Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein

This study [1] uses meta-analysis in a novel way to investigate mechanisms of disease in order to better understand the clinical importance of lipid and nonlipid effects of statin therapy. The study evaluates the relationship between group changes in low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) for healthy or stable subjects participating in statin and nonstatin interventions for lowering LDL cholesterol.

A systematic review of English literature in Medline and other databases for studies that evaluated LDL and high-sensitivity CRP was conducted up until August 2005. Among the 23 trials meeting the criteria for study inclusion (original randomized placebo-controlled data), a total of 57 groups were treated with statin-only therapy (58%), a combination of statin-ezetimibe (23%), ezetimibe-only (9%) and other non-statin drug therapy (10%), e.g. fish oils, fibrate, niacin, or diet.

Across all interventions, the pooled estimate of reduction in CRP was 28% (95% confidence interval [CI] 26% to 30%; P<0.0001). Significantly greater reductions in CRP were found for combination statin-ezetimibe and statin-alone interventions as compared with other LDL-lowering therapies; studies using 80 mg/day of statins as compared with lower doses of statins; and a dose-response relationship with greater LDL reduction. Meta-regression analysis was used to evaluate the relationship of average LDL change and the use of statin therapy to average change in CRP. A significant correlation was found between change in LDL and change in CRP (regression coefficient or slope for change in LDL=0.89, 95% CI 0.70–1.09, P<0.001). The variance adjusted correlation between change in LDL and change in CRP was r=0.80 (P<0.001). After accounting for the change in LDL, no significant effect of statin therapy, or any other therapy, was found on CRP. The multivariate model used in this study demonstrated that 98% to 89% of the CRP reduction was related to LDL reduction and 2% to 22% of CRP changes was related to statin effects that were independent of LDL reduction.

Based on these findings, the author concluded that “this analysis clearly revealed a strong relationship between the change in LDL cholesterol and change in CRP, a marker of inflammation in atherosclerosis.” The author pointed out the utility of this approach since “assessing change in CRP and LDL across many studies diminishes the diluting effect of intraindividual variation to reveal a strong relationship,” which might not have been observed in single studies due to measurement error. He also noted that “the high correlation between changes in LDL and CRP (r=0.80) strongly supports a causal link between changes in LDL and arterial inflammation in atherosclerosis, and complements histopathological studies in animals and humans using a variety of statin and nonstatin therapies.” Kinlay summarized his findings as “this study supports the concept of intensive LDL lowering to achieve maximum reductions in inflammation to stabilize atherosclerotic plaque” and emphasized that “LDL cholesterol is not only a primary target for prevention of cardiovascular disease, but also should remain the primary measure of the efficacy of statin and nonstatin LDL-lowering therapies.”

[1] Kinlay S. Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein. J Am Coll Cardiol 2007;49(20):2003-2009

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Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006

This study [1] used data from the multinational, observational cohort study, Global Registry of Acute Coronary Events (GRACE), to examine whether changes in hospital management of patients with acute coronary syndrome (ACS) over time are associated improved clinical outcomes.

Between July 1, 1999, and December 31, 2006, a total of 44,372 patients ≥18 years of age from 113 hospitals in 14 countries admitted for ACS were enrolled in the study. Of this total, 27,558 had non-ST-segment elevation (NSTE) ACS and 16,814 had ST-segment elevation myocardial infarction (STEMI). Patients were followed up at 6 months after hospital discharge for death, stroke or myocardial infarction. The primary outcomes were in-hospital death, recurrent myocardial infarction, heart failure, stroke, and cardiogenic shock. Temporal trends in use of evidence-based pharmacological and interventional therapies were examined over time.

During the course of the study, there was an increase in the use of pharmacological medications (β-blockers, statins, angiotensin-converting enzyme inhibitors, thienopyridines with or without percutaneous coronary intervention [PCI], glycoprotein (Gp) IIb/IIIa inhibitors, low-molecular-weight heparin; a P<0.001). In patients with STEMI, pharmacological reperfusion declined by -22 percentage points (95% confidence interval [CI], -27 to -17). On the other hand, PCI increased by 37 percentage points (95% CI, 33–41) for the STEMI patients and 18 percentage points for non-STEMI patients (95% CI, 15–20). For both STEMI and NSTE ACS patients, the rates of congestive heart failure and pulmonary edema declined by -9 percentage points (95% CI, -12 to -6) and -6.9 percentage points (95% CI, -8.4 to -4.7) respectively. Hospital death decreased by 18 percentage points (95% CI, -5.3 to -0.5) and cardiogenic shock by -24 percentage points (95%CI, -4.3 to -0.05) in STEMI patients. In NSTE ACS patients, risk-adjusted hospital deaths declined by 0.7 percentage points (95% CI, -1.7 to 0.3). In STEMI patients, 6-month follow-up rates declined by -0.8 percentage points for stroke (95% CI, -1.7 to 0.1) and by -2.8 percentage points for myocardial infarction (95% CI, -6.4 to 0.9). In NSTE ACS patients, 6-month follow-up rates for death declined by -1.6 percentage points (95% CI, -6.4 to 0.1) and stroke by 0.7 percentage points (95% CI, -1.4 to 0.1).

The authors conclude that “these data … demonstrate evidence of a change in practice for both pharmacologic and interventional treatment in patients with either STEMI or NSTEA ACS.” The authors note that this study is has limitations since the “participating clusters reflect regional practices and outcomes, but do not necessary reflect practice for specific countries; there is no means to “determine whether improvements in adherence to evidence-based medications are taking place nationwide or are limited to participating sites;” and “increasing use of troponin measurement throughout the study may have led to underestimation of the detection of small reinfarctions if troponin was already elevated at presentation and if the patient did not evolve new electrocardiographic changes in myocardial infarction.” Nevertheless, this study did show changes in the management of these patient populations over the course of the study from 1999 to 2006, including a marked increase in interventional therapy in both patient populations and changes in pharmacological therapy that included increased use of β-blockers, statins, ACE inhibitors, and thienopyridines in patients with ACS and Gp IIb/IIIa inhibitors in patients with STEMI. The authors note that “this study population is the first demonstration of significant reductions observed in hospital rates of new heart failure in ACS patients, over time, and of reductions in mortality.”

[1] Fox KAA, Steg G, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA 2007;297(17):1892-1900

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Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with CAD

This study [1] explores the benefit and cost-effectiveness of high-dose statin therapy in reducing the risk of cardiovascular events in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD) as compared with conventional-dose statin therapy.

A Markov decision-analysis model was used to evaluate the actual benefits obtained with high-dose statin therapy in a hypothetical 60-year old cohort and a threshold analysis was performed to evaluate at what cost difference high-dose statin therapy, as compared with conventional-dose statin therapy, would remain cost-effective. A pooled analysis of clinical end points (all cause mortality, myocardial infarction, stroke, rehospitalization, and revascularization) from four clinical trials that compared high-dose with conventional-dose statin therapy were used to quantify the incremental clinical benefit of the high-dose statin therapy into quality-adjusted life-years (QALYs). These trials were divided into two groups, ACS trials and CAD trials, because of differences in the study populations and trial follow-ups.

The mean duration of follow-up in the ACS and stable CAD trials were 2 and 5 years, respectively. In the threshold analysis, a model of the price difference between a high- and conventional-dose statin at which a high-dose statin strategy would remain under a $50,000, $100,000, and $150,000 per QALY threshold was developed. This model was adopted instead of modeling separate costs for high- and conventional-dose since the actual costs of statins are in flux and subject to change over time. For the ACS patients, a high-dose statin resulted in a gain of 0.35 QALYs as compared with conventional-dose statin. The threshold analysis showed that a high-dose statin strategy consistently produced incremental cost-effective ratios below $30,000 per QALY. For the stable CAD patients, a high-dose statin produced a gain of only 0.10 QALYs and was sensitive to model assumptions about statin efficacy (sustained benefit of high-dose statins beyond 5 years). In order to produce incremental cost-effective ratios below $50,000, $100,000 and $150,000 per QALY, the daily cost difference between a high- and conventional-dose statin would need to be <$1.70, $2.65, and $3.55.

Based on these findings, the authors concluded that “this study found that a strategy of high-dose statin therapy in patients with ACS would be effective (net gain of 0.35 QALYs) and cost effective, with effectiveness mediated primarily through reductions in all-cause mortality,” while, “in contrast, in patients with stable CAD, a high-dose statin strategy was only able to achieve a net gain of 0.10 QALYs, with half of the gains achieved through a reduction in stroke risk.” The authors suggest “that routine use of decision analysis along with the reporting of clinical trials that use composite end points may provide an effective tool for interpreting the value of new treatments.” They note several study limitation that included: possible over simplification of assumptions in the decision-analysis model; incorporation of estimates for statins from a relatively small number of trials that compared high- versus conventional-dose statin therapy and at face value; homogeneity of statin efficacy was assumed among statins of similar potencies; and lack of applicability to older or young patients if a significant treatment-by age interaction exists since the model used a hypothetical 60-year-old cohort with ACS and stable CAD. The authors conclude, however, that “use of high-dose statins can be supported on health economic grounds in patients with ACS, but the case is less clear for patients with stable CAD.”

[1] Chan PS, Nallamothu BK, Gurm HS, et al. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation 2007;115(18):2398-2409

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Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease

This prespecified secondary analysis of the TNT (Treating to New Targets) study [1] examines the efficacy and safety of high-dose atorvastatin treatment in patients of at least 65 years of age.

Following a run-in phase, 10,001 patients in the TNT study with low-density lipoprotein (LDL) cholesterol levels less than 3.4 mmol/l (<1380 mg/dl) were randomly assigned to receive double-blind therapy with atorvastatin (10 or 80 mg/d). These patients were followed for a median of 4.9 years. Of this total, 3809 (38%) were at least 65 years of age (mean age 69.9 years) and were included in this secondary analysis (1872 received 10 mg of atorvastatin; 1937 received 80 mg). At baseline, the two groups had similar characteristics and LDL, high-density lipoprotein (HDL), and total cholesterol and triglyceride levels. The primary end point was the occurrence of a first major cardiovascular event, which was defined as death from coronary heart disease (CHD), nonfatal non-procedure-related myocardial infarction (MI), resuscitated cardiac arrest, or fatal or nonfatal stroke.

Among this cohort of patients of at least 65 years of age, 199 patients (10.3%) who received 80 mg of atorvastatin and 235 patients (12.6%) who received 10 mg experienced a primary event. This represents a 2.3% absolute reduction in the rate of major cardiovascular events and a 19% relative reduction in risk in favor of the high-dose group (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.67 to 0.98; P=0.032). The risk reductions associated with 80 mg atorvastatin after adjustment for well-established risk factors (sex, race, smoking status, history of diabetes, and history of hypertension) were similar to the unadjusted results (HR,0.81; 95% CI, 0.67 to 0.98; P=0.032). The 80 mg atorvastatin group, as compared with the 10 mg group, had lower rates of death due to CHD, nonfatal non-procedure-related myocardial infarction, and fatal and nonfatal stroke (ischemic, embolic, hemorrhagic, or unknown origin), but the difference was not statistically significant for each individual component. No cases of persistent elevation in creatinine kinase levels to greater than 10 times the upper limit of normal were observed.

Wenger et al concluded that “for patients 65 years of age or older with stable CHD, intensive lipid-lowering treatment with 80 mg of atorvastatin statistically significantly reduced the rate of major cardiovascular events compared with 10 mg atorvastatin.” They point out that their results support the findings of previous placebo-controlled studies [2,3] are consistent with current ACC and AHA secondary prevention recommendations [4], and suggest that aggressively treating older patients to reduce LDL cholesterol levels to less than 2.6 mmol/l (<100 mg/dl) has added clinical benefit. They note several study limitations as follows: 1) The ability to detect subtle treatment effects with confidence would have been strengthened by including a greater number of elderly patients. 2) No determination could be made as to whether the clinical benefit observed among older patients was related to the higher statin dose, lower resultant LDL cholesterol level, or both.

[1] Wenger NK, Lewis SJ, Herrington DM, et al. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med 2007;147(14):1-9

[2] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002:360:7-22

[3] Shepherd J, Blauw GJ, Murphy MB, et al. PROspective study of Pravastatin in the elderly at risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002:360:1623-1630

[4] Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-2372

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ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction

The newly published Guidelines for the Management of Patients with Unstable Angina (UA)/Non-ST-Elevation Myocardial Infarction (NSTEMI), jointly sponsored by The American College of Cardiology/American Heart Association (ACC/AHA), provide recommendations that are based on a comprehensive review of the clinical evidence since the 2002 release of the guidelines, as well as expert opinion [1]. The recommendations are stratified by size of the treatment effect, e.g. Class I–IV with Class I having the most effect and Class IV the least, and by an estimate of certainty of treatment effect based on the research that is ranked from the highest (A) to lowest (B) weight of the evidence. The guidelines are intended to assist cardiovascular specialists and nonspecialists in the proper evaluation and management of patients with an acute onset of symptoms suggestive of UA and the closely related condition of NSTEMI. Moreover, they provide recommendations and supporting evidence for the continued management of these patients in both inpatient and outpatient settings. The 2007 guidelines address such issues as the need for earlier access to medical evaluation of acute coronary syndrome (ACS), new technologies for imaging, biomarkers, new anticoagulants, support for thienopyridine use, updates on percutaneous coronary intervention (PCI) and secondary prevention, and include an expanded section on special patient groups (women, patients with diabetes mellitus, post coronary artery bypass grafting (CABG) patients, older adults, patients with chronic kidney disease, cocaine and methamphetamine users, patients with variant (Prinzmetal’s) angina and patients with cardiovascular “Syndrome X”).

Important points to remember regarding the management of patients with UA/NSTEMI have been identified by Gurm and Eagle [2] and are highlighted in the description of the sections that follows.

Initial Evaluation and Management

The 2007 guidelines provide an overview of ACS that focuses on UA and NSTEMI and emphasize the need for early identification. In initial evaluation and management, to reduce morbidity and mortality from ACS, rapid assessment of symptoms by health care providers, access to the emergency medical system (EMS) and a shorter time to definitive treatments are stressed. Specific recommendations include advising patients with chest pain who have been prescribed nitroglycerin (NTG) to take an initial dose of NTG and if there is no relief within 5 min to contact EMS before taking more NTG and advising patients with chronic stable angina that if symptoms are significantly improved by the initial dose of NTG that they may take up to a maximum of three doses of NTG at 5-min intervals while waiting for EMS. The guidelines note that traditional risk factors for coronary artery disease (CAD) are not as important as the symptoms, electrocardiogram (ECG) findings and cardiac biomarkers. Subsequently, it is recommended that an electrocardiogram (ECG) be performed within 10 min of arrival to the emergency department (ED) or outpatient facility. Additionally, it is recommended that all patients who present with chest pain consistent with ACS be measured for cardiac biomarkers. Cardiac-specific troponin is identified as the preferred biomarker.

It is noteworthy that B-type natriuretic peptide, a new biomarker, is now included in the recommendations as possibly useful. In patients with possible ACS, but who have normal ECG and biomarkers over 12–16 hours, it is recommended that a stress test be performed prior to discharge from the ED or within 72 hours of discharge and that appropriate pharmacotherapy be provided prior to the stress test. It is also noteworthy that computed tomography angiography is recommended instead of a stress test for patients identified with a low probability of coronary artery disease (CAD) and possible ACS. Two newer imaging modalities, cardiac magnetic resonance and multidetector CT for coronary calcification are identified as promising alternative or supplementary imaging modalities for the assessment of patients presenting with chest pain syndromes.

Early Hospital Care

The guidelines recommend that patients with hemodynamic instability or ongoing symptoms be admitted to a coronary care unit while others should be admitted to a step-down unit. After admission and in early hospital care, it is recommended that the optimal management of UA/NSTEMI for the relief of ischemia and prevention of serious adverse outcomes include anti-ischemic therapy, anticoagulant therapy, ongoing risk stratification, and appropriate use of invasive procedures. Of note are recommendations that 1) oral beta-blockers be instituted within the first 24 hours in the absence of contraindications (intravenous beta-blockers should only be used for specific indications and not as routine therapy) and 2) nonsteroidal anti-inflammatory drugs (COX-1 or COX-2 inhibitors) other than aspirin (ASA) should be discontinued on admission in patients with ACS. It is also pointed out that while morphine sulfate is reasonable for patients whose symptoms are not relieved despite NTG or recur despite adequate anti-ischemic therapy, use of morphine has been associated with a poorer outcome in observational studies and the guidelines have downgraded it from a Class I to a Class IIa recommendation.

The guidelines stress that “anticoagulant therapy is essential to modify the ACS disease process and its adverse consequence” and that “a combination of ASA, an anticoagulant, and additional antiplatelet therapy represents the most effective therapy.” As soon as ACS is diagnosed or suspected, an initial dose of ASA (between 162 and 325 mg) is recommended unless contraindicated and thereafter indefinitely. (NB clopidogrel should be used in patients with ASA allergy or intolerance.) In addition to ASA, clopidogrel should be initiated in patients who are being considered for either a conservative (calls for invasive evaluation only with symptomatic failure of medical therapy or other objective evidence of recurrent or latent ischemia) or an early invasive therapy (generally undergo coronary angiography within 4 to 24 hours of admission) and for whom the possibility of surgical disease requiring early CABG is low. In UA/NSTEMI patients being treated with an initial invasive strategy, antiplatelet therapy with both clopidogrel and an IV GP IIb/IIIa inhibitor should be considered, but abxicimab, as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to PCI (NB Abciximab can be used safely for PCI in patients who have not received upstream glycoprotein (GP) IIb/IIIa inhibitors and may be better than tirofiban for this population of patients). Upstream use of eptifibatide or tirofiban should be considered in high-risk patients and those with troponin elevation, especially in cases where invasive therapy is being considered. When a conservative strategy is selected, the preferred anticoagulant regimens may be (in order) fondaparinex, enoxaparin, or unfractionated heparin (UFH). For patients in which an invasive strategy is selected, enoxaparin or UFH-based regimens have the most supporting evidence. Specific to patients undergoing CABG, ASA should be continued, while clopidogrel should be discontinued 5–7 day before, and low-molecule GP IIb/IIIa inhibitors stopped 4 hours before the surgery; enoxaparin should be discontinued 12–24 hours prior and fondaparinux discontinued 24 hours prior to CABG, and UFH should be started. Patients who receive intravenous GP IIb/IIIa inhibitors must also receive concomitant UFH or another antithrombotic agent.

Coronary Revascularization

In high-risk patients with ongoing symptoms or hemodynamic instability, early invasive therapy is preferable while other patients can be considered for either early invasive or conservative therapy based on physician and patient preference. The decision to perform surgical versus percutaneous revascularization should be determined based on a patient’s anatomy, left ventricular (LV) function, and the presence or absence of diabetes and other comorbidities. Of note, patients with NSTEMI and totally occluded vessels on angiography were not shown to benefit from PCI in the OAT trials. Thus, PCI should not be considered for these patients. Since the risk of death or recurrent MI is highest in the first 2 months and returns to a baseline risk of those with stable CAD by 3 months, low-risk patients (and fully revascularized patients) should be followed up at 2–6 weeks while high-risk patients should be re-evaluated within 2 weeks.
 
Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care

The guidelines stress that “two broad goals during the hospital discharge phase are 1) to prepare the patient for normal activities to the extent possible and 2) to use the acute event as an opportunity to reevaluate care, focusing on lifestyle and aggressive risk factor modification.” It is noted that an interdisciplinary team is best for preparing the patient for discharge.

In general, all patients with ACS should receive ASA, statins, beta-blockers, and clopidogrel. It is recommended that angiotensin-converting enzyme inhibitors be given to patients with heart failure, LV dysfunction, hypertension, or diabetes mellitus unless contraindicated. The goal for blood pressure should be <140/90 mmHg for all patients and 130/80 mmHg for patients with diabetes mellitus or chronic kidney disease. For ACS patients with elevated LDL-C levels ≥100 mg/dL, cholesterol-lowering therapy should be initiated or intensified to achieve an LDL-C of <100 mg/dL. Patients with ACS should not start hormone replacement therapy (HRT) or should be advised to discontinue it if they are on HRT at the time of ACS. Of note, antioxidant vitamin supplements, e.g. vitamins E, C or beta carotene, and folic acid, with or without B6 and B12, are not recommended for secondary prevention in ACS patients.

While return to activity should be guided by an exercise tolerance test, exercise training can be initiated within 1–2 weeks after coronary revascularization. It is recommended that patients be encouraged to engage in moderate aerobic activity, e.g. brisk walking or other physical activity, for at least 30–60 minutes per day for at least 5 days a week and preferably 7 days. Unless prohibited by law, patients with uncomplicated NSTEMI ACS can begin driving within 1 week of discharge although patients with complicated MI should delay driving for 2–3 weeks.

Special Groups

For special populations, aggressive glucose control treatment of patients with diabetes while hospitalized and emphasis on special attention to drug dosing and altered pharmacodynamics while treating the elderly and patients with renal impairment are recommended.

(1) Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction). J Am Coll Cardiol 2007;50:el-157

2. Gurm, HS and Eagle K. Twenty points to remember from the 2007 UA/NSTEMI guideline update. Available online at Cardiosource

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See also: Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: The ACUITY Timing Trial

Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis

This study [1] represents a pre-specified subgroup analysis of the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25) trial to assess the efficacy and safety of the a strategy of either enoxaparin or unfractionated heparin (UHF) to support fibrinolysis in patients with ST-elevation myocardial infarction (STEMI).

In ExTRACT-TIMI 25, 20,479 patients (≤18 years of age) who presented within 6 hours of the onset of symptoms of STEMI and who were scheduled to undergo fibrinolysis were treated with a fibrinolytic agent (16,283 or 79.7% with alteplase, tenectepiase, or reteplace; 4139 or 20.3% with streptokinase [SK]) and randomly assigned in a 1:1 ratio to receive either enoxaparin or unfractionated heparin (UFH) in a double-blinded fashion with a double-dummy design. The primary efficacy end point of ExTRACT-TIMI 25 and this subgroup analysis was the composite of all-cause mortality or nonfatal recurrent MI in the first 30 days after randomization. The primary secondary endpoint was the composite of death from any cause, nonfatal reinfarction, or recurrent myocardial ischemia leading to urgent revascularization in the first 30 days. The primary safety end point was TIMI major bleeding.

At 30 days follow-up, death or nonfatal recurrent MI occurred in 12.0% of patients in the UFH group and 9.8% of patients in the enoxaparin group when treated with fibrin-specific lytics (odds ratio adjusted [ORadj] 0.78; 95% confidence interval [CI] 0.70=0.87; P<0.001) and 11.8% vs. 10.2%, respectively, when treated with SK (ORadj 0.83; 95% CI 0.66–1.04; P=0.10; Pinteraction = 0.58). The rates of major bleeding, including intracranial hemorrhage, within the fibrin-specific cohort were 1.2% and 1.0% in the UFH and enoxaparin groups respectively (P<0.001) and 2.0% in UHF and 2.5% in enoxaparin patients in the SK cohort (P=0.16). Interaction tests for the risk of major bleeding and intracranial hemorrhage were not found to be significant between fibrin-specific vs. SK cohorts and anticoagulant assignment (P=0.40 and 0.12, respectively). In the fibrin-specific cohort, the rates of all-cause mortality, nonfatal reinfarction, and major bleeding were 12.7% and 10.8% for patients treated with UFH and enoxaparin, respectively (ORadj 0.82; 95% CI 0.74–0.91; P<0.001). In the SK cohort, the rates of all-cause mortality, nonfatal reinfarction, and major bleeding were not found to be significant, but were directionally in favor of enoxaparin (11.8%) vs. UFH (13.0%) (ORadj 0.89; 95% CI 0.72–1.10; P=0.29; Pinteraction=0.53).

The authors concluded that their findings “demonstrate the superiority of anticoagulant therapy with a strategy of enoxaparin throughout the index hospitalization over the standard strategy of 2 days of UFH in STEMI patients undergoing pharmacological re-perfusion across the spectrum of four lytics available around the world that were used in ExTRACT-TIMI 25.” They also point out that there was a significant reduction in all-cause mortality, or nonfatal recurrent MI as well as death, nonfatal reinfarction, or urgent revascularization in patients who received enoxaparin in both the fibrin-specific lytic cohort and each of the fibrin-specific lytics analyzed independently. Similar reductions were also seen with enoxaparin in the SK cohort although the extent of the benefit was somewhat smaller than in the fibrin-specific cohort. The authors suggest that “the advantage of enoxaparin over UFH may be related to both a direct anticoagulant benefit as suggested by a significant decrease in the primary end point after 24 h of treatment and to the longer duration of therapy as seen by the incremental advantage after UFH is stopped.” They also note that “despite major bleeding, net clinical benefit analyses favoured the enoxaparin strategy in both fibrin-specific and SK cohort” and suggest that this finding supports concomitant antithrombin therapy in fibrinolysis with both fibrin-specific agents and SK. The authors noted a number of study limitations, e.g. the non-randomized nature of the fibrinolytic therapy as a potential confounder and insufficient power to detect differences between subgroups. In terms of clinical implications, they point out that “these findings strongly suggest that a strategy of enoxaparin is preferred over UFH to support fibrinolysis for STEMI across the range of lytics in common clinical use.”

[1] Giraldez RR, Nicolau JC, Corbalan R, et al. Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis. Eur Heart J 2007;28:1566-1573

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Coronary artery involvement in children with Kawasaki Disease. Risk factors from analysis of serial normalized measurements

This study [1] is a secondary analysis of data from the Pediatric Heart Network’s Randomized Trial of Pulse Steroid Therapy in Kawasaki Disease that uses serial assessment of normalized coronary artery dimensions to determine the spectrum and early time course of coronary artery involvement and to define associated clinical and laboratory factors using these data.

A total of 190 patients were included in this analysis and randomly assigned to receive either a single dose of intravenous methylprednisolone or an identifiable placebo before receiving conventional-dose IVIG and aspirin. Clinical, laboratory, and echocardiographic measurements were obtained at baseline and 1 and 5 weeks after presentation. At baseline, the study population consisted of 62% males (mean age of 3.3 years with a range 2 months to 12.3 years and a mean duration of illness of 6.6±1.4 days at the time of enrollment) with a racial/ethnic composition of 58% white, 18% black, 14% Asian, 5% American Indian or Alaskan Native, <1% Native Hawaiian or other Pacific islander, 7% more than one race or ethnic group, <1% unknown, and 17% Hispanic.

Upon initial assessment, the z scores for the majority of patients were well above a normal population predicted value of zero (median of 1.43). The z scores remained elevated throughout the study although some decreases were found at 1 and 5 weeks. For 26% of the patients, at least 1 pRCA or pLAD z score was ≥2.5; 5% of the patients had at least one z score ≥5. Forty-four patients (23%) met dimensional criteria for involvement by Japanese Ministry of Health criteria. At enrollment, younger patient age was independently associated with a greater z score at all points. Moreover, other factors found to be independently associated with a greater z score at any time included greater number of days from disease onset to treatment with IVIG, a lower IgM level measured at baseline, and a lower minimum albumin level found over the 5-week period. z Scores were found to be higher for the proximal right coronary artery than the left anterior descending branch.

McCriddle and colleagues concluded that “analyses of serial normalized coronary artery measurements in optimally treated Kawasaki disease patients demonstrated that for most patients, measurement are greatest at baseline and subsequently diminish; baseline measurements appear to be good predictors of involvement during early follow-up” and note that “when a more precise assessment is used, risk factors for coronary artery involvement are similar to those defined with arbitrary dichotomous criteria.” They point out a number of study limitations as follows: 1) The study findings may not be completely generalizable to the total population of patients identified with potential Kawasaki disease in clinical practice because of some types of Kawasaki disease patients were excluded from the analysis. 2) Normalization as z scores was based on regression equations resulting from observations in nonfebrile, normal children. 3) Normative data were not available for distal coronary artery segments so the analyses focused on normalized measurement of the pLAD and pRCA rather than the entire coronary artery tree. 4) Patients were followed for 5 weeks after presentation so longer-term changes were not studied. 5) The incidence of severe coronary artery involvement was lower in this study population as compared with other studies that have addressed associated factors. McCriddle and colleagues stressed that “understanding the risk factors for coronary artery involvement in KD patients may facilitate the identification of low-risk children in whom extensive and frequent testing may be unnecessary, as well a high-risk children who may require closer monitoring and may be candidates for additional therapies.”

[1] McCrindle BW, Li JS, Minich LL, et al. Coronary artery involvement in children with Kawasaki Disease. Risk factors from analysis of serial normalized measurements. Circulation 2007;116:174-179

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Differences in mortality and use of revascularization in black and white patients with acute MI admitted to hospitals with and without revascularization services

This retrospective cohort study [1] examines racial differences in the patterns of care (hospital transfer and coronary revascularization) and mortality for black and white patients with acute myocardial infarction (AMI) who were admitted to hospitals with and without revascularization services.

The data for this study were obtained from the Centers for Medicare & Medicaid Services (CMS) and come from the Medicare Provider Analysis and Review (MedPAR) data files for calendar years 2000 to 2005. A total of 121,594 black and white beneficiaries who were ≥68 years of age and admitted with AMI between January 1, 2000, and June 30, 2005, to 4627 hospitals in the United States with or without revascularization services were included in the study. Of this total, 699,926 (57.6%) were admitted to 1169 hospitals with full revascularization services and 515,998 (42.4%) were admitted to 3488 hospitals that did not offer full revascularization services. The primary outcome measures were transfer to another acute care hospital with revascularization services for patients admitted to hospitals without these services and risk-adjusted rates of 30-day coronary revascularization and 1-year mortality.

For patients in both hospitals, with or without revascularization services, black patients, as compared with white patients, were more likely to be female, younger and live in urban areas or areas with lower median household income. Overall, black patients were more likely to have congestive heart failure, diabetes, peripheral vascular disease, renal failure, weight loss, dementia, and subendocardial infarctions, but less likely to have arrhythmia or chronic obstructive pulmonary disease and anterior, lateral, inferior or posterior infarctions. Black patients were less likely to be transferred if they were initially admitted to hospitals without revascularization services (25.2% vs. 31.0%; P<0.001). Regardless of type of hospital (with or without revascularization services), black patients, in comparison with white patients, were less likely to undergo revascularization (34.3% vs. 50.2% and 28.3% vs. 25.9%; P<0.001) and had higher mortality at 1-year follow up (35.3% vs. 30.2% and 39.7% vs. 37.6%; P<0.001). Even after adjustment for sociodemographics, comorbidity, and illness severity, the differences for black patients for transfer to a hospital with revascularization services (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.75–0.81; P<00.1) and undergoing revascularization in hospitals with or without revascularization (HR, 0.71; 95% CI, 0.69–0.74; P<0.001; and HR, 0.68; 95% CI, 0.65–0.70; P<0.001 respectively) remained significant. Black patients had a lower risk-adjusted mortality during the first 30 days after admission (HR, 0.91; 95% CI, 0.88–0.93; P<0.001; and HR, 0.90; 95% CI, 0.87–0.92; P<0.001 in hospitals with and without revascularization respectively), which was higher from this time period on.

The authors point out that “the current findings complement previous studies of racial disparities in the care of patients after AMI …” They also note that while the available data on racial disparities is great, “less is known about how different patterns of hospital care may contribute to population-based disparities.” They emphasize the importance of these kinds of data, especially in light of recent arguments for regionalization of coronary revascularization and other high-technology services. They note limitations to the study that include: 1) There may be unmeasured aspects of medical decision making that may impact the process of care, e.g. patient and family preference, that were not available. 2) Important clinical indicators for transfer and revascularization were not accounted for in the study, e.g. use of thrombolytics and economic factors. 3) Development of risk-adjustment models based on administrative data has limitations and the reliability of individual diagnosis codes may vary across study hospitals. 4) The results may not be generalizable to younger patients or to patients enrolled in Medicare managed care. Nevertheless, these authors conclude that “the current study provides evidence that racial differences in the use of revascularization after AMI are of similar magnitude for patients admitted to hospitals with and without full revascularization capability and persist even for patients transferred from hospitals without full invasive cardiac services to hospitals providing these services.” They emphasize the need to standardize post-AMI treatments with evidence-based protocols and aggressive risk-factor management in order to eliminate racial differences in care for AMI and other coronary syndromes.

[1] Popescu I, Vaughan-Sarrazin MS, Rosenthal GE. Differences in mortality and use of revascularization in black and white patients with acute MI admitted to hospitals with and without revascularization services. JAMA 2007;397(22):2489-2495

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Springer’s booth and staff will be at the forthcoming AHA Scientific Sessions 2007 in Orlando’s Orange County Convention Center, Orlando, FL from 3rd-6th November.

Come to the Springer booth (#1061) to browse our content-rich selection of Cardiology publications, including Cardiovascular Medicine, Third Edition, by Willerson, Cohn, Wellens, and Holmes; Atlas of Cardiovascular Computed Tomography by Budoff, Achenbach, and Narula; and other essential books and journals for your personal library.

We look forward to seeing you there!