent.10 To obtain a more reliable estimate of the long-term outcome and efficacy, we have now extended the study to include all patients in Sweden who received a stent during the 2003–2006 period for whom at least 1 year of follow-up until the end of 2007 was available. We have also focused primarily on patients who received only one drug-eluting stent as compared with those who received one bare-metal stent, thereby allowing the adjustment for characteristics of lesions and stents in addition to characteristics of patients.

Methods

Study Population

In the present study, we included all patients in Sweden who had received a coronary stent during the period from January 1, 2003, through December 31, 2006, and for whom follow-up data were available for at least 1 year and up to 5 years. The analyses were based on the type of stent implanted at the first recorded procedure. In the primary analysis, patients who received only one drug-eluting stent at the initial percutaneous coronary intervention (PCI) were compared with patients who received only one bare-metal stent. In a secondary analysis, all patients who received any stent were included. For these analyses, patients who received at least one drug-eluting stent were assigned to the drug-eluting–stent group, regardless of whether they received a stent of another type at any time; all other patients were assigned to the bare-metal–stent group.

The SCAAR Data

The SCAAR records information on consecutive patients from all 29 centers that perform coronary angiography and PCI in Sweden. The list of the most important variables is shown in Table 1.11 Patients were informed about the registration, but written informed consent is not required by Swedish law.

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Table 1. Baseline Characteristics and Treatments in the Cohort of Patients Who Received Only One Stent and in the Cohort of All Patients Who Received One or More Stents.


Long-term follow-up data were obtained by merging the SCAAR database with other national registries on the basis of the unique 10-digit personal identification number that all Swedish citizens have. Vital status and date of death were obtained from the National Population Registry, and information on the incidence of myocardial infarction (International Classification of Diseases, 10th revision, codes I21 and I22) was obtained from the National Public Registry (in which information on diagnoses at hospital discharge are recorded); all this information was obtained through December 31, 2007. Merging of the registries was performed by the Epidemiologic Centre of the Swedish National Board of Health and Welfare and was approved by the ethics committee at Uppsala University. Since March 1, 2004, the electronic case-report form of the SCAAR requires that information about restenosis in every implanted stent be recorded at the time of any subsequent coronary angiography for a clinical indication.

The study and the statistical analysis were designed and interpreted by the authors, all of whom contributed to the final report and participated in the decision to submit the findings for publication. No stent manufacturer had any role in the study.

Statistical Analysis

The study methods have been described in detail previously.10 The primary objective was to evaluate late-occurring events after the implantation of a drug-eluting stent. The primary end point was the composite of death or myocardial infarction. Secondary end points were death, myocardial infarction, and restenosis. To compensate for the nonrandomized design of this study, propensity-score methods12 were used. The propensity score was defined as the conditional probability of receiving a drug-eluting stent on the basis of available variables and was estimated with a multiple logistic-regression model. All prespecified variables were included in the respective models (Table 1). To determine whether the propensity score would balance the baseline variables, a standardized mean of each variable was calculated for the drug-eluting–stent group. Standardization was performed according to the propensity-score distribution (categorized in deciles) in the bare-metal–stent group.

To provide separate descriptions of the early and late relative risks of events, we performed "landmark analyses"13 with a prespecified landmark set at 6 months. Adjusted relative risks were estimated with the use of Cox regression models in which the propensity score and the stent group were entered as covariates.

The risk of restenosis was evaluated in the complete sample of patients who received only one stent and in subgroups previously found to be at an increased risk for restenosis.5,14 We report the rate of restenosis at 1 year as well as the rate per 100 person-years, which was calculated as the ratio of the number of patients with an event within 1 year to the sum of the time at risk. The number of patients who would need to be treated with a drug-eluting stent to prevent one case of restenosis was calculated according to the method of Altman and Andersen.15 All analyses were performed with the use of the R statistical program, version 2.7.2.16

Results

Characteristics of Patients and Stents

During the 2003–2006 period, 48,892 patients were treated with 86,552 stents during a total of 55,465 PCIs in Sweden. The 925 patients (1.9%) with incomplete baseline data were excluded from the analyses. Table 1 shows the characteristics of the cohort of 10,294 patients who received one drug-eluting stent and 18,659 patients who received one bare-metal stent at the index procedure (one-stent cohort), as well as of the total cohort of 19,681 patients who received at least one drug-eluting stent and 28,286 patients who received one or more bare-metal stents but no drug-eluting stent. In the total cohort, the drug-eluting–stent group, as compared with the bare-metal–stent group, included a higher proportion of women and a larger number of patients who had features associated with a high risk of restenosis. In addition, more stents were implanted in the drug-eluting–stent group than in the bare-metal–stent group. Pretreatment with clopidogrel was more common and treatment with glycoprotein IIb/IIIa inhibitors was less common in the drug-eluting–stent group than in the bare-metal–stent group. The mean stent length was longer and the diameter smaller with drug-eluting stents than with bare-metal stents. On the other hand, as compared with patients in the drug-eluting–stent group, patients in the bare-metal–stent group were older and more likely to have cancer, three-vessel disease, and incomplete revascularization. Patients in the bare-metal–stent group were also treated with primary PCI for ST-segment elevation myocardial infarction considerably more often than patients in the drug-eluting–stent group (Table 1). After adjustment for the propensity score, however, the groups were similar with respect to all baseline characteristics.

Baseline characteristics for the one-stent cohort, stratified by year of inclusion in the study, are shown in Table 1 of the Supplementary Appendix (available with the full text of this article at NEJM.org). The regional differences in the use of drug-eluting stents were large and persisted over time. The frequencies of pretreatment with clopidogrel and the use of primary PCI for ST-segment elevation myocardial infarction increased in both the drug-eluting–stent group and the bare-metal–stent group over the course of the study. The average rate of use of drug-eluting stents during the entire period was 35.6% (18.8% in 2003, 32.9% in 2004, 47.7% in 2005, and 38.8% in 2006). Paclitaxel-eluting stents (TAXUS Express and TAXUS Liberté, Boston Scientific) were used in 6247 patients (21.6% of all patients in the one-stent cohort), sirolimus-eluting stents (CYPHER and CYPHER SELECT, Cordis, Johnson & Johnson) in 3351 (11.6%), and zotarolimus-eluting stents (Endeavor, Medtronic) in 686 (2.4%).

Death and Myocardial Infarction

During the 1 to 5 years of follow-up (mean, 2.7), a total of 5578 events occurred in 5046 patients in the one-stent cohort: 3198 myocardial infarctions (2044 in the bare-metal–stent group and 1154 in the drug-eluting–stent group) and 2380 deaths (1616 and 764 in the two groups, respectively). After adjustment for the propensity score, there was no overall difference in the composite incidence of death or myocardial infarction between the two groups (Figure 1A). During the initial 6 months, the event rate was lower in the drug-eluting–stent group than in the bare-metal–stent group (relative risk, 0.79; 95% confidence interval [CI], 0.71 to 0.87), but this difference was offset by a higher event rate in the drug-eluting–stent group thereafter (relative risk, 1.11; 95% CI, 1.01 to 1.23). There were no significant differences in event rates among patients who received paclitaxel-eluting stents, those who received sirolimus-eluting stents, and those who received zotarolimus-eluting stents (data not shown).

Figure 1
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Figure 1. Cumulative Rates of the Primary Composite End Point and Two of the Secondary End Points.

Cumulative event rates, estimated at the mean propensity score, are shown for patients who received one drug-eluting stent and those who received one bare-metal stent (Panels A, C, and D) and for those who received one or more drug-eluting stents (regardless of whether they received a stent of another type at any time) and those who received only bare-metal stents (one or more) (Panel B). The relative risks (with 95% confidence intervals [CIs]) are for the occurrence of an event among patients who received drug-eluting stents, as compared with those who received bare-metal stents.


In the total cohort, 9812 events occurred in 8824 patients; 5565 had at least one myocardial infarction (3292 in the bare-metal–stent group and 2273 in the drug-eluting–stent group), and 4247 died (2706 and 1541 in the two groups, respectively), with no overall difference between the groups (Figure 1B).

Adjusted mortality alone in the one-stent cohort was lower with drug-eluting stents than with bare-metal stents during the initial 6 months (relative risk, 0.76; 95% CI, 0.64 to 0.91) and was similar thereafter (relative risk, 1.08; 95% CI, 0.94 to 1.24), with the result that there was no overall long-term difference between the groups (Figure 1C). The adjusted rate of myocardial infarction was also lower with drug-eluting stents than with bare-metal stents during the initial 6 months (relative risk, 0.79; 95% CI, 0.70 to 0.90) but was higher thereafter (relative risk, 1.16; 95% CI, 1.03 to 1.32), with the result that there was no overall difference between the groups (Figure 1D). In addition, in the total cohort, mortality and rates of myocardial infarction were similar between the groups (relative risk of death with drug-eluting stents, 0.96; 95% CI, 0.89 to 1.03; relative risk of myocardial infarction with drug-eluting stents, 1.01; 95% CI, 0.95 to 1.08) (see Fig. IA and IB in the Supplementary Appendix).

Outcome Stratified by Indication

In subgroups defined according to the indication for implantation of a stent, there were no significant differences in the outcomes between the drug-eluting–stent group and the bare-metal–stent group. In the one-stent cohort, the adjusted event rate for the combined end point was lower with drug-eluting stents than with bare-metal stents during the initial 6 months but was similar during the subsequent period, with a similar pattern for all clinical indications (Figure 2).

Figure 2
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Figure 2. Landmark Analyses of the Primary Composite End Point in the One-Stent Cohort, Stratified According to the Indication for Stent Implantation.

Cumulative rates of death or myocardial infarction, estimated at the mean propensity score, are shown for the first 6 months and for the subsequent period among patients who received one drug-eluting stent and those who received one bare-metal stent. The relative risks (with 95% confidence intervals) are for the occurrence of an event among patients who received a drug-eluting stent, as compared with those who received a bare-metal stent. CAD denotes coronary artery disease, and STEMI ST-segment elevation myocardial infarction.


Outcome Stratified by Year of First Stent Implantation

In the one-stent cohort of patients treated in 2003, the rate of the composite end point was similar in the two groups during the initial 6 months (Figure 3A). During the subsequent 4.5 years of follow-up, the event curves diverged, with a significantly higher rate in the drug-eluting–stent group than in the bare-metal–stent group. In the 2004 cohort, the event rates were similar during the initial 6 months (Figure 3B), as well as during the subsequent 3.5 years of follow-up. In contrast, in the 2005 and 2006 cohorts, there were significantly lower event rates in the drug-eluting–stent group during the initial 6 months (Figure 3C and 3D), with similar event rates thereafter.

Figure 3
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Figure 3. Landmark Analyses of the Primary Composite End Point in the One-Stent Cohort, Stratified According to the Year of Stent Implantation.

Cumulative rates of death or myocardial infarction, estimated at the mean propensity score, are shown for the first 6 months and for the subsequent period among patients who received one drug-eluting stent and those who received one bare-metal stent. The relative risks (with 95% confidence intervals) are for the occurrence of an event among patients who received a drug-eluting stent, as compared with those who received a bare-metal stent.


In the 2003–2004 cohort, for whom data for up to 3 years were reported previously, extended follow-up for up to 5 years showed no significant difference in the primary event rates, because a trend toward a lower combined event rate with drug-eluting stents during the initial 6 months (relative risk, 0.89; 95% CI, 0.80 to 1.00) was offset by a higher event rate thereafter (relative risk, 1.19; 95% CI, 1.09 to 1.29) (Fig. II in the Supplementary Appendix).

Restenosis and New Revascularization

On the basis of SCAAR data for the period from March 2004 through May 2008, restenosis occurred in 683 of 12,358 patients who received bare-metal stents (5.5%), as compared with 387 of 8648 patients who received drug-eluting stents (4.5%). In a Cox regression analysis that adjusted for differences in baseline clinical characteristics of the patients as well as characteristics of the lesions and stents at baseline, the rate of restenosis was lower among patients who received drug-eluting stents than among those who received bare-metal stents (relative risk, 0.43; 95% CI, 0.36 to 0.52) (Table 2). Accordingly, to prevent one case of restenosis per year, 39 lesions would need to be treated with drug-eluting stents. Stent diameter was the most important factor contributing to the reduction in the rate of restenosis with drug-eluting stents. For stents that were less than 3 mm in diameter, the absolute rate of restenosis at 1 year was 3.6 percentage points lower with drug-eluting stents than with bare-metal stents; the corresponding adjusted risk reduction was 65%, and the number needed to treat was 22. The number needed to treat was more than twice as high in the case of larger stents. The incidence of clinical restenosis was highest among patients with diabetes who received bare-metal stents that were 20 mm long or longer and less than 3 mm wide; the absolute rate of restenosis for this subgroup was 8.3 percentage points higher per year than the rate for patients with diabetes who received equivalent-size drug-eluting stents, and the number needed to treat was 10.

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Table 2. Restenosis in Subgroups of Patients Who Received Only One Stent.


In the group that received drug-eluting stents, 1571 patients (15.3%) underwent a repeat PCI and 222 (2.2%) underwent coronary-artery bypass grafting during the 1 to 5 years of follow-up. In the bare-metal–stent group, the corresponding numbers were 2780 (14.9%) and 501 (2.7%), respectively. Among the 1423 patients who received a second stent, the median intervals to repeat PCI were similar (696 days in the drug-eluting–stent group and 693 in the bare-metal–stent group). In a Cox regression analysis, the drug-eluting–stent group, as compared with the bare-metal–stent group, had lower adjusted rates of any repeat revascularization (relative risk, 0.89; 95% CI, 0.83 to 0.96) and of a repeat PCI (relative risk, 0.90; 95% CI, 0.84 to 0.97). In addition, the rate of coronary-artery bypass grafting tended to be lower in the drug-eluting–stent group than in the bare-metal–stent group (relative risk, 0.87; 95% CI, 0.72 to 1.06).

Discussion

In this study, we evaluated the long-term outcome with drug-eluting stents as compared with bare-metal stents in a very large cohort of unselected, consecutive patients, from all interventional centers in Sweden, in whom a coronary stent was implanted. The conclusion of our previous study10 was based on the total patient population for the 2003–2004 period, which included patients who received multiple stents. With the extended study period, we were able to collect data on a sufficient number of patients (28,953) and primary-outcome events to evaluate patients who received only one stent (either a drug-eluting stent or a bare-metal stent) during the index procedure. This one-stent cohort was more than 30% larger than the total patient cohort in the earlier SCAAR study, which included patients who received any number of stents (19,771),10 and the total number of patients in a network meta-analysis that included 23 randomized trials (18,023).4 The one-stent cohort allowed for adjustments for lesion, vessel, and stent characteristics in the multivariable analyses, which provided a better balance between the drug-eluting–stent group and the bare-metal–stent group. The availability of this information reduced the difference in the outcome between the two cohorts, explaining in part the difference between the findings for the previous total cohort and the current one-stent cohort.

One factor that may explain the difference in the outcome between the current and previous analyses is a change in the outcome over time, with an early outcome that became gradually worse in the bare-metal–stent group and gradually better in the drug-eluting–stent group. The most important change in clinical practice during the extended study period was an increase in the use of primary PCI for patients with ST-segment elevation myocardial infarction. The proportion of such patients who received stents increased more in the bare-metal–stent group than in the drug-eluting–stent group. An increasing proportion of patients pretreated with clopidogrel, progressively higher balloon pressures, and a gradual increase in the duration of clopidogrel treatment after the implantation of drug-eluting stents might have contributed to the relatively lower rate of late events in the drug-eluting–stent group in the current study as compared with the rates in our previous study.

The average use of drug-eluting stents increased during the study period, but the variations among centers and among indications for stent implantation remained large. Although the geographic differences accounted for most of the difference in the use of drug-eluting stents, stent selection was also based on risk criteria for restenosis, as suggested by the higher percentage of patients with high-risk clinical and angiographic features in the drug-eluting–stent group.17 Stent selection was also based on the clinical risk of an adverse outcome, since ST-segment elevation myocardial infarction was more common in the bare-metal–stent group. However, the multivariable propensity-score analysis was very effective in adjusting for differences in the characteristics for which we had data (Table 1).

There was no significant difference in the primary composite end point between the drug-eluting–stent group and the bare-metal–stent group during long-term follow-up. In the initial 6 months, mortality tended to be lower in the group that received drug-eluting stents than in the group that received bare-metal stents, a finding that is consistent with the results of other registry studies.5,8,18 In contrast to the results of our previous study of SCAAR data, the current study shows no late-occurring increase in mortality after implantation of drug-eluting stents. This finding is consistent with the results of randomized trials, meta-analyses, and large-scale registry studies.4,19,20 Although late and very-late stent thromboses appear to occur infrequently,8,9 they might still affect mortality.21 The lower clinical need for reinterventions with drug-eluting stents (with an adjusted rate that was 10% lower than that with bare-metal stents) may, however, have led to a subsequent reduction in fatal events, offsetting a possible increase in the risk of late stent thrombosis.22

There seemed to be a trend toward a very-late increase in the rate of myocardial infarction among patients who received drug-eluting stents, a finding that is consistent with the slightly higher rate of myocardial infarction after the cessation of clopidogrel therapy in other registry studies and in extended follow-up analyses of data from randomized trials.5,8,23,24 However, the upward shift in the rate of myocardial infarction that occurred very late in the drug-eluting–stent group appears to represent an increased event rate only among patients who were treated in 2003, rather than an actual increase of events in the total cohort. Unmeasured selection bias during the period when drug-eluting stents were first available may have contributed to this result. In the subgroups of patients who had stent procedures in 2004, 2005, and 2006, the event rates were similar between the drug-eluting–stent group and the bare-metal–stent group, without any signal of an increase in late events.

The average crude absolute rate of restenosis at 1 year was low with both stent types and was 1.5 percentage points lower with drug-eluting stents than with bare-metal stents, corresponding to an average 50% relative reduction in the adjusted rate of clinical restenosis. The overall absolute rate of restenosis in this study was lower than the rates in randomized clinical trials but similar to the rates in other registry studies.25,26,27 The low rates of restenosis and of reintervention after implantation of bare-metal stents and the small absolute difference between these rates and the rates for drug-eluting stents do not support the use of drug-eluting stents in patients who are at low or intermediate risk for restenosis. On the basis of the data from the one-stent cohort, this trial clearly shows that when lesions require stents that are less than 3 mm in diameter and 20 mm or more in length, the event rate for restenosis with bare-metal stents is approximately 11 per 100 person-years in patients without diabetes and 15 per 100 person-years in patients with diabetes, a risk that is reduced with drug-eluting stents to approximately 4 in patients without diabetes and 5 in patients with diabetes. For patients with such lesions, drug-eluting stents provide a clear clinical benefit, with one case of restenosis averted for every 10 to 14 lesions treated — a number needed to treat that is reduced by a factor of four as compared with that for patients at average risk and by a factor of six as compared with that for patients at low risk for restenosis.

The inherent limitations of a nonrandomized, registry study should be acknowledged. Despite appropriate statistical adjustments, unknown confounders may have affected the results. Moreover, it is not possible to attribute individual events to the individual stents or the stented vessel. Another major limitation of our study is the lack of information about the duration of clopidogrel treatment, making it impossible to determine whether the timing of events was related to discontinuation of the drug.8 Prolongation of clopidogrel treatment in later years may have contributed to the differences in the outcome over time.

In conclusion, in the present study, which included a very large, consecutive cohort of all patients who received a coronary stent in Sweden during a 4-year period and who were followed for 1 to 5 years, there was no difference in long-term survival or in the risk of myocardial infarction between the patients who received drug-eluting stents and those who received bare-metal stents. Among patients who required stents that were less than 3 mm in diameter and 20 mm or more in length, there was a relative reduction of approximately 70% and an absolute reduction of more than 10 percentage points in the rate of clinical restenosis. Thus, the use of drug-eluting stents is safe and, in patients with lesions at high risk for restenosis, is also very effective in reducing the risk of clinical restenosis.

Supported by grants from the Swedish Association of Local Authorities and Regions and the Swedish Heart–Lung Foundation (to SCAAR and the Uppsala Clinical Research Center) and the Swedish Board of Health and Welfare and the Swedish Medical Products Agency.

Dr. James reports receiving lecture fees from Boston Scientific, Cordis, and Eli Lilly; and Dr. Scherstén, consulting fees from Medtronic. No other potential conflict of interest relevant to this article was reported.

* Members of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) study group are listed in the Appendix.


Source Information

From the Department of Cardiology, Uppsala University Hospital, Uppsala (S.K.J., L.W., B.L.); the Department of Cardiology, University Hospital Linköping, Linköping (U.S.); the Department of Cardiology, Länssjukhuset Kalmar, Kalmar (J.C.); the Department of Cardiology, Helsingborg Lasarett, Helsingborg (F.S.); Svensk PCI, Karlstad Lasarett, Karlstad (T.N.); and Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala (S.K.J., J.L., L.W., B.L.) — all in Sweden.

Address reprint requests to Dr. James at the Uppsala Clinical Research Center, Uppsala University Hospital, 751 85 Uppsala, Sweden, or at stefan.james@akademiska.se.

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Appendix

The members of the SCAAR study group are as follows: SCAAR Steering Committee — S. James, Uppsala (chair); B. Lagerqvist, Uppsala (vice chair); T. Nilsson, Karlstad; E. Omerovic, Göteborg; J. Carlsson, Kalmar; J. Nilsson, Umeå; N. Saleh, Stockholm; O. Fröbert, Örebro; A. Flinck, Göteborg; F. Scherstén, Helsingborg; G. Olivecrona, Lund. Uppsala Clinical Research Center — L. Wallentin (director); R. Svensson (system developer); O. Felton (system developer); K. Spångberg (data manager); E. Svensson (monitor). Epidemiologic Center, Swedish Board of Health and Welfare — M. Köster (statistician). SCAAR hospitals and participating physicians — Borås: L. Robertson; Danderyd: T. Särev; Eskilstuna: F. Hjortevang; Falun: I. Sjögren; Gävle: L. Hellsten; Halmstad: P. Hårdhammar; Helsingborg: L. Sandhall; Karolinska University in Huddinge: B. Lindvall; Kalmar: J. Carlsson; Karolinska University in Solna: N. Saleh; Karlskrona: C.-M. Pripp; Kristianstad: R. Uher; Linköping University: U. Stenestrand; Lund University: B. Thorvinger; Ryhov in Jönköping: W. Puskar; Malmö University: C.-G. Gustavsson; Sahlgrenska University in Göteborg: P. Albertsson; Skövde: A. Kallryd; St. Göran in Stockholm: H. Enhörning; Sunderby in Luleå: A. Johansson; Södersjukhuset in Stockholm: M. Aasa; Trollhättan: D. Ioanes; Umeå University: J. Nilsson; Uppsala University: B. Lagerqvist; Västerås: O. Herterich; Örebro University: O. Fröbert.




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