Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study [1] was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone with heparin plus a glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor in patients with ST-segment elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention (PCI).

Three thousand six hundred and two patients who presented 12 hours after the onset of STEMI symptoms were randomly assigned to PCI with heparin plus a GP IIb/IIIa inhibitor or to treatment with bivalirudin alone. Primary endpoints of the study were major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke within 30 days. In large-scale randomized trials, bivalirudin alone has been shown to reduce major and minor bleeding and thrombocytopenia after PCI in patients with stable angina, unstable angina, and non-ST-segment elevation myocardial infarction (NSTEMI). However, HORIZONS-AMI was conducted to determine bivalirudin’s safety and effectiveness in STEMI patients undergoing primary PCI.

Compared with heparin plus GP IIb/IIIa inhibitors, anticoagulation with bivalirudin alone resulted in a reduced 30-day rate of net adverse clinical events (9.2% vs. 12.1%; relative risk [RR], 0.76%; 95% confidence interval [CI] 0.63–0.92; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; RR, 0.60; 95% CI, 0.46–0.77; P<0.001). Although there was an increased risk of acute stent thrombosis within 24 hours in the bivalirudin group, no significant increase was present by 30 days. Treatment with bivalirudin alone resulted in significantly lower 30-day rates of death from cardiac causes as compared with heparin plus GP IIb/IIIa inhibitors (1.8 vs. 2.9 %; RR, 0.62; 95% CI, 0.40–0.95; P=0.03) and in death from all causes (2.1% vs. 3.1%; RR, 0.66; 95% CI, 0.44–1.00; P=0.047).

The results of the trial show that in patients with STEMI who are undergoing PCI, anticoagulation with bivalirudin significantly reduces the 30-day rates of major bleeding and adverse events and net adverse clinical events. Additional study of the use of bivalirudin alone is warranted.

[1] Stone GW, Witzenbichler B, Guagliumi G et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.

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Further information: Surgical Treatment of Coronary Artery Disease (see p1051) from Cardiovascular Medicine, 3rd Edn*

The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) was a study designed to determine the safest and most effective antifibrinolytic drug to use during surgery to minimize bleeding and the need for blood transfusions in patients undergoing high-risk cardiac surgery [1].

High-risk cardiac surgery was defined as surgery with an average mortality of at least twice the normal average for isolated coronary artery bypass grafting (CABG) and with a high risk for repeat surgery. The three antifibrinolytic drugs that have been used effectively to reduce bleeding and the need for blood transfusions are aprotinin, a naturally occurring serine protease inhibitor, and two lysine analogues, tranexamic acid and aminocaproic acid. However, because of limited comparative evidence evaluating the overall safety of one drug over the other, these investigators conducted a randomized, multicenter, blinded trial and enrolled 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding, and the secondary outcomes included death from any cause at 30 days.

Although patients receiving aprotinin had less massive bleeding, the trial terminated early because of a high rate of death from any cause in patients receiving aprotinin. Seventy-four patients (9.5%) in the aprotinin group had massing bleeding as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin for both comparisons, 0.79; 95% confidence interval [CI], 0.59–1.05). However, at 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk [RR], 1.55; 95% CI, 0.99–2.42) and 4.0% in the aminocaproic acid group (RR, 1.52; 95% CI, 0.98–2.36). The RR of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06–2.22). Among the patients who died in the aprotinin group, the proportion who died of cardiogenic shock, right ventricular failure, congestive heart failure, or myocardial infarction was significantly higher than in the other two groups. The negative mortality trend associated with aprotinin when compared to the lysine analogues should preclude its use in high-risk cardiac surgery.

[1] Fergusson DA, Hébert PC, Mazer CD et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319-31.

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Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) study [1] was designed to test the hypothesis that in patients with ST-Elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) that was facilitated with the use of a combination of abciximab and reduced-dose reteplase would be more effective than primary PCI when abciximab is administered in the catheterization laboratory immediately before PCI. A third group was included using abciximab alone to help clarify the contribution of this component of the combination therapy to the clinical outcome. Current guidelines from the American College of Cardiology (ACC) call for a time-to-treatment of 90 minutes for patients presenting with acute STEMI, but many factors extend the time from onset of symptoms to PCI. Therefore, the optimal pharmacologic therapy for reperfusion before and in conjunction with PCI, especially when PCI is delayed, has not been determined.

FINESSE was an international, double-blind, placebo-controlled study in which a total of 2452 patients who presented 6 hours or less after the onset of STEMI were randomly assigned to receive combination-facilitated PCI, abciximab-facilitated PCI, or primary PCI. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary endpoint was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization.

More patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; P=0.01 and P=0.003 respectively). The primary endpoint occurred in 9.8%, 10.5%, and 10.7% of the patients in the combination-facilitated PCI group, abciximab-facilitated PCI group, and primary PCI group, respectively (P=0.55); 90-day mortality rates were 5.2%, 5,5%, and 4.5%, respectively (P=0.49).

The results showed that neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab alone significantly improved the clinical outcomes in STEMI patients when compared with abciximab given at the time of PCI.

[1] Ellis SG, Tendera M, de Belder MA et al. Facilitated PCI in Patients with ST-Elevation Myocardial Infarction. N Engl J Med 2008;358:2005-17.

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Further information: Smoking, Secondhand Smoke, and Cardiovascular Disease (see p2649) and Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

In an effort to evaluate the effects of both obesity and smoking in late adolescence on adult mortality, the investigators conducted a study based on a cohort of 49,321 Swedish men in a required nationwide military enrollment who registered from 1969–1970 at 16-19 years of age and were followed for 38 years [1]. The investigators’ primary hypothesis was that the effect of obesity and smoking in late adolescence increased the risk of adult mortality, and the secondary hypothesis was that excess risk of mortality in underweight people was due to smoking. In the cohort studied, 2897 men died.

Compared with normal weight men, risk of mortality was increased in overweight men (hazard ratio [HR] 1.33 [1.15–1.53]; incidence rate [IR] 23 [20–26]) and obese men (HR 2.14 [1.61–2.85], IR 38, 27 to 48), with similar relative estimates in separate analyses of smokers and non-smokers. No increased risk was detected in underweight men (HR 0.97 [0.86–1.08]; IR 18 [16–19]). The relative excess risk due to interaction between BMI and smoking status was not significant in any stratum. Additionally, all estimates of interaction were of small magnitude, except for the combination of obesity and heavy smoking (RR 1.5 [-0.7–3.7]). Compared with non-smokers (IR 14 [13–15]), risk was increased in both light (HR 1.54 [1.41–1.70]; IR 15 [14–16]) and heavy smokers (HR 2.11, 1.92 to 2.31; IR 26 [24–27]).

The results showed that regardless of smoking status, adult mortality increased when men were overweight or obese as adolescents. In addition, smoking was as hazardous to the men as being obese or overweight. There was no interaction between smoking and obesity status. These findings indicate the need for public health initiatives to target obesity and smoking in the adolescent years.

[1] Neovius M, Sundtrom J, Rasmussen F et al. Combined effects of overweight and smoking in late adolescence on subsequent mortality: nationwide cohort study. BMJ 2009:338:b496

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Further information: Management of Cholesterol Disorders (see p 2667) from Cardiovascular Medicine, 3rd Edn*

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) was a randomized, double-blind, placebo-controlled, multicenter trial conducted at 1315 sites in 26 countries in which 17,802 patients were enrolled [1]. The enrollees included apparently-healthy men 50 years of age or older and women 60 years or older, if they did not have a history of cardiovascular (CV) disease and if they had a low-density lipoprotein (LDL) cholesterol level of less than 130 mg per deciliter and a high-sensitivity C-reactive protein (hsCRP) level of 2.0 mg per liter or more. The primary objective of the trial was to investigate whether or not treatment with rosuvastatin, 20 mg daily, as compared with placebo, would decrease the rate of first major CV events. Currently, statins are prescribed for patients with established CV disease, diabetes, and overt hyperlipidemia. However, at least half of all myocardial infarctions (MI) and strokes occur in apparently healthy men and women with levels of LDL that are below the levels recommended for treatment. Since hsCRP has been previously shown to be a predictor of CV events, and statins also lower levels of hsCRP, as well as of LDL cholesterol, the investigators hypothesized that persons with elevated hsCRP, but without hyperlipidemia, might benefit from statin treatment.

The trial was stopped after a median follow-up of 1.9 years, with 5.0 years being the maximum follow-up. Rosuvastatin reduced LDL cholesterol levels by 50% and hsCRP levels by 37%. The rates of the primary endpoint were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio [HR] for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46–0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for MI (HR, 0.46; 95% CI. 0.30–0.70; P=0.0002), 0.18 and 0.34 for stroke (HR 0.52; 95% CI, 0.34–0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (HR 53; 95% CI, 0.40–0.70; P<0.00001), 0.45 and 0.85 for the combined endpoint of MI, stroke, or death from CV causes (HR, 0.53; 95% CI, 0.40–0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (HR, 0.80; 95% CI, 0.67–0.97; P=0.02). The rosuvastatin group reported a non-significant increase in myopathy or cancer, but did show a higher incidence of physician-reported diabetes.

The results of the trial showed that in the patient population enrolled, i.e. men and women without hyperlipidemia but with elevated hsCRP, rosuvastatin proved effective in reducing the incidence of CV events. These results raise several issues for consideration: is there a need for a randomized trial focused on the evaluation of hsCRP; should statin treatment be expanded; and in what ways should measurements of hsCRP be used in the future?

[1] Ridker PM, Danielson E, Fonseca FAH et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207

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Further information: Cardiovascular Complications of Obesity and the Metabolic Syndrome (see p2693) from Cardiovascular Medicine, 3rd Edn*

The authors [1] used the European Prospective Investigation into Cancer and Nutrition (EPIC) to determine whether the use of waist circumference and waist-to-hip ratio should be used to access risk of death along with body-mass index (BMI). Body mass index is measured as an individual’s weight in kg divided by the square of the individual’s height in meters.

EPIC included a cohort of 359,387 men and women who between 1992 and 2000 were ages 25–70 years and were from nine European countries. Of the studies that have examined general and abdominal adiposity and risk of death, few were conducted in Europe, and the large studies conducted in the United States did not assess waist circumference or waist-to-hip ratio along with BMI. This study examined the association of BMI, waist circumference, and waist-to-hip ratio on the cohort. Patients were followed for 9.7 years. During that time, 14,723 participants died.

The lowest risks of death related to BMI were found at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks (RR) among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80–2.33) and 1.78 (95% CI, 1.56–2.04), respectively, and in the highest quintile of waist-to-hip ratio, the RRs were 1.68 (95% CI, 1.53–1.84) and 1.51 (95% CI, 1.37–1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001).

[1] Pischon T, Boeing H, Hoffman K et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med 2008;359:2105-2120

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Further information: Sudden Cardiac Death (see p2039) from Cardiovascular Medicine, 3rd Edn*

The authors [1] evaluated whether the incidence and outcome of out-of-hospital cardiac arrest (OHCA) differ according to the geographic residence of patients. A prospective observational study, the Resuscitation Outcomes Consortium (ROC), was designed to evaluate all OHCAs in 10 North American sites (eight in the US and two Canadian) from May 1, 2006 to April 30, 2007. These patients were followed to hospital discharge, thus data were included as of June 28, 2008.

Patients (aged 0–108 years) were assessed by organized emergency medical services (EMS) personnel, did not have traumatic injury, and either received attempts at external defibrillation of chest compressions, or resuscitation was not attempted. Rates were adjusted for age and gender. Among the 10 sites, the population studied totaled 21.4 million. Of the total, 20,520 cardiac arrests were documented. Resuscitation was attempted in 11,898 cases, and of those, 2729 had initial rhythms of ventricular fibrillation, ventricular tachycardia, or rhythms shockable by an automatic external defibrillator (AED). Nine hundred fifty-four patients (4.6%) were discharged alive.
The median incidence of EMS-treated cardiac arrest across sites was 52.1 (interquartile range [IQR], 48.0–70.1) per 100,000 population; survival ranged from 3.0% to 16.3%, with a median of 8.4% (IQR, 5.4%–10.4%). Median ventricular fibrillation incidence was 12.6 (IQR, 10.6–5.2) per 100,000 population; survival ranged from 7.7% to 39.9%, with a median of 22.0% (IQR, 15.0%–24.4%). According to data documented in the five tables in this study, there were significant and important regional differences in incidence and outcome of OHCA. This report helps to provide an accurate estimation of the burden of OHCA and may assist local regions in improving public health by improving the ability to assess and treat cardiovascular disease in centers throughout North America.

[1] Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of hospital cardiac arrest incidence and outcome. JAMA 2008;300(12):1423-1431

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