Aspirin use is associated with an improved long-term survival in an unselected population presenting with unstable angina.

BACKGROUND: Few published data are available on the benefits of aspirin use in patients with unstable angina (UA). HYPOTHESIS: Aspirin use carries a mortality benefit in a population-based cohort of patients presenting with UA. METHODS: All residents of Olmsted County, Minnesota presenting to local emergency departments with acute chest pain from January 1985 through December 1992 having symptoms consistent with UA were identified through medical records. A total of 1628 patients were identified with UA and were stratified by aspirin use in-hospital and at discharge. Cardiovascular mortality and nonfatal myocardial infarction and stroke were assessed over a median of 7.5 years follow-up and all-cause mortality data over a median of 16.7 years. The mean age of patients with UA was 65 years, and 60% were men. RESULTS: After a median of 7.5 years follow-up, all-cause and cardiovascular-mortality rates were lower among patients prescribed versus not prescribed aspirin on discharge. There were 949 postdischarge deaths over the median follow-up of 16.7 years. After multivariable adjustment, aspirin use at discharge was associated with a lower long-term mortality (hazard ratio 0.78; 95% confidence interval, 0.65-0.93). CONCLUSIONS: Aspirin use at hospital discharge following UA is associated with a reduction in long-term mortality. This long-term study extends prior trial results from select populations to a population-based cohort.

Crushed clopidogrel administered via nasogastric tube has faster and greater absorption than oral whole tablets.

OBJECTIVES: To compare the absorption of 300 mg clopidogrel administered crushed via nasogastric (NG) tube versus whole tablets taken orally in healthy volunteers. BACKGROUND: Earlier antiplatelet therapy has proven benefits in treatment of myocardial infarction and in patients undergoing PCI. Aspirin can be delivered early in crushed form via NG tube after CABG surgery to prevent graft occlusion. If clopidogrel given crushed via NG tube provides faster absorption, it could allow earlier clopidogrel loading. METHODS: Nine healthy human subjects (34.7 +/- 11.1 years, 5 males) were given 300 mg clopidogrel in crushed form via NG tube with 30 mL water after 8 hours of fasting. Plasma levels of the primary circulating inactive clopidogrel metabolite SR26334 were measured after 20 minutes, 40 minutes, 1, 2, 4, 8, 12, and 24 hours of dosing. Following >or=2 week washout, same subjects swallowed 300 mg clopidogrel (four 75 mg tablets) after an 8-hour fasting and SR26334 levels were measured at the same time points. RESULTS: Plasma SR26334 concentrations peaked earlier after crushed delivery than after oral intake (44 vs. 70 minutes, P = 0.023) and the median peak was 80% higher (13,083 vs. 7,255 ng/mL, respectively, P = 0.021). At 40 minutes, area under the curve was almost twofold greater with NG administration than oral administration (geometric means ratio = 0.5299, 95% CI = 0.28-0.99, P = 0.048), but was similar over the 24-hour period with both administration methods (geometric means ratio = 1.05, 95% CI = 0.84-1.32, P = 0.646). CONCLUSIONS: A 300 mg loading dose of crushed clopidogrel administered via NG tube provides faster and greater bioavailability than an equal dose taken orally as whole tablets. The clinical benefits of this strategy need to be investigated.

A comparison of the blood pressure changes of lumiracoxib with those of ibuprofen and naproxen.

The 52-week Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) investigated the gastrointestinal and cardiovascular safety profile of lumiracoxib 400 mg once daily compared with 2 traditional nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen 800 mg 3 times daily and naproxen 500 mg twice daily. Data from TARGET were analyzed to examine the effect of lumiracoxib compared with ibuprofen and naproxen on blood pressure (BP), incidence of de novo and aggravated hypertension, prespecified edema events, and congestive heart failure. Lumiracoxib resulted in smaller changes in BP as early as week 4. Least-squares mean change from baseline at week 4 for systolic BP was +0.57 mm Hg with lumiracoxib compared with +3.14 mm Hg with ibuprofen (P<.0001) and +0.43 with lumiracoxib compared with +1.80 mm Hg with naproxen (P<.0001). In conclusion, the use of lumiracoxib and traditional NSAIDs results in differing BP changes; these might be of clinical relevance.

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.

It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrombosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with clopidogrel, but none with heparin. Coronary patients (n = 18, 59 +/- 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor- Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [EoI], and four hours and eight hours after EoI, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI were 11%, 19% and 27%, respectively (p < 0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson's r = 0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein IIbIIIa inhibition.

Stress testing and troponin in unstable coronary syndromes: the status trial-clinical outcomes and resource use.

Cardiac troponins are markers used to diagnose acute myocardial infarction, but their value in guiding management in low- to intermediate-risk patients is not well established. Using a randomized design, the authors compared a strategy using stress testing with blinded troponins vs a troponin I-guided strategy for risk stratification and management of 241 patients with intermediate-risk unstable angina. Fewer stress-tested patients required coronary care unit admission and repeat hospitalization for acute coronary syndrome, at a lower cost. There was no significant difference in rates of death and myocardial infarction due to acute coronary syndrome at 6 months' follow-up. For patients with intermediate-risk acute coronary syndrome, stress testing is as safe as, and more cost-effective than, a troponin I-guided strategy. Patients with marginal troponin I elevations can safely undergo stress testing. Further studies combining stress testing and a troponin I-guided strategy are warranted.

Direct thrombin inhibitors are not equally effective in vivo against arterial thrombosis: in vivo evaluation of DuP714 and argatroban in a porcine angioplasty model and comparison to r-hirudin.

BACKGROUND: Qualitative differences in antithrombotic efficacy between thrombin inhibitors may be explained by the affinity for which they bind thrombin. This affinity is inversely proportional to the inhibitory constant for the agent (Ki). Thrombin inhibitors, DuP714 (Ki=10(-11)) and argatroban (Ki=10(-8)), were compared to our previous studies with r-hirudin (Ki=10(-13)). METHODS AND RESULTS: Prior to balloon angioplasty, thirty pigs randomly received DuP714 (0.1 mg/kg bolus and 0.6 mg/kg/h infusion; n=8), argatroban (0.2 mg/kg/min. continuous infusion; n=9), or saline (n=17). Injured arterial segments were measured for (111)In-platelet and 125I-fibrin(ogen) deposition and the incidence of macroscopic thrombus. In DuP714-treated animals, platelet and fibrin(ogen) deposition were significantly lower than controls in both carotid (10+/-2 vs. 62+/-18 and 20+/-4 vs. 74+/-6) and coronary (10+/-4 vs. 160+/-63 and 17+/-3 vs. 86+/-22) arteries (p<0.005). In contrast, platelet and fibrin(ogen) deposition were similar when comparing argatroban to saline in carotid (41+/-20 vs. 40+/-9 and 71+/-5 vs. 49+/-7) and coronary (92+/-33 vs. 151+/-45 and 114+/-37 vs. 89+/-38) arteries (p=0.82 and 0.38, respectively). Compared to argatroban, fibrin(ogen) (p<0.001) and coronary platelet deposition (p<0.05) were significantly reduced in animals treated with DuP714 with no significant difference in carotid platelet deposition (p=0.10). Neither inhibitor prevented macroscopic thrombosis. In previous studies with r-hirudin in this model, platelet deposition was limited to a monolayer with complete inhibition of macroscopic thrombus. CONCLUSIONS: Direct thrombin inhibitors do not equally prevent arterial thrombosis. Qualitative differences may be explained in part by the affinity for which they bind thrombin.

Acute coronary syndromes: pathogenesis, acute diagnosis with risk stratification, and treatment.

Acute ischemic chest pain at rest consistent with unstable angina or non-ST-elevation myocardial infarction is a common problem that may cause death or recurrent myocardial infarction within 30 days unless identified and risk stratified acutely. The latter may be done within 15 minutes by the history, physical exam, and electrocardiogram, and is aided by the measurement of troponin T/I. According to the Agency for Health Care Policy and Research guidelines, low-risk patients can be discharged home and rechecked within 72 hours. Intermediate-risk patients with no ST-segment changes with continuous monitoring and no elevation of troponin should undergo exercise stress testing by electrocardiogram (or nuclear or echocardiographic evaluation if electrocardiogram is non-analyzable). Patients with a negative stress test are low risk (no death or myocardial infarction at 30 days or 6 months) and can be discharged home. Patients with a positive test or who are at high risk according to the Agency for Health Care Policy and Research guidelines should undergo acute invasive testing for possible revascularization. Aspirin and low molecular weight heparin or unfractionated heparin, along with anti-ischemia therapy, is indicated in intermediate- or high-risk patients. The addition of clopidogrel is indicated in these patients, except in those who are potential candidates for coronary artery bypass graft. Platelet glycoprotein IIb/IIIa inhibitors are indicated in high-risk patients likely to undergo percutaneous coronary intervention, should be started early if recurrent ischemia occurs, but are not indicated in lower-risk patients who do not require percutaneous coronary intervention. Intensive secondary prevention should be started before dismissal.

The incremental value of troponin-I testing in patients with intermediate risk unstable angina.

BACKGROUND: Classification of patients with unstable angina (UA) by Agency for Health Care Policy and Research (AHCPR) guidelines in the emergency department reliably stratifies risk of death or myocardial infarction (MI) for triage to outpatient evaluation (low-risk), hospitalization (high-risk), or additional testing (intermediate-risk). Cardiac troponin-I elevation may identify patients at higher risk, but the incremental value may vary with AHCPR clinical risk. HYPOTHESIS: The objective of this study was to determine whether cardiac troponin-I had any additional value beyond triage based upon history, physical examination, and electrocardiogram, in the evaluation of patients with UA. METHODS: In all, 212 consecutive patients with UA and normal serum creatine kinase (CK)-MB levels and elevated troponin-I were risk stratified by AHCPR guidelines to evaluate the incremental value of adding routine troponin-I measurements to our current model for risk stratification. RESULTS: Primary events (death/nonfatal MI) occurred in 35% of high-risk, 15% of intermediate-risk, and 0% of low-risk patients (p < 0.001 by chi-square for trend). High troponin-I (> or =2.0 ng/dl) occurred in 48% of high-risk, 21% of intermediate-risk, and 19% of low-risk patients. The remaining patients in each risk group had indeterminate troponin-I levels (> or =0.4 < 2 ng/dl). Of those with high troponin-I, a primary event occurred in 36, 42, and 0% in the respective high-, intermediate-, and low-risk groups (p < 0.001). High troponin-I levels corresponded with a statistically significant increased rate of primary events only in patients at AHCPR intermediate risk: 42.4 vs. 7.3%, p < 0.001. CONCLUSION: The AHCPR guidelines risk stratify patients with UA. High troponin-I adds significant (p < 0.001) prognostic value in the patients at AHCPR intermediate risk and should be evaluated further in larger trials of such patients.

Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial.

BACKGROUND: The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen. METHODS: 18325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat. FINDINGS: 81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0.75 [0.20-2.79], p=0.6669), overall (0.66 [0.21-2.09], p=0.4833), and in patients taking aspirin (0.47 [0.04-5.14], p=0.5328). INTERPRETATION: The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin.

Direct thrombin inhibitor therapy in the cardiovascular patient.

Direct thrombin inhibitors in cardiovascular patients are discussed. Patients presenting with acute coronary syndromes (ACS) of ST- and non-ST-segment elevation myocardial infarction (STEMI and NSTEMI, respectively) or unstable angina develop mural thrombi within minutes of plaque disruption or erosion. Initial acute therapy includes heparin and aspirin. Up to 60% of patients have coronary revascularization to reduce the high risk of death, new myocardial infarction (MI), or recurrent angina. In addition, heparin may initiate a serious allergic, prothrombotic drug reaction, heparin-induced thrombocytopenia (HIT), in 1-5% of patients. Acute cessation of heparin and initiation of direct thrombin inhibitor (DTI) therapy for suspected HIT are vital and well established. Several clinical trials comparing DTIs with heparin have been done in ACS and percutaneous coronary intervention (PCI), and have shown excellent potency in inhibiting thrombus formation and reducing coronary events. An overview of results from published studies evaluating the use of bivalent and univalent DTIs in the cardiovascular patient is presented. Four DTIs are discussed: two r-hirudins (lepirudin and desirudin), both bivalent with stable chain and renal excretion; bivalirudin, bivalent with rapid-chain metabolism; and argatroban, univalent with hepatic metabolism. The extensive clinical experience with r-hirudin in cardiovascular patients suggests that it is an excellent choice for managing patients with HIT and is easy to use in converting to warfarin, since it does not significantly change the prothrombin time.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

New Accelerated rt-PA Strategy Has Sufficient Advantage over Older Streptokinase Strategies that It should Be the Trhombolytic Strategy of Choice in Anterior and Large Infarctions.

The major goal of myocardial reperfusion therapy is to restore normal coronary blood flow as quickly as possible and to maintain coronary patency in the highest number of patients with acute myocardial infarction. Recent studies support the hypothesis that more rapid and complete restoration of coronary flow through the infarct-related artery results in improved ventricular performance and lower mortality. Accelerated tissue plasminogen activator therapy appears to produce the most favorable effects compared to other lytic strategies, particularly in patients with anterior and large myocardial infarctions. However, the finding in GUSTO II trial, that even with the best strategy only 54% of patients had TIMI grade 3 flow, suggests that further improvement in the treatment of acute myocardial infarction may be possible in the future. The effectiveness of thrombolytic therapy may be enhanced by earlier identification of evolving myocardial infarction and reduced time delays in the initiation of thrombolytic therapy, bolus thrombolytic therapy, new thrombolytic agents, or more potent adjunctive antithrombotic strategies.