Further information: Hypertension (see p1833) and Endocrine Disorders and the Heart (see p2295) from Cardiovascular Medicine, 3rd Edn*

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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Further information: Atherosclerosis: Pathogenesis, Morphology, and Risk Factors (see p1593) and Hematologic Disease and Heart Disease (see p2409) from Cardiovascular Medicine, 3rd Edn*

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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Further information: Coronary Artery Disease: Pathologic Anatomy and Pathogenesis (see p593), Arterial Compliance (see p1811), Atrial Fibrillation and Flutter (see p1955), and Sudden Cardiac Death (see p2039) from Cardiovascular Medicine, 3rd Edn*

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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Further information: Hypertension (see p1833) and Endocrine Disorders and the Heart (see p2295) from Cardiovascular Medicine, 3rd Edn*

This review features two studies focusing on patients with diabetes mellitus that were recently presented at the American College of Cardiology Scientific Sessions in Atlanta. Both segments of the ACCORD trial are summarized here.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) [1] was conducted in diabetic patients who were at high-risk of cardiovascular (CV) events to determine if a combination therapy that included a fibrate to raise HDL cholesterol and to lower triglyceride levels and a statin to lower LDL cholesterol was more effective than treatment with statin therapy alone. Between January 11, 2001 and October 29, 2005, 5518 patients in 77 clinical sites who were already being treated with open-label simvastatin were randomized to also receive either masked fenofibrate or placebo. Prespecified primary outcome was the first occurrence of a major CV event, including nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV causes. Secondary outcomes were a combination of the primary outcome plus revascularization or hospitalization for congestive heart failure (HF), a combination of a fatal CV event, nonfatal MI, or unstable angina; nonfatal MI; fatal or nonfatal stroke; death from any cause or from CV causes; and CV death due to HF. The average follow-up for patients who did not have an event was 5.6 years. There were no significant differences in the primary outcome for either the fenofibrate group (annual rate, 2.2%) or the placebo group (annual rate, 2.4%), with hazard ratio (HR) in fenofibrate group, 0.92; 95% confidence interval (CI), 0.79–1.08; P=0.32. There were also no significant differences in secondary outcomes. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (HR, 0.91; 95% CI, 0.75–1.10; P=0.33). ACCORD investigators concluded that combination therapy did not reduce CV risk in high-risk patients with type 2 diabetes.

This study [2] draws from the same cohort of patients with type 2 diabetes mellitus as the previous paper; however, the focus of this study was to determine if lowering the systolic blood pressure (BP) to less than 120 mm Hg was more effective in reducing CV events than the current target strategy of lowering systolic BP to below 135–140 mmHg. The 4733 patients with type 2 diabetes were randomly assigned to receive intensive therapy that would target a systolic pressure of less than 120 mmHg, or a standard therapy of pressure less than 140 mmHg. The same primary and secondary outcomes were in effect for both ACCORD trials. In the intensive therapy group after one year, the mean systolic BP was 119.3 mm Hg, and in the standard therapy group, mean systolic BP was 133.5 mmHg. In the intensive therapy group, the annual rate of outcome was 1.87%, and it was 2.09% in the standard therapy group (HR with intensive therapy, 0.88; .95% CI, 0.73–1.06; P=0.20). There were no significant differences in annual rates of death. The annual rates of stroke were 0.32% in intensive therapy patients and 0.53% in the standard therapy patients. Of the 2362 patients in the intensive therapy group, 77 had serious adverse events related to antihypertensive treatment (3.3%), as did 30 of 2371 patients in the standard therapy group (1.3%). Investigators concluded that targeting a systolic BP of less than 120 mmHg did not reduce risk of CV events in patients with type 2 diabetes.

[1] The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 (10.1056/NEJMoa1001282)

[2] The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010 (10.1056/NEJMoa1001286)

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Further information: Venous Disease (see p1705) from Cardiovascular Medicine, 3rd Edn*

After myocardial infarction (MI) and stroke, venous thromboembolism (VT) is the third most common cause of vascular death. The anticoagulant warfarin is the current standard treatment for VT, but it requires constant monitoring and is subject to interactions with foods and other drugs. In this study, the investigators for the RE-COVER study [1] conducted a double-blind, double-dummy, randomized trial to compare the use of dabigatran, as an alternate therapy, with warfarin for patients with AVT. From April 2006 through November 2008, 2539 patients were enrolled from 228 clinical centers in 29 countries. The patients were 18 years of age or older and had acute, symptomatic, proximal deep-vein thrombosis of the legs or pulmonary embolism and were patients for whom 6 months of anticoagulant therapy was appropriate. A total of 1274 patients received a dose of 150 mg of dabigatran twice daily, and 1265 patients received warfarin that was dose-adjusted to achieve an international normalized ratio (INR) of 2.0–3.0. The primary outcomes were a recurrent incidence of VT and related deaths at 6-months. The safety end points were bleeding events, acute coronary syndromes (ACS), other adverse events, and results of liver-function tests.

Results showed that the effectiveness and the safety of each drug were similar. For patients given dabigatran, 30 had recurrent thromboembolism, as compared to 27 patients who were in the warfarin arm. The difference in risk was 0.4% (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). Hazard ratio (HR) for dabigatran patients was 1.10 (95% CI, 0.65–1.84). Twenty dabigatran patients had major bleeding episodes, as compared to 24 warfarin patients (HR with dabigatran, 0.82; 95% CI, 0.45–1.48). For episodes of any bleeding, 205 occurred in dabigatran patients and 277 in warfarin patients (HR with dabigatran, 71; 95% CI, 0.59–0.85). For both groups of patients, the number of deaths, ACS, and abnormal liver-function tests were similar. The data from this study support the use of dabigatran because it has no known interactions with foods, minimal interactions with other drugs, and thus, does not require routine monitoring.

On the Cardiovascular-Medicine.com website, a summary of an article from The New England Journal of Medicine (N Engl J Med 2009;361:1139-1151) was posted on October 27, 2009 on the use of the dabigatran as compared to warfarin for patients with atrial fibrillation (AF) [2], and it may be of interest to the readers of this summary.

[1] Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER). N Engl J Med 2009;361:2342-52

[2] Dabigatran Versus Warfarin in Patients with Atrial Fibrillation (RE-LY). http://cardiovascular-medicine.com/?p=193

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Further information: Restrictive Cardiomyopathy (see p1285) and Autonomic Dysfunction and Hypotension (see p1883) from Cardiovascular Medicine, 3rd Edn*

From a pool of 233 patients who presented with systemic amyloidosis between 1990 and May 2008 to centers in Bologna and Pavia, Italy, the investigators of this study [1] compared the diagnostic/clinical profiles of the three types of systemic cardiac amyloidoses, namely acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated, transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). There were 157 AL patients, 61 ATTRm patients, and 15 ATTRwt patients in this longitudinal study.

Myocardial involvement is common in all three forms, but while there are profound pathogenic differences in each form, most clinical studies to this point have addressed the disease as a single form. Generally considered a restrictive cardiomyopathy, the primary noninvasive marker of that form of cardiomyopathy (restrictive filling pattern) is not present in a majority of patients in each of the three groups. Although ventricular wall thickness, as well as systolic and diastolic function, commonly describe the severity of cardiac amyloidosis, these cardiac indicators are expressed differently in each of the three types. In addition, each group showed relevant hemodynamic differences and considerable allelic genetic heterogeneity. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except one were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients displayed low QRS voltage less frequently (25% vs. 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1±0.5 vs.0.9±0.5; P=0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events.

The investigators concluded that AL, ATTRm, and ATTRwt should be evaluated as three different cardiac diseases from disease classification, diagnosis, and clinical management of the disease.

[1] Rapezzi C, Merlini G, Quarta CC, et al. Systemic Cardiac Amyloidoses. Circulation 2009;120:1203-1212

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Further information: Peripheral Arterial Diseases (see p1681), Carotid Artery Intervention (see p1741), and Endovascular Procedures for the Treatment of Peripheral Vascular Disease (see p1755) from Cardiovascular Medicine, 3rd Edn*

Investigators conducted the Dutch Echocardiographic III (DECREASE III) trial [1] to determine whether or not statin therapy could reduce the postoperative incidence of adverse cardiac events in patients undergoing noncardiac, elective vascular surgery. Patients were eligible for this randomized, double-blind, placebo-controlled trial if they had not previously taken a statin, were over 40 years of age, and were scheduled for noncardiac vascular surgery at Erasmus Medical Center between June 2004 and April 2008. The types of surgery included abdominal aortic aneurysm repair, distal aortoiliac reconstruction, lower-limb arterial reconstruction, or carotid-artery endarterectomy. From a total of 497 patients enrolled, 250 patients were assigned to fluvastatin and 247 to placebo a median of 37 days before surgery. The primary end point of the study was the development of myocardial ischemia, either as transient ECG signs of ischemia, release of troponin T, or both within 30 days post-surgery. The secondary end point was the composite of death from cardiovascular causes and nonfatal myocardial infarction (MI).

The primary end point of myocardial ischemia within 30 days post-surgery occurred in 27 (10.8%) of 250 patients in the fluvastatin group, and the secondary end point of cardiovascular death occurred in a total of six patients in the fluvastatin group. The primary end point occurred in 47 (19.0%) of the 247 patients who took placebo. There were 12 patient deaths in the placebo group, and eight were cardiovascular deaths. Although the pathophysiology of perioperative cardiac events is not clear, it is thought that a statin worked for these patients by reducing the risk of atherosclerotic plaque rupture-induced MI by stabilizing unstable coronary plaques.

The authors of this paper concluded that the use of fluvastatin therapy in patients having vascular surgery reduced adverse events postoperatively.

[1] Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-989.

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Further information: Peripheral Arterial Disease (see p1681) and Hypertension (see p1833) from Cardiovascular Medicine, 3rd Edn*

The Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) trial was a double-blind, two-by-two factorial, active, and placebo-controlled study in patients who had suffered a recent ischemic stroke. Two studies from the trial were published in a recent issue of The New England Journal of Medicine [1,2].

One of the articles primarily focused on patients randomized to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole (ASA-ERDP) twice a day or 75 mg of clopidogrel once-daily in order to study the efficacy and safety of the two antiplatelet regimens [1]. The same group of patients received either telmisartan (80 mg once-daily) or placebo for control of blood pressure (BP), a study that was the primary focus of the second article [2]. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction (MI), or death from vascular causes. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (HR 1.01; 95% CI, 0.92–1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (HR for ASA-ERDP, 0.99; 95% CI, 0.92–1.07). There were more major hemorrhagic events among ASA-EDRP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (HR, 1.15; 95% CI, 1.00–1.32), including intracranial hemorrhage (HR, 1.42; 95% CI, 1.11–1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-EDRP recipients [11.7%] vs. 1156 clopidogrel recipients [11.4%]; HR, 1.03; 95% CI, 0.95–1.11).

The trial showed that in the group of patients studied, i.e. patients having suffered a recent ischemic stroke, the risks of recurrent stroke, MI, or death from vascular causes were similar in patients receiving ASA-ERDP and in those receiving clopidogrel. In those receiving ASA-ETDP versus ones receiving clopidogrel, there was an increase in hemorrhagic stroke, but the net benefit in regard to the risk of recurrent stroke or major hemorrhagic events was similar. There was no significant difference between the two treatments in the risk of fatal or disabling strokes. These findings provide additional safety and efficacy data that physicians can use to make individual treatment decisions for prevention of recurrent stroke.

The second article [2] primarily focused on patients randomized to receive either telmisartan (80 mg once-daily) or placebo for control of BP. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction (MI), or death from vascular causes. Of the of total of 20,332 patients, 10,146 were randomized to receive 80 mg daily of telmisartan, a renin-angiotensin system inhibitor (ARB), and 10,186 to receive placebo. The median interval for initiation of therapy was 15 days after an ischemic stroke and continued for 2.5 years.

The mean BP was 3.8/2.0 mmHg lower in the ARB group than in the placebo group. A total of 880 patients (8.7%) in the ARB group and 934 patients (9.2%) in placebo had a subsequent stroke (hazard ratio [HR] in the ARB group, 0.95% confidence interval [CI], 0.86–1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the ARB group and 1463 patients (14.4 %) in placebo (HR, 0.94; 95% CI, 0.87–1.01; P=0.11). New-onset diabetes occurred in 1.7% of the ARB group and 2.1% in the placebo group (HR, 0.82; 95% CI, 0.65–1.04; P=0.10). Results showed that the addition of ARB therapy to the use of other antihypertensive drugs soon after a stroke and continued for a mean of 2.5 years did not significantly reduce the risk of subsequent stroke, major cardiovascular events, or new-onset diabetes.

[1] Sacco RL, Diener HC, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-51

[2] Yusuf S, Diener HC, Sacco RL et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-37

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Further information: Hypertension (see p1833) from Cardiovascular Medicine, 3rd Edn*

The purpose of this trial [1], the third European Cooperative Acute Stroke Study (ECASS III), was to test the hypotheses that the efficacy of alteplase administered in patients with acute ischemic stroke could safely extend to 3–4.5 hours after the onset of stroke symptoms.

ECASS III was a double-blind, parallel-group trial that enrolled patients from multiple centers across Europe. Patients were 18–80 years of age, had received a clinical diagnosis of acute ischemic stroke, had not suffered a brain hemorrhage or major infarction, and were randomized in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, range=0–6, with 0 indicating no symptoms and 6 indicating death) or an unfavorable outcome (2–6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points were death, symptomatic intracranial hemorrhage, or other adverse events. A total of 821 patients were enrolled, and 418 received alteplase and 403 received placebo. The median time for administration of alteplase was 3 hours 59 minutes.

More patients in the alteplase group than in placebo had a favorable outcome (52.4% vs. 45.2%; odds ratio [OR], 1.34; 95% confidence interval [CI], 1.02–1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (OR, 1.28; 95% CI, 1.00–1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for intracranial hemorrhage, 27% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (77.7% and 8.4%, respectively; P=0.68). No significant differences were indicated in the rates of other serious adverse events.

Although the results of the trial showed a modestly significant improvement in the clinical outcome of patients presenting with acute ischemic stroke who were treated with intravenous alteplase 3–4.5 hours after onset of symptoms, the investigators emphasized that patients should be treated with alteplase as early as possible to maximize the benefit of the treatment.

[1] Hacke W, Kaste M, Bluhmke E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29

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Further information: Venous Disease (see p1705) from Cardiovascular Medicine, 3rd Edn*

Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is the first randomized trial [1] to evaluate statin therapy in the prevention of venous thromboembolism (VTE). The trial recruited 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg/ dL and high-sensitivity C-reactive protein (hsCRP) levels of 2.0 mg/L or higher, randomly assigning them to 20 mg/day of rosuvastatin or placebo. VTE is a common, but serious and potentially fatal condition. Although statins are well-known in the prevention of heart attack and stroke, data from JUPITER have now shown that they also are effective in preventing VTE.

In the median follow-up of 1.9 years (maximum 5.0), symptomatic VTE occurred in 34 patients in the rosuvastatin group and 60 patients in the placebo group developed systematic VTE. The rates of VTE were 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups respectively (hazard ratio [HR] with rosuvastatin, 0.57; 95% confidence interval [CI], 0.37–0.86; P=0.007). The corresponding rates for unprovoked VTE (occurring in the absence of malignancy, trauma, hospitalization, or surgery) were 0.10 and 0.17 (HR, 0.61; 95% CI, 0.35–1.09; P=0.09) and for provoked VTE (occurring with malignancy, during trauma, hospitalization, or surgery) they were 0.08 and 0.16 (HR, 0.52; 95% CI, 0.28–0.96; P=0.03). Rates of pulmonary embolism (PE) were 0.09 in the rosuvastatin group and 0.12 in the placebo group (HR, 0.77; 95% CI, 0.41–1.45; P=0.42), whereas the rates of deep-vein thrombosis only were 0.09 and 0.20, respectively (HR, 0.45; 95% CI, 0.25–0.79; P=0.004). Risk reductions were seen for both VTE and PE. These risk reductions through the use of statins appear to be an independent benefit of its use.

[1] Glynn RJ, Danielson E, Fonseca FAH et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-1861

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