Combining necrosis and platelet markers for perfecting myocardial infarction rule out: how close are we?

Each year, at least 5 million patients in the United States present to hospital emergency departments with the complaint of chest pain, and more than 10% of them will be diagnosed with acute myocardial infarction. One of the foremost tasks of the emergency department physician is to avoid unnecessary admissions and concomitantly to minimize the number of patients discharged home inappropriately. Currently available diagnostic tools, including the electrocardiogram and myocardial markers, have several shortcomings, including low specificity, and delayed sensitivity for the timely detection of myocardial necrosis. Therefore, the search for better methods of rapidly identifying patients with unstable coronary syndromes is one of the utmost priorities of modern emergency medicine. Available biochemical diagnostic tools are discussed in this review, focusing on the potential benefits of combining myocardial necrosis markers with indicators of platelet activation. It is hypothesized that such a combined approach may be more powerful in myocardial infarction risk stratification than separate marker determination.

Prodromal unstable angina in acute myocardial infarction: prognostic value of short- and long-term outcome and predictor of infarct size.

BACKGROUND: An estimated 50% of patients with myocardial infarction have prodromal unstable angina. There is controversy over whether prodromal unstable angina identifies a group of patients at lower risk of short- and long-term death and the clinical importance of recording this event. METHODS: Of 207 patients enrolled at a single Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) site, 196 survived the 24 hours after presentation, achieved peak creatine kinase MB concentrations, and were classified as having either abrupt symptom onset or prodromal unstable angina in the 2 weeks before myocardial infarction. Creatine kinase MB peak was used to categorize infarct size as aborted myocardial infarction, minor myocardial damage, or extensive myocardial injury. Follow-up was performed at 24 hours, 30 days, 1 year, and 5 years. Multiple variables, including prodromal unstable angina, time to treatment, age, sex, previous infarction and infarct location, were analyzed for predicting infarct size. Also, these variables plus peak creatine kinase MB level and a combined variable of prodromal unstable angina and peak creatine kinase MB level were examined for predicting survival. RESULTS: Mortality rate was 2.5% within 24 hours, 9.0% at 30 days, 13.5% at 1 year, and 27.1% at 5 years. Patients categorized as either aborted infarction or minor myocardial damage were significantly more likely to have prodromal unstable symptoms (81.3% vs 51.2%, P <.001) and better survival at each follow-up period. Prodromal presentation was the most significant predictor of infarct size category (P =.001). Five-year survival was predicted by age (P <.0001), peak creatine kinase MB level (P =.007), infarct location (P =.009), the combined variables (P =.029), and prodromal unstable angina (P =.017). Prodromal unstable angina had the highest odds ratio for 5-year survival at 3.83 (95% confidence interval 1.27-11.47). CONCLUSIONS: Prodromal unstable angina is a strong predictor of infarct size and survival. Recognizing prodromal unstable angina is important for clinically assessing prognosis.

Role of soluble and platelet-bound P-selectin in discriminating cardiac from noncardiac chest pain at presentation in the emergency department.

BACKGROUND: It has been reported that selectins participate in the pathogenesis of acute coronary syndromes by modulating platelet-leukocyte-endothelium interactions. Elevated P-selectin level also has been observed in the clinical setting of myocardial ischemia and reperfusion; however, its utility in differentiating cardiac from noncardiac origins of chest pain is unknown. METHODS AND RESULTS: Soluble and platelet fractions of P-selectin were measured for 122 patients with chest pain and 14 healthy persons acting as controls. Patients with a cardiac problem (unstable angina, congestive heart failure, acute myocardial infarction) had significantly elevated levels of soluble P-selectin (156.0 +/- 58.8 ng/mL, P =.002) and platelet-bound P-selectin (11.7% +/- 6.4% positive cells, P =.013) compared with the P-selectin profile among controls (102.6 +/- 29.0 ng/mL, 4.1% +/- 1.2% positivity) and among patients with noncardiac chest pain (114.7 +/- 36.6 ng/mL, 5.7% +/- 2.9% positivity). With a cutpoint of 10% positivity for membrane and 120 ng/mL for soluble P-selectin, the sensitivities were 0.442 and 0. 558, and the specificities were 0.915 and 0.553. CONCLUSIONS: When a patient arrives in the emergency department, measurement of membrane P-selectin may serve as an additional diagnostic tool to detect heightened platelet activity, which is most prevalent among patients with a cardiac origin of chest pain. However, low sensitivity limits the utility of the P-selectin profile alone in suitably differentiating acute coronary syndromes within the overall population of patients with chest pain.

Chest pain centers: moving toward proactive acute coronary care.

Ischemic heart disease is the major cause of death, disability and lost productivity in the developed countries of the world. The evolution of cardiac care units has improved patient survival from myocardial infarctions, but requires a high-tech, very expensive treatment facility. Chest pain centers, located in emergency departments, present an efficient alternative to triage patients with chest pain, providing prompt and accurate diagnosis, risk evaluation and appropriate treatments. Hospitals benefit from this cost-effective approach as resources are used more efficiently, and patients benefit from a supportive treatment facility that focuses on early intervention. Early recognition of prodromal unstable angina symptoms and intercession with newly developed treatment can help move the cardiologist toward a more proactive role that minimizes or avoids myocardial infarctions rather than reacting to the acute event.

Increased baseline levels of platelet P-selectin, and platelet-endothelial cell adhesion molecule-1 in patients with acute myocardial infarction as predictors of unsuccessful thrombolysis.

BACKGROUND: Platelets play a pivotal role in the pathogenesis of acute myocardial infarction and their activation can cause thrombolysis to fail. METHODS: Baseline aggregation of platelets and expression of major surface receptors measured by flow cytometry were compared with clinical outcome after thrombolysis for 23 patients enrolled in the GUSTO-III trial. RESULTS: Failure to reperfuse (n = 3) and recurrent ischemia (n = 2) were observed in five patients who subsequently underwent emergency angioplasty. These patients were treated later in their course of disease than were the 18 patients who were successfully reperfused and remained free of recurrent ischemia. Greater than normal expression of platelet P-selectin (33.7 +/- 1.1 versus 28.1 +/- 1.9, P = 0.01) and expression of platelet--endothelial cell adhesion molecule-1 (PECAM-1; (57.1 +/- 2.3 versus 50.2 +/- 2.8, P = 0.02) were observed in members of the group with recurrent ischemia or failed reperfusion. CONCLUSION: Greater than normal baseline expression of P-selectin and PECAM-1 platelet receptors was correlated to delayed and unsuccessful coronary thrombolysis among patients presenting with acute myocardial infarction.

Antecedent aspirin therapy inhibits baseline platelet activity in patients presenting with acute myocardial infarction. The GUSTO-III Platelet Substudy.

Aspirin therapy and platelet inhibition reduce the risk for the development of acute myocardial infarction (AMI). However, the effects of aspirin on baseline platelet activity in patients presenting with AMI are not known. We determined the effect of long-term aspirin use on baseline platelet activity in patients presenting with AMI, enrolled in the GUSTO-III Platelet Study. Platelet characteristics were investigated by aggregometry, flow cytometry and enzyme-linked immunosorbent assay in 23 patients before thrombolysis. Sixteen AMI patients were aspirin free, and 7 patients were using aspirin (81-500 mg/daily). The aspirin-treated patients exhibited a mild but consistent reduction of platelet activity which reached significance for 5 microM (p = 0.02), and 10 microM (p = 0.01) adenosine diphosphate induced aggregation. The surface expression of P-selectin (p = 0.02) and PECAM-1 (p = 0.03) and the plasma level of soluble P-selectin (p = 0.02) were also reduced. As previously observed in normal humans and patients with stable coronary artery disease, long-term aspirin therapy is also associated with diminished platelet activation in patients presenting with AMI. Long-term aspirin therapy mildly reduces baseline platelet activity; however, this degree of relative platelet inhibition does not appear to be cardioprotective.

The concept and the development of chest pain emergency departments as a strategy in the war against heart attack.

Critical nurses in the CPED can have a very fulfilling role in expanding their influence within the hospital setting, as well as within the community to become part of the needed change to significantly reduce deaths from MI in the United States. The mission impossible becomes possible when critical care nurses are part of this challenging process. Nowhere can these efforts be better started than in emergency department committed to continuous quality improvement changes under this new paradigm. The person who can best help make this strategy work the best is the critical care nurse in charge.

Effects of reteplase and alteplase on platelet aggregation and major receptor expression during the first 24 hours of acute myocardial infarction treatment. GUSTO-III Investigators. Global Use of Strategies to Open Occluded Coronary Arteries.

OBJECTIVES: We sought to compare platelet characteristics after reteplase and alteplase therapy in the setting of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-III trial. BACKGROUND: Platelet function may be impaired during thrombolysis in patients with an acute myocardial infarction. The effects of reteplase and alteplase on platelet aggregation and major surface antigen expression during the first 24 h of infarction therapy are unknown. METHODS: Platelet aggregation and receptor expression by flow cytometry were determined in 23 patients before thrombolysis and thereafter at 3, 6, 12 and 24 h. RESULTS: Aggregation was higher after reteplase at 24 h when induced by 5 micromol/liter adenosine diphosphate (ADP) (p = 0.007), 10 micromol/liter ADP (p = 0.02), collagen (p = 0.003) and thrombin (p = 0.009) than after alteplase. Reteplase therapy exhibited greater glycoprotein (GP) IIb/IIIa (p = 0.04), very late antigen-2 (p = 0.04) and platelet/endothelial cell adhesion molecule-I (p = 0.002) expression at 24 h. Trends toward decreased receptor expression early (3 to 6 h), followed by a progressive increase at 12 h and especially at 24 h occurred after both agents. CONCLUSIONS: In this prospective clinical ex vivo platelet study, similar patterns of platelet aggregation and surface receptor expression occurred during the first 24 h of coronary thrombolysis with reteplase and alteplase. However, after reteplase, indicators of platelet activity were higher at 24 h after thrombolysis than after alteplase. These data suggest that GP IIb/IIIa inhibitors or other antiplatelet strategies may be particularly advantageous when used 12 to 24 h after thrombolysis, especially after reteplase therapy. It is at this time point during the first day of coronary thrombolysis that GP IIb/IIIa is markedly expressed and platelets are most active.

Depressed platelet status in an elderly patient with hemorrhagic stroke after thrombolysis for acute myocardial infarction. GUSTO-III Investigators.

BACKGROUND: Impaired platelet function has been reported in acute myocardial infarction (AMI) and stroke. However, prospective data on the changes of platelet status in patients before the occurrence of hemorrhagic stroke after thrombolytic therapy are unavailable. CASE DESCRIPTION: An 86-year-old male patient was among the 23 AMI patients enrolled in the platelet study for the GUSTO-III trial. He received 325 mg of aspirin daily for at least 6 years, suffered an AMI, and was successfully reperfused with alteplase, but after 44 hours developed a large hemorrhagic stroke resulting in paraplegia. Platelet aggregation and receptor expression were measured by flow cytometry and ELISA before thrombolysis and at 3, 6, 12, and 24 hours thereafter. The percentage of platelet aggregation was lower in the stroke patient at every time point when induced by 5 micromol/L of ADP, by 10 micromol/L of ADP, and by thrombin than in the rest of the AMI group. Ristocetin and collagen-induced aggregability were within the group range. Decreased platelet glycoprotein Ib, IIb, IIIa, and IIb/IIIa and vitronectin receptor expression were observed in the stroke patient. No other differences in p24 (CD9), very late antigen-2, P-selectin, and platelet/endothelial cell adhesion molecule-1 expression were determined. CONCLUSIONS: Profound depression of platelet status preceded the occurrence of hemorrhagic stroke in an elderly long-term aspirin user treated with thrombolytic therapy. Initial "exhausted" platelets may be responsible for the increased risk for hemorrhagic stroke after coronary thrombolysis.

The early heart attack care strategy in the war against heart attack deaths utilizing the chest pain center approach in emergency departments.

The focus of this symposium is Maryland's heart attack problem. The question is: Can the known evidence-based data on heart attacks be interpreted and applied in a systematic way that will unite efforts to reduce the significant heart attack deaths within the state? To determine this we need to go beyond what is currently being done and aim at a higher level of performance. Despite the medical advances in clot-dissolving therapies and minimally invasive surgeries, the acute prevention of heart attack death and damage has not been substantial. However, significant progress is possible. Better delivery systems, linking hospitals and communities, are needed. To accomplish this, emergency physicians and nurses, cardiologists, and paramedics need to form part of a team and have the support of the individual hospitals and the emergency medical system. Chest pain centers must function efficiently and cost effectively and bring about a community involvement that can significantly reduce heart attack deaths locally and, when combined with other hospitals, statewide.

Can Maryland become the first state to take heart disease out of first place where it has been since the turn of the century?

Heart disease has been the number one health problem in the United States since the turn of the century. It kills more Americans each year than all the American soldiers killed in all of this country's previous wars. Does it have to continue? Can this be reversed with re-engineering of information presently available? The hypothesis postulated here is that if a strategy can be successfully carried out in one state, then other states may be able to follow and pursue other strategies attempting to do the same. To accomplish this on a statewide level it is necessary to have individual hospitals proactively involved with their communities by having a game plan for penetration, identification, activation, and early management of patients with ischemic heart disease. Florida, under the leadership of Henry McIntosh, M.D., has attempted to put this into effect with a complicated strategy. Maryland attempts to logically put into place a chest pain strategy utilizing the principle of keeping it simple for widespread utilization.

A path forward for chest pain care: what are the expectations of each team member?

It would be impossible to expect that an immediate solution to the heart attack problem in the United States can come out of this multidisciplinary conference. A more practical goal would be the conferees coming together, seeing better what needs to be done, and using interpretative abilities to put together a logical approach which would unite both the community hospital and the community by the first step on the learning curve. Future progress will come about from the multidisciplinary team with research studies and a commitment to solving this problem on a local level. Acting locally and thinking globally will enable us to move forth and find the expectations of each member of the team. The challenge will find us many times in the years ahead.

Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial.

BACKGROUND: Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina. METHODS AND RESULTS: Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms. CONCLUSIONS: Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

The EHAC (early heart attack care) strategy: Citizens Chart the Course for Healthy People in the Year 2000.

Within the last four years, more than 500 chest pain centers have developed in response to new paradigms for early heart attack care. These shifting paradigms now focus on acute prevention, in terms of both early thrombolytic therapy and cardioprotection of patients with prodromal symptoms of a heart attack.