Further information: Medical Treatment of Unstable Angina, Acute Non-ST Elevation Myocardial Infarction (see p937) and Coronary Artery Spasm and Treatment of Acute ST-Elevation Myocardial Infarction (see p963) from Cardiovascular Medicine, 3rd Edn*

“The Limiting UNdertreatment of Lipids in ACS with Rosuvastatin (LUNAR)” study was a 12-week randomized, open-label, multicenter Phase IIIb study that compared efficacy and safety of rosuvastatin 20 mg and 40 mg with that of atorvastatin 80 mg in lowering levels of low-density lipoprotein cholesterol (LDL-C), with enrollment conducted over a period of 6–12 weeks in subjects with acute coronary syndrome (ACS). The investigators of LUNAR conducted the study on adults hospitalized for acute ST-segment elevation myocardial infarction (STEMI), non-STEMI, or unstable angina (UA) [1].

Five hundred and seven patients were analyzed, and of those, 212 were admitted for STEMI, 176 for non-STEMI, and 119 for UA. Patients ranged in age from 18–75 years and had not been on lipid-lowering medication for at least the preceding 4 weeks. The investigators analyzed the data from LUNAR by assessing lipid level changes 1–4 days after onset of ACS and before initiation of study treatment. Although current guidelines recommend that serum lipids be measured upon admission of patients, less that one-half have serum lipids measured within 24 hours of admission. Therefore, in prior studies that have been conducted, LDL-C was not measured directly, and often measurements were retrospective or blood was not drawn when the patient was fasting. In order to provide a direct measurement of serum lipid levels before study treatments were started, blood samples were taken at median times after onset of ACS symptoms of day 1, either fasting or non-fasting sample; day 2, a fasting sample; and day 4, a fasting sample. The study showed that LDL-C levels decreased in the 24 hours after admission (from 136.2–133.5 mg/dl, followed by an increase over the subsequent 2 days (to 141.8 mg/dl), but these changes did not seem to be clinically relevant.

The authors concluded that reliable knowledge of serum lipid levels early after a patient is admitted for ACS should help determine the initiation of lipid-lowering therapy, allow a more knowledgeable selection of drug dosage, and identify the potential need for adjunctive lipid-altering therapy. The study showed that LDL-C and other lipids varied little in the early days of hospital admission, and this fact should provide an impetus to measure lipids early after admission in order to provide a basis for clinical decision about lipid-lowering therapy.

[1] Pitt B, Loscalzo J, Ycas J, et al. Lipid levels after acute coronary syndromes (ACS). J Am Coll Cardiol 2008;51:1440-45

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Further information: Drug-Eluting Coronary Stents (see p1031) from Cardiovascular Medicine, 3rd Edn*

The SPIRIT III trial evaluated the everolimus-eluting stent as compared to the paclitaxel-eluting stent in patients with coronary artery disease [1]. SPIRIT III was a prospective, multicenter, randomized, single-blind, controlled clinical trial that included 65 academic and community-based US institutions and extended from June 22, 2005 to March 15, 2006.

The investigators randomized 1002 men and women with de novo coronary stenosis 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm to receive either an everolimus-eluting stent (669 patients) or a paclitaxel-eluting stent (333 patients). The primary end point was in-segment late loss at the time of an 8-month angiography and the secondary end point was noninferiority assessment of target vessel failure (revascularization at any location within the target vessel). Additionally, the evaluation of major adverse cardiac events, cardiac death, myocardial infarction (MI), or revascularization at 9 and 12 months, was a secondary end point.

In the everolimus-eluting stent group, angiographic in-segment loss was significantly less than in the paclitaxel-eluting stent group. At 9 months, the everolimus-eluting stent was also noninferior to the paclitaxel-eluting stent for target vessel failure (7.2% vs. 9.0%, respectively; difference, -1.9% [95% confidence interval [CI], -5.6%–1.8%); relative risk [RR], 0.79 [95% CI, 0.51–1.23]; P<0.001). Major adverse cardiac events were fewer in the everolimus group at one year (6.0% vs. 10.3%; RR, 0.58 [95% CI, 0.37–0.90]; P=0.02), due to fewer MIs and target lesions revascularization procedures. Definite stent thrombosis was infrequent (0.8% vs. 0.0%, P=0.18) for the everolimus and paclitaxel stents, respectively.

This trial showed that in de novo coronary lesions, an everolimus-eluting stent resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events when compared with a paclitaxel-eluting stent at 1 year follow-up.

[1] Stone GW, Midei M, Newman W, et al. Comparison of an Everolimus-Eluting Stent and a Paclitaxel-Eluting Stent in Patients with Coronary Artery Disease (CAD): SPIRIT III. JAMA 2008;299(16):1903-13

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

The “Revitalization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty versus Surgical Revascularization (MAIN-COMPARE)” registry contains data on patients who had underwent either percutaneous coronary angioplasty (PCA) or coronary artery bypass graft (CABG) in Korea between January 2000 and January 2006 for unprotected left main coronary artery disease (CAD), the coronary disease that inflicts the greatest danger to the left ventricle. Investigators of the current study [1] evaluated 1102 patients who had PCA and 1138 patients who underwent CABG. Of the patients who underwent PCA, 1073 (97%) had conditions that made them eligible for either PCA or CABG, but PCA was used due to either the patient’s or physician’s preference. The remaining 37% had underlying conditions making them poor candidates for surgery. In PCA group, 318 patients received bare metal stents (BMS) and 784 received drug-eluting stents (DES). Death, a composite outcome of death, Q-wave MI, or stroke, and target-vessel revascularization were the adverse outcomes that were compared with proprietary score matching in the overall cohort and in separate subgroups according to the type of stent.

The investigators found that in matched cohorts of patients with unprotected left main coronary artery disease, PCA and CABG had similar long-term rates of death (hazard ratio [HR] for the stenting group, 1.18; 95% confidence interval [CI], 0.77–1.80), as well as the composite end points of death, Q-wave myocardial infarction, or stroke (HR for the stenting group 1.10; 95% CI, 0.75–1.62). Rates of target-vessel revascularization were higher in the group that received stents than in the group that underwent CABG (HR, 4.76; 95% CI, 2.80–8.11). In a comparison of the BMS group and CABG group and the DES group and CABG group, the DES group showed a trend toward a higher rate of death and composite end point.

[1] Seung KB, Park DW, Kim YH et al. Stents versus coronary-artery bypass grafting for left main coronary artery disease. N Engl J Med 2008;358:1781-92

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Further information: Coronary Disease in Women (see p713) from Cardiovascular Medicine, 3rd Edn*

Investigators in this study [1] used 44,636 women from the Nurses’ Health Study, a cohort that was established in 1976 when a questionnaire on medical history and lifestyle was completed by 121,700 female nurses in the US to study the relationship between abdominal adiposity and cardiovascular disease (CVD). Follow-up of the cohort is repeated every 2 years via a questionnaire that updates information related to risk factors and newly diagnosed diseases, such as CVD, diabetes, and cancers. The investigators restricted their analysis to the 44,636 women who reported waist circumference (WC) in the 1986 questionnaire update and who were free of a prior history of CVD and cancer. WC and waist-to-hip ratio (WHR) are measurements commonly used in epidemiological studies as indicators of abdominal adiposity. With overall body adiposity having increased over the past 15 years, data collected between 2003 and 2004 show that over half of the adults in the US have abdominal obesity, and the current study evaluates the association of premature death resulting from CVD and cancer with all-cause and specific-cause mortality.

During the follow-up period of 16 years, 3507 deaths were identified, and that included 751 CV deaths and 1748 cancer deaths. Following adjustments for body mass index (BMI) and potential confounders, the relative risks (RR) across the lowest to the highest WC quintiles were 1.00, 1.11, 1.17, 1.31, and 1.79 (95% confidence interval [CI], 1.47–1.98) for all-cause mortality; 1.00, 1,04, 1.04, 1.28, and 1.99 (95% CI, 1.44–2.73) for CVD mortality; and 1.00, 1.18, 1.20, 1.34, and 1.63 (95% CI, 1.32–2.01) for cancer mortality (all P<0.001 for trend). Among normal-weight women, BMI 18.5 to <25 kg/m^2, abdominal obesity was significantly associated with elevated CVD mortality: RR associated with WC ≥ 88 cm was 3.02 (95% CI, 1.31–6.99) and for WHR > 0.88 was 3.45 (95% CI, 2.02–6.92). After adjustment for WC, hip circumference was significantly and inversely associated with CVD mortality. Although maintaining a healthy weight is significant in the prevention of CVD and premature death, it is also significant to maintain a healthy WC and to prevent abdominal obesity.

[1] Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation 2008;117:1658-67

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Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients with Clopidogrel Resistance

Further information: Treatment of Acute ST-Elevation Myocardial Infarction from Cardiovascular Medicine, 3rd Edn*

Investigators of the current study [1] conducted a prospective, randomized, multicenter study that included 4 centers in Marseille, France to evaluate the clinical impact of adjusting the dose of clopidogrel that is administered after percutaneous coronary intervention (PCI) according to vasodilator-stimulated phosphoprotein (VASP) index. All patients undergoing PCI for refractory angina pectoris under optimal medical therapy, silent ischemia, non-ST-segment elevation myocardial infarction (NSTEMI) were eligible, and a total of 162 patients were included. Eighty-four were randomized to the control group and 78 were randomized to the VASP-guided group. Both groups had similar demographic, as well as similar biological characteristics. The VASP-guided group received up to three additional loading doses in an attempt to obtain a VASP index under 50%. The VASP index was measured 24 hours after the first 600-mg bolus of clopidogrel.

In the VASP-guided group, dose adjustment was efficient in 67 patients (86%) and VASP index was significantly decreased (from 69.3±10 to 37.6±13.8; P<0.001). Eight major adverse events (5%) were recorded during the 1-month follow-up, with a lower rate of significance in the VASP-guided group compared with the control group (0% vs. 10%; P=0.007). There was no difference in the rate of major and minor bleeding (5% vs. 4%; P=1). Data from this study suggest that by adjusting the clopidogrel loading dose according to the VASP index among patients with clopidogrel resistance, the clinical outcome after PCI may be significantly improved, and this study is the first to demonstrate such benefit.

[1] Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance. J Am Coll Cardiol 2008;51:1404-11

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Death and Acute Myocardial Infarction Associated with Stopping Clopidogrel after Acute Coronary Syndrome

Further information: Treatment of Acute ST-Elevation Myocardial Infarction from Cardiovascular Medicine, 3rd Edn*

The efficacy of clopidogrel therapy after hospitalization for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI) has been established by clinical trials. Early in 2007, the American Heart Association and the American College of Cardiology recommended 12 months of dual antiplatelet therapy for patients who received drug-eluting stents and from one month to one year for patients treated medically or with a bare-metal stent, and the groups warned against the cessation of the use of clopidogrel. Investigators in this study [1] sought to determine whether or not patients are at increased short-term risk for adverse events after clopidogrel is stopped and to evaluate a clustering of events that support the possibility of a “rebound effect” if the drug is stopped.

The authors conducted a retrospective cohort study of 31337 patients with ACS who were discharged from 127 Veterans Affairs hospitals on clopidogrel between October 1, 2003 and March 31, 2005. Primary outcome was the rate of all-cause mortality or AMI after stopping clopidogrel treatment. In medically treated patients, 302 days was the average period of clopidogrel treatment.

All-cause death (n=155) or acute myocardial infarction (AMI) (n=113) occurred in 17% (n=268) of patients, with 61% (n=163) of the events occurring 0–90 days, 21% (n=57) occurring during 91–180 days, and 10% (n=26) occurring 181 to 270 days after stopping clopidogrel. Further analysis showed that the interval of 0 to 90 days was associated with nearly twice the risk than the interval of 91–180 days. In PCI patients, 278 days was the average period of clopidogrel. All-cause death (n=68) or AMI (n=56) occurred in 8% of patients (n=124), and 59% (n=73) of the events occurring during 0-90 days. For the period of 91–180 days, 23% (n=29) events occurred, and for 181–270 days, 7% (n=8) occurred after stopping clopidogrel. After appropriate adjustments were made, researchers determined that the period of 0–90 days after stopping clopidogrel was associated with an 82% increased risk when compared with the interval of 91–180 days. Researchers determined that from 0–90 days was associated with nearly twice the risk of adverse events as compared with 91–180 days.

Investigators concluded that additional studies were needed to understand the mechanism of a possible clustering of events that support the “rebound effect” theory.

[1] Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008;299:532-539

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Primary PCI in ST-Segment Elevation Myocardial Infarction

Further information: Treatment of Acute ST-Elevation Myocardial Infarction from Cardiovascular Medicine, 3rd Edn*

In an effort to shorten door to balloon times in patients presenting with ST-segment elevation myocardial infarction (STEMI), researchers in Ottawa, Canada developed a strategy in which all such patients in the metropolitan area would be referred to the University of Ottawa Heart Institute for primary percutaneous coronary intervention (PCI) [1]. In this strategy, whenever possible, paramedics who had been trained to perform and interpret 12-lead ECGs responded to 911 calls from callers having chest pain, and they were able to triage patients and send those with STEMI directly to the primary PCI center. The intent of the system was to determine whether or not there was a difference in door-to-balloon times between patients who were referred directly from the field by these trained paramedics and patients who were referred by emergency department physicians. The study involved 344 STEMI patients referred for PCI during the first year of the program, with 135 referred directly from the field and 209 referred from the four emergency departments in the city’s hospitals.

The median door to balloon time was shorter in patients referred from the field (69 min; interquartile range, 43–87) than in patients needing interhospital transfer (123 min; interquartile range, 101–153; P<0.001). Door-to-balloon times of less than 90 min were achieved in 79.7% of patients who were transferred from the field and in 11.9% of those transferred from emergency departments (P<0.001). When patients were triaged by trained paramedics and triaged to a designated primary PCI center, desired door-to-balloon times were achieved and exceeded the results obtained when patients were referred from emergency departments.

[1] Le May MR, So, DY, Dionne R, et al. A citywide protocol for primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2008;358:231-40

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