Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

Discrepancies found between physician and patient expectations of PCI

Fernandez A. Ann Intern Med. 2010;153:342-343.

Rothberg M. Ann Intern Med. 2010;153:307-313.

Substantial differences exist between patients’ and physicians’ perceptions of percutaneous coronary intervention, including most patients who expect the procedure to lower their risk for MI, results from a new study suggest.

The study included 153 patients who consented to elective coronary catheterization, 10 interventional cardiologists and 17 referring cardiologists. Of the patients, 68% had angina, 42% activity-limiting angina, 77% had a positive stress test and 29% had previous MI. Researchers measured patients’ and cardiologists’ perception about the benefits of PCI.

They reporte that nearly three-quarters of patients said they believed that without PCI, they would likely have MI within 5 years. Further, 88% of patients expected PCI to lower MI risk, with patients significantly more likely than physicians to believe that PCI would prevent MI (prevalence ratio, 4.25; 95% CI, 2.31-7.79) or fatal MI (prevalence ratio, 4.83; 95% CI, 2.23-10.46).

Among the study limitations were the small population size, single-center design and limited availability of information concerning pre-catheterization counseling.

“Most patients undergoing the procedure still believe that PCI will prevent infarction or death,” the researchers concluded. “Further efforts should be directed toward improving communication of medical evidence to help patients make informed decisions about this common procedure.”

In an accompanying editorial, Alicia Fernandez, MD, associate professor of clinical medicine with the University of San Francisco, said most clinicians will not find these results surprising because patients commonly overestimate or misunderstand the benefits of treatment.

“That the processes we typically use fail to accurately convey information on expected benefits is particularly distressing for stable CAD, a model condition for ‘preference-sensitive decision-making,’” she said, adding that informed consent requires physicians to do more than tell their patients about the risks of the offered treatments. “We need to make sure our patients also fully understand the anticipated benefits.”
__________________________________________________ ________________________
Education less preventive of CVD in low- to mid-income countries vs. high-income countries
Goyal A. Circulation. 2010;doi:10.1161/circulationaha.109.919274.
Participants’ educational level was not preventive of CVD in low- and middle-income countries. However, in high-income countries, researchers reported an inverse association with several key CV risk factors.

“Atherothrombotic diseases — coronary heart disease, cerebrovascular disease and peripheral arterial disease — are the leading cause of death worldwide,” the REACH investigators wrote in their study. “Attained educational level is a socioeconomic indicator that strongly predicts CV outcomes.”

The Reduction of Atherothrombosis for Continued Health (REACH) Registry was a prospective study of participants (n=67,888) with either established atherothrombotic disease or multiple atherothrombotic risk factors enrolled from physician practices (n=5,587) located in 44 countries. Attained educational level was self-reported at baseline in 61,332 participants. Researchers stratified outcomes, including baseline prevalence of atherothrombotic risk factors and the rate of incident CV events, by sex and world region through 23 months across AEL groups.

According to study data, attained educational level was directly associated with hypercholesterolemia but inversely related to age and diabetes mellitus in all participants. Researchers also reported that attained educational level was inversely associated with risk factors such as obesity, hypertension, smoking and baseline burden of vascular disease in high-income countries, but not in low- and middle-income countries. The protective effect of greater attained educational levelon incident CV events from high-income countries was most pronounced in men (P<.0001) than in women (P=.0026), whereas the association was not statistically significant in men or women from low- and middle-income countries.

“These results indicate that studies that report a protective association between attained educational level and CV outcomes in [high-income countries] do not extrapolate to [low- and middle-income countries], especially in women,” the researchers concluded. “Further studies dedicated to [low- and middle-income countries] settings are essential to investigate the association between socioeconomic indicators and CV outcomes in these regions.”

[Chevychelov]

Title: Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrel in Patients With Atrial Fibrillation
Date Posted: September 13, 2010
Authors: Hansen ML, Sørensen R, Clausen MT, et al.
Citation: Arch Intern Med 2010;170:1433-1441.

Study Question:
What is the risk of hospitalization or death due to bleeding after treatment with warfarin, aspirin, clopidogrel, and combinations of these drugs?
Methods:
The investigators performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding.
Results:
A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least one prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined endpoint was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin + clopidogrel, 1.83 (1.72-1.96) for warfarin + aspirin, 3.08 (2.32-3.91) for warfarin + clopidogrel, and 3.70 (2.89-4.76) for warfarin + aspirin + clopidogrel.
Conclusions:
The authors concluded that in patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding.
Perspective:
This study suggests that in patients with AF, the risk of bleeding increased in proportion to the number of antithrombotic agents used. Patients receiving dual therapy with warfarin and clopidogrel and those receiving triple therapy with warfarin, aspirin, and clopidogrel had a more than threefold higher risk of bleeding than did patients treated solely with warfarin. Furthermore, there was a significantly increased risk of death after a nonfatal bleeding episode and a nonbeneficial effect in terms of preventing ischemic stroke. These results underscore the importance of appropriate selection of patients for combination therapies, and physicians should consider the expected benefits and risks carefully before prescribing combination therapy, and only for a short time when such treatments are mandatory.

[Chevychelov]

Title: ESC Guidelines for the Management of Grown-up Congenital Heart Disease (new version 2010): The Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC)
Date Posted: September 13, 2010
Authors: Baumgartner H, Bonhoeffer P, De Groot NM, et al.
Citation: Eur Heart J 2010;Aug 27:[Epub ahead of print].

Perspective:
The following are 10 points to remember from the updated European Society of Cardiology guidelines for the management of adult congenital heart disease:

1. Cardiac magnetic resonance imaging is an important technique for the evaluation of adults with congenital heart disease. It is particularly important for quantification of right ventricular size and function; quantification of pulmonary insufficiency; evaluation of extracardiac structures including the pulmonary arteries, veins, and the aorta; and detection of myocardial fibrosis and scar.

2. Device closure is the preferred method for closure of most atrial septal defects, and is indicated if signs of right ventricular volume overload are present. Atrial septal defect closure should be avoided in patients with Eisenmenger physiology.

3. Patients with ventricular septal defects should be monitored for long-term complications including endocarditis, development of double-chambered right ventricle, subaortic stenosis, and aortic insufficiency due to leaflet prolapse (particularly in patients with supracristal ventricular septal defects).

4. Percutaneous closure of patent ductus arteriosus is appropriate when left ventricular volume overload is present. Closure of a “silent ductus” is not indicated. Closure of patent ductus arteriosus is not appropriate in the setting of Eisenmenger physiology.

5. Patients with repaired coarctation of the aorta are at risk for multiple long-term complications including arterial hypertension, recurrent coarctation, aneurysms of the ascending aorta or coarctation repair site, premature coronary artery disease, and berry aneurysms of the circle of Willis.

6. Indications for intervention in adults with coarctation of the aorta include a noninvasive pressure difference ≥20 mm Hg between the upper and lower extremities with upper extremity hypertension, pathologic blood pressure response to exercise, and significant left ventricular hypertrophy.

7. All patients with tetralogy of Fallot should be seen at a specialized adult congenital heart program. The presence or absence of pulmonary insufficiency must be determined. Pulmonary valve replacement (PVR) should be performed in symptomatic patients with severe pulmonary insufficiency for stenosis (Class I, level of evidence C). PVR should be performed in asymptomatic patients with declining exercise capacity, progressive right ventricular dilatation, progressive tricuspid regurgitation, right ventricular outflow tract obstruction with right ventricular systolic pressure greater than 80 mm Hg, and sustained atrial or ventricular arrhythmias (Class IIa, level of evidence C).

8. All patients with single-ventricle physiology following the Fontan procedure should be seen at an adult congenital center. Long-term complications include progressive heart failure, cyanosis, development of atrial arrhythmias, chronic venous insufficiency, and protein losing enteropathy.

9. Patients with a Rastelli procedure, pulmonary atresia, common arterial trunk, and previous Ross operation will have had a conduit placed between the right ventricle and pulmonary arteries. Such patients are now candidates for percutaneous pulmonary valve replacement when conduit insufficiency or stenosis develops.

10. Bosentan should be initiated in patients with Eisenmenger syndrome who are World Health Organization-Functional Class III. Patients with Eisenmenger require meticulous follow-up and avoidance of high-risk states including pregnancy, iron deficiency anemia, dehydration, vaccine preventable infectious disease, smoking, transvenous pacemaker and defibrillator leads, strenuous exercise, and acute heat exposure as in hot tubs or saunas.

[Chevychelov]

Title: Quality of Life and Cost-Effectiveness of a 3-Year Trial of Lifestyle Intervention in Primary Health Care
Date Posted: September 13, 2010
Authors: Eriksson MK, Hagberg L, Lindholm L, Malmgren-Olsson EB, Österlind J, Eliasson M, et al.
Citation: Arch Intern Med 2010;170:1470-1479.

Study Question:
Does a primary care-based lifestyle intervention program improve quality of life, while being cost-effective?
Methods:
Men and women at high risk for cardiovascular disease were enrolled in the Swedish Björknäs Study and randomized to a primary health care-based lifestyle intervention program with standard care, or to standard care alone. The lifestyle intervention was comprised of supervised exercise sessions and diet counseling for 3 months, followed by regular group meetings over a 3-year follow-up period. Quality of life was measured with the EuroQol (EQ-5D) and the EuroQol-Vas (EQ-VAS), the 36-Item Short Form Health Survey (SF-36), and the 6-dimensional Short-Form 6D (SF-6D). Cost-effectiveness was assessed with a cost-utility analysis with a societal perspective. Cost-effective ratios were based on gained quality-adjusted life-years (QALYs), and net costs for the intervention group were compared with the control group.
Results:
A total of 151 adults, ages 18-65 years, were included in this study. The mean age of the participants was 54.4 years, 57% were female, and the majority had one or more cardiovascular risk factors. Over 86% were overweight or obese and over 50% were sedentary or minimally active. Compared to those randomized to usual care, patients who received the lifestyle intervention were more likely to report improvement in quality of life. Over a 3-year period, differences between the two groups were observed for measures of quality of life including EQ-VAS (p = 0.002), SF-6D (p = 0.01) and SF-36 (p = 0.04), and physical summary. No differences between the two groups were observed for EQ-5D or SF-36 mental component summary. The mean number of family physician visits decreased by 0.28 per 6 months compared to baseline in the intervention group, and increased by 0.10 in the control group. Savings in office visits was $493 for the 3-year period. The net savings were $47 per participant. Costs per gained QALY, savings not counted, were $1,668-$4,813. Probabilities of cost-effectiveness were 89-100% when the amount of $50,000 was used as stakeholder’s threshold of willingness to pay for a gained QALY.
Conclusions:
The investigators concluded that lifestyle intervention in primary care can improve quality of life and is cost-effective in comparison to standard care.
Perspective:
These findings suggest that lifestyle modification programs based in the primary care setting can be cost-effective. Given the prevalence of overweight or obese Americans, adoption of such wellness programs may prove cost-effective in the United States as well.

[Chevychelov]

Anatomical, procedural information linked to esophageal ulceration in patients undergoing radiofrequency catheter ablation
Martinek M. Heart Rhythm. 2010;doi:10.1016/j.hrthm.2010.02.027.
For the first time, a link between anatomical and procedural information and esophageal ulceration in patients with atrial fibrillation undergoing radiofrequency catheter ablation has been found, according to a new study appearing in Heart Rhythm.
The study featured 267 patients who were consecutively screened for esophageal ulceration (ESUL) 24 hours after radiofrequency catheter ablation of AF via endoscopy of the esophagus. Researchers performed a standardized ablation approach utilizing a 25 W energy maximum at the posterior left atrial wall without esophagus visualization, temperature monitoring or intracardiac ultrasound.
Among patients, 2.2% (n=6) presented with ESUL. Parameters exposing a specific patient to risk of developing ESUL in univariate analysis included: persistent AF (5 of 95, P=.023), additional lines performed (roofline: 6 of 114, P=.006; left atrial isthmus: 4 of 49, P=.011; coronary sinus: 5 of 66, P=.004) and left atrial enlargement (P=.001), leading to what researchers termed as a “sandwiching of the esophagus between the left atrium and thoracic spine.”
Furthermore, according to researchers, multivariate analysis revealed the anatomical risk factor of a small left atrium-to-esophageal distance as the most important factor in ESUL development.
“This study is the first to link anatomical information and procedural considerations to the development of ESUL in radiofrequency ablation for AF,” the researchers wrote in their study. “Our data give new insights into risk factors for ESUL development, especially on the linkage of these parameters and the correlation to each other. Identifying high-risk patients for esophageal injury potentially has an impact on follow-up or treatment of these individuals by endoscopy or prophylactic proton pump inhibitor treatment.”
__________________________________________________ ______________________

RE-LY: Select doses of dabigatran reduced stroke, bleeding vs. warfarin
Wallentin L. Lancet. 2010;doi:10.1016/S0140-6736(10)61194-4.

New data suggest that dabigatran at 150 mg reduced stroke, at 110 mg reduced bleeding, and at both doses reduced intracranial bleeding compared with warfarin, irrespective of centers’ quality of international normalized ratio control.
Researchers performing the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial randomly assigned patients (n=18,113; 951 sites) to 110 mg or 150 mg dabigatran (Boehringer Ingelheim) twice daily vs. warfarin dose adjusted to INR 2.0 to 3.0. Study centers were placed into one of four groups based on each center’s mean time in therapeutic range (cTTR): less than 57.1%, 57.1% to 65.5%, 65.5% to 72.6%, and more than 72.6%. The median follow-up was 2 years.
During follow-up, researchers reported no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg or 150 mg dabigatran vs. warfarin, nor were there any significant interactions with cTTR regarding intracranial bleeding. However, a significant interaction (P=.003) was noted between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin, with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than warfarin, irrespective of cTTR.
The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding vs. warfarin were consistent, irrespective of centers’ quality of INR control,” researchers concluded. “For all vascular events, non-hemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.”

[Chevychelov]

Intra-atrial reentrant tachycardia found lower than previous studies
Stephenson EA. J Am Coll Cardiol. 2010;56:890-896.

Rates of intra-atrial reentrant tachycardia were lower in a recent cross-sectional, multicenter study than previous studies had reported, which researchers attribute in part to changes in surgical strategy.
The Pediatric Heart Network Fontan Cross-Sectional study was composed of 520 children from seven centers who were aged 6 to 18 years. Each of the children had undergone a Fontan procedure at least 6 months before entering the study. Study data within 3 months of enrollment featured echocardiograms, electrocardiograms, exercise testing results, health status questionnaires and medical history from a review of the medical record.
Supraventricular tachycardias were reported in 9.4% of patients, whereas intra-atrial reentrant tachycardia (IART) was present in 7.3% of the population. Four to 6 years after Fontan, the hazard of IART decreased, but it increased after this time period.
Researchers identified the following independent associations of time to occurrence of IART: lower Child Health Questionnaire physical summary score (P<.001); predominant rhythm (P=.002; highest risk with paced rhythm); and type of Fontan operation (P=.037; highest risk with atriopulmonary connection).
“This contemporary cohort of Fontan survivors represents one of the largest datasets available in this unique population,” the researchers wrote. “Overall prevalence of IART (7.3%) is lower in the current cohort than in previous reports. Independent associated factors of IART development include a paced rhythm, lower functional status, and an atriopulmonary connection Fontan, a previously suspected risk factor for atrial tachycardia.”
In an accompanying editorial, George F. Van Hare, MD, from Washington University/St. Louis Children’s Hospital, St. Louis, commented on the Fontan procedure and its role in clinical practice.
“It is disappointing, but perhaps not altogether surprising, that one observes some atrial arrhythmias in patients with the external conduit Fontan,” he said. “The Fontan is not a legacy operation like the Senning procedure for transposition, and with improved survival for the Norwood/Sano operation, more and more children will be coming to surgery for Fontan completion, and so the management of these arrhythmias will continue to occupy us.”
__________________________________________________ ______________________

CRT at endocardial sites may be more effective than conventional pacing
Derval N. J Am Coll Cardiol. 2010;56:782-783. Spragg DD. J Am Coll Cardiol. 2010;56:774-781.

Left ventricular endocardial pacing yielded substantial improvements in left ventricular mechanics vs. traditional coronary sinus-based cardiac resynchronization therapy, according to study results.
The study consisted of 11 men (68 ± 5 years of age) with ischemic cardiomyopathy. Researchers measured the peak rate of LV pressure increase (dP/dtmax) at baseline, during VDD pacing at the right ventricular apex, and during biventricular pacing from the right ventricular apex and 51 ± 14 different LV endocardial sites. Electroanatomic 3-D maps with color-coded dP/dtmax response defined optimal pacing regions, delivering 85% of maximal increase in dP/dtmax.
According to study results, endocardial biventricular pacing improved dP/dtmax over right ventricular apex pacing in all patients (mean increase, 241
± 38 mm Hg/s; P < .0001). Researchers noted that among patients with pre-existing cardiac resynchronization therapy (CRT) leads, LV endocardial vs. epicardial pacing at transmural sites led to equivalent dP/dtmax values; however, dP/dtmax at the best endocardial site surpassed that achieved with the pre-implanted CRT device (mean increase, 111 ± 25 mm Hg/s; P=.004). Additionally, researchers found that optimal pacing sites were typically located in LV territories away from the infarct zone by 9.3 ± 3.6 cm.
These findings, the researchers wrote, have clear implications for how best to deliver resynchronization therapy in patients with ischemic cardiomyopathy. “In addition, our report contributes to a growing body of data about the merits of endocardial vs. epicardial LV pacing, the impact of scar burden on CRT response, and the impact of inter-patient variability in optimal LV pacing site location,” they said.
In an accompanying editorial, Nicolas Derval, MD, and Pierre Jaïs, MD, researchers based at Université Victor Segalen Bordeaux II in Pessac, France, said the findings depict some of the clinical limitations of CRT in daily practice.
“The results demonstrate the critical impact of the LV pacing site selection in optimizing hemodynamic results of CRT and the need to individualize the approach to CRT in current clinical practice,” they wrote. “To date, there is no way to identify the optimal pacing site before implantation, and the protocol used in this study is lengthy and may not be practical for routine clinical practice. However, the results … are impressive in these end-stage HF patients for whom CRT is often the last therapeutic option.”

[Chevychelov]

Title: Importance of Refractory Pain and Hypertension in Acute Type B Aortic Dissection. Insights From the International Registry of Acute Aortic Dissection (IRAD)
Date Posted: September 15, 2010
Authors: Trimarchi S, Eagle KA, Nienaber CA, et al.
Citation: Circulation 2010;122:1283-1289.

Study Question:
What is the impact of refractory pain and/or refractory hypertension on the outcomes of acute type B aortic dissection (ABAD)?
Methods:
Three hundred sixty-five patients affected by uncomplicated ABAD, enrolled in the International Registry of Acute Aortic Dissection (IRAD) from 1996 to 2004, were categorized according to risk profile into two groups. Patients with recurrent and/or refractory pain or refractory hypertension (group I; n = 69) and patients without clinical complications at presentation (group II; n = 296) were compared. “High-risk” patients with classic complications were excluded from this analysis.
Results:
The overall in-hospital mortality was 6.5% and was increased in group I compared with group II (17.4% vs. 4.0%; p = 0.0003). The in-hospital mortality after medical management was significantly increased in group I compared with group II (35.6% vs. 1.5%; p = 0.0003). Mortality rates after surgical (20% vs. 28%; p = 0.74) or endovascular management (3.7% vs. 9.1%; p = 0.50) did not differ significantly between group I and group II, respectively. A multivariable logistic regression model confirmed that recurrent and/or refractory pain or refractory hypertension was a predictor of in-hospital mortality (odds ratio, 3.31; 95% confidence interval, 1.04-10.45; p = 0.041).
Conclusions:
The authors concluded that recurrent pain and refractory hypertension appeared as clinical signs associated with increased in-hospital mortality in patients with acute aortic dissection, particularly when managed medically.
Perspective:
This study suggests that after adjustment for known risk factors, refractory pain and/or hypertension is an independent predictor for in-hospital mortality in ABAD. ABAD patients presenting with refractory hypertension and/or pain symptoms, in the absence of other complications, are at intermediate risk for an adverse in-hospital outcome. These observations suggest that aortic intervention, such as via an endovascular approach, may be appropriate in this intermediate-risk group of patients with ABAD.
__________________________________________________ _____________________

Title: Increased Platelet Inhibition After Switching From Maintenance Clopidogrel to Prasugrel in Patients With Acute Coronary Syndromes: Results of the SWAP (Switching Anti Platelet) Study
Date Posted: September 13, 2010
Authors: Angiolillo DJ, Saucedo JF, DeRaad R, et al.
Citation: J Am Coll Cardiol 2010;56:1017-1023.

Study Question:
What is the effect of switching from clopidogrel to prasugrel on platelet function?
Methods:
After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10-14 days, patients were randomly assigned to one of the following three treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 hours, 24 hours, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein phosphorylation.
Results:
A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum ADP-induced platelet aggregation (20 µM) by light transmittance aggregometry at 1 week (primary endpoint) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD + MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 hours, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 µM adenosine diphosphate, VerifyNow P2Y12, and vasodilator-stimulated phosphoprotein phosphorylation assays.
Conclusions:
For patients receiving maintenance clopidogrel therapy after an acute coronary syndrome (ACS) event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 hours with the administration of a prasugrel LD.
Perspective:
Both clopidogrel and prasugrel treatment result in irreversible inhibition of the P2Y12 receptor. The antiplatelet response to clopidogrel is variable between patients likely due to variable generation of the active metabolite. Prasugrel has previously been shown to produce more consistent and greater platelet inhibition than clopidogrel, an effect associated with reduced ischemic events following percutaneous coronary intervention, but with increased bleeding risk. This pharmacodynamic study demonstrates that a higher antiplatelet effect can be achieved in patients already on clopidogrel by switching them to prasugrel. The clinical outcomes of this strategy in terms of ischemic events and bleeding risk will need to be assessed in future studies.

[Chevychelov]

FDA panel unanimously recommends approval for dabigatran

The FDA’s Cardiovascular and Renal Drugs Advisory Committee has voted 9-0 for approval of the investigational anticoagulant dabigatran, according to a press release. The panel also unanimously agreed that dabigatran, which is intended to prevent stroke and systemic embolism in patients with atrial fibrillation, is at least as effective as warfarin.

The vote follows a positive review issued by the FDA, which recommended that the 150-mg dose of dabigatran be approved. The review, however, also recommended against approval of the 110-mg dose.

The panel based its decision on the results of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. The study involved 18,113 patients across 951 sites who were randomly assigned to receive 110 mg or 150 mg of dabigatran twice daily compared with a warfarin dose adjusted to INR 2.0 to 3.0.

Data indicated that both doses of dabigatran demonstrated noninferiority to warfarin (P<.001). The 150-mg dose also appeared superior to warfarin, with a RR of 0.66 (95% CI, 0.53-0.82), but the FDA review stipulated that Boehringer Ingelheim cannot claim the drug’s superiority to warfarin upon approval.

Major bleeding, the only serious adverse event, was reported in 2.75% of patients taking the low dose and 3.36% of patients taking the high dose. Rates of life-threatening bleeding, intracranial bleeding and major or minor bleeding, however, were higher in patients receiving warfarin.

In a post hoc analysis of the RE-LY trial results funded by Boehringer Ingelheim, researchers said the benefits of dabigatran persisted, even as treatment centers’ INR control varied.

“The benefits of 150-mg dabigatran at reducing stroke, 110-mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding vs. warfarin were consistent irrespective of centers’ quality of INR control,” they wrote.

The researchers said, however, that dabigatran’s positive effects on vascular and non-hemorrhagic events and mortality improved with better INR control.

An addendum to the FDA review also outlined concerns about an unexplained increase in rates of MI among patients in the dabigatran arm compared with those in the warfarin arm of the RE-LY trial. The reviewer recommended including this potential adverse event on the drug’s label until further information is available.
__________________________________________________ ______________________

Combination warfarin, aspirin, clopidogrel linked to higher risk for bleeding after AF
Hansen ML. Arch Intern Med. 2010;170:1433-1441.

Combination warfarin and clopidogrel, as well as warfarin, aspirin and clopidogrel, for treatment after atrial fibrillation was associated with a more than threefold increased risk for fatal and nonfatal bleeding compared with warfarin alone, according to data from a Danish cohort study.

Researchers obtained data from nationwide registries for 82,854 patients aged 30 years or older who were hospitalized for AF between 1997 and 2006. All of the patients included in the study had at least one prescription for warfarin, aspirin or clopidogrel filled after being discharged from the hospital. Using Cox proportional hazard models, the researchers estimated the risk for fatal and nonfatal bleeding associated with the combination therapies.

Mean follow-up was 3.3 years, during which time 11.4% of patients had nonfatal or fatal bleeding. Combination clopidogrel and warfarin therapy and combination clopidogrel, warfarin and aspirin therapy had the highest incidence rates for bleeding (13.9% per year for dual therapy and 15.7% per year for triple therapy). Using warfarin monotherapy as a reference, the researchers reported that the HR for warfarin and clopidogrel combined was 3.08 (95% CI, 2.32-3.91) and for triple therapy was 3.70 (95% CI, 2.89-4.76). The HR for aspirin alone was 0.93 (95% CI, 0.88-0.98), for clopidogrel alone was 1.06 (95% CI, 0.87-1.29), for aspirin and clopidogrel combined was 1.66 (95% CI, 1.34-2.04) and for warfarin and aspirin combined was 1.83 (95% CI, 1.72-1.96). The risk for death was higher among patients with a nonfatal bleeding episode (HR=2.45; 95% CI, 2.37-2.57), and combination therapy was not associated with improvement in the risk for ischemic stroke.

“These results stress that appropriate selection of patients for these therapies is important and that physicians should consider the expected benefits and risks carefully before prescribing combination therapy,” the researchers wrote.

[Chevychelov]

Low levels of vitamin D biomarker linked with an increased risk of HF-related death

Heart Failure Society of America 14th Annual Scientific Meeting

SAN DIEGO – Adults with decreased levels of serum 25-hydroxyvitamin D concentration had a significantly higher risk for death from HF and premature death, indicated new research presented here.
“Studies of national representative samples to examine the association between serum 25-hydroxyvitamin D [25(OH)D] concentration, a biomarker of vitamin D, and risk of mortality from HF and premature death are scarce,” Howard J. Eisen, MD, chief of the division of cardiology at Drexel University College of Medicine, Philadelphia, and researcher involved with the study, said in his presentation.

In order to determine this association, Eisen and fellow researchers utilized the Third National Health and Nutrition Examination Survey (NHANES) conducted from 1988 to 1994, which was followed for mortality through 2000. The sample size was 13,131 patients aged 35 and older enrolled in the prospective cohort analysis. Baseline serum 25(OH)D levels were measured using a radioimmunoassay kit and premature death was defined as those who died before 75 years of age.

During a mean follow-up of eight years, there were 3,266 (24.9%) deaths, including 101 HF deaths (0.8%). Nearly one-third (n=1,066; 32.6%) of the deaths were premature and death from CV disease accounted for roughly 34% of these deaths. Among those who died from HF, 37% had serum 25(OH)D levels < 20ng/mL, the amount defined as vitamin D deficiency. For non-HF-related death, vitamin D deficiency was present in only 26% of the population (P<.001).

After researchers adjusted for age, sex, race and baseline medical conditions, a Cox model revealed that those with vitamin D deficiency had 3.4 times higher risk of death from HF than those who had serum 25(OH)D ≥ 30ng/mL, which is defined as the normal value (P<.001). Additionally, the RR of premature death for subjects with vitamin D deficiency was 1.45 (95% CI, 1.22-1.72) vs. those with normal serum levels (P<.001).

“Adults with decreased serum 25(OH)D levels have significantly higher risk of death from HF and premature death, and this may beget additional justification for the study of vitamin D supplementation in appropriate patients to determine if there is causality and if this is a treatable condition,” Eisen concluded. – by Brian Ellis
__________________________________________________ _______________________

PEERLESS-HF: Ventricular elastic support therapy associated with risk reductions in HF

Heart Failure Society of America 14th Annual Scientific Meeting

SAN DIEGO – Patients with HF treated with ventricular elastic support therapy along with optimal HF therapy safety experienced a reduced risk of HF when compared to those taking HF therapy alone, in addition to no increased risk of all cause mortality, according to new data presented here.

This prospective, randomized, controlled trial study featured patients randomized 1:1 who were 18-75 years of age with Stage C symptomatic ischemic or non-ischemic HF for at least 6 months. Patients also had stable, evidence-based HF therapy for at least 3 months before randomization, as well as left ventricular ejection fraction ≤35%. The primary safety endpoint of all cause mortality by non-inferiority analysis was assessed at 1 year.

Of the 217 randomized patients, 114 were treated with optimal HF therapy alone and 103 (92 treated, 11 not treated) were placed in the optimal HF therapy plus ventricular elastic support therapy (HeartNet Ventricular Elastic Support System, Paracor Medical, Inc.) arm. According to William T. Abraham, MD, director of the Division of Cardiovascular Medicine at Ohio State University Medical Center, and researcher involved with the study, the trial was terminated early after recommendation by the Data and Safety Monitoring Board due to futility which resulted from the lack of a demonstrable difference between treatment and control arm in change in PVO2.

At the 12 month follow up, study results indicated a survival rate in the treatment arm of 93.4% and 92.4% in the control arm (P=.056). There was evidence of reverse remodeling favoring the treatment group at 6 months, and of a reduction in serious HF events, including CV death and HF hospitalization in the treatment group. In addition, Abraham added, “In a subgroup of patients with cardiac resynchronization therapy (CRT) at baseline, there appeared to be a better reduction in serious HF events [in the treatment group].

“These findings support undertaking a clinical trial that targets this patient population with CRT, but with an inadequate CRT response,” he concluded.

Abraham served as member and principal investigator in the steering committee in which he received consultant fees. The trial was sponsored by Paracor Medical, Inc. – by Brian Ellis

[Chevychelov]

LEADERS Three-Year Results Suggest Improved Safety and Efficacy of BioMatrix Flex™ over Cypher® Select™
Washington DC, USA, 21 September 2010 – Biosensors International Group, Ltd (“Biosensors”, “Company”, BIG:SP) today announced three-year results of the LEADERS trial, which showed a continuing positive trend towards a safety and efficacy benefit for BioMatrix Flex™, Biosensors’ Biolimus A9™-eluting stent system with abluminal biodegradable polymer, compared to Cypher® Select™, Johnson & Johnson’s sirolimus-eluting stent system with a durable polymer. Results were presented by Professor Patrick W. Serruys, Erasmus Medical Center, Netherlands, at the 22nd annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, sponsored by the Cardiovascular Research Foundation.
In the overall study population, there were similar outcomes for BioMatrix Flex and Cypher Select in respect of MACE (major adverse cardiac events) at three years. There was a diverging trend towards a lower rate of MACE (15.7% vs. 19.0%; P value for superiority = 0.09) in patients treated with BioMatrix Flex versus those treated with Cypher Select when compared to both one and two year results.
In the high risk sub-group of STEMI patients (ST Elevation Myocardial Infarction), a statistically significant reduction in MACE rate was demonstrated with BioMatrix Flex compared to Cypher Select (9.6% vs. 20.7%; P value for superiority = 0.01). In another high-risk group of patients, those with SYNTAX High scores (>16), there was a significant 57% reduction in risk of cardiac death for BioMatrix Flex compared to Cypher Select (4.6% vs. 10.4%; P value for superiority = 0.02).
Although this was an all-comers study, occurrence of very late stent thrombosis (VLST) events was very low: a cumulative 0.2% for BioMatrix Flex out to three years, compared with 0.9% for Cypher Select observed within the same period. No VLST events were observed in BioMatrix Flex patients between years two and three of the study. VLST events in the BioMatrix Flex group were limited to patients with Saphenous Vein Grafts (SVG), who are traditionally excluded from drug-eluting stent trials. It was also notable there were no VLST events in patients treated with the BioMatrix Flex stent after discontinuation of dual anti-platelet therapy (DAPT).
“These further follow-up results from LEADERS confirm that the BioMatrix Flex stent continues to be safe and effective three years after implantation in an all-comers population, reflecting patients treated in routine clinical practice”, commented Professor Serruys.
“We are very encouraged by these results, which demonstrate that BioMatrix Flex continues to offer superior patient benefits compared to the industry standard over the longer term”, added Jeffrey B. Jump, President & CEO of Biosensors. “Our innovative drug-eluting stent, with its unique combination of anti-restenotic drug and abluminal biodegradable polymer, is providing an increasingly attractive alternative to conventional drug-eluting stents with durable polymers.”
The nine-month results from LEADERS, presented at the European Society of Cardiology (“ESC”) congress in 2008 and simultaneously published in The Lancet, demonstrated the BioMatrix Flex stent to be non-inferior to the Cypher Select stent in respect of the primary endpoint, incidence of MACE at nine months. This non-inferiority was confirmed in the one and two year results, during which time an increasing trend towards a safety benefit for the BioMatrix Flex stent was observed.
Sponsored by Biosensors, LEADERS was independently designed, implemented and analyzed by the study investigators. Data management and analysis were performed by an independent academic institution.

[Chevychelov]

CT coronary angiography provided independent, incremental information in patients with suspected CAD
Russo V. Circ Cardiovasc Imaging. 2010;3:351-359.

Multidetector CT coronary angiography is capable of delivering independent and incremental information in a patient population with suspected coronary artery disease, including showing an association between the disease and hard cardiac events, new study data have indicated.

The study consisted of 441 patients (mean age, 59.7 ± 11.6 years) with suspected CAD. Physicians performed multidetector CT coronary angiography to evaluate the presence and severity of the disease and followed up to determine the occurrence of hard cardiac events, including cardiac death, nonfatal MI and unstable angina requiring hospitalization.

Researchers detected coronary lesions in 297 (67.3%) patients. During follow-up (mean 31.9 ± 14.8 months), they reported 44 hard cardiac events in 40 patients. There was a statistically significant incremental prognostic value in CT calcium scoring vs. a baseline clinical risk model (P=.018). However, multidetector CT coronary angiography provided an additional incremental prognostic value vs. a baseline clinical risk model plus calcium scoring if considering both non-obstructive vs. obstructive CAD (P=.016) or plaque composition (calcified vs. noncalcified and/or mixed plaques, P=.0001).

According to researchers, the presence of noncalcified or mixed plaques, regardless of lesion severity, was found to be the strongest predictor of events (P<.0001) as a potential marker of plaque vulnerability.

“According to these results, multidetector CT has been confirmed as an extremely accurate noninvasive tool in coronary artery evaluation, capable of providing information about two of the most significant independent predictors of hard cardiac events — the presence and severity of CAD and the composition of atherosclerotic plaques,” they wrote.
--------------------------------------------------------------------------------------

FDA adds warning to gadolinium-based contrast agents

The FDA is now requiring that gadolinium-based contrast agents carry new label warnings about the risk for nephrogenic systemic fibrosis, a rare but potentially fatal condition, if the drug is given to certain patients with kidney disease, according to a press release.

All gadolinium-based contrast agent labels will now urge physicians to screen patients for acute kidney injury or chronic severe kidney disease before administering the drug. Three gadolinium-based contrast agents — Magnevist (Bayer Healthcare), Omniscan (GE Healthcare) and Optimark (Covidien) — were associated with a greater risk for nephrogenic systemic fibrosis development and will be described as inappropriate for use among patients with acute kidney injury or chronic severe kidney disease, according to the release.

Nephrogenic systemic fibrosis is a condition involving the formation of excess fibrous connective tissue in the internal organs, skin, joints and eyes. Symptoms can include scaling, tightening and hardening of the skin, dark patches on the skin and stiffness. If the internal organs are involved, the condition can be fatal, according to the release.

“The FDA is requiring these labeling changes to enhance the safe use of gadolinium-based contrast agents, including avoidance of certain agents among patients at highest risk for nephrogenic systemic fibrosis,” Rafel Rieves, MD, director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research, said in the release.

The FDA has issued the following recommendations for physicians using gadolinium-based contrast agents:
Estimate kidney function via laboratory testing for patients at risk for chronically reduced kidney function.
Do not use gadolinium-based contrast agents in patients suspected or known to have impaired drug elimination unless the imaging is absolutely necessary and not available without contrast.
Monitor for signs and symptoms of nephrogenic systemic fibrosis if a gadolinium-based contrast agent is administered to a patient with acute kidney injury or chronic severe kidney disease.
Only administer a gadolinium-based contrast agent once during an imaging session.

For more information, view the FDA’s “Gadolinium Safety Announcement” or “Questions and Answers Page on Gadolinium-Based Contrast Agents.”

[Chevychelov]

LV geometry influential in DSMR-wall motion accuracy
Gebker R. Circ Cardiovasc Imaging. 2010;3:507-514.

Left ventricular geometry influenced the effectiveness of dobutamine stress magnetic resonance-wall motion for the detection of coronary artery disease, study findings indicated. In addition, for patients with concentric remodeling and concentric hypertrophy, additional first-pass perfusion imaging improved diagnostic accuracy for detecting coronary artery disease.

Researchers performed combined dobutamine stress magnetic resonance (DSMR)-wall motion and DSMR-perfusion imaging in a single session in patients (n=187) scheduled for invasive coronary angiography. Then, they classified patients into four categories based on LV mass (normal: ≤81 g/m2 in men, ≤62 g/m2 in women) and relative wall thickness (normal,<0.45): normal geometry (normal mass, normal relative wall thickness), concentric remodeling (normal mass, increased relative wall thickness), concentric hypertrophy (increased mass, increased relative wall thickness) and eccentric hypertrophy (increased mass, normal relative wall thickness). Significant CAD was defined as at least 70% stenosis.

Study results showed that in patients with increased LV concentricity, sensitivity and accuracy of DSMR-wall motion were significantly reduced (63% sensitivity, 73% accuracy; P<.05) compared with patients without increased LV concentricity (90% sensitivity, 88% accuracy; P<.05). Additionally, the accuracy of DSMR-wall motion vs. DSMR-perfusion was superior in patients with eccentric hypertrophy (90% vs. 85%; P<.05), whereas DSMR-perfusion had higher accuracy in patients with concentric hypertrophy (82% vs. 71%; P<.05).

“This study highlighted the influence of different LV geometric patterns on diagnostic accuracy of DSMR-wall motion and the potential benefit of performing additional first-pass DSMR-perfusion imaging,” researchers concluded. “We thus recommend adding DSMR-perfusion to a routine stress protocol in patients with increased LV concentricity.”

[Chevychelov]

Efficacy and Safety of Dabigatran Compared With Warfarin at Different Levels of International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation: An Analysis of the RE-LY Trial
Wallentin L, Yusuf S, Ezekowitz MD, et al., on behalf of the RE-LY Investigators.
Lancet 2010;Aug 27:[Epub ahead of print].
Study Question: Does the time in therapeutic range (TTR) affect the efficacy of warfarin relative to dabigatran?

Prevalence and Predictors of Off-Label Use of Cardiac Resynchronization Therapy in Patients Enrolled in the National Cardiovascular Data Registry Implantable-Cardiac Defibrillator Registry
Implantable-Cardiac Defibrillator Registry
Fein AS, Wang Y, Curtis JP, Masoudi FA, Varosy PD, Reynolds MR, on behalf of the National Cardiovascular Data Registry.
J Am Coll Cardiol 2010;56:766-773.
Study Question: In clinical practice, how often is the use of cardiac resynchronization therapy (CRT) not consistent with evidence-based guidelines?

Ivabradine and Outcomes in Chronic Heart Failure (SHIFT): A Randomised Placebo-Controlled Study
Swedberg K, Komajda M, Bohm M, et al., on behalf of the SHIFT Investigators.
Lancet 2010;376:875-885.
Study Question: Does ivabradine, a selective sinus node If channel inhibitor, reduce adverse events in systolic heart failure?

Associations Between Physician Characteristics and Quality of Care
Reid RO, Friedberg MW, Adams JL, McGlynn EA, Mehrotra A.
Arch Intern Med 2010;170:1442-1449.
Study Question: Patients are encouraged to select physicians on the basis of characteristics such as education, board certification, and malpractice history. In a large sample of Massachusetts physicians, what is the relationship between physician characteristics and performance on a broad range of quality measures?

Initial Clinical Results Using Intracardiac Electrogram Monitoring to Detect and Alert Patients During Coronary Plaque Rupture and Ischemia
Fischell TA, Fischell DR, Avezum A, et al.
J Am Coll Cardiol 2010;56:1089-1098.
Study Question: Can intracardiac electrocardiogram (ECG) monitoring be used to detect ST segment shifts and alert patients to thrombotic events?

Evidence of Pre-Procedural Statin Therapy: A Meta-Analysis of Randomized Trials
Winchester DE, Wen X, Xie L, Bavry AA.
J Am Coll Cardiol 2010;56:1099-1109.
Study Question: Do statins improve clinical outcomes when used before invasive procedures?

Markers of Renal Function and Acute Kidney Injury in Acute Heart Failure: Definitions and Impact on Outcomes of the Cardiorenal Syndrome
Lassus JP, Nieminen MS, Peuhkurinen K, et al., for the FINN-AKVA Study Group.
Eur Heart J 2010;Aug 27:[Epub ahead of print].
Study Question: How useful is cystatin C as a marker of early acute kidney injury (AKI) in acute heart failure (AHF)?

Importance of Refractory Pain and Hypertension in Acute Type B Aortic Dissection. Insights From the International Registry of Acute Aortic Dissection (IRAD)
Trimarchi S, Eagle KA, Nienaber CA, et al.
Circulation 2010;122:1283-1289.
Study Question: What is the impact of refractory pain and/or refractory hypertension on the outcomes of acute type B aortic dissection (ABAD)?

Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes
The CURRENT–OASIS 7 Investigators.
N Engl J Med 2010;363:930-942.
Study Question: What is the ideal dose of aspirin and clopidogrel in patients with acute coronary syndromes (ACS)?

[Chevychelov]

Trial Summary PARTNER
Title: Placement of Aortic Transcatheter Valves
Trial Sponsor: Edwards Lifesciences
Year Presented: 2010
Year Published: 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 09/22/2010
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: NOTHING TO DISCLOSE
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.

Description:

As many as one-third of patients with severe aortic stenosis (AS) are high-risk surgical candidates and are conservatively managed. However, nonsurgical management of symptomatic AS is associated with a median survival of about 2 years. The PARTNER trial sought to compare outcomes between standard therapy and transcatheter aortic valve implantation (TAVI) in patients with inoperable AS. TAVI is a new procedure in which a bioprosthetic aortic valve is inserted through a catheter and implanted within the diseased native aortic valve.
Hypothesis:

TAVI would be superior to standard therapy in patients who are at high risk for mortality with aortic valve surgery.
Drugs/Procedures Used:

TAVI was performed under general anesthesia, and under transesophageal echocardiographic guidance. A standard balloon aortic valvuloplasty (BAV) was initially performed, followed by transfemoral insertion of either a 22- or 24-French sheath (for a 23 or 26 mm valve, respectively). The valve itself was part of the Edwards SAPIEN heart-valve system, which consists of a trileaflet bovine pericardial valve mounted on a balloon-expandable, stainless steel support frame. This system was advanced across the native aortic valve. The valve and support frame were then balloon expanded across the native valve during rapid ventricular pacing. Standard therapy consisted of medical management and BAV alone if deemed necessary.
Concomitant Medications:

All patients undergoing TAVI received heparin during the procedure, and dual antiplatelet therapy consisting of aspirin and clopidogrel for 6 months after the procedure.
Principal Findings:
Of the more than 3,000 patients with severe AS who were screened, a total of 358 patients (12%) were randomized across 21 sites, 179 to TAVI, and 179 to standard therapy. Baseline characteristics were fairly similar between the two arms. The mean Society of Thoracic Surgeons (STS) score was 11.6%, with a corresponding mean logistic EuroSCORE of 28.4. Other conditions contributing to a high-risk designation included heavily calcified (“porcelain”) aorta in 15.1%, chest wall deformity or irradiation (13.1%), oxygen-dependent respiratory insufficiency (23.5%), and frailty based on prespecified criteria (23.1%).

About 93% of the patients had New York Heart Association (NYHA) class III or IV symptoms, with a mean aortic valve area of 0.6 cm2, and a mean aortic valve gradient of 44 mm Hg. The mean left ventricular ejection fraction (LVEF) was 52%, with moderate to severe mitral regurgitation present in about 23% of the patients. Pulmonary hypertension was present in about 43% of the patients. Coexisting coronary artery disease was noted in about 71% of the patients, with 41% having undergone prior coronary artery bypass grafting, and 27% prior percutaneous coronary intervention. About 20% of patients had undergone BAV at some point prior to randomization.

There was no difference in 30-day mortality between the TAVI and standard therapy arms (5.0% vs. 2.8%, p = 0.41). However, at 1 year, the primary endpoint of all-cause mortality was significantly lower in the TAVI arm (30.7% vs. 50.7%, hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.40-0.74, p < 0.001).

Other outcomes such as cardiovascular death at 1 year (20.5% vs. 44.6%, HR 0.39, 95% CI 0.27-0.56, p < 0.001) and death or rehospitalization at 1 year (42.5% vs. 71.6%, HR 0.46, 95% CI 0.35-0.59, p < 0.001) were also lower in the TAVI arm. Major strokes at 30 days (5.0% vs. 1.1%, p = 0.06) and at 1 year (7.8% vs. 3.9%, p = 0.18) were numerically higher in the TAVI arm. Major vascular complications were significantly higher in the TAVI arm, both at 30 days (16.2% vs. 1.1, p < 0.001) and at 1 year (16.8% vs. 2.2%, p < 0.001). Similarly, major bleeding was higher in the TAVI arm at 30 days (16.8% vs. 3.9%, p < 0.001) and at 1 year (22.3% vs. 11.2%, p = 0.007).

Other complications such as acute kidney injury, endocarditis, and new pacemaker requirement were similar between the two arms. BAV was necessary in 36.9% of the patients in the standard therapy arm over 1 year of follow-up, whereas repeat TAVI was necessary in three (1.7%) patients in that time frame.

Echocardiographic parameters such aortic valve area (0.6-1.5 cm2) and mean aortic valve gradient (44.5-11.1 mm Hg) showed significant improvement in the TAVI arm at 30 days (p < 0.001 for both). Moderate or severe paravalvular and valvular aortic regurgitation were noted in 11.8% and 1.3% of the patients at 30 days, respectively, in the TAVI arm. NYHA class demonstrated significant improvements in the TAVI arm at 30 days and at 1 year, as compared with the standard therapy arm (p < 0.001).
Interpretation:
PARTNER is a landmark trial in the field of structural heart disease and in the management of patients with severe AS. Patients in this trial were very high risk to begin with, as evidenced by >50% mortality at 1 year in the standard therapy arm. The results of the inoperable group of patients (cohort B) are reported here. TAVI resulted in 45% reduction in all-cause mortality and 61% reduction in cardiovascular mortality at 1 year in these high-risk AS patients compared with standard therapy. Echocardiographic criteria such as aortic valve area and mean aortic valve gradients, and symptom criteria such as NYHA class, also demonstrated a significant improvement.

The procedure is complex and fraught with numerous complications, however, as evidenced by a significantly higher risk of major vascular complications and major bleeding, and a trend towards a higher risk of major stroke in the TAVI arm. Thus, while the overall results are very encouraging, the high complication rate should temper any tendencies toward the overaggressive use of TAVI (if FDA approved for the treatment of AS) in lower-risk patients, and surgical AVR should still be considered the gold standard for treatment of AS in these patients. The availability and performance of smaller profile TAVI delivery systems, a comparison of transfemoral to transapical TAVI (cohort A patients), and long-term follow-up are eagerly awaited.

On another note, the design and execution of the PARTNER trial highlight the importance of close collaboration between interventional cardiologists and cardiac surgeons in the management of this complex group of patients.
Conditions:
Valvular heart disease
Study Design:
Parallel. Randomized.
Primary Endpoints:
All-cause mortality at 1 year
Hierarchical composite of all-cause mortality or time to the first occurrence of repeat hospitalization after the index procedure due to valve-related or procedure-related clinical deterioration
Secondary Endpoints:
Cardiovascular mortality at 1 year
Repeat hospitalization after the index procedure due to valve-related or procedure-related clinical deterioration
NYHA class at 1 year
Six-minute walk distance at 1 year
Valve performance based on echocardiographic parameters at 1 year
Complications at 1 year
Patient Population:
Severe senile degenerative native valve AS (aortic valve area <0.8 cm2, mean aortic valve gradient ≥40 mm Hg, or peak aortic jet velocity ≥4 m/sec on Doppler echocardiography)
NYHA class II, III, or IV symptoms
High-risk surgical candidates (either an STS score of ≥10%, presence of coexisting conditions that would be associated with a predicted risk of death 30 days after surgery of ≥15%, presence of coexisting conditions that would be associated with a predicted risk of death or serious comorbidity of ≥50% within 30 days of surgery)
Agreement between at least two cardiac surgeons that patient was not a suitable candidate for surgery

Number of screened applicants: 3,105
Number of enrollees: 358
Duration of follow-up: 1 year
Mean patient age: 83.2 years
Percentage female: 54%
Ejection fraction: 52%
NYHA class: II (7%), III or IV (93%)
Exclusions:
Unicuspid, bicuspid, or noncalcified aortic valve
Aortic or mitral valve regurgitation >3+
Substantial coronary artery disease requiring revascularization
LVEF <20%
Aortic annulus diameter <18 mm or >25 mm
Transient ischemic attack/stroke within the preceding 6 months
Acute myocardial infarction within the preceding 6 months
Severe renal insufficiency (serum creatinine >3.0 mg/dl, or needing chronic dialysis)
Any invasive therapeutic coronary procedure within 30 days (or 6 months if drug-eluting stent implantation)
Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe mitral annular calcification
White blood cell count <3000/mm3, hemoglobin <9 mg%, or platelet count <50,000/mm3
Bleeding diathesis or coagulopathy
Hemodynamic instability needing inotropic therapy or mechanical support devices
Need for emergent surgery for any reason
Hypertrophic obstructive cardiomyopathy
Active peptic ulcer disease or gastrointestinal bleeding within 3 months
Life-expectancy <12 months due to noncardiac causes
Significant abdominal or thoracic aortic disease
Iliofemoral vessel characteristics that would preclude safe placement of 22- or 24-French sheaths, such as severe calcification, severe tortuosity, or vessel diameter <7 mm (for 23 mm valve/22-French system) ,and <8 mm (for 26 mm valve/24-French system)
Bulky calcified aortic valve leaflets in close proximity to coronary ostia
Active bacterial endocarditis or other infections

[Chevychelov]

Trial Summary
LANCELOT ACS
Title: Lesson from Antagonizing the Cellular Effect of Thrombin–Acute Coronary Syndromes
Trial Sponsor: Eisai, Inc.
Year Presented: 2010
Topic(s): General Cardiology, Interventional Cardiology
Summary Posted: 09/23/2010
Writer: Dharam J. Kumbhani, M.D., S.M.
Author Disclosure: NOTHING TO DISCLOSE
Reviewer: Christopher P. Cannon, M.D., F.A.C.C.
Reviewer Disclosure: CONSULTING FEES/HONORARIA: Novartis, Alnylam, BMS EQUITY I

Description:

Atopaxar is a novel protease-activated receptor-1 (PAR-1) antagonist (formerly known as E5555) that has shown promising results in early clinical studies. The LANCELOT ACS trial was a phase II trial designed to study the safety and efficacy of atopaxar in patients admitted with acute coronary syndrome (ACS).
Hypothesis:

Atopaxar would be safe and efficacious, as compared with placebo, in the treatment of patients admitted with ACS.
Drugs/Procedures Used:

Patients presenting with ACS were randomized in a 1:1:1:1 fashion to receive either placebo, or atopaxar 400 mg loading dose followed by 50 mg daily maintenance dose, atopaxar 400 mg loading dose followed by 100 mg daily maintenance dose, or atopaxar 400 mg loading dose followed by 200 mg daily maintenance dose.
Concomitant Medications:

Aspirin (97%), thienopyridine (82%), statin (88%), beta-blocker (85%), and glycoprotein IIb/IIIa inhibitor (15%)
Principal Findings:
A total of 603 patients were randomized, 142 to placebo, 156 to atopaxar 50 mg daily, 157 to atopaxar 100 mg daily, and 148 to atopaxar 200 mg daily. Baseline characteristics were fairly similar between the four arms. About 22% had diabetes mellitus, 27% had prior myocardial infarction (MI), 3% had prior stroke, and 5% had known peripheral arterial disease.

The primary endpoint of major bleeding (as defined in the CURE trial) was noted to be similar between the placebo, atopaxar 50 mg, 100 mg, and 200 mg arms, respectively (0% vs. 0.6% vs. 3.2% vs. 1.4%, p = 0.28).The rate of major bleeding for all doses of atopaxar combined was 1.8% vs. 0% for placebo (p = 0.18). CURE-defined minor bleeding was also similar for placebo versus the three ascending doses of atopaxar (2.2% vs. 0.7% vs. 2.6% vs. 0.7%, p = 0.81). Similar results were noted when analyzed by the Thrombolysis in Myocardial Infarction (TIMI) definitions for major, minor, and minimal bleeding. The incidence of cardiovascular death, stroke, MI, or recurrent ischemia was similar between the four arms (7.8% vs. 3.9% vs. 10.8% vs. 9.5%, p = 0.26). The incidence of ischemia, as detected by 48-hour Holter monitoring, was lower in the combined atopaxar arm, as compared with placebo (18.7% vs. 28.1%, p = 0.02).

Platelet function studies demonstrated a dose-dependent inhibition of platelet aggregation (as measured with 15 µM of thrombin receptor-activated peptide) with the 50 mg, 100 mg, and 200 mg maintenance doses of atopaxar (77% vs. 90% vs. 95% at 2 weeks, and 63% vs. 79% vs. 97% at 8 weeks). Significant inhibition of platelet aggregation with the loading dose of 400 mg was seen within 1-3 hours of administration (74%).

There was a dose-related increase in the incidence of alanine aminotransferase ≥3 x upper limit of normal (ULN) with higher doses of atopaxar (2.2% vs. 2.2% vs. 5.5%) compared with placebo (2.5%). Mean QTc was higher across the three atopaxar doses (410.9 vs. 414.4 vs. 417.8 msec), as compared with placebo (409.4 msec), although no malignant arrhythmias or syncope were noted.
Interpretation:
The results of the phase II LANCELOT ACS trial demonstrate the safety of atopaxar in terms of major bleeding in patients with ACS, as compared with placebo (on a background of aspirin and a thienopyridine), although higher doses were associated with a higher incidence of transaminitis and QTc prolongation. The trial was underpowered to study clinical outcomes, but they seemed to be similar between the placebo and atopaxar arms. A high level of platelet aggregation inhibition was achieved with the 400 mg loading dose within 1-3 hours of administration, and this was sustained with the maintenance doses in a dose-response fashion. Similar safety and efficacy results were noted in the recently presented and published J-LANCELOT trial in Japanese patients with ACS, coronary artery disease, or high-risk clinical characteristics.

Atopaxar is a PAR-1 antagonist, and thus, has a novel mechanism of antiplatelet action. Further phase III trials are awaited. Clinical outcomes trials with another PAR-1 antagonist, vorapaxar, are also underway.
Study Design:
Blinded. Parallel. Placebo Controlled. Randomized.
Primary Endpoints:
Major bleeding, as per CURE definition
Patient Population:
Male or female; ages 18-80 years
Presenting with features of unstable angina or non-ST-elevation MI
At least one of the following:
o Troponin T or I or creatine kinase-myocardial band ≥ULN
o ECG changes compatible with ischemia (i.e., ST depression at least 1 mm in two contiguous leads or T-wave inversion >3 mm or any dynamic ST shift or transient ST elevation)
o Randomization and treatment ≤72 hours of the onset of symptoms

Number of enrollees: 603
Duration of follow-up: 12 weeks
Mean patient age: 61 years (median)
Percentage female: 32%
Exclusions:
Increased risk of bleeding, anemia (hemoglobin <10 g/dl), thrombocytopenia (<100 x 103/μL), history of pathological intracranial findings
Planned elective major surgery
Planned use of oral anticoagulants (e.g., warfarin), fibrinolytics, or regular nonsteroidal anti-inflammatory drugs
Known hepatic disease or creatinine clearance <30 ml/min