Risk stratification in non-ST segment elevation acute coronary syndromes with special focus on recent guidelines.

Patients with unstable angina or non-ST segment elevation (non-Q-wave) myocardial infarction are a heterogeneous group with respect to their risk of developing clinically significant adverse events such as subsequent myocardial infarction and death. Recent guidelines promote risk stratification of these patients, targeting high-risk patients for maximal antithrombotic and antiischemic therapy and low-risk patients for early discharge. We reviewed current and future modalities for risk stratification of patients and the predictive value of these methods in context with available pharmacologic agents. Unfortunately, most of the data identifying a particular pharmacologic regimen as beneficial in high-risk patients are retrospectively derived from large trials. Until prospective studies that use markers to guide therapy are available, clinicians should be familiar with the use of these risk markers and their application to the role of a given management strategy, including pharmacologic therapy.

Cilostazol for prevention of thrombosis and restenosis after intracoronary stenting.

OBJECTIVE: To evaluate the potential use of cilostazol in intracoronary stenting. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-March 2001). Key search terms included cilostazol, intracoronary stenting, and coronary angioplasty. Abstracts of clinical trials presented at major cardiology professional association meetings were also reviewed. DATA SYNTHESIS: Intracoronary stent placement represents the fastest growing medical device implant. Complications of stent implantation include acute and subacute vessel closure, as well as late restenosis. Currently, antiplatelet agents are used for preventive therapy. Cilostazol is a vasodilating antiplatelet agent that reversibly inhibits platelet aggregation induced by many factors. In seven randomized trials comparing cilostazol with either aspirin or ticlopidine, cilostazol was found to be superior to aspirin and equivalent to ticlopidine in decreasing both cardiac events and rates of restenosis. In addition, cilostazol was found to be well tolerated, with no reports of adverse hematologic events. CONCLUSIONS: Although further comparative trials are required, cilostazol appears to be a safe and effective alternative to clopidogrel and glycoprotein IIb/IIIa receptor antagonists following intracoronary stent implantation.

Update on strategies to improve thrombolysis for acute myocardial infarction.

Therapy for acute myocardial infarction involves rapid restoration of blood flow through a coronary artery that has been occluded by a ruptured atherosclerotic plaque. Thrombolytic therapy, the pharmacologic standard to achieve this outcome, significantly improves survival; however, current regimens have limitations: they can fail to achieve complete reperfusion, they can cause significant bleeding events, and they can result in reocclusion. In addition, complex regimens of some agents can cause dosing errors. Accordingly, newer compounds were developed to address some of these issues, and alternative strategies are being implemented. The combination of platelet glycoprotein IIb-IIIa receptor inhibitors plus thrombolytic agents produced promising results in clinical trials, including faster clot lysis and greater flow rates than either therapy alone. The addition of unfractionated heparin or low-molecular-weight heparin to thrombolytic-antiplatelet therapy is being evaluated, as is administration of thrombolytic-antiplatelet before percutaneous coronary intervention.

New recommendations from the 1999 American College of Cardiology/American Heart Association acute myocardial infarction guidelines.

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST-segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. Beta-adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

Predictive performance study of two digoxin assays in subjects with various degrees of renal function.

This prospective study was conducted to compare the predictive performance of fluorescence polarization immunoassay (FPIA, Abbott TDx Digoxin II) and radioimmunoassay (RIA, Kallestad Labs) with combined low-pressure liquid chromatography/RIA (LPLC/RIA) digoxin assay in measuring 15-17 serum digoxin concentrations (SDC) obtained after a single 10 microg/kg intravenous digoxin dose in patients with various degrees of renal function and at different SDC ranges. Eighteen men and women were stratified into 3 age- and gender-matched groups based upon renal function [N = 6 in each, group I (Cl(cr) < 10 mL/min), group II (Cl(cr) = 10-50 mL/min), and group III (Cl(cr) > 50 mL/min)]. Serum digoxin concentrations were measured at time zero; at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hours; and at 2, 3, 4, and 5-7 days after the digoxin dose, using the three different digoxin assays. TDx Digoxin II was unbiased [mean error -0.09 (95% CI -0.19, 0.01)] and RIA biased [mean error -0.29 (95% CI -0.36, -0.21)] to over-predict SDC by 14.2%. In group I patients, the analysis revealed a bias to over-predict SDC by 6.0% for TDx Digoxin II [mean error -0.16 (95% CI -0.29, -0.07)] and an unbiased performance by RIA. In groups II and III, both TDx Digoxin II and RIA showed biased performance, the mean magnitude of bias was low (< 20%). For intermediate SDC range (> 0.5 ng/mL and < or = 3.0 ng/mL), TDx Digoxin II was unbiased in predicting SDC, whereas RIA was biased to under-predict SDC [mean error 0.13 (95% CI 0.10, 0.16)] by 9.9%. The magnitude of bias observed in all cases was less than 20%. Both assays, TDx Digoxin II and RIA, imprecisely measured SDC for all samples combined, different groups and SDC ranges. In all time-paired samples, TDx Digoxin II (FPIA) performed better than the RIA. In conclusion, the magnitude of bias observed with either assay at different groups and SDC ranges was not likely to be clinically relevant. Therefore, either assay may be used to measure SDC in clinical practice.

Update on the interaction between aspirin and angiotensin-converting enzyme inhibitors.

We summarized recent published literature regarding the significance of an interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors in patients with various cardiovascular diseases. A MEDLINE search (January 1998-July 1999) was performed and abstracts from the 1999 American College of Cardiology and 1998 American Heart Association annual scientific sessions were reviewed to identify pertinent studies. Material for discussion was identified through a MEDLINE search from January 1996-July 1999 and through cited references. The results of several studies added to our understanding of the clinical ramifications of an aspirin-ACE inhibitor interaction, but also introduced questions. These studies are largely contradictory, but do reiterate the possibility of an interaction, if only in certain subsets of patients. Low dosages (< or = 100 mg/day) of aspirin appear to be safer in this regard than higher dosages. The frequency and severity of the interaction and possible predisposing factors await future research.

Clinical trials of low-molecular-weight heparins in cardiology.

Our understanding of the pathophysiology of acute coronary syndromes is evolving as the role of prognostic coagulation markers and the different effects unfractionated heparin and low-molecular-weight heparins have on these coagulation markers are investigated. The results of recent clinical trials of low-molecular-weight heparins in acute coronary syndromes are summarized, and an economic evaluation of enoxaparin for these indications is reviewed.

Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan.

The ability of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors. This trial studied the interaction between aspirin (ASA) and enalapril, an ACE inhibitor, and ASA and losartan, an angiotensin subtype 1 receptor antagonist. Seventeen essential hypertensive patients were studied, maintained on a stable dose of either enalapril (n = 7) or losartan (n = 10) monotherapy for > or =12 weeks before and throughout the study. Each patient received a 2-week course of placebo, 81 mg/day ASA, and 325 mg/day ASA, each treatment separated by a 2-week washout period. Blood pressure (BP) and serum thromboxane B2 (TXB2) samples were obtained at the end of each treatment period. Placebo was compared with each dose of ASA for each group. In both the enalapril and losartan groups, mean, systolic, and diastolic BP were unchanged with the addition of ASA. Concentrations of TXB2 were suppressed to <10% in both groups with ASA. This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan.

Does aspirin interfere with the therapeutic efficacy of angiotensin-converting enzyme inhibitors in hypertension or congestive heart failure?

We conducted a MEDLINE search of published literature from 1966 to January 1998 regarding the impact of aspirin (ASA) on the therapeutic effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and congestive heart failure. Selected references from these articles and results of recent clinical trials were also included. By inhibiting cyclooxygenase, ASA may interfere with the prostaglandin-mediated hemodynamic effects of ACE inhibitors. Although other nonsteroidal antiinflammatory drugs may increase blood pressure in hypertensive patients taking an ACE inhibitor, low-dosage (< or = 100 mg/day) ASA does not. However, higher dosages of ASA may attenuate the benefits of ACE inhibitors in patients with hypertension and/or congestive heart failure (CHF). Low-dosage ASA appears to interact little with ACE inhibitors, whereas higher dosages may produce a more significant interaction. Patients with CHF may also be more susceptible to this interaction because of underlying disease.

Thrombolytic therapy for acute myocardial infarction.

Numerous factors must be considered when determining the formulary status of thrombolytic agents for the treatment of acute myocardial infarction. Defined treatment options, predicted outcomes, and the economic consequences of this disorder continue to evolve from clinical trials. Pharmacists have a major role in delivering patient care, with responsibility for evaluating, procuring, and monitoring thrombolytic agents and drug therapy in general. By participating in the development and implementation of treatment guidelines, evaluating economic and therapeutic outcomes, providing timely optimal drug therapy, and educating health care providers and the public, they contribute significantly to the health care team.

Clinical presentation and analysis of risk factors for infectious complications of implantable cardioverter-defibrillator implantations at a university medical center.

The objective of this report is to describe the characteristics of patients who develop infections associated with implantable cardioverter-defibrillators (ICDs) implanted with sternotomy and thoracotomy approaches. A retrospective chart review identified all patients who underwent ICD implantation at a university medical center from November 1982 through February 1990. Several patient and procedural variables were compared between infected patients and noninfected patients. One hundred fifty-seven patients underwent 202 ICD generator implantations (45 generator changes), and nine of these patients developed infection (4.5% per implantation and 5.7% per patient). Of the patient variables analyzed, a significant correlation (P < .0001) was made only with a diagnosis of diabetes mellitus: 36% of diabetics versus 3.9% of nondiabetics were infected. The only patient- or procedure-specific variable that was found to correlate with the development of infection was the presence of diabetes mellitus.

Intravenous nitroglycerin tolerance in patients with ischemic cardiomyopathy and congestive heart failure.

A daily nitrate-free interval (NFI) lasting 4-7 hours was instituted in four patients with severe congestive heart failure secondary to myocardial ischemia who were awaiting orthotopic heart transplantation. The duration of intravenous nitroglycerin therapy ranged from 14-55 days, and the maximum dosage was 50-400 microg/minute. Anginal events occurred more frequently during the NFI than during intravenous therapy. An NFI of 8-12 hours reduces tolerance in patients with congestive heart failure and stable angina. However, the experience in these patients with recurrent ischemia does not support its use to prevent ischemic events during hospitalization.

Low-molecular-weight heparins for acute coronary syndromes.

OBJECTIVE: To review published literature regarding the use of low-molecular-weight heparins (LMWHs) for the acute coronary syndromes of unstable angina and acute myocardial infarction (MI). METHODS: A MEDLINE search (January 1986-August 1997) was performed to identify all pertinent articles. Selected references from these articles and abstracts of recent clinical trials were also included. DISCUSSION: LMWHs have several distinct advantages over standard unfractionated heparin (UFH). These advantages include convenient once- or twice-daily standardized administration without the need for activated partial thromboplastin time monitoring. While the use of LMWHs as prophylaxis and treatment of venous thromboembolism is fairly well-established, the use of LMWHs for treating acute myocardial ischemia is evolving. Published studies and abstracts have shown LMWHs to be as effective as or more effective than UFH in preventing death, myocardial infarction, and recurrent ischemia in patients with unstable angina or acute MI. The comparative incidence of bleeding between LMWHs and UFH is controversial, with some studies reporting lower or similar rates of bleeding with LMWHs, while one study demonstrated a higher bleeding rate than with UFH. The cost-effectiveness of using LMWHs over UFH for acute coronary syndromes also remains to be established. CONCLUSIONS: LMWHs appear to be as effective as, and potentially more effective than, UFH in preventing complications of acute coronary syndromes. However, further studies are needed to better define the comparative bleeding risks of LMWHs and UFH. This, plus the lack of published peer-reviewed trial results and pharmaco-economic analyses, preclude the recommendation of routinely using LMWHs for treating unstable angina and acute MI at this time.

Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group.

OBJECTIVE: The predictive performance of 10 equations used to estimate creatinine clearance (Clcr) was assessed retrospectively from data collected on 420 patients. DESIGN: This study is a retrospective data analysis of information collected on hemodynamically stable patients awaiting coronary angiography during the Iohexol Cooperative Study. SETTING: The Iohexol Cooperative Study was a multicenter study that compared nephrotoxicity of high- and low-osmolar contrast media in patients undergoing coronary angiography. Data used for this analysis were preangiography 24-hour urine collections that were primarily collected in hospitalized patients. PATIENTS: Patients selected from the Iohexol Cooperative Study database for analysis were participants categorized into one or more of six subgroups: elderly (n = 222), hypoalbuminemic (n = 25), chronic renal insufficiency (n = 128), low serum creatinine (n = 115), obese (n = 208), and diabetic (n = 191) who had baseline urine collections of at least 24 hours. OUTCOME MEASURES: Predictive performance was assessed using bias, precision, slopes, and y-intercepts. RESULTS: The Salazar-Corcoran equation was unbiased in the entire group as well as in five of the subgroups. The Cockcroft-Gault equation was unbiased in three of the subgroups. All other equations were biased in predicting Clcr in the entire group as well as in at least four of the subgroups. Precision was generally poor. All slopes were significantly different than one and all y-intercepts were significantly different than zero (p < 0.01). Correlation coefficients were between 0.63 and 0.79 with the exceptions of the low serum creatinine subgroup (r values 0.35-0.64) and the Davis-Chandler equation (r values 0.35-0.71 across groups). CONCLUSIONS: Of the equations studied, Salazar-Corcoran and Cockcroft-Gault appear to be the best for predicting Clcr.

Prehospital-initiated thrombolysis.

OBJECTIVE: To evaluate the feasibility, safety, and efficacy of prehospital-initiated thrombolysis in decreasing the mortality rate due to acute myocardial infarction. DATA SOURCES: English-language clinical studies, abstracts, and review articles identified from MEDLINE searches and bibliographies of identified articles. Epidemiologic data were extracted from the Internet. STUDY SELECTION: Eight randomized clinical trials and two meta-analyses that compared prehospital-initiated thrombolysis with in-hospital-initiated thrombolysis. DATA EXTRACTION: Pertinent studies were selected and the data were synthesized into a review format. DATA SYNTHESIS: Early reperfusion of an infarct-related coronary artery is associated with lower mortality rates. Most of the delay in initiating treatment is caused by patient delay rather than transport delay or hospital delay. In addition, more than 30% of eligible patients do not receive thrombolytic therapy. Prehospital initiation of thrombolysis has been evaluated as a means of decreasing hospital delay and increasing the number of eligible patients receiving thrombolysis. Clinical trials document that prehospital-initiated thrombolysis is feasible and safe, and saves time. Of the eight randomized trials, three demonstrated a decrease in either cardiac or total mortality with prehospital thrombolysis. All studies were limited by relatively small sample sizes. Two published meta-analyses suggest a 16-17% reduction in mortality with prehospital thrombolysis. In the US, prehospital thrombolysis is not routinely recommended due to medical issues related to diagnostic accuracy and monitoring, legal concerns, and economic implications. Additional strategies, such as community-wide education and prehospital diagnostic electrocardiograms (ECGs), are being studied. CONCLUSIONS: In clinical trials, prehospital-initiated thrombolytic therapy was shown to be safe and probably more effective than in-hospital administration of thrombolytic therapy, but this has not proven feasible in the US at this time. Despite time-savings by decreasing treatment delay with prehospital-initiated thrombolysis, patient delay still persists and accounts for the majority of delay. Future investigations will center on increasing the number of patients treated with thrombolytic agents through patient education, in-patient and out-patient programs that rapidly identify eligible patients, as well as prehospital diagnostic ECGs.