Routine Invasive Versus Ischemia-Guided Strategy in Patients with Acute Inferior ST-Elevation Myocardial Infarction who Received Fibrinolytic Therapy: A Prospective Randomized Controlled Pilot Trial

ABSTRACT: Aims. We sought to compare a routine invasive strategy of early coronary angiography and intended revascularization, with an ischemia-guided strategy in patients with acute inferior ST-elevation myocardial infarction (STEMI) who received fibrinolytic therapy. Methods. We enrolled 60 consecutive patients with acute inferior STEMI who received fibrinolytic therapy within 6 hours. Patients were randomly assigned to either a routine invasive strategy in which coronary angiography was performed within 48 hours with intended revascularization if eligible (Group A), or an ischemia-guided strategy in which catheterization was based on the presence of myocardial ischemia and viability as demonstrated by stress myocardial perfusion imaging (Group B). Patients were prospectively followed up for 6 months. The primary endpoint was a composite of cardiac death, recurrent myocardial infarction, recurrent ischemia or stroke at 6-month follow-up. Total costs per patient were calculated over 6 months. Results. The mean age of the whole series was 52 ± 9.8 years (15% females). The primary endpoint occurred more frequently in group A as compared to group B, however, the difference did not meet statistical significance (36.7% versus 23.3%, respectively, p >0.05). The mean cost per patient at 6-month follow-up was significantly higher in Group A as compared to that in Group B ($4953.5 ± 3108.5 versus $2764.6 ± 2636.7, respectively, p <0.01). Conclusions. In patients presenting with inferior STEMI who received fibrinolytic therapy, a routine invasive strategy with early coronary angiography and intended revascularization, achieved a clinical outcome similar to an ischemia-guided strategy; yet, at a significantly higher cost.

J INVASIVE CARDIOL 2011;23:316–321

Key words: myocardial infarction; percutaneous coronary intervention; myocardial perfusion imaging

_____________________________________________

Acute myocardial infarction (MI) is a major cause of death and disability worldwide.¹ Prognosis of patients following acute MI depends on the severity of left ventricular damage,^2,3 and patency of the infarct-related artery (IRA) after reperfusion therapy.⁴ Fibrinolytic therapy remains the most common form of reperfusion therapy for ST-elevation myocardial infarction (STEMI) in many countries, despite the proven advantages of primary percutaneous coronary intervention (PCI), owing to the limited availability of hospitals with cardiac catheterization facilities or the long times needed for transfer of patients from distant areas to these hospitals. Yet, many studies showed that in the first 1–2 hours after the onset of chest pain, the benefit of fibrinolytic therapy was greatest with an ensuing 50% mortality reduction.^5,6

The best subsequent management after fibrinolytic therapy remains controversial. It is unclear whether an “invasive strategy” with routine early coronary angiography (CA) after fibrinolytic therapy is better than a “conservative strategy” in which catheterization is reserved to patients with clinical evidence of ischemia. Many studies have shown an improvement of clinical outcome with the routine invasive strategy; hence, they advocated that STEMI patients treated with fibrinolytic therapy should be routinely transferred to PCI within 24 hours from initial hospitalization.^7,8 So far, being an invasive procedure, catheterization always carries an inherent risk; therefore, it is important to select those patients who would eventually gain the highest benefit from angioplasty to the IRA following a recent MI.⁹ The absence of ischemia on myocardial perfusion imaging (MPI) in the aftermath of MI, suggests that a conservative management strategy would be appropriate.¹⁰ Guidelines of 2002 and 2003 on cardiac radionuclide stress imaging recommended the use of radionuclide imaging techniques for assessment of risk, prognosis, and subsequently, for planning immediate and long-term therapy following STEMI.^11,12

Since most patients presenting with acute inferior STEMI ultimately have a normal or near normal left ventricular systolic function following fibrinolytic therapy, there was a trend toward a more conservative strategy in this patient category. In a prospective randomized pilot study design, we sought to compare a routine invasive strategy of early CA and intended revascularization, with an ischemia-guided strategy in which catheterization is based on risk stratification by stress MPI, in patients with acute inferior STEMI who received fibrinolytic therapy.

Patients and Methods

Patient selection. The current study enrolled 60 consecutive patients who presented to the intensive care unit during the period from May 2008 to July 2009 with acute inferior STEMI and received fibrinolytic therapy within 6 hours of the onset of chest pain. Acute inferior STEMI was defined as ≥1 mm ST segment elevation in at least 2 of the inferior leads with rise of biochemical markers of myocardial necrosis (CK-MB and troponin), at least twice the upper limit of normal lab reference. We excluded patients with left bundle branch block, those with a contraindication to fibrinolytic therapy, those with unsuccessful fibrinolytic therapy as evidenced by less than 50% ST-segment resolution 90 minutes following the infusion of fibrinolytic agent, and pregnant patients. An informed written consent was obtained from each patient, after full explanation of the study protocol, and the study protocol was reviewed and approved by our local Institutional Human Research Committee as it conforms to the ethical guidelines of the American Physiological Society.

Study design. Patients were randomly assigned to one of the following 2 therapeutic strategies:

Routine invasive strategy (Group A), which included 30 patients who were scheduled for routine CA performed within 48 hours of the onset of acute MI with intended revascularization if eligible.

Ischemia-guided strategy (Group B), which included 30 patients who were scheduled for risk stratification based on stress MPI performed within one week of the onset of acute MI.

Randomization was performed by an independent statistician who has drawn a computer-generated randomization list, and provided it to the intensive care unit. Individual patient randomization was performed once the patient developed signs of successful fibrinolytic therapy, as evidenced by 50% or more ST segment resolution 90 minutes following the infusion of fibrinolytic agent.

Pharmacological intervention. All patients received fibrinolytic therapy in the form of streptokinase given at a dose of 1 500,000 U, administrated by intravenous infusion for 30–60 minutes, started within 6 hours of the onset of chest pain. Patients received oral chewable aspirin 300 mg initially at the time of admission, followed by 150 mg daily orally, indefinitely. Clopidogrel (Plavix^®, Sanofi-Aventis, France) was initiated in a loading oral dose of 300 mg given at the time of admission, followed by 75 mg daily orally. Clopidogrel was continued for one month in patients who did not undergo revascularization; while in patients who underwent revascularization with coronary stenting, clopidogrel was given for at least one month, extended thereafter at the operator’s discretion. Intravenous enoxaparin (Clexane^®, Sanofi-Aventis, France) 30 mg was given immediately after fibrinolytic therapy, followed by a dose of 1 mg/kg given by subcutaneous injection every 12 hours for at least 72 hours. Other anti-ischemic treatment was given according to the contemporary guidelines.

Coronary angiography and revascularization. CA was performed to all patients in Group A within 48 hours of the onset of acute MI and revascularization was performed to eligible patients. In Group B, CA was performed if stress MPI showed ischemia and viability (≥ 50% radiotracer uptake) in the index vessel territory or if the patient had ongoing ischemia (persistent chest pain and/or dynamic ECG changes) despite optimal medical treatment, hemodynamic or rhythm instability. Cardiac catheterization was carried out via a right or left femoral artery puncture. Additional heparin was administered in the cath lab according to the timing of the last dose of enoxaparin, according to the updated guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) for the management of acute STEMI, and further doses of heparin were administered according to the activated clotting time (ACT), with a target ACT of 250 seconds. Significant coronary stenosis was defined as 70% or more luminal obstruction of at least one sizable epicardial coronary artery (measuring 2.5 mm or more in diameter), seen in 2 different projections, or at least 50% luminal obstruction of the left main coronary artery. Total coronary occlusion was defined as 100% luminal obstruction with Thrombolysis In Myocardial Infarction (TIMI) grade 0 forward flow distal to the site of obstruction. Angioplasty was performed during the same catheterization, to culprit and non-culprit lesions unless CA identified diffuse disease not amenable to revascularization. Direct stenting was attempted in all cases. Lesions were treated according to the contemporary interventional techniques. Procedural success was defined as successful implantation of stent with TIMI grade 3 distal flow, and residual stenosis < 20%, without dissection or thrombus formation. Coronary artery bypass grafting was recommended in patients with extensive three-vessel disease or significant left main disease and was performed as soon as possible (within one week) following diagnostic catheterization.

Stress MPI protocol. Stress MPI study was performed only for patients in Group B within one week of the onset of acute MI. Two-day protocol with stress and rest imaging was adopted being performed on two separate days using 99mTc-sestamibi agent. A submaximal exercise test was performed according to the modified Bruce protocol and the radiotracer (8-10 mCi of 99mTc-sestamibi) was injected through an indwelling intravenous cannula when one of the following occurred: target heart rate achieved, significant ST depression or chest discomfort. Exercise testing was then continued for another 45–60 seconds. Imaging was ultimately performed 1–2 hours later. Patients underwent the rest study on the second day and another dose of the radiotracer (24–30 mCi of 99mTc-sestamibi) was injected at rest then imaging was performed 1–2 hours later. Image acquisition was implemented using a single-head gamma camera (General Electric Star-cam 4000i, United Kingdom) equipped with a low-energy high-resolution all-purpose collimator. An arc of 180° was used, spanning from the 45° right anterior oblique to the 45° left posterior oblique projections. A total of 32 images were obtained, 20 seconds each, using a 64 x 64 acquisition matrix with photon energy limits set at 20% window around the 140-keV peaks of 99mTc-sestamibi. All studies were subjected to quality-control checks and corrections when necessary for camera non-uniformity, center-of-rotation offsets, patient motion, and “upward creep”.¹³

99mTc-sestamibi image analysis. Two experienced nuclear cardiologists analyzed the 99mTc-sestamibi images. Assignment of myocardial segments to the vascular distribution of major coronary arteries was performed according to the 17-segment scoring system.¹⁴ The presence of fixed or reversible perfusion defects within and outside the infarct territory was determined. Patients with demonstrated ischemia and viability (defined as ≥ 50% radiotracer uptake) in the index vessel territory were scheduled for CA with intended revascularization, if eligible. Patients with no demonstrated ischemia or with demonstrated ischemia without viability (< 50% radiotracer uptake) in the index vessel territory, were scheduled for optimal medical treatment alone.

Study endpoints and definitions. The primary endpoint was a composite of cardiac death, recurrent MI, recurrent ischemia or cerebrovascular stroke at 6-month follow-up. The secondary endpoint was a composite of cardiac death or recurrent MI at 6-month follow-up. Recurrent MI was defined as recurrent ischemic symptoms at rest lasting ≥ 30 minutes and accompanied by 1) new or recurrent ST segment elevation ≥ 1 mm in at least two contiguous leads, 2) new left bundle branch block, or 3) elevated biochemical markers of myocardial necrosis > twice the upper limit of normal lab reference (or ≥ 50% above the lowest level measured previously in case of in-hospital recurrent MI). Recurrent ischemia was defined as recurrent ischemic symptoms at rest associated with new ST segment depression or T wave changes, hypotension or pulmonary edema. Cerebrovascular stroke was defined as focal neurological symptoms persisting for > 24 hours.

Clinical follow-up. Patients were prospectively followed for a period of 6 months from the onset of randomization, by means of clinic visits or telephone contacts by the attendant cardiologists. Follow-up stressed upon the occurrence of the study endpoints. Echocardiographic reassessment was repeated 4–6 months from the onset of acute MI. Any noninvasive tests (as stress test or MPI) or repeated revascularization were also reported during the period of follow-up.

Statistical analysis. Continuous variables were presented as mean ± SD, if they were normally distributed. Data were tested for normal distribution using the Kolmogorov-Smirnov test. Categorical variables were described with absolute and relative (percentage) frequencies. Comparisons between the 2 individual groups were performed using the unpaired t-test for continuous variables, and Pearson’s χ2 test for categorical variables. Pearson’s correlation coefficient test was performed to study the correlation between the primary and secondary endpoints on one hand and the different clinical and angiographic characteristics, on the other. Then, multivariate logistic regression analysis was performed to identify the independent predictors of the primary and secondary endpoints. Finally, Kaplan Meier’s event-free survival curves were depicted for the 2 groups and the differences between the 2 curves was assessed using Log rank test. All tests were two-sided and a probability value of p < 0.05 was considered statistically significant. Analyses were performed with SPSS version 12.0 statistical package (SPSS Inc., Chicago, Illinois).

Cost analysis. All enrolled patients consented access to their hospital bills. Summary charge reports for the index hospitalization were obtained from the Hospital Finance Office. The total hospital costs were calculated for each individual patient (including the cost of catheterization and revascularization procedures, or MPI) and were registered in a central database. Hospital costs were then added to the costs of subsequent dual anti-platelet therapy; subsequent hospitalization, if any; subsequent noninvasive tests (as stress test or MPI) or repeat revascularization, if any; from the time of hospital discharge to the end of follow-up period.

Results

Baseline characteristics. A total of 30 patients were randomly assigned to the routine invasive strategy and 30 randomly assigned to the ischemia-guided strategy. Baseline characteristics and echocardiographic data are shown in Table 1. The mean age of the whole series was 52 ± 9.8 years (15% females). There were no statistically significant differences between the 2 groups regarding the coronary risk factors and echocardiographic parameters (p > 0.05 for all). The pharmacological regimens received were balanced between the 2 groups. All patients in Group A underwent CA, however, revascularization was performed in 24 patients (80%); 23 cases of PCI and one case of coronary artery bypass grafting. In Group B, 24 patients (80%) underwent CA, however, revascularization was performed in 16 patients (53.3%); 14 cases of PCI and 2 cases were referred for coronary artery bypass grafting; one of them died during preparation for surgery. Six patients (20%) in Group B were scheduled for optimum medical therapy alone; based on their stress MPI results (Table 2). There were no statistically significant differences between the 2 groups regarding the angiographic characteristics, as shown in Table 3 (p > 0.05 for all).

Follow-up data. Follow-up data are shown in Table 4. The primary endpoint occurred more frequently in Group A as compared to Group B, however, the difference did not meet statistical significance (36.7% versus 23.3%, respectively, p >0.05). On the other hand, the secondary endpoint occurred more frequently in Group B as compared to Group A; again, the difference did not meet statistical significance (16.7% versus 13.3%, respectively, p > 0.05). Univariate and multivariate logistic regression analyses did not identify any predictors of the primary or secondary endpoints. Kaplan Meier’s event-free survival curves revealed no significant difference in the time distribution of events (Figure 1).

Cost analysis. The mean cost per patient from the onset of admission till the end of follow-up period was significantly higher in Group A as compared to that in Group B ($4953.5 ± 3108.5 versus $2764.6 ± 2636.7, respectively, p <0.01).

Discussion

The current pilot study demonstrated that in patients with acute inferior STEMI who received fibrinolytic therapy, the adoption of a routine invasive strategy with early CA and intended revascularization in eligible patients, achieved a clinical outcome that was not superior to a ‘conservative’ ischemia-guided strategy based on the presence of myocardial ischemia and viability as demonstrated by MPI results; yet, at a significantly higher cost.

In view of the current literature. An early invasive strategy is assumed to achieve rapid stabilization of the culprit ‘vulnerable’ plaque in patients who might otherwise develop recurrent ischemic events following an initially successful fibrinolytic therapy. Additionally, it can restore coronary blood flow in patients with persistently occluded IRA, who are sometimes difficult to discriminate, solely, on the basis of symptom relief and ST segment resolution. Routine early PCI after fibrinolytic therapy has been recommended, based on the results of many randomized controlled trials published over the past decade, as a favored strategy to optimize early reperfusion and prevent re-infarction and recurrent ischemia.^5,15–20 Yet, the most updated guidelines of European Society of Cardiology and ACC/AHA, have ‘granted’ just a Class IIa recommendation for routine early PCI within 3–24 hours following successful fibrinolytic therapy.^21,22 This reluctance of the world’s 2 foremost authorities to fully recommend the routine invasive strategy, reflected the lack of reduction of the ‘hard’ endpoints such as death and re-infarction in any of these trials, at the time these guidelines were released. Nevertheless, a recent metanalysis of the aforementioned trials demonstrated a significant reduction of re-infarction, recurrent ischemia, and the composite of death/re-infarction at 30 days, with routine early PCI; benefits persisted at 6-12 months follow-up.²³

The category of inferior MI. Inferior MI is usually associated with less myocardial damage, smaller infarct size, a better preserved left ventricular systolic function, and hence a better prognosis, as compared with anterior MI. The enrollment of patients with inferior MI (who have a relatively lower risk) together with anterior MI patients (with the offending high risk) in the aforementioned randomized controlled trials, would have diluted the results and contributed, at least in part, for the absence of reduction of the ‘hard’ endpoints in each trial individually, and the absence of mortality reduction even in the metaanalysis of all trials. In our quest to support this hypothesis, and in a trial to put forward a clinically useful paradigm for the management of patients with inferior MI who received fibrinolytic therapy, we sought to identify the best subsequent strategy in this particular category of patients. To the best of the authors’ knowledge, the current study is the first to date in literature to compare a routine ‘early invasive’ strategy with a more conservative ischemia-guided strategy, exclusively in patients presenting with inferior MI.

Clinical implications. The fact that the routine invasive strategy did not achieve a significant reduction of the composite endpoints, nor their individual components, in this patient category would underscore the importance of a more ‘selective’ approach for the adoption of the routine invasive strategy in post-MI patients who received fibrinolytic therapy. Moreover, the achievement of a similar clinical outcome with the implementation of the ischemia-guided strategy, with a significant reduction of the ‘cost per patient’, would suggest this strategy is the one ‘of first choice’ in the specific category of patients with inferior MI. In the modern era of escalating healthcare costs, physicians will do both the patients and the ‘Healthcare System’ a great favor by resorting to “less-costly” means of managing post-MI patients. Further prospective randomized controlled trials are needed to compare the 2 strategies, exclusively, in patients presenting with anterior MI.

Conclusions

In a pilot study, we demonstrated that in patients presenting with inferior STEMI who received fibrinolytic therapy, a routine invasive strategy with early CA and intended revascularization, achieved a clinical outcome similar to an ischemia-guided strategy based on the results of stress MPI; yet, at a significantly higher cost. Further large-scale studies are needed for solid conclusions to be drawn.

Limitations of the study. Our findings are based on a single center study with a relatively small sample size of the cohort. Multi-center studies using the same protocol and examining a larger number of patients are needed. Moreover, we employed streptokinase, a non-fibrin-specific lytic agent, with lower rates of reperfusion as compared to fibrin-specific agents used in most randomized controlled trials, and this would complicate the direct comparison with these trials. Since the study was not blinded, outcome should have been adjudicated in a blinded manner. Although the incidence of cerebrovascular stroke was assessed as a safety endpoint, bleeding – an important safety endpoint – was not assessed; hence the results should be taken with caution from the safety point of view. Ultimately, further extended periods of follow-up would be more useful to delineate the long-term outcome of the index strategies.

References

1. Fonarow GC. Practical considerations of beta-blockade in the management of the post-myocardial infarction patient. Am Heart J 2005;149:984–993.
2. Lee KS, Marwick TH, Cook SA, et al. Prognosis of patients with left ventricular dysfunction with and without viable myocardium after myocardial infarction: Relative efficacy of medical therapy and revascularization. Circulation 1994;90:2687–2694. 
3. Underwood SR, Godman B, Salyani S, et al. Economics of myocardial perfusion imaging in Europe-the EMPIRE Study. Eur Heart J 1999;20:157–166.
4. Goldman LE, Eisenberg MJ. Identification and management of patients with failed thrombolysis after acute myocardial infarction. Ann Intern Med 2000;132:556–565.
5. Goldstein P, Wiel E. Management of prehospital fibrinolytic therapy in ST-segment elevation acute coronary syndrome (< 12 hours). Minerva Anesthesiol 2005;71:297–302.
6. Coccolini S, Fresco C, Fioretti M. Early prehospital thrombolysis in acute myocardial infarct: A moral obligation? Ital Heart J Suppl 2003;4:102–111.
7. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomized, multicentre trial. Lancet 2008;371:559–568.
8. Wijeysundera HC, You JJ, Nallamothu BK, et al. An early invasive strategy versus ischemia-guided management after fibrinolytic therapy for ST-segment elevation myocardial infarction: A meta-analysis of contemporary randomized controlled trials. Am Heart J 2008;156:564–572.
9. van Loon RB, Veen G, Kamp O, Bronzwaer JG, et al. Early and long-term outcomes of elective stenting of the infarct-related artery in patients with viability in the infarct-area: Rational and design of the Viability-guided Angioplasty after acute Myocardial Infarction-trial (The VIAMI-trial). Curr Control Trials Cardiovasc Med 2004;5:11.
10. Udelson JE, Flint EJ. Radionuclide imaging in risk assessment after acute coronary syndromes. Heart 2004;90:v16–25.
11. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging-executive summary: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical use of Cardiac Radionuclide Imaging). Circulation 2003;108:1404–1418.
12. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging-executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical use of Cardiac Radionuclide Imaging). J Am Coll Cardiol 2003;42:1318–1333.
13. Knudsen AS, Darwish AZ, Nørgaard A, et al. Time course of myocardial viability after acute myocardial infarction: An echocardiographic study. Am Heart J 1998;135:51–57.
14. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539–542.

15. Le May MR, Wells GA, Labinaz M, et al. Combined Angioplasty and Pharmacological Intervention versus Thrombolysis Alone in Acute Myocardial Infarction (CAPITAL AMI study). J Am Coll Cardiol 2005;46:417–424.
16. Fernandez-Avilés F, Alonso JJ, Castro-Beiras A, et al. Routine invasive strategy within 24 hours of thrombolysis versus ischemia-guided conservative approach for acute myocardial infarction with ST-segment elevation (GRACIA-1): A randomized controlled trial. Lancet 2004;364:1045–1053.
17. Armstrong PW; WEST Steering Committee. A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: The WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J 2006;27:1530–1538.
18. Bøhmer E, Hoffmann P, Abdelnoor M, et al. Efficacy and safety of immediate angioplasty versus ischemia-guided management after thrombolysis in acute myocardial infarction in areas with very long transfer distances. Results of the NORDISTEMI (NORwegian study on District treatment of ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2010;55:102–110.
19. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009;360:2705–2718.
20. Scheller B, Hennen B, Hammer B, et al. Beneficial effect of immediate stenting after thrombolysis in acute myocardial infarction. J Am Coll Cardiol 2003;42:634–641.
21. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909–2945.
22. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:210–247.
23. Borgia F, Goodman SG, Halvorsen S, et al. Early routine percutaneous coronary intervention after fibrinolysis vs. standard therapy in ST-segment elevation myocardial infarction: A meta-analysis. Eur Heart J 2010;31:2156–2169.

_____________________________________________

From the Cardiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 19, 2011 and accepted May 6, 2011.
Address for correspondence: Samah Abdul-Rahman, MSc, Cardiology Department, Ain Shams University Hospitals, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt P.O. 11361. Email: sesame882000@yahoo.com