Effect of Thrombolytic Therapy on the Risk of Cardiac Rupture and Mortality in Older Patients With First Acute Myocardial Infarction

General Cardiology

both before and after PCI without a significant increase in major or minor bleeding. These data add further support to the early use of clopidogrel in STEMI and the broader strategy of clopidogrel pretreatment in patients undergoing PCI. The PCI-CLARITY study provides important data, and suggests that patients receiving thrombolytic therapy for STEMI should also receive a 300-mg loading dose of clopidogrel followed by 75 mg daily. All patients not receiving a loading dose within several days of angiography should also be considered for clopidogrel retreatment (i.e., repeat loading dose) at the time of PCI. Debabrata Mukherjee

Abstracts Effect of Clopidogrel Pretreatment Before Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction Treated With Fibrinolytics: The PCI-CLARITY Study Sabatine MS, Cannon CP, Gibson CM, et al. for the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. JAMA 2005;294:1224 –32.

Effect of Thrombolytic Therapy on the Risk of Cardiac Rupture and Mortality in Older Patients With First Acute Myocardial Infarction

Study Question: To determine whether clopidogrel pretreatment before PCI in patients with recent ST-segment elevation myocardial infarction (STEMI) is superior to clopidogrel treatment initiated at the time of PCI in preventing major adverse cardiovascular events. Methods: The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study was a prospectively planned analysis of the 1863 patients undergoing PCI after mandated angiography. Patients received aspirin and were randomized to receive either clopidogrel (300 mg loading dose, then 75 mg once daily) or placebo initiated with fibrinolysis and given until coronary angiography, which was performed 2 to 8 days after initiation of the study drug. For patients undergoing coronary artery stenting, it was recommended that open-label clopidogrel (including a loading dose) be administered after the diagnostic angiogram. The primary outcome was the incidence of the composite of cardiovascular death, recurrent MI, or stroke from PCI to 30 days after randomization. Secondary outcomes included MI or stroke before PCI and the aforementioned composite from randomization to 30 days. Results: Pretreatment with clopidogrel significantly reduced the incidence of cardiovascular death, MI, or stroke following PCI (34 [3.6%] vs. 58 [6.2%]; adjusted odds ratio [OR], 0.54 [95% CI 0.35– 0.85]; p⫽0.008). Pretreatment with clopidogrel also reduced the incidence of MI or stroke prior to PCI (37 [4.0%] vs. 58 [6.2%]; OR, 0.62 [95% CI 0.40 – 0.95]; p⫽0.03). Overall, pretreatment with clopidogrel resulted in a highly significant reduction in cardiovascular death, MI, or stroke from randomization through 30 days (70 [7.5%] vs. 112 [12.0%]; adjusted OR, 0.59 [95% CI 0.43– 0.81]; p⫽0.001; number needed to treat ⫽ 23). There was no significant excess in the rates of TIMI major or minor bleeding (18 [2.0%] vs. 17 [1.9%]; p⬎0.99). Conclusions: The investigators concluded that clopidogrel pretreatment significantly reduces the incidence of cardiovascular death or ischemic complications both before and after PCI and without a significant increase in major or minor bleeding. Perspective: This study suggests that in high-risk patients with STEMI treated with fibrinolytic therapy, a strategy of clopidogrel pretreatment significantly reduces the incidence of cardiovascular death and ischemic complications

Bueno H, Martı´nez-Sellés M, Pérez-David E, López-Palop R. Eur Heart J 2005;26:1705–11. Study Question: To evaluate the effect of thrombolysis on mortality and its causes in older patients with acute myocardial infarction (AMI). Methods: The population consisted of all patients ⱖ75 years old admitted to the coronary care unit of Hospital General Universitario’ within 24 h from symptom onset with a definite diagnosis of first ST-segment elevation/left bundle branch block myocardial infarction. Clinical outcomes were analyzed according to the type of reperfusion therapy received by the patients. Results: An analysis of 706 consecutive patients ⱖ75 years old with a first AMI showed that although there were important differences in baseline characteristics among patients treated with thrombolysis, primary angioplasty (PA) and those who did not receive reperfusion therapy, 30-day mortality did not differ (29%, 25% and 32%, respectively). The main cause of death in patients treated with thrombolysis was cardiac rupture (54%), whereas most of the other patients died in cardiogenic shock. Patients who received thrombolysis had a higher (p⬍0.0001) incidence of free wall rupture (FWR) (17.1%) compared with those who did not receive reperfusion therapy (7.9%) or who underwent PA (4.9%). By multivariable analysis, patients treated with thrombolytic therapy (TT) showed an excess risk of FWR (OR 3.62; 95% CI 1.79 –7.33), a hazard not observed in patients who underwent PA. When compared with patients who did not receive reperfusion therapy, the OR of 30-day mortality was 1.07 (95% CI 0.65–1.76) for patients treated with thrombolysis and 0.78 (95% CI 0.45–1.34) for those who underwent PA. The figures for 24-month mortality were 0.78 (95% CI 0.65–1.76) and 0.67 (95% CI 0.28 – 0.81), respectively. Conclusions: The investigators concluded that treatment of first AMI with TT increases the risk of FWR in very old patients, a risk not observed in patients treated with PA. Perspective: The study suggests that in elderly patients, treatment of first AMI with thrombolytic therapy increases the risk of FWR, an effect that may attenuate its early

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Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes

benefit, particularly when treatment is started after the first 6 h from symptom onset and especially in women and in infarcts of anterior location. This risk is not observed in patients treated with primary angioplasty. Further research on the optimal time and type of reperfusion therapy in older patients is needed. Debabrata Mukherjee

Werner N, Kosiol S, Schiegl T, et al. N Engl J Med 2005;353:999 –1007. Study Question: To assess the number of endothelial progenitor cells in patients with coronary artery disease (CAD) and prospectively analyze cardiovascular (CV) outcomes during a 12-month follow-up period. Methods: The number of endothelial progenitor cells positive for CD34 and kinase insert domain receptor (KDR) was determined with the use of flow cytometry in 519 patients with CAD as confirmed on angiography. After 12 months, the researchers evaluated the association between baseline levels of endothelial progenitor cells and death from CV causes, the occurrence of a first major CV event (myocardial infarction [MI], hospitalization, revascularization, or death from CV causes), revascularization, hospitalization, and death from all causes. Results: A total of 43 participants died, 23 from CV causes. A first major CV event occurred in 214 patients. The cumulative event-free survival rate increased stepwise across three increasing baseline levels of endothelial progenitor cells in an analysis of death from CV causes, a first major CV event, revascularization, and hospitalization. After adjustment for age, gender, vascular risk factors, and other relevant variables, increased levels of endothelial progenitor cells were associated with a reduced risk of death from CV causes (hazard ratio [HR] 0.31; 95% confidence interval [CI] 0.16 – 0.63; p⫽0.001), a first major CV event (HR 0.74; 95% CI 0.62– 0.89; p⫽0.002), revascularization (HR 0.77; 95% CI 0.62– 0.95; p⫽0.02), and hospitalization (HR 0.76; 95% CI 0.63– 0.94; p⫽0.01). Endothelial progenitorcell levels were not predictive of MI or of death from all causes. Conclusions: The researchers concluded that the level of circulating CD34⫹KDR⫹ endothelial progenitor cells predicts the occurrence of CV events and death from CV causes. Perspective: The study results suggest that circulating endothelial progenitor cells in patients with CAD can be used to identify patients at high risk for major adverse cardiac events. This finding supports the concept that immature cells may play an important role in the pathogenesis of atherothrombotic disease and that the measurement of endothelial progenitor cells may improve risk stratification. Additional studies assessing the therapeutic targeting of circulating endothelial progenitor cells are needed to ascertain the biologic concept that endothelial-cell regeneration through circulating endothelial progenitor cells is necessary for vascular healing. Debabrata Mukherjee

Serum Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels Are Elevated in Acute Coronary Syndrome: A Novel Marker for Early Diagnosis Hayashida K, Kume N, Murase T, et al. Circulation 2005;112:812– 8. Study Question: What is the usefulness of lectin-like oxidized LDL receptor-1 (LOX-1) as an early diagnostic marker of ACS? Methods: The investigators examined serum sLOX-1 levels in 521 subjects, consisting of 427 consecutive patients undergoing coronary angiography, including 80 ACS patients, 173 symptomatic coronary heart disease patients, 122 patients with significant coronary stenosis without ischemia, and 52 patients without apparent coronary atherosclerosis plus 34 patients with noncardiac acute illness and 60 patients with noncardiac chronic illness. Timedependent changes in sLOX-1 and TnT levels were analyzed in an additional 40 ACS patients. Results: Serum sLOX-1 levels were significantly higher in ACS than the other groups and were associated with ACS as shown by multivariable logistic regression analyses. Given a cutoff value of 1.0 ng/mL, sLOX-1 can discriminate ACS from other groups with 81% and 75% of sensitivity and specificity, respectively. The sLOX-1 can also discriminate ACS without ST elevation or abnormal Q waves and ACS without TnT elevation from non-ACS with 91% and 83% of sensitivity, respectively. Peak values of sLOX-1 in ACS were observed earlier than those of TnT. Conclusions: The researchers conclude that sLOX-1 appears to be a useful marker for early diagnosis of ACS. Perspective: Rupture of atheromatous plaques, followed by thrombus formation, is a crucial step in the pathogenesis of ACS. Atherosclerotic plaques with abundant lipid-laden macrophages and activated smooth muscle cells in the intima appear to be prone to rupture. In such vulnerable plaques, LOX-1 is expressed prominently by smooth muscle cells and macrophages and appears to be a useful marker for early diagnosis of ACS. The study does not tell us exactly when serum sLOX-1 levels begin to increase before the onset of ACS; however, sLOX-1 levels at the time of visit showed almost the peak values for each patient, suggesting that serum sLOX-1 levels may begin to rise before the clinical onset of ACS. Further large-scale prospective studies may tell us more about the value of serum sLOX-1 for predicting ACS onset. Debabrata Mukherjee

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