Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

Title: A Randomized Comparison of the Endeavor Zotarolimus-Eluting Stent Versus the TAXUS Paclitaxel-Eluting Stent in de novo Native Coronary Lesions: 12-Month Outcomes From the ENDEAVOR IV Trial
Topic: Interventional Cardiology
Date Posted: 3/5/2010
Author(s): Leon MB, Mauri L, Popma JJ, et al., on behalf of the ENDEAVOR IV Investigators.
Citation: J Am Coll Cardiol 2009;55:543-54.
Clinical Trial: yes
Related Resources
JACC Article: A Randomized Comparison of the Endeavor Zotarolimus-Eluting Stent Versus the TAXUS Paclitaxel-Eluting Stent in De Novo Native Coronary Lesions: 12-Month Outcomes From the ENDEAVOR IV Trial
Trial: Randomized, Controlled Trial of the Medtronic Endeavor Drug-Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (ENDEAVOR IV)

Study Question: What is the relative safety and efficacy of the zotarolimus-eluting stent (ZES) versus the paclitaxel-eluting stent (PES)?
Methods: The authors reported the 1-year results of the ENDEAVOR IV trial. This trial randomized 1,548 patients undergoing percutaneous coronary intervention to PES or ZES. The primary endpoint of the trial was 9-month target vessel failure defined as cardiac death, myocardial infarction, or target vessel revascularization (TVR).
Results: ZES was noninferior to PES at 9 months, with a target vessel failure of 6.6% versus 7.1%, (p [noninferiority] < 0.001). Patients randomized to ZES had a lower risk of periprocedural myocardial infarctions (0.5% vs. 2.2%, p = 0.007). There was no difference in the incidence of cardiac death, myocardial infarction, TVR, or stent thrombosis. Binary angiographic restenosis was higher in patients treated with ZES (15.3% vs. 10.4%), but it did not translate into a difference in target lesion revascularization (4.5% vs. 3.2%) or TVR (6.2% vs. 6.8%).
Conclusions: Use of ZES is associated with a similar clinical outcome compared with PES.
Perspective: The long-term follow-up of this trial (Leon MB, et al., JACC Cardiovasc Interv 2009;2:1208-18), which interestingly was published before the 1 year data, clearly supports the clinical efficacy and safety of the ZES. More long-term data are needed to assess if the trend towards lower stent thrombosis with ZES seen in this trial will be maintained. While awaiting the results of the larger ongoing trials, these data provide an evidence context to support use of ZES in simple native coronary artery lesions. Hitinder S. Gurm, M.B.B.S., F.A.C.C.

Title: Increased Rate of Stent Thrombosis and Target Lesion Revascularization After Filter Protection in Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: 15-Month Follow-Up of the DEDICATION (Drug Elution and Distal Protection in ST Elevation Myocardial Infarction) Trial
Topic: Interventional Cardiology
Date Posted: 3/4/2010
Author(s): Kaltoft A, Kelbжk H, Klшvgaard L, et al.
Citation: J Am Coll Cardiol 2010;55:867-871.
Clinical Trial: No
Related Resources
JACC Article: Increased Rate of Stent Thrombosis and Target Lesion Revascularization After Filter Protection in Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: 15-Month Follow-Up of the DEDICATION Trial
Trial: Drug Elution and Distal Protection in ST-Elevation Myocardial Infarction (DEDICATION: Distal Protection Study)
Trial: Drug Elution and Distal Protection in Acute Myocardial Infarction (DEDICATION: Stent Study)

Study Question: What are the long-term effects of distal protection during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI)?
Methods: The 626 STEMI patients were assigned to distal protection (DP) (n = 312) or conventional treatment (CT) (n = 314). Clinical follow-up was performed after 1, 6, and 15 months, and angiographic follow-up after 8 months. All target lesion revascularizations (TLRs) were clinically driven. They reported the prespecified endpoints of stent thrombosis according to the criteria of the Academic Research Consortium, TLR, and reinfarction after 15 months.
Results: The total number of stent thrombosis was 11 in the DP group and 4 in the CT group (p = 0.06). The rate of definite stent thrombosis was significantly increased in the DP group compared with the CT group, with 9 cases versus 1 (p = 0.01). Clinically driven TLRs (31 patients vs. 18 patients, p = 0.05) and clinically driven target vessel revascularizations (37 patients vs. 22 patients, p = 0.04) were more frequent in the DP group.
Conclusions: The authors concluded that in primary PCI for STEMI, the routine use of DP increased the incidence of stent thrombosis and clinically driven target lesion/vessel revascularization.
Perspective: The current study found no benefit of distal filter protection during primary PCI for STEMI with respect to short-, intermediate-, or long-term angiographic or clinical endpoints. Furthermore, there was a significantly increased rate of adverse cardiac events within 15 months in the group of patients treated with routine distal protection. Together with the results of the EMERALD, PROMISE, and PREMIAR trials, the results of this study demonstrate that routine use of a filter wire cannot be advocated and should be avoided with primary PCI for STEMI. On the contrary, aspiration thrombectomy appears to be beneficial in patients undergoing primary PCI and should be routinely considered. Debabrata Mukherjee, M.D., F.A.C.C.

[Chevychelov]

Title: Recommendations for Cardiovascular Magnetic Resonance in Adults With Congenital Heart Disease From the Respective Working Groups of the European Society of Cardiology
Topic: Noninvasive Cardiology
Date Posted: 3/3/2010
Author(s): Kilner PJ, Geva T, Kaemmerer H, Trindade PT, Schwitter J, Webb GD.
Citation: Eur Heart J 2010;Jan 11:[Epub ahead of print].
Clinical Trial: No
Perspective: The following are 10 points to remember about these recommendations.

1. Cardiac magnetic resonance (CMR) in adult congenital heart disease (ACHD) should be performed by appropriately trained specialists who can participate in the performance of studies and optimize acquisition protocols to best answer the clinical question as related to the underlying cardiac anatomy.

2. Many ACHD patients benefit from a baseline CMR study to identify anatomic issues not previously noted and to establish a baseline for comparison in the future.

3. The interval for follow-up CMR should be determined by the anatomic lesion involved, and for the potential for change or progression with time.

4. CMR can be useful for identification of anomalies of the systemic or pulmonary venous return.

5. In adults with coarctation of the aorta, CMR allows for assessment for recurrence of coarctation or aneurysm formation at a previous repair site. It can also assistant in planning of repeat procedures including percutaneous stent placement or surgical intervention.

6. CMR is an important tool in the assessment of the ACHD patient with tetralogy of Fallot. CMR allows for measurement of biventricular size and function, quantification of pulmonary insufficiency, and evaluation of the branch pulmonary arteries.

7. CMR may be used to determine all sources of pulmonary blood flow in patients with major aortopulmonary collateral arteries (MAPCAS) to optimize a surgical or percutaneous approach to treatment.

8. In adults with transposition of the great arteries who have undergone atrial switch type of procedures (i.e., Mustard or Senning procedure), CMR can be useful for assessing right ventricular function, assessing for baffle stenosis, and quantifying tricuspid insufficiency.

9. In adults with congenitally corrected transposition of the great arteries, CMR can assess right ventricular function, identify coexisting lesions, and quantify tricuspid insufficiency.

10. CMR can be used in patients following the Fontan procedure to assess the cavo-pulmonary connection, branch pulmonary arteries, ventricular size and function, and ventricular outflow tract. If contrast is used, timing of the contrast injection as well as possibility of dilution by lower extremity venous return should be considered. Timothy B. Cotts, M.D., F.A.C.C.

Title: Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults
Topic: Prevention/Vascular
Date Posted: 3/3/2010 5:00:00 PM
Author(s): Selvin E, Steffes MW, Zhu H, et al.
Citation: N Engl J Med 2010;362:800-811.
Clinical Trial: No
Study Question: Is the glycated hemoglobin in persons without diabetes predictive of cardiovascular outcomes?
Methods: The prognostic value of glycated hemoglobin and fasting glucose were assessed for their ability to identify adults at risk for diabetes or cardiovascular disease. Glycated hemoglobin (glycohemoglobin or HgA1c) was measured in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990–1992 period) of the Atherosclerosis Risk in Communities (ARIC) study.
Results: Fifty-eight percent were women, 77% were white, 32% had hypertension, and 22.7% had a family history of diabetes. Mean values for risk factors were as follows: age 57 years, fasting blood sugar (FBS) 105 mg/dl, glycated hemoglobin 5.5%, low-density lipoprotein cholesterol 133 mg/dl, high-density lipoprotein cholesterol 51 mg/dl, and body mass index 27.7 kg/m2. The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios for diagnosed diabetes were 0.52, 1.00 (reference), 1.86, 4.48, and 16.47, respectively. For coronary heart disease, the hazard ratios were 0.96, 1.00 (reference), 1.23, 1.78, and 1.95, respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose.
Conclusions: In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause, as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.
Perspective: Persons with a glycated hemoglobin ≥6.5% or FBS >126 mg/dl are characterized as diabetics. The former represent the average blood sugar over 2 to 3 months. A level greater than 5.5% is associated with an increase in risk for diabetes and coronary disease independent of other variables, and the relative risk for 0.5% increments is considerable. The authors concluded that a glycated hemoglobin exceeding 6% may be a useful marker to identify persons at risk for development of diabetes, and cardiovascular disease and death. Consideration should be given to replacing the FBS with glycated hemoglobin for risk stratification of adults with and without vascular disease. Melvyn Rubenfire, M.D., F.A.C.C.

[Chevychelov]

Red Yeast Rice or Statins?
H1N1 and Myocarditis
Prognosis of Cardiac CT
[Ссылки доступны только зарегистрированным пользователям ]

[Chevychelov]

Title: Low Diagnostic Yield of Elective Coronary Angiography
Topic: Interventional Cardiology
Date Posted: 3/10/2010 4:00:00 PM
Author(s): Patel MR, Peterson ED, Dai D, et al.
Citation: N Engl J Med 2010;362:886-895.
Clinical Trial: No
Study Question: What is the diagnostic yield of coronary angiography among patients with coronary artery disease (CAD) in a contemporary national sample?
Methods: From January 2004 to April 2008, at 663 hospitals in the American College of Cardiology National Cardiovascular Data Registry, the authors identified patients without known CAD who were undergoing elective cardiac catheterization. The patients' demographic characteristics, risk factors, and symptoms and the results of noninvasive testing were correlated with the presence of obstructive CAD, which was defined as stenosis of 50% or more of the diameter of the left main coronary artery, or stenosis of 70% or more of the diameter of a major epicardial vessel.
Results: A total of 398,798 patients were included in the study. The median age was 61 years; 52.7% of the patients were men, 26% had diabetes, and 69.6% had hypertension. Noninvasive testing was performed in 83.9% of the patients. At catheterization, 149,739 patients (37.6%) had obstructive CAD. No CAD (defined as <20% of stenosis in all vessels) was reported in 39.2% of patients. Independent predictors of obstructive CAD included male sex (odds ratio [OR], 2.70; 95% confidence interval [CI], 2.64-2.76); older age (OR per 5-year increment, 1.29; 95% CI, 1.28-1.30); presence of insulin-dependent diabetes (OR, 2.14; 95% CI, 2.07-2.21); and presence of dyslipidemia (OR, 1.62; 95% CI, 1.57-1.67). Patients with a positive result on a noninvasive test were moderately more likely to have obstructive CAD than those who did not undergo any testing (41.0% vs. 35.0%, p < 0.001; adjusted OR, 1.28; 95% CI, 1.19-1.37).
Conclusions: The authors concluded that in this study, only a minority of patients without known coronary disease who underwent elective cardiac catheterization had obstructive CAD.
Perspective: This analysis of a contemporary national sample of patients suggests that only a minority of patients undergoing coronary angiography have obstructive CAD. The assessment of coronary stenosis was made by the interpreting/performing physician and it is possible that more stringent assessment may further lower the fraction of patients with obstructive CAD. It should also be noted that this study addresses only overutilization and not underutilization of coronary angiography in appropriate patients. However, it is obvious from this study that the current strategies used to make decisions for proceeding to coronary angiography, including clinical assessment and noninvasive testing, need substantial modification and improvement to increase the diagnostic yield of coronary angiography and prevent over- or underutilization to improve overall quality of patient care. Debabrata Mukherjee, M.D., F.A.C.C.

[Chevychelov]

Title: Endovascular Valve Edge-to-Edge Repair Study II (EVEREST II)
Year Presented: 2010
Topic(s): Cardiovascular Surgery
Summary Posted: 3/14/2010
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Description
The goal of the trial was to evaluate treatment with the percutaneous MitraClip device compared with surgical mitral valve repair/replacement among patients with severe mitral regurgitation.
Hypothesis
Percutaneous mitral valve repair would be noninferior in regards to effectiveness and superior in regards to safety.
Drugs/Procedures Used
Patients with severe mitral regurgitation (3 to 4+) were randomized to the percutaneous mitral valve clip (n = 184) versus surgical repair/replacement (n = 95).
Principal Findings
Overall, 279 patients were enrolled. In the mitral clip group, the mean age was 67 years, 63% were men, 34% had atrial fibrillation, the mean ejection fraction was 60%, 8% had diabetes, 73% had a degenerative mitral valve, and 27% had functional mitral regurgitation. The only baseline characteristic that was different between the groups was congestive heart failure, which was present in 91% of the clip group and 78% of the control group (p < 0.01).

In the per-protocol analysis, 41 patients in the clip group did not achieve procedural success and were not analyzed further. Major adverse events at 30 days occurred in 9.6% of the clip group versus 57% of the control group (p < 0.0001 for superiority). This outcome was driven by increased need for blood transfusion in the control group. Clinical success rate at 12 months was 72% versus 88% (p = 0.0012 for noninferiority), respectively.

In the intention-to-treat analysis, major adverse events at 30 days occurred in 15% of the clip group versus 48% of the control group (p < 0.0001 for superiority). Clinical success rate at 12 months was 67% versus 74% (p = 0.0005 for noninferiority), respectively.

In the per-protocol group, 82% achieved 2+ or less mitral regurgitation versus 97% in the control group. New York Heart Association (NYHA) class I or II at follow-up was 98% in the clip group versus 88% in the control group.
Interpretation
Among patients with severe mitral regurgitation, repair with a percutaneous mitral valve clip was feasible. This therapy demonstrated improved safety at 30 days compared with surgery, largely by reducing the need for blood transfusion. The mitral valve clip was also noninferior for effectiveness at 12 months.
Conditions
• Valvular heart disease
• Prevention
Study Design
Randomized. Parallel.
Patients Enrolled: 279
Mean Follow-Up: 12 months
Mean Patient Age: 67 years
% Female: 38%

Mean Ejection Fraction: 60%
Primary Endpoints
Primary effectiveness endpoint: Freedom from death, surgery for mitral valve dysfunction, and >2+ mitral regurgitation at 12 months
Primary safety endpoint: Death, myocardial infarction, re-operation for failed surgical repair/replacement, nonelective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, ventilation for more than 48 hours, gastrointestinal complication requiring surgery, new-onset atrial fibrillatin, sepsis, and transfusion of ≥2 U blood
Secondary Endpoints
Quality of life
NYHA functional class
Patient Population
Patients with severe mitral regurgitation (3 to 4+) and candidate for mitral valve surgery
Symptomatic: left ventricular (LV) ejection fraction >25% and LV end-systolic dimension <56 mm
Asymptomatic (with one or more of the following): LV ejection fraction 25-60%, LV end-systolic dimension >39, or new-onset atrial fibrillation, or pulmonary hypertension
Exclusions:
Myocardial infarction within 12 weeks
Need for other cardiac surgery
Serum creatinine >2.5 mg/dl
Endocarditis
Rheumatic heart disease
Mitral valve anatomical exclusions: mitral valve area <4 cm2, leaflet flail width (>14 mm) and gap (>9 mm), or leaflet tethering/coaptation depth (>11 mm) and length (<2 mm)
References: Presented by Dr. Ted Feldman at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial (ACCORD BP)
Trial Sponsor: National Heart, Lung, and Blood Institute
Year Presented: 2010
Year Published 2010
Topic(s): General Cardiology, Noninvasive Cardiology
Summary Posted: 3/14/2010 8:00:00 AM
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: ACCORD BP
Related Trial: United Kingdom Prospective Diabetes Study (UKPDS)
Related Trial: Hypertension Optimal Treatment Study (HOT)

Description
The goal of the trial was to evaluate a target systolic blood pressure <120 mm Hg compared with <140 mm Hg among patients with type 2 diabetes.
Hypothesis
Intensive blood pressure lowering would be effective in preventing cardiovascular events.
Drugs/Procedures Used
Half of the patients within the initial ACCORD trial with type 2 diabetes were randomized to a goal systolic blood pressure <120 mm Hg (n = 2,362) versus <140 mm Hg (n = 2,371).

The other half of the patients within the initial ACCORD trial were randomized to fenofibrate plus statin therapy versus placebo plus statin therapy.
Principal Findings
Overall 4,733 patients were enrolled. The mean age was 62 years, 48% were women, previous cardiovascular event was present in 34%, mean systolic blood pressure was 139 mm Hg, and mean glycated hemoglobin (HbA1c) was 8.3%.

At 1 year, mean systolic blood pressure was 119 mm Hg in the intensive group versus 134 mm Hg in the standard group, and mean number of antihypertensives was 3.4 versus 2.1, respectively.

The annual rate of cardiovascular mortality, myocardial infarction, or stroke was 1.9% versus 2.1% (p = 0.20), all-cause mortality was 1.3% versus 1.2% (p = 0.55), nonfatal myocardial infarction was 1.1% versus 1.3% (p = 0.25), and stroke was 0.3% versus 0.5% (p = 0.01), respectively, for intensive versus standard blood pressure target.

Serious adverse events were 3.3% versus 1.3% (p < 0.001), hypokalemia was 2.1% versus 1.1% (p = 0.01), and elevated serum creatinine was 12.9% versus 8.4% (p < 0.001), respectively.
Interpretation
Among patients with type 2 diabetes at high risk for cardiovascular events, a goal systolic blood pressure <120 mm Hg was not superior to a goal <140 mm Hg. This intensive target did not reduce composite cardiovascular events; however, there was a small reduction in any stroke from 0.5% to 0.3%. In the intensive systolic blood pressure group, there were more serious adverse events, hypokalemia, and elevated serum creatinine.

These findings contrast with the UKPDS and HOT trials, which documented benefit from blood pressure reduction; however, the mean systolic blood pressure in the intensively treated groups in those trials was 144 mm Hg.
Conditions
• Diabetes mellitus
• Hypertension
Therapies
• Medical
Study Design
Randomized. Parallel.
Patients Enrolled: 4,733
Mean Follow-Up: 5 years
Mean Patient Age: 62 years
% Female: 48%

Primary Endpoints
First occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
Patient Population
Patients with type 2 diabetes with an HbA1c ≥7.5%
Age 40-79 years with clinical cardiovascular disease or age 55-79 years with subclinical cardiovascular disease or at least two additional cardiovascular risk factors
Systolic blood pressure 130-180 mm Hg on 0-1 antihypertensive medications, 130-170 mm Hg on two medications, or 130-160 mm Hg on three medications
Exclusions:
Creatinine >1.5 mg/dl
Marked proteinuria
References: The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;Mar 14:[Epub ahead of print].

Presented by Dr. William Cushman at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Action to Control Cardiovascular Risk in Diabetes Lipid Trial (ACCORD Lipid)
Trial Sponsor:
National Heart, Lung, and Blood Institute
Fenofibrate was donated by Abbott
Simvastatin was donated by Merck

Year Presented: 2010
Year Published 2010
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 3/14/2010 8:00:00 AM
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Related Trial: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT)
Journal Scan: Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

Description
The goal of the trial was to evaluate treatment with fenofibrate compared with placebo among patients with type 2 diabetes treated with an open-label statin medication.
Hypothesis
The addition of fenofibrate to statin therapy would be effective in preventing cardiovascular events.
Drugs/Procedures Used
Half of the patients within the initial ACCORD trial with type 2 diabetes treated with a statin medication were randomized to fenofibrate 160 mg daily (n = 2,765) versus placebo (n = 2,753). The other half of the patients within the initial ACCORD trial were randomized to a systolic blood pressure goal <120 mm Hg versus <140 mm Hg.
Concomitant Medications
At baseline, the use of insulin was 33%, metformin was 62%, any sulfonylurea was 52%, any thiazolidinedione was 18%, angiotensin-converting enzyme inhibitor was 54%, angiotensin-receptor blocker was 15%, aspirin was 56%, statin was 60%, and any lipid-lowering agent was 65%.
Principal Findings
Overall, 5,518 patients were enrolled in the study. The mean age was 62 years, 31% were women, 37% had a previous cardiovascular event, mean systolic blood pressure was 134 mm Hg, and mean glycated hemoglobin (HbA1c) was 8.1.

In the fenofibrate group, low-density lipoprotein (LDL) cholesterol decreased from 100 to 81 mg/dl, high-density lipoprotein (HDL) cholesterol increased from 38 to 41.2 mg/dl, and triglycerides decreased from 189 to 147 mg/dl. In the placebo group, LDL cholesterol decreased from 101 to 80 mg/dl (p = 0.16 between groups), HDL cholesterol increased from 38 to 40.5 mg/dl (p = 0.01 between groups), and triglycerides decreased from 186 to 170 mg/dl (p < 0.001 between groups).

The primary outcome, rate of major fatal or nonfatal cardiovascular event was 2.2 events/year with fenofibrate versus 2.4 events/year with placebo (p = 0.32).

The primary outcome plus revascularization or hospitalization for congestive heart failure was 5.4 events/year versus 5.6 events/year (p = 0.30), major coronary event was 2.6 events/year versus 2.8 events/year (p = 0.26), and all-cause mortality was 1.5 events/year versus 1.6 events/year (p = 0.33), respectively, for fenofibrate versus control.

Study drug was discontinued because of a decrease in estimated glomerular filtration rate in 2.4% versus 1.1%, respectively. In subgroup analysis, men appeared to benefit, while women appeared to be harmed from fenofibrate therapy (p for interaction = 0.01). Also, a high triglyceride (>203)/low HDL (<35) profile appeared to benefit (p for interaction = 0.06).
Interpretation
Among diabetic patients at high risk for cardiovascular disease, the addition of fenofibrate to statin therapy was not superior to statin therapy alone. Fenofibrate was not able to reduce rates of cardiovascular disease. Although fenofibrate reduced triglyceride levels, although there was only a small difference in mean HDL cholesterol between groups, which could help to explain lack of benefit. This agent may still have a role among individuals with a high triglyceride/low HDL profile. The possible harm noted among women deserves further study. This study is in contrast to the benefit of gemfibrozil seen in the HHS and VA-HIT trials.
Conditions
• Diabetes mellitus
• Hypercholesterolemia / Hyperlipidemia
Therapies
• Lipid-lowering agent
• Medical
Study Design
Placebo controlled. Randomized. Blinded. Parallel.
Patients Enrolled: 5,518
Mean Follow-Up: 4.7 years
Mean Patient Age: 62 years
% Female: 31%

Primary Endpoints
First occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
Secondary Endpoints
Combination of the primary outcome plus revascularization or hospitalization for heart failure
Combination of a fatal coronary event, nonfatal myocardial infarction, or unstable angina
Nonfatal myocardial infarction
Fatal or nonfatal stroke
Nonfatal stroke
All-cause death
Cardiovascular death
Hospitalization or death due to heart failure
Patient Population
Patients with type 2 diabetes with an HbA1c ≥7.5%
Age 40-79 years with clinical cardiovascular disease or age 55-79 years with subclinical cardiovascular disease or at least two additional cardiovascular risk factors
LDL cholesterol level between 60 and 180 mg/dl, HDL cholesterol <55 mg/dl for women and blacks or <50 mg/dl for all others, and triglycerides <750 mg/dl not on lipid therapy or <400 mg/dl on lipid therapy
References: The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;Mar 14:[Epub ahead of print].

Presented by Dr. Henry Ginsberg at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)
Trial Sponsor: Novartis Pharma
Year Presented: 2010
Year Published 2010
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 3/14/2010 8:00:00 AM
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: NAVIGATOR

Description
The goal of the trial was to evaluate treatment with nateglinide (a short-acting insulin secretagogue), valsartan, or both among patients with impaired glucose tolerance.
Hypothesis
Nateglinide and valsartan would be more effective in preventing type 2 diabetes and cardiovascular events.
Drugs/Procedures Used
Patients with impaired glucose tolerance were randomized in a factorial manner to nateglinide (n = 4,645) versus placebo (n = 4,661) and to valsartan (n = 4,631) versus placebo (n = 4,675).

Valsartan was started at 80 mg daily and increased to 160 mg daily after 2 weeks. Nateglinide was started at 30 mg three times daily and increased to 60 mg three times daily after 2 weeks.

All patients underwent clinic and telephone-based lifestyle intervention aimed at reducing weight, limiting saturated fats, and increasing physical activity.
Concomitant Medications
At baseline, the use of any antihypertensive drug was 73%, lipid-lowering drug was 39%, and aspirin or another antiplatelet drug was 37%.
Principal Findings
Overall, 9,306 patients were randomized. There was no difference in baseline characteristics between the groups. In the valsartan group, the mean age was 64 years, mean weight was 84 kg, mean systolic blood pressure was 139 mm Hg, history of heart disease was present in 25% of patients, mean low-density lipoprotein (LDL) cholesterol was 177 mg/dl, and mean high-density lipoprotein (HDL) cholesterol was 50 mg/dl.

Considering the effect of valsartan: At a mean follow-up of 5 years, incident diabetes occurred in 33% of the valsartan group versus 37% of the placebo group (p < 0.001). The extended cardiovascular outcome occurred in 15% versus 15% (p = NS) and the core cardiovascular outcome occurred in 8.1% versus 8.1% (p = NS), respectively, for valsartan versus placebo. Hypotension-related adverse events occurred in 42% versus 36% (p < 0.001) and study drug discontinuation occurred in 12% versus 11% (p = NS), respectively.

Considering the effect of nateglinide: At a mean follow-up of 5 years, incident diabetes occurred in 36% of the nateglinide group versus 34% of the placebo group (p = 0.05). The extended cardiovascular outcome occurred in 14% versus 15% (p = NS) and the core cardiovascular outcome occurred in 7.9% versus 8.3% (p = NS), respectively, for nateglinide versus placebo. Hypoglycemia occurred in 20% versus 11% (p < 0.001) and study drug discontinuation occurred in 11% versus 10% (p = 0.23), respectively.
Interpretation
Among patients with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors, valsartan was effective at reducing incident diabetes. Despite this benefit, valsartan did not reduce long-term adverse cardiovascular events. Nateglinide reduced neither incident diabetes, nor adverse cardiovascular events. In fact, diabetes was marginally increased in the nateglinide group.

It is unknown why these agents were unable to reduce adverse cardiovascular events; however, patients also underwent lifestyle modification, which may have diminished any treatment effect. Also, blood pressure was fairly well-controlled, and the use of other risk-reducing therapies was good. Valsartan may have implications for the treatment of hypertension since thiazide agents and beta-blockers have been associated with the development of diabetes.
Conditions
• Diabetes mellitus
Therapies
• Angiotensin-receptor blocker / Valsartan
• Medical
Study Design
Placebo controlled. Randomized. Blinded. Parallel. Stratified.
Patients Screened: 43,502
Patients Enrolled: 9,306
Mean Follow-Up: 5 years
Mean Patient Age: 64 years
% Female: 50

Primary Endpoints
Onset of type 2 diabetes
Extended cardiovascular outcome: composite of cardiovascular death, nonfatal myocardial infarction, stroke, revascularization, and hospitalization for heart failure or unstable angina
Core cardiovascular outcome: composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure
Patient Population
Patients with impaired glucose tolerance, fasting glucose level between 95 and 125 mg/dl
At least 50 years of age with known cardiovascular disease,
Or at least 55 years of age with at least one risk factor for cardiovascular disease
Exclusions:
Any laboratory abnormality or condition that could interfere with the assessment of drug efficacy and safety
Use of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for hypertension
Use of an antidiabetic medication within the last 5 years
References: The NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;Mar 14:[Epub ahead of print].

The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;Mar 14:[Epub ahead of print].

Presented by Dr. Robert Califf at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

ACC Cardio Career Guide: Get the latest information and advice you need to help you advance your career.
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[Chevychelov]

Title: Cryoballoon Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation (STOP-AF)
Trial Sponsor: Medtronic Cryocath LP
Year Presented: 2010
Topic(s): Arrhythmias
Summary Posted: 3/15/2010 9:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: STOP-AF

Description
Although radiofrequency ablation (RFA) after pulmonary vein isolation (PVI) for atrial fibrillation (AF) has been shown to be associated with a reduction in symptomatic AF, especially paroxsymal AF, it often requires multiple lesions, and may be associated with complications. Further, antiarrhythmic drugs (AAD) can also be associated with significant morbidity and mortality. Accordingly, the investigators sought to assess the safety and effectiveness of a novel cryoballoon ablation technology designed to achieve PVI with a continuous cryolesion.
Hypothesis
Cryoballoon ablation would be safe and efficacious in the treatment of symptomatic AF.
Drugs/Procedures Used
Patients were randomized in a 2:1 fashion to either PVI with the cryoballoon, or treatment with a nonfailed AAD. Cryoballoons were available in two sizes, 23 mm and 28 mm. This is a double balloon, and is delivered by a steerable balloon through a 14F sheath. PVI was done without any ablation lines.
Principal Findings
A total of 245 patients were enrolled, 163 to the cryoballoon, and 82 to AAD. Baseline characteristics were fairly similar between the two arms. Most patients were highly symptomatic, with a mean of 23 symptomatic episodes in the 2 months prior to enrollment. About 22% of the patients had early permanent AF, whereas the rest had paroxysmal AF. In addition, 45% had a history of atrial flutter. Subjects had previously failed ≥1 AAD (36% flecainide, 47% propafenone, 29% sotalol). The mean CHADS2 score was 0.6, and mean left atrial diameter was 4.1 cm.

Balloon-only isolation of PVs was achieved in 90.8%, and the overall procedural success (≥3 PVs isolated) was achieved in 98.2% of the patients. The number of deliveries per PV ranged from 2.9 to 3.4. The mean duration of delivery ranged from 196 to 230 seconds, with a mean 62.8 minutes. The cryoballoon temperatures ranged from -49 to -54 degrees Celsius. About 40% of the patients also underwent cavo-tricuspid isthmus ablation. In addition, about 19% of the patients needed a repeat cryoablation procedure within the 90-day blanking period. There was also a high amount of cross-over from the AAD arm to the cryoballoon arm.

The incidence of the primary endpoint of treatment success was significantly better in the cryoablation arm, as compared with the AAD arm (69.9% vs. 7.3%, p < 0.001). A single ablation procedure was associated with success in 60.1% of the patients. In addition, 57.7% of patients in the cryoballoon arm were on no AADs at the end of follow-up, whereas 12.3% were still on one or more AADs. Of the 95% of patients in the cryoballoon arm who were on warfarin at baseline, only 24% were still on it at 12 months. Symptomatic AF was reduced from 100% at baseline to 19.6% in the cryoballoon arm. The incidence of new atrial flutter was higher in the AAD arm (3.7% vs. 15.9%).

The overall rate of procedural complications with cryoballoon ablation was 6.3%, which was lower than the projected rate of 14.8%. The incidence of combined AF events (disease and procedure related) was 3.1% vs. 8.5% in the cryoballoon and AAD arms, respectively (p < 0.001). The incidence of combined procedural events and major adverse AF events was similar between the two arms (6.1% vs. 8.5%, p = 0.60). Procedural complications with cryoballoon included PV stenosis (3.1% vs. 2.4%), and phrenic nerve palsy (13.5% vs. 7.3%). Of the 11.2% of patients who had phrenic nerve palsy post-procedure, only four (13.8%) had persistent phrenic nerve palsy at 12 months.
Interpretation
The results of the STOP-AF trial indicate that cryoballoon ablation is safe and efficacious in the treatment of symptomatic AF, as compared with AAD alone. A significant proportion of patients in the cryoballoon arm were free of AAD and warfarin use at the end of 12 months, as compared with baseline.

While these early results are interesting, they are tempered by a high incidence of procedural complications, especially phrenic nerve palsy with cryoballoon ablation. The mean number of applications per PV was about three, and it is likely that there is a steep learning curve associated with this procedure.

One potential limitation of this study was that about 45% of the patients had a history of atrial flutter, and a significant number of patients in the cryoballoon arm also underwent cavo-tricuspid isthmus ablation. Not surprisingly, new atrial flutter over the duration of follow-up was higher in the AAD arm, and would have contributed to the overall arrhythmia burden. Further studies will need to evaluate the efficacy of cryoballoon ablation versus conventional RFA with PVI.
Conditions
• Arrhythmias / Atrial fibrillation
Study Design
Randomized. Parallel.
Patients Enrolled: 245
NYHA Class (% I, II, II, IV): I (94%)
Mean Follow-Up: 12 months
Mean Patient Age: 56.6 years
% Female: 23

Mean Ejection Fraction: 60%
Primary Endpoints
Effectiveness:
Combined treatment failure (no detectable AF, no use of nonstudy drugs, no AF intervention)

Safety:
Major adverse AF events (composite of disease and treatment safety adverse events)
Composite of device and procedure-related adverse events
Patient Population
≥2 AF episodes in 2 months with ECG documentation of one
Treatment failure of ≥1 AAD
References: Presented by Dr. Douglas Packer at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Rate Control Efficacy in Permanent Atrial Fibrillation: A Comparison Between Lenient Versus Strict Rate Control II (RACE II)
Trial Sponsor: Netherlands Heart Foundation, and grants from AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, Roche, and Sanofi Aventis.
Year Presented: 2010
Year Published 2010
Topic(s): Arrhythmias, General Cardiology
Summary Posted: 3/15/2010 8:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: RACE II
Related Trial: Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE)
Related Trial: Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)

Description
Although rate control has been shown to be associated with similar outcomes, as compared with rhythm control in patients with atrial fibrillation (AF), the optimal level of heart rate (HR) control/lowering is unclear. Current guidelines recommend strict rate control, although data to support this approach are lacking. Accordingly, the RACE II trial sought to investigate whether lenient rate control would be noninferior to strict rhythm control in patients with permanent AF.
Hypothesis
Lenient rate control would be noninferior to strict rate control in patients with permanent AF.
Drugs/Procedures Used
Patients were randomized to either a lenient rate control strategy (target resting HR <110 bpm), or strict control strategy (target resting HR <80 bpm, and <110 bpm with moderate exercise). HR control was achieved with the use of beta-blockers (45%), non-dihydropyridine calcium-channel blockers (6%) or digoxin (7.2%), or a combination of these. A small number of patients also received sotalol (5.0) and amiodarone (1.3%).
Concomitant Medications
Angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (49.8%), statin (28.8%), vitamin K antagonist (98.7%), aspirin (1.6%)
Principal Findings
A total of 614 patients were randomized, 311 to lenient control, and 303 to strict control. Baseline characteristics were fairly similar between the two arms. The resting baseline HR was 96 bpm. The median duration of AF was 18 months, while the median duration of permanent AF was 3 months. About 20% had coexisting valvular heart disease. About 56.7% of these patients had symptomatic AF, and 1.8% had lone AF. The majority of patients had a CHADS2 score of 0 or 1 (60.7%), whereas 13.4% had a CHADS2 score >2.

The mean HR at the end of the dose-adjustment phase was 93 ± 9 bpm in the lenient control group, as compared with 76 ± 12 bpm in the strict control group (p < 0.001). Only nine patients in both groups were in normal sinus rhythm at the end of follow-up. Target HR was achieved in 97.7% of the patients in the lenient control arm, as compared with 67.0% in the strict control arm (p < 0.001). Only 1.9% of patients in the lenient control arm and 75.2% of patients in the strict control arm had resting HR <80 bpm. About 72.6% of patients in the strict control arm achieved an exercise HR of <110 bpm. About half of the patients in the strict control arm could not achieve target HR due to drug-related adverse events or was noted to be impossible to achieve with drugs.

The 3-year estimated cumulative incidence of the primary endpoint (cardiovascular [CV] death, hospitalization for heart failure and stroke, systemic embolism, major bleeding, arrhythmic events, and implantation of permanent pacemaker [PPM] or implantable cardioverter defibrillator [ICD]) was similar between the lenient and strict control arms (12.9% vs. 14.9%, hazard ratio 0.84, 90% confidence interval 0.58-1.21, p for noninferiority = 0.001). This was true for patients irrespective of CHADS2 score. Secondary outcomes, including CV death (2.9% vs. 3.9%), congestive heart failure (3.8% vs. 4.1%), bleeding (5.3% vs. 4.5%), syncope (1% vs. 1%), and PPM implantation (0.8% vs. 1.4%) were similar between the two arms. The incidence of stroke was significantly lower in the lenient control arm, as compared with the strict control arm (1.6% vs. 3.9%, p < 0.05).
Interpretation
The results of this trial indicate that a lenient rate control strategy, with a target resting HR <110 bpm is easier to achieve with beta-blockers, calcium-channel blockers, and/or digoxin, as compared with a strict control strategy, with a target resting HR <80 bpm, and an exercise HR <110 bpm. The former strategy is also noninferior for CV outcomes, and is associated with a reduction in the incidence of strokes.

Target HR was achieved in only 67% of the patients in the strict control arm. Hence, it is possible that if other means of achieving a lower HR were pursued, there may have been a difference in the strict control strategy. Furthermore, the majority of patients in this study were low risk (CHADS2 score 0-1). Although the investigators did not note a difference in patients with a higher CHADS2 score, few patients were available for this analysis. This also will need to be explored in further analyses.
Conditions
• Arrhythmias / Atrial fibrillation
Therapies
• Medical
Study Design
Randomized. Blinded. Parallel.
Patients Enrolled: 614
NYHA Class (% I, II, II, IV): I (65.1%), II (30.1%), III (4.7%)
Mean Follow-Up: 3 years
Mean Patient Age: 68 years
% Female: 34

Mean Ejection Fraction: 52%
Primary Endpoints
CV death, hospitalization for heart failure and stroke, systemic embolism, major bleeding, arrhythmic events, and implantation of PPM or ICD
Secondary Endpoints
CV death
Hospitalization for congestive heart failure and stroke
Systemic embolism
Major bleeding
Arrhythmic events
Implantation of PPM or ICD
All-cause mortality
Symptoms
Functional status
Patient Population
Permanent AF for up to 12 months
Age ≤80 years
Mean resting HR >80 bpm
Current use of anticoagulation (or aspirin alone, if deemed at low risk for thromboembolism)
Exclusions:
Paroxysmal AF
Known contraindications for either strict or lenient rate control (e.g., previous adverse effects on negative chronotropic drugs)
Unstable heart failure defined as New York Heart Association class IV heart failure or heart failure necessitating hospital admission <3 months before inclusion
Cardiac surgery <3 months
Any stroke
Current or foreseen pacemaker, ICD, and/or cardiac resynchronization therapy
Signs of sick sinus syndrome or AV conduction disturbances (i.e., symptomatic bradycardia or asystole >3 seconds or escape rate <40 bpm in awake symptom-free patients
Untreated hyperthyroidism or <3 months of euthyroidism
Inability to walk or bike
References: Van Gelder CI, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;Mar 15:[Epub ahead of print].

Presented by Dr. Isabelle C. Van Gelder at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Duration of Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents (DES-LATE)
Trial Sponsor: Grants from the Cardiovascular Research Foundation (Korea), and a grant from the Korean Ministry of Health & Welfare as part of the Korea Health 21 Research & Development Project
Year Presented: 2010
Year Published 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 3/15/2010 11:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: DES-LATE
Related Trial: Comparison of Sirolimus and Paclitaxel-Eluting Stents Versus Zotarolimus-Eluting Stents in Real World Practice (ZEST — Presented at ACC.09/i2)

Description
Drug-eluting stents (DES) are associated with decreased restenosis and need for target lesion revascularization, as compared with bare-metal stents, in patients undergoing percutaneous coronary intervention (PCI). However, there is a higher risk of late stent thrombosis with DES, especially after clopidogrel is stopped.

Current guidelines mandate dual antiplatelet therapy (DAT) with aspirin and clopidogrel for at least 12 months after DES PCI, and it is sometimes continued as long as possible. The optimal long-term duration of DAT is thus unknown. DES-LATE is a composite of two separate clinical trials (REAL-LATE and ZEST-LATE), which were both designed to study the optimal duration of DAT following DES PCI.
Hypothesis
DAT with aspirin and clopidogrel would be superior to aspirin alone in patients who had undergone PCI at least 12 months earlier.
Drugs/Procedures Used
Patients in both trials received either clopidogrel 75 mg daily with low-dose aspirin (100-200 mg), or low-dose aspirin alone in an open-label fashion.
Concomitant Medications
Statins (79%), beta-blockers (66%), and angiotensin-converting enzyme inhibitors (46%)
Principal Findings
A total of 2,701 patients were randomized (1,625 in REAL-LATE and 1,076 in ZEST-LATE), of which 1,357 received DAT, whereas 1,344 received aspirin monotherapy. The two trials were merged due to slow enrollment. All patients were enrolled in South Korea. Baseline characteristics were fairly similar between the two arms. About 26% had diabetes, 3.5% had prior myocardial infarction (MI), and 12.5% had prior angioplasty. About 37.5% of patients underwent PCI for stable PCI, whereas the rest had acute coronary syndromes, including unstable angina (40.8%), ST-elevation MI (11%) and non-ST-elevation MI (10.7%). Multivessel disease was noted in about 48% of the patients, whereas the left anterior descending artery was revascularized in about 49% of the patients. The mean number of stents per lesion was 1.3, with a mean stented length of 31.4 mm. The majority of DES were sirolimus-eluting stents (SES; 57%); others included paclitaxel-eluting stents (PES; 24%), and zotarolimus-eluting stents (ZES; 19%).

The median time from index procedure to randomization was 12.8 months, and only 12% of patients were on DAT beyond 18 months prior to randomization. Although about 98.3% of the patients were still taking aspirin at the end of 2 years of follow-up, only 83% of patients in the DAT arm and 4.4% of the patients in the aspirin arm were taking clopidogrel at the end of 2 years of follow-up.

The incidence of the primary endpoint (MI or cardiovascular death) at 2 years was similar between the DAT and aspirin monotherapy arms (1.8% vs. 1.2%, hazard ratio 1.65, 95% confidence interval 0.80-3.36, p = 0.17). No difference was noted when the analysis was conducted separately for each trial. There was also no difference between the two arms in the incidence of all-cause mortality (1.6% vs. 1.4%, p = 0.24), MI (0.8% vs. 0.7%, p = 0.49), stroke (1.0% vs. 0.3%, p = 0.19), definite stent thrombosis (0.4% vs. 0.4%, p = 0.76), or need for repeat revascularization (3.1% vs. 2.4%, p = 0.22). The composite endpoint of MI, stroke, or all-cause mortality showed a trend towards being higher in the DAT arm compared with the aspirin arm at the end of 2 years (3.2% vs. 1.8%, p = 0.051); the rates at the end of 1 year were identical (1.1% vs. 1.1%, p=NS). TIMI major bleeding was similar between the two arms (0.2% vs. 0.1%, p = 0.35).
Interpretation
Although the risks of late stent thrombosis with DES, especially after cessation of DAT, are well known, the optimal duration of DAT following DES PCI is unknown. Data from observational studies have been conflicting, and no randomized trial has been conducted on this topic yet. This trial thus seeks to answer a very important question. In this trial, patients who had been on DAT for at least 12 months following DES PCI were randomized to continuing DAT for another 2 years, or stopping clopidogrel, and continuing aspirin only. The investigators found no difference in the incidence of any of the endpoints studied, including stent thrombosis. They did note a trend towards harm for the composite endpoint of death, MI, or stroke with DAT.

One limitation of this trial is that it represents the combination of two separate trials, which were merged due to slow enrollment. ZEST-LATE was a continuation of the ZEST trial, which compared ZES to SES, and had slightly different enrollment criteria as compared with REAL-LATE, which included a broader patient population. Thus, there may be some heterogeneity between the patients in the two trials. Further, despite the merger, the overall trial was still underpowered to detect differences in clinical outcomes between the two trials, since the event rates were <25% of anticipated. Moreover, the results of this trial suggest that continuation of DAT beyond 12-24 months after DES PCI is not associated with superior clinical outcomes, as compared with discontinuation of clopidogrel after this period.

Most patients in this trial received first-generation DES. It is thus unknown if these results will be applicable to second- and third-generation DES as well. Further, it is unclear whether the results of this trial can be applied to non-Asian populations. Individual variability in response to clopidogrel can be as high as 30% among different ethnic groups, and this has a bearing on ischemic and thrombotic outcomes. Future larger trials, confirming the above results in a more diverse patient population, are thus necessary.

Finally, it should be noted that patients who had experienced a major adverse cardiac event (MACE) or bleeding since implantation were excluded from this trial. The optimal duration of DAT in such patients, as well as high-risk patients, such as those with left main stents, is likely to be longer.
Conditions
• Coronary heart disease
Therapies
• Antiplatelet agent / Clopidogrel
• Antiplatelet agent / Aspirin
Study Design
Randomized. Parallel.
Patients Enrolled: 2,701
Mean Follow-Up: 19.2 months
Mean Patient Age: 62 years
% Female: 30

Mean Ejection Fraction: 59.5%
Primary Endpoints
Cardiovascular death or MI
Secondary Endpoints
All-cause mortality
Stroke
MI
Stent thrombosis
Repeat revascularization
Death, MI, or stroke
Cardiovascular death, MI, or stroke
TIMI major bleeding
Patient Population
DES implantation at least 12 months before enrollment
No MACE or major bleeding since stent implantation
On DAT at the time of enrollment
Exclusions:
Contraindication to antiplatelet therapy
Established indication for continuing clopidogrel, such as peripheral arterial disease
Life-expectancy <1 year
Anticipated noncompliance
Participation in another drug or coronary device study
References: Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med 2010;Mar 15:[Epub ahead of print].

[Chevychelov]

Title: Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA Pilot Study)
Trial Sponsor: St. Jude Medical Foundation
Year Presented: 2010
Topic(s): Arrhythmias
Summary Posted: 3/15/2010 10:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: CABANA Pilot Study
Related Trial: ThermoCool AF

Description
The recently published ThermoCool AF study demonstrated the superiority of catheter ablation with pulmonary vein isolation (PVI) over antiarrhythmic drugs (AAD) in the management of patients with symptomatic atrial fibrillation (AF), who had failed at least one AAD. The CABANA pivotal trial tested the hypothesis that primary catheter ablation for the elimination of AF is superior to state-of-the-art drug therapy for reducing recurrent AF in high-risk patients.
Hypothesis
Catheter ablation would be superior to medical management in the treatment of recurrent AF in high-risk patients.
Drugs/Procedures Used
Catheter ablation was performed percutaneously, with isolation of all four pulmonary veins (PVI). Additional adjunctive linear or circumferential ablation was conducted as necessary. In the medical management arm, patients could be treated with rhythm (16%), rate control (13%), or both (71%).
Principal Findings
A total of 60 patients were randomized, in which 29 patients were randomized to catheter ablation, and 31 patients to medical management. Baseline characteristics were fairly similar between the two groups. About 80% had hypertension, 18% had diabetes, and 17% had underlying cardiomyopathies. About 35% had coronary artery disease, and 36% had class II or III heart failure. Paroxysmal AF was noted in 32%, and 68% had persistent or long-standing persistent AF. Prior antiarrhythmic drugs had been tried in 30%, with 25% having failed one AAD. About 23% of patients had a history of atrial flutter. About 39% of the patients had a CHADS2 score of ≥2.

The incidence of freedom from symptomatic AF after the blanking period was significantly higher in the catheter ablation arm, as compared with AAD (65% vs. 41%, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.21-0.99, p = 0.03). However, the incidence of any AF, atrial flutter, or atrial tachycardia was similar between the two arms (66% vs. 72%, HR 0.69, 95% CI 0.37-1.32, p = 0.26). About 13% of patients crossed over from the AAD arm to the catheter ablation arm over the duration of follow-up, and 21% of patients in the catheter ablation arm needed at least one other ablation procedure.

Adverse events after catheter ablation included moderate PV stenosis in one patient; no cases of severe PV stenosis. In addition, two patients developed an AV fistula or a pseudoaneurysm, with no atrial esophageal fistulas.
Interpretation
The results of the CABANA pilot study indicate that catheter ablation is associated with a reduction in symptomatic AF in high-risk patients, as compared with AAD. In this small group of patients, there was no difference in the incidence of AF, atrial flutter, or atrial tachycardia between the two groups. Adverse event rates were low, including the incidence of PV stenosis.

The results of the CABANA pilot study will be used for designing the CABANA pivotal study.
Conditions
• Arrhythmias / Atrial fibrillation
Therapies
• Antiarrhythmic
Study Design
Randomized. Parallel.
Patients Enrolled: 60
NYHA Class (% I, II, II, IV): II or III (36%)
Mean Follow-Up: 12 months
Mean Patient Age: Median age: 61 years
% Female: 23

Mean Ejection Fraction: 55%
Primary Endpoints
AF recurrence
Secondary Endpoints
Complications with therapy
Change in left atrial volume and morphology
Recurrent hospitalization
Quality-of-life outcomes
Patient Population
• ≥2 paroxysmal AF episodes (≥1 hour) over 4 months or ≥1 persistent AF episode (>1 week)

• ≥65 years of age, or <65 years with ≥1 risk factor:
Hypertension
Diabetes
Heart failure
Prior cerebrovascular accident or transient ischemic attack
Left atrial size >5.0 cm (volume index ≥40 cc/m2)
Ejection fraction ≤35%

• Eligible for ablation and ≥2 rhythm control and/or ≥3 rate control drugs
References: Presented by Dr. Douglas Packer at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: A Randomized Clinical Trial of Three Doses of a Long-Acting Oral Direct Factor Xa Inhibitor Betrixaban in Patients With Atrial Fibrillation (EXPLORE-Xa)
Trial Sponsor: Portola Pharmaceuticals and Merck
Year Presented: 2010
Topic(s): Arrhythmias, Congenital Heart Disease, Prevention/Vascular
Summary Posted: 3/15/2010 10:00:00 AM
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: EXPLORE-Xa

Description
The goal of the phase 2 trial was to evaluate treatment with three doses of the long-acting oral direct factor Xa inhibitor betrixaban compared with warfarin among patients with nonvalvular atrial fibrillation.
Hypothesis
Betrixaban would be superior in preventing significant bleeding events.
Drugs/Procedures Used
Patients with nonvalvular atrial fibrillation were randomized to one of three doses of betrixaban (40 mg, n = 127; 60 mg, n = 127; 80 mg, n = 127) versus warfarin, with goal international normalized ratio (INR) 2-3 (n = 127).
Principal Findings
Overall, 508 patients were randomized. The median age was 74 years, 54% had an estimated glomerular filtration rate >70 ml/min, mean CHADS2 score was 2.2, and 33% were women.

At 3 months, the number of major or clinically relevant nonmajor bleeds was one in the betrixaban 40 mg group, four in the betrixaban 60 mg group, five in the betrixaban 80 mg group, and four in the warfarin group. The number of strokes was 0, 1, 1, and 0 and the number of deaths was 1, 0, 0, 1, respectively, for the four groups.

Considering the extent of follow-up, the lowest hazard for the primary outcome was in the betrixaban 40 mg group, intermediate in the 60 mg and 80 mg groups, and highest in the warfarin group (p = 0.35, for betrixaban groups compared with warfarin).

Alanine aminotransferase (ALT) >2x ULN was 2.4% in the betrixaban groups and 2.4% in the warfarin group. Vomiting, nausea, and diarrhea were more common with betrixaban.
Interpretation
Among patients with atrial fibrillation, the three tested doses of betrixaban appeared to be well-tolerated. Bleeding seemed to be lowest with the betrixaban 40 mg group, compared with higher-dose betrixaban or warfarin. Larger clinical trials are warranted to determine the efficacy and safety of betrixaban.
Conditions
• Arrhythmias / Atrial fibrillation
Therapies
• Anticoagulant
• Medical
Study Design
Randomized. Blinded. Parallel.
Patients Screened: 561
Patients Enrolled: 508
Mean Follow-Up: 3-12 months
Mean Patient Age: 73 years
% Female: 33%

Primary Endpoints
Time to occurrence of major or clinically relevant nonmajor bleeding
Secondary Endpoints
Time to occurrence of any bleeding (major, clinically relevant nonmajor, and minimal)
Time to occurrence of death, stroke, myocardial infarction, or other systemic embolism
Patient Population
Patients with nonvalvular atrial fibrillation with at least one risk factor for stroke
Age at least 18 years of age
No uncontrolled hypertension
Aspirin ≤162 mg daily
INR ≤2.2 at randomization or unable to comply with INR monitoring
Exclusions:
Weight <40 kg
Hemodialysis withing the last year
Atrial fibrillation due to reversible cause
Mechanical prosthetic valve
Condition other than atrial fibrillation requiring anticoagulation
Systolic blood pressure >160 mm Hg
Active endocarditis
Scheduled major surgery or pulmonary vein isolation procedure
Stroke, systemic embolic event, or acute coronary syndrome within 30 days
Limited life expectancy
Thrombocytopenia
Elevated liver transaminases
History of long QT syndrome
Use of aspirin >162 mg daily
Use of verapamil
Use of an investigational drug or device within 30 days
Noncompliance with INR monitoring
Inability to provide informed consent
References: Presented by Dr. Michael Ezekowitz at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

[Chevychelov]

Title: Comparison of Zotarolimus-Eluting Stents and Sirolimus-Eluting Stents in Patients With Coronary Artery Disease (SORT OUT III)
Trial Sponsor: Cordis and Medtronic
Year Presented: 2008
Topic(s): Interventional Cardiology
Summary Posted: 3/15/2010 11:00:00 AM
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Summary Slide: SORT-OUT III trial
Presentation Slides: SORT OUT III
Journal Scan: Efficacy and Safety of Zotarolimus-Eluting and Sirolimus-Eluting Coronary Stents in Routine Clinical Care (SORT OUT III): A Randomised Controlled Superiority Trial
Related Trial: Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions (ENDEAVOR II: Results Through 4 Years )
Related Trial: Randomized Controlled Trial of the Medtronic Endeavor Drug-Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (ENDEAVOR III: Results Through 3 Years)
Related Trial: Randomized, Controlled Trial of the Medtronic Endeavor Drug-Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions (ENDEAVOR IV)
Related Trial: Comparison of Paclitaxel- and Sirolimus-Eluting Stents in Everyday Clinical Practice (SORT OUT II)

Description
Zotarolimus-eluting stents (ZES) are newer drug-eluting stents that have recently become available. The SORT OUT III study sought to compare the relative safety and efficacy of ZES with sirolimus-eluting stents (SES).
Hypothesis
ZES would be similar in efficacy and safety to SES.
Drugs/Procedures Used
Percutaneous coronary intervention (PCI) with ZES or SES in a 1:1 fashion
Concomitant Medications
Dual antiplatelet therapy for 12 months; lipid-lowering therapy (70%), glycoprotein IIb/IIIa inhibitors (17%)
Principal Findings
A total of 2,333 patients were randomized, 1,162 to ZES and 1,170 to SES. Baseline characteristics were fairly similar between the two groups. About 15% of the patients had diabetes. About one-half of the patients (52%) underwent PCI for stable angina, 38% for unstable coronary syndromes, and 7% for ST-elevation myocardial infarction (STEMI). Most patients (70%) had one-vessel disease. The mean number of stents per patient was 1.7, with a mean stent length of 18.0 mm.

The incidence of the composite endpoint at 9 months was significantly higher with ZES compared with SES (6% vs. 3%, hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.43-3.23, p = 0.0002). There was no difference between ZES and SES in the incidence of all-cause mortality at 9 months (2% vs. 2%, HR 1.40, 95% CI 0.76-2.56, p = 0.28). MI was significantly higher in the ZES arm compared with the SES arm (2% vs. <1%, HR 4.55, 95% CI 1.54-13.4, p = 0.006). Similarly, definite stent thrombosis was significantly higher in the ZES arm compared with the SES arm (1% vs. <1%, p = 0.05). The need for target lesion revascularization was also significantly higher with ZES compared with SES (4% vs. 1%, HR 4.25, 95% CI 2.26-7.97, p < 0.0001), with a significantly higher rate of in-stent restenosis (3% vs. 1%, HR 6.28, 95% CI 2.65-14.9, p < 0.0001).

At 18 months, there was still an increase in the incidence of the composite endpoint in the ZES arm compared with SES (10% vs. 5%, p < 0.0001), as well as mortality (4% vs. 3%, p = 0.035), MI (2% vs. 1%, p = 0.03), target lesion revascularization (6% vs. 2%, p < 0.0001), and in-stent restenosis (5% vs. 1%, p < 0.0001). The incidence of definite stent thrombosis was similar between the two arms (1% vs. 1%, p = 0.13).
Interpretation
The results of the SORT-OUT III trial indicate that the ZES are associated with a higher incidence of MI, target lesion revascularization, clinically significant restenosis, as well as definite stent thrombosis at 9 months, compared with SES. In addition, patients receiving ZES had a significantly higher mortality, as compared with patients receiving SES at 18 months. Both groups were on dual antiplatelet therapy for at least 12 months. In this trial, the investigators tried to include as diverse a population as possible, with no major exclusions, thus mirroring "real-world" practice as best as possible.

One limitation of this trial is that although they prospectively followed patients, outcomes data were obtained from national registries, rather than direct patient contact. Thus, although it is unlikely that there would be a differential bias with respect to outcomes, there could be an under-reporting or a lag in reporting of certain outcomes. In events with a low incidence rate, such as stent thrombosis, this might be an important consideration.
Conditions
• Coronary heart disease
Therapies
• Stent/drug-eluting
Study Design
Randomized. Parallel.
Patients Screened: 9,221
Patients Enrolled: 2,333
Mean Follow-Up: 18 months
Mean Patient Age: 64.3 years
% Female: 26

Mean Ejection Fraction: 51%
Primary Endpoints
Safety:
All-cause mortality
Cardiac mortality
MI
Definite stent thrombosis

Efficacy:
Clinically driven target lesion revascularization
Clinically significant re-stenosis (ISR)
Patient Population
Patients undergoing PCI for any indication
References: Rasmussen K, Maeng M, Kaltoft A, et al. Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial. Lancet 2010;Mar 15:[Epub ahead of print].

Presented by Dr. Michael Maeng at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Presented by Dr. Jens Flensted Lassen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2008), Washington, DC, October 2008.