Investigators in the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) trial focused on treatments for ischemic stroke, the third leading cause of death and the leading most debilitating condition in adults worldwide [1]. Two treatments used for both symptomatic and non-symptomatic patients are carotid artery stenting and carotid endarterectomy. Although earlier trials have been conducted to compare the two methods, results have not clearly favored one method over the other. This trial was conducted to obtain additional comparative data.

From December 2000 to July 2008, 2522 patients were enrolled at 108 US centers and nine Canadian centers, and were randomly assigned to one of the two treatment options. The primary endpoint was the composite of any type of stroke, myocardial infarction (MI), or death during the periprocedural period or ipsilateral stroke within 4 years after randomization. Compilation of data from CREST showed little difference in treatment in regard to primary endpoint, although in the periprocedural period, stenting carried a higher risk of stroke while endarterectomy had a higher risk of MI.

The authors of an accompanying editorial [2] stated that in comparing CREST findings with earlier comparative trials, they believed that the most important issue was the choice and timing of the primary end-point. The editorial also expressed concern that while the increased risk of stroke by stenting was offset by an increased risk of MI with an endarterectomy, ischemic stroke has more long-term health and quality of life issues than MI. The conclusion that the authors drew was that endarterectomy should be the preferred treatment, but individualized choice was appropriate.

[1] Brott TG, Hobson RW, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11-23

[2] Davis SM, Donnan GA. Carotid-artery stenting in stroke prevention. N Engl J Med 2010;363:80-82

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The wisdom of discouraging the performance of percutaneous coronary intervention (PCI) in non-infarct related arteries (non-IRA) concurrently with primary PCI was evaluated by investigators in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial [1]. Guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) discourage the practice of performing PCI in non-IRAs concurrently with primary PCI in stable ST-elevation myocardial infarction (STEMI) patients. However, additional examination of the issue was needed because the guideline recommendations were based on observational studies from an earlier era. Therefore, the investigators used the data from the APEX-AMI trial, the largest report of its kind to date, to reach a more timely recommendation by examining 90 day outcomes following non-IRA interventions performed at the time of primary PCI. After comparing the current data with the data obtained from the earlier studies, the investigators found the interventions were associated with increased mortality and adverse outcomes, and they continue to strongly support the ESC and ACC/AHA guideline recommendations.

[1] Toma M, Buller CE, Westerhout CM, et al. Non-culprit coronary artery percutaneous coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial. European Heart Journal 2010;31:1701-7

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ESC Clinical Practice Guidelines for the Management of Grown-Up Congenital Heart Disease (2009) (ESC website accessed 08/27/10)   Full text

The implantable cardioverter-defibrillator (ICD) is a widely used and trusted therapy for the prevention of sudden death from ventricular arrhythmia (VA). The design of the ICD requires the use of transvenous leads. Complication of lead insertion that result in difficulty obtaining venous access, as well as lead failure, led the investigators [1] to conduct two short-term trials to evaluate a subcutaneous ICD system that eliminated the need for placement of sensing and therapy electrodes within or on the heart. The first trial enrolled 78 patients from September 2001 to February 2004, and was conducted to identify the best electrode configuration out of four options for the subcutaneous ICD. Each patient was temporally implanted subcutaneously with an ICD to test the defibrillation threshold. After testing, the device was explanted, and a conventional ICD was implanted in each patient. The second short-term trial enrolled 49 patients from April 2004 to June 2005 in order to test the best of the previously tested subcutaneous ICD devices. In this trial, both a subcutaneous and a transvenous device were implanted in the same procedure. The defibrillation thresholds were compared, and after data were compiled, the subcutaneous device was explanted. Subsequently, two trials involving permanent implantation of a subcutaneous ICD were conducted. In a pilot trial in Australia, six patients were permanently implanted, and in a second trial conducted in New Zealand and Europe, 55 patients were permanently implanted. Investigators concluded that in these small, nonrandomized trials, the subcutaneous ICD was consistent and successful in detecting VA. There were 12 episodes of ventricular tachyarrhythmia that were also detected and treated.

[1] Bardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36-44

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The 70th Scientific Sessions of the American Diabetes Association (ADA) was held June 25–29, 2010 in Orlando, Florida.  Papers of major significance related to diabetes and cardiovascular disease were presented, and three of the issues that were addressed will be discussed here: blood pressure control in hypertensive diabetics with heart disease, the significant increase in risk of vascular disease in diabetics, and an ongoing controversy over the use of thiazolidinediones, specifically rosiglitazone, for glycemic control in diabetic patients.

Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients with Diabetes and Coronary Artery Disease

This is a subgroup analysis of 6400 participants in the International Verapamil SR-Trandolapril Study (INVEST), a trial that enrolled 22,576 subjects between September 1997 and December 2000 and followed them through 2008.  The current analysis [1] of the patient cohort aimed at determining whether improved cardiovascular outcomes were better achieved by maintaining tight control and lowering systolic blood pressure (BP) to less than 130 mmHg or usual control where BP ranged from 130 mmHg to less than 140 mmHg.  Uncontrolled was considered 140 mmHg or higher.  Results showed that a primary outcome event occurred in 12.7% of patients who had maintained tight control, 12.6% of patients who had maintained usual control, and 19.8% of patients who had uncontrolled systolic BP.  Similarly, in the results for the cardiovascular event rate and the rate for all-cause mortality, little difference existed between participants in the tight control group and those in the usual control group.  Investigators concluded that tight control of systolic BP in diabetic patients with coronary artery disease did not result in improved cardiovascular outcomes over the patients who maintained usual control.  Also on the Cardiovascular Medicine website [2], the results of the ACCORD trial [3] were reported and would be of interest to the reader of this report.  

Diabetes Mellitus, Fasting Blood Glucose Concentration, and Risk of Vascular Disease: a Collaborative Meta-Analysis of 102 Prospective Studies

The June 26, 2010 issue of The Lancet was a themed issue in collaboration with the 70th Scientific Sessions of The American Diabetes Association in Orlando, Florida on June 26–29, 2010.  The following study [4] and accompanying Editorial [5] report on a recent study conducted in an effort to understand the increased risk of vascular disease for diabetic patients.

The strong association between diabetic patients and their elevated risk across the entire gamut of  vascular disease, both ischemic and hemorrhagic, has not been explained by conventional risk factors, such as obesity, blood pressure, lipids, inflammatory markers, or renal function.  Even when those risk factors are controlled, diabetics still have a significant increase in incidence of vascular disease.  In an effort to understand the cause of the increase risk, the Emerging Risk Factors Collaborators conducted a meta-analysis of 102 prospective studies that included data for 698,782 diabetic patients without known vascular disease initially [4].  Combined within-study regressions were adjusted for age, gender, smoking status, systolic blood pressures, and body mass index and used to calculate hazard ratios (HR) for vascular disease. Adjusted HRs for a diabetic’s incidence of coronary artery disease were 2.00 (1.83–2.19), for ischemic stroke were 2.27 (1.95–2.65), hemorrhagic stroke were 1.56 (1.19–2.05), for unclassified stroke were 1.84 (1.59–2.13), and for other vascular deaths were 1.73 (1.51–1.98).  The collaborators also conducted a separate analysis of risk associated with fasting blood glucose concentrations and after evaluating all data and accounting for all relevant risk factors, concluded that diabetic patients carry a two-told risk for the entire range of vascular diseases that are independent of conventional risk factors, including a 56% risk of hemorrhagic stroke.  For people without diabetes, impaired fasting glucose status did not impact risk of vascular disease when combined with information about conventional risk factors.

In an accompanying editorial [5],  Dr. Hertzel Gerstein states that the current study has made a significant contribution to the relationship between fasting glucose and cardiovascular  risk in that the defect regarding glucose is not the only factor to be considered.  There are other abnormalities that might promote cardiovascular disease in diabetic patients, and long-term trials in insulin-replacement therapy that are currently underway might shed more light on the link between diabetes and serious cardiovascular outcomes.

[1] Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 2010;304:61-8

[2] Effects of combination lipid therapy and intensive blood-pressure control in type 2 diabetes mellitus. http://cardiovascular-medicine.com/?p=231

[3] The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362:1575-85

[4] The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22

[5] Gerstein HC. More insights on the dysglycaemia-cardiovascular connection. Lancet 2010; 375:2195-6

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One of the most controversial issues in cardiology in recent years has been to define the indications for closure of a patent foramen ovale (PFO). The newest indication for closure of the PFO has been to control migraine headaches. Not uncommon, PFOs have been found to occur in 10–25% of the population in the USA, and as much as 6% of the male population and 15–18% of the female population suffer from migraine headaches. Observational studies have suggested a pathophysiologic relationship in the prevalence of migraine headaches in patients who also have PFOs, and that closure of the PFO alleviated symptoms. In fact, the early studies came from a reported beneficial effect in the relief of migraine symptoms in patients who were undergoing closure for other indications.

The currently reported study [1] was the first large, prospective case-control study designed to test the association by using quantitative measures of migraine severity and core laboratory assessment of PFO with transthoracic echocardiography (TTE) and transcranial Doppler (TCD). Between August 2004 and December 2005, 360 subjects, 195 case subjects and 165 control subjects, were enrolled. Final matching yielded 144 subjects in each category for analysis. Odds ratios were calculated with conditional logistic regression in the matched cohort (n=288).

In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4% vs. 25.7%; odds ratio (OR) 1.04, 95% confidence interval (CI) 0.62–1.74, P=0.90). There was no difference in PFO prevalence in those with migraine with aura and those without (26.8% vs. 26.1%; OR 1.03, 95% CI 0.48–2.21, P=0.93). Therefore, no association between migraine headaches and the presence of PFO was found, and the investigators conclude that the focus should be on other mechanisms in the search to find the cause of migraine headaches.

In an editorial accompanying this article [2], the authors conclude that sufficient evidence does not exist for closure of a PFO for migraine to be considered standard medical practice and that further investigation into the mechanisms of migraine headaches is essential.

[1] Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale. Circulation 2010;121:1406-12

[2] Gersony WM, Gersony DR. Migraine headache and the patent foramen ovale. Circulation 2010;121:1377-78

Results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial were published in 2006 in The New England Journal of Medicine [1] and the trial was the longest and largest study ever conducted to evaluate the risks of dual antiplatelet therapy (DAPT) in patients who had undergone percutaneous coronary intervention with either bare metal or drug-eluting stents. The study determined that dual antiplatelet therapy (DAPT), aspirin and clopidogrel, reduced thrombotic events in patients with ST-segment elevation acute coronary syndromes and with non-ST-segment elevation acute coronary syndromes.

Two areas of uncertainly addressed by the current analysis [2] of the CHARISMA data were the amount of time DAPT should be continued in patients with known risk factors, as well as in stable patients with known vascular disease, by studying the frequency and time course of bleeding and whether bleeding is associated with mortality. Data from 15,603 patients were analyzed. Bleeding risk was found to be greatest in the first year: with clopidogrel, severe bleeding occurred in 1.7% vs. 1.3% on placebo (P=0.087), moderate bleeding occurred in 2.1% vs. 1.3%, respectively (P=0.001). Investigators found that when a patient did not have either severe or moderate bleeding the first year, bleeding thereafter was no more likely than for placebo patients. Multivariable analysis showed a strong relationship between moderate bleeding and all-cause mortality (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.71–3.80; P<0.0001), as well as with myocardial infarction (HR, 2.92; 95% CI, 2.04–4.18; P<0.0001), and stroke (HR, 4.20; 95% CI, 3.05–5.77; P<0.0001). This analysis of the CHARISMA data provides important data for the clinician as to the risks and benefits of DAPT in the treatment of stable patients or patients with vascular disease or known risk factors for vascular disease.

[1] Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17

[2] Berger PB, Bhatt DL, Fuster V, et al. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease (CHARISMA). Circulation 2010;121:2575-83

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The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial was conducted to evaluate whether lowering blood levels of homocysteine with folic acid plus vitamin B12 had a protective effect in preventing cardiovascular disease and stroke [1]. Although earlier observational studies [2,3] have indicated that significantly lowering blood levels of homocysteine resulted in lower risk of coronary heart disease (CAD) and stroke, data that showed definite protective effects had not resulted from any of the large-scale randomized trials.

SEARCH was a double-blind randomized trial that enrolled 12,064 survivors of myocardial infarction (MI). The trial was conducted at 88 hospitals in the United Kingdom, and men and women between 18 to 80 years of age with a history of MI were enrolled between 1998 and 2008. Patients were randomized to receive either 2 mg of folic acid plus 1 mg of vitamin B12 or placebo. The primary outcome was a major vascular event, such as coronary death, MI, or coronary revascularization, stroke, or noncoronary revascularization.

During the follow-up period for patients randomized to folic acid plus vitamin B12, major vascular events occurred in 1537 of the 6033 participants (25.5%) vs. 1493 of 6031 (24.8%) of patients on placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97–1.12; P=0.28). No apparent effects were shown for major coronary events (folic acid/vitamins, 1229 [20.4%], vs. placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97–1.13), stroke (folic acid/vitamins, 269 [4.5%], vs. placebo, 265 [4.4%; RR, 1.02; 95% CI, 0.86–1.21, or noncoronary revascularization (folic acid/vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18, 95%, CI, 0.95–1.46). No significant differences in numbers of deaths were due to vascular causes (folic acid/vitamins, 578 [9.6%], vs. placebo, 559 [9.3%]) or nonvascular causes (folic acid/vitamins, 405 [6.7%], vs. placebo, 392 [6.5%]).

SEARCH investigators concluded that folic acid/vitamin supplementation did not produce a benefit for major vascular events overall or in any of the subgroups, nor was benefit shown for incidence of stroke prevention.

[1] Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effect of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors. JAMA 2010;303:2486-94

[2] Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Eng J Med 1991;324:1149-55

[3] Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57

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In 1985 and 1986 respectively, two articles were published in Circulation [1,2] that reported that myocardial platelet thrombi were embolic and that the emboli were a cause of acute coronary syndromes (ACS). Although prior histopathological studies had shown intramyocardial microemboli and microvascular obstruction (MVO) were present in patients with ischemic cardiac death, the association between culprit coronary morphology and intramyocardial emboli had not been reported. Therefore, the investigators in this study [3] determined to evaluate the frequency of intramyocardial microemboli and MVO in sudden cardiac death from acute coronary thrombosis. Differentiating between plaque rupture and plaque erosion were important elements of the study. Plaque rupture was defined as “disruption of a fibrocellular cap overlying a pool of lipid with pultaceous debris,” and plaque erosion was defined as “surface ulceration of the upper plaque layers without rupture into a lipid core.”

Through analysis at autopsy of coronary arteries of 44 hearts, 26 plaque ruptures and 21 erosions were found, and there was a mean of 4.5 microemboli per heart. Microemboli and MVO occurred in eroded plaques more often, and although all vessels contained fibrin and platelets, microemboli and occluded intramyocardial vessels were more common in the LAD of the coronary artery. The mean stenosis of the culprit lesion was 74% in the arteries with microemboli and 75% in those without (P=NS). Intramyocardial microemboli were more common in plaque erosion than in plaque rupture.

The investigators concluded that plaque erosion was dominant in the histopathology of clot embolization causing sudden cardiac death, was more likely to occur in vessels of less than 120 µm, and was associated with focal necrosis.

[1] Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699-708

[2] Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418-27

[3] Schwartz RS, Burke A, Farb A, et al. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death. J Am Coll Cardiol 2009;54:2167-73

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This article [1] contains observations from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 36) Trial (MERLIN-TIMI 36), a trial conducted at 440 sites between 2004 and 2007 to determine the efficacy and safety of ranolazine in long-term treatment of 6500 patients with non-ST segment elevation acute coronary syndromes (ACS). As part of the MERLIN-TIMI 36 trial, investigators designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with ACS. Because elevated BNP and the N-terminal portion of BNP prohormone identify patients at high risk of death and heart failure (HF), intense effort is being made to find treatments that would mitigate the risk of elevated BNP. There were 4543 baseline samples in which BNP had been measured from patients who had been randomized to ranolazine or placebo, and the patients were followed for 343 days. BNP elevation was defined as >80 pg/ml. The primary end point was a composite of cardiovascular (CV) death, myocardial infarction (MI), and recurrent ischemia.

Results showed that in 1935 patients with elevated BNP (>80 pg/ml), the risk of the primary end-point was higher (26.4% vs. 20.4%, P=0.0001), higher for CV death (8.0% vs. 2.1%, P<0.001, and higher for MI (10.6% vs. 5.8%, P<0.001) at 1 year. The primary end-point was reduced by ranolazine (hazard ratio [HR]; 0.79; 95% confidence internal [CI]: 0.66–0.94, P=0.009). For recurrent ischemia in patients with elevated BNP, the effect of ranolazine was directionally similar (HR: 0.78; 95% CI: 0.62–0.98; P=0.04) and CV death or MI (HR: 0.83; 95% CI: 0.66–1.05, P=0.12). Ranolazine had no effect on patients without elevated BNP, did not reduce BNP concentration over time, and did not reduce the clinical end-point for patients with new or worsening HF. Nevertheless, it did identify patients at high risk of recurrent myocardial ischemia ameliorated by ranolazine. Therefore, the investigators concluded that the effects of ranolazine warrant additional study.

In an editorial [2] in this same issue of JACC, the authors stated that while this carefully done study does not provide conclusive evidence that ranolazine should be used in patients with ACS and elevated BNP levels, it does lay the groundwork for a prospective clinical trial.

[1] Morrow DA, Scirica BM, Sabatine MS, et al. B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients with Non-ST Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2009;55:1189-96

[2] Califf RM, Shah SH, Newby LK. Biomarker Bonanza? J Am Coll Cardiol 2009;55:1197-99
 
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