Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

FDA approves combination sitagliptin, simvastatin
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The FDA today announced approval of a fixed-dose combination therapy containing sitagliptin and simvastatin for the treatment of adults with type 2 diabetes and high cholesterol.

“This is the first product to combine a type 2 diabetes drug with a cholesterol-lowering drug in one tablet,” Mary H. Park, MD, director of the division of metabolism and endocrinology products in the FDA Center for Drug Evaluation and Research, said in a press release. “However, to ensure safe and effective use of this product, tablets containing different doses of sitagliptin and simvastatin in fixed-dose combination have been developed to meet the different needs of individual patients. Dose selection should factor in what other drugs the patient is taking.”

The combination tablet (Juvisync; Merck) was approved in sitagliptin/simvastatin dosage strengths of 100 mg/10 mg, 100 mg/20 mg and 100 mg/40 mg. According to the FDA, treatment should only be prescribed when patients require treatment with both sitagliptin (Januvia, Merck) and simvastatin (Zocor, Merck).
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MRI deemed safe for patients with selected implanted cardiac devices

Nazarian S. Ann Intern Med. 2011;155:415-424.
Reynolds MR. Ann Intern Med. 2011;155:470-472.
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MRI can be performed safely in patients with selected pacemaker and implantable cardioverter defibrillators when using device selection and programming protocol, new data suggest.

Patients with clinical indication for MRI and an implantable device were enrolled in a study between February 2003 and April 2010. Researchers enrolled 438 patients (54% had a pacemaker; 46% had ICDs) who underwent 555 MRI examinations. Most MRIs were of the brain, 22% of the spine, 16% of the heart, 13% of the abdomen or pelvis and 9% of an extremity.

Immediately after MRI, right ventricular sensing (median change, 0 mV), and atrial (median change, –2 Ù) and right (median change, –4 Ù) and left (–11 Ù) ventricular lead impedances were reduced, according to researchers. At long-term follow-up, 61% of patients had decreased right ventricular sensing (median, 0 mV), right ventricular lead impedance (median, –3 Ù), battery voltage (median, –0.01 V) and increased right ventricular capture threshold (median, 0 V).

Three patients had their device reverted to a transient backup programming mode, with no long-term effects. According to the researchers, this was the “primary clinically significant event attributable to MRI.”

They concluded that “MRI was performed safely in all patients.” However, image distortion, signal voids or bright areas, and poor fat suppression were noted when the device was located in the MRI field of view. “Given the potential for changes in device variables and programming, monitoring by device experts is necessary,” they wrote.

The researchers said patients were selected and treated based on previous safety studies. Only patients with pacemakers manufactured after 1998 and defibrillators manufactured after 2000 were enrolled, and researchers followed programming and monitoring protocol.

“The risks and benefits of MRI in a patient with a cardiac rhythm management device should be assessed on an individualized basis, as with any important medical decision,” Matthew R. Reynolds, MD, MSc, and Peter Zimetbaum, MD, of the division of cardiology, Beth Israel Deaconess Medical Center, wrote in an accompanying editorial. “The authors have not demonstrated that MRI in these patients is risk-free, only that the risks are quantitatively small. Therefore, before permitting a patient to have MRI, the potential benefits of the MRI relative to alternative diagnostic strategies should be established.
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600-mg loading dose of clopidogrel reduced infarct size in STEMI patients

Patti G. J Am Coll Cardiol. 2011;58:1592-1599.
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A reduction of infarct size and improvement of angiographic results, residual cardiac function and 30-day major adverse CV events were associated with pretreatment with a 600-mg loading dose of clopidogrel vs. a 300-mg loading dose before primary percutaneous coronary intervention in STEMI patients, according to an analysis of the ARMYDA-6 MI study.

Patients with STEMI undergoing primary PCI were enrolled in the study. Researchers randomly assigned a 600-mg or 300-mg loading dose of clopidogrel to patients before the procedure. The primary endpoint was defined as the evaluation of infarct size, and secondary endpoints were the prevalence of thrombolysis in MI flow grade of more than 1 before PCI and less than 3 after PCI; left ventricular ejection fraction by transthoracic echocardiography at discharge; incidence of major adverse CV events at 30 days; and occurrence of bleeding or entry site complications.

Overall, the primary endpoint concluded that infarct size was lower in patients assigned to the 600-mg dose. Looking at secondary endpoints, TIMI flow grade of more than 1 at diagnostic coronary angiography before PCI was found in 21.4% of patients in the 600-mg arm vs. 12.2% in the 300-mg arm, whereas a lower incidence of TIMI flow grade of less than 3 was associated with the 600-mg dose (P=.031). Study results showed that LVEF early after PCI was similar in the two arms (P=.42), but was higher in the 600-mg dose at discharge (P=.026). The 600-mg group also had a reduced incidence of 30-day major adverse CV events vs. the 300-mg group (P=.049).

Researchers also found that symptom-to-balloon (P=.86) time and clopidogrel load-to-balloon time (P=.45) were similar in the two arms.

The results are somewhat limited by a small sample, but having said that, they are significant. Furthermore while 600 mg improved non fatal outcomes, the important fact was the benefit was achieved without an increase in bleeding or other measured side effect. Furthermore, there appears to be a finite number of receptors bound by a P2Y12 inhibiter so increasing the dosage improves the possibility of achieving an important therapeutic level early while not paying a price for the higher loading dose.

[Chevychelov]

Statins Protect Brain in Head Trauma

By Crystal Phend, Senior Staff Writer, October 11, 2011

Action Points
Explain that seniors on a statin at the time of moderate-to-severe head trauma were 76% less likely to die in hospital although the study could not imply a direct causal effect of statins.

Note that statin users were 13% more likely to have made a good functional recovery by 12 months.
Review
Statins may make traumatic brain injury much more survivable for older adults, a national study suggested.

Seniors on a statin at the time of moderate-to-severe head trauma were 76% less likely to die in hospital (relative risk 0.24, 95% confidence interval 0.08 to 0.69), Eric B. Schneider, PhD, of Johns Hopkins, and colleagues found.

Statin users were also 13% more likely to have made a good functional recovery by 12 months (RR 1.13, 95% CI 1.01 to 1.26), the group reported in the October issue of the Journal of Trauma.

Although cardiovascular comorbidities appeared to eliminate any protective advantage, statins warrant further study as possible protective agents to be given when patients of any age present with head trauma, the researchers suggested.


After the damage from direct impact or acceleration and deceleration of the brain, secondary injury occurs from inflammatory and immune processes, the group explained.

Statins' pleiotropic effects on inflammation, thrombosis, and endothelial function may help prevent that secondary injury, although their primary role in lowering cholesterol likely has little impact, Schneider and colleagues suggested.

Animal studies have suggested a protective effect even when statins are started soon after brain injury.

"Right now there really isn't anything that can be prescribed to help people with a serious brain injury, and this is a glimmer of hope," Schneider told MedPage Today in an interview.

However, he recommended against administering the drugs for traumatic brain injury until further confirmation of benefit and safety.

Schneider's group examined outcomes through the National Study of Costs and Outcomes of Trauma database, which receives reports from 69 U.S. hospitals.

They excluded deaths within 24 hours of hospitalization and cases admitted with fixed dilated pupils indicating likely nonsurvivable injury that statins wouldn't reasonably be expected to affect. The cohort was also limited to the age group more likely to be taking statins.

Among the 523 individuals in the database 65 and older with a head injury and Abbreviated Injury Score of at least 3, statin use at the time of injury was recorded for 22%.

Death before discharge occurred among 9.1% of statin users as compared with 15.4% of nonstatin users (P=0.047), an advantage that remained significant at 76% after adjustment for other factors remained.

At three months, statin users were a nonsignificant 23% more likely to have made a good functional recovery (RR 0.77, 95% CI 0.42 to 1.41).

Although the 13% advantage at 12 months was statistically significant overall, it wasn't among statin users who had cardiovascular comorbidities (RR 1.11, 95% CI 0.82 to 1.50).

For inhospital mortality, the same pattern emerged, with a significant benefit only among those without cardiovascular comorbidities (RR 0.17, 95% CI 0.05 to 0.63).

"If statin-induced peri-injury endothelial homeostasis in fact underlies the improved outcomes seen in this and other studies, we suspect that statins may not benefit head trauma victims with significantly compromised endothelium (e.g., cardiovascular disease)," Schneider's group wrote in the paper.

They cautioned that the observational study could not imply a direct causal effect of statins, as the results could have been confounded by a "healthy user bias."

Another limitation was the lack of data on statin type, indication, dose, or duration of treatment, the group added.

[Chevychelov]

Heart Rate in Afib No Guarantee for Quality of Life

By Crystal Phend, Senior Staff Writer,
Published: October 11, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that a study randomizing patients with permanent atrial fibrillation to lenient or strict rate control did not result in differences in perceived quality of life between the groups.

Note that many patients were not symptomatic at baseline in either group and that quality of life was determined by answers to a questionnaire.

Stricter rate control for patients with permanent atrial fibrillation doesn't improve quality of life, a clinical trial showed.

More lenient control to a resting heart rate under 110 beats per minute showed no difference on any quality-of-life measure compared with strict control to less than 80 bpm, Isabelle C. Van Gelder, MD, of the University Medical Center Groningen, the Netherlands, and colleagues found.

Factors that did matter for well-being were symptoms, sex, age, and underlying disease severity, they reported in the Oct. 18 issue of the Journal of the American College of Cardiology.

These substudy results from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial add to the primary endpoint showing no advantage to strict control for adverse outcomes.

Those findings go against common clinical assumptions, noted Paul Dorian, MD, MSc, of St. Michael's Hospital, and Andrew C.T. Ha, MD, of Toronto General Hospital, both in Toronto.

"For example, many physicians may assume that a rapid and irregular heart rate is undesirable, and implicitly subjectively undesirable, compared with a slower, more well-controlled rate," they wrote in an accompanying editorial.

That this wasn't the case for the study population -- largely those with "long-standing and not terribly symptomatic atrial fibrillation" -- points to the need to individualize decisions to intensify rate control, Dorian and Ha argued.

"Clinicians need to be aware that patient personality, treatment expectations, and factors unrelated to the arrhythmia itself will have important, potentially determining influences on the extent to which atrial fibrillation causes suffering," they wrote.

The researchers agreed that different groups, such as highly symptomatic patients, might feel better with tighter rate control.

RACE II included 614 permanent atrial fibrillation patients randomized to rate control classified as lenient or strict based on a target of less than 110 bpm at rest versus less than 80 bpm or less than 110 bpm if exercising moderately.

The substudy included the 437 who completed quality-of-life questionnaires at baseline, one year, and at the end of study after a median of three years.

The prevalence of symptoms -- largely dyspnea, fatigue, and palpitations -- declined somewhat during follow-up to 48% from 58% at baseline, though without a difference between rate control groups.

Initial heart rate didn't predict quality of life at baseline, nor did change in quality-of-life correlate with heart rate.

The strict and lenient rate control groups came out similar for all quality of life measures at 12 months and at the end of the study on the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire.

The atrial fibrillation severity scale and the Multidimensional Fatigue Inventory-20 likewise showed no differences between rate control strategies at any point and a lack of correlation with heart rate.

The lack of relative improvement with stricter control of heart rate may have reflected that patients were already at a relatively low symptom level at baseline and so had little room for improvement whatever the treatment strategy, the researchers noted.

Indeed one of the determinants of improvement on the SF-36 and atrial fibrillation severity scale was symptoms at baseline.

Other predictors of improvement on the SF-36 included absence of symptoms at the end of the study, higher left ventricular ejection fraction, younger age, and a thinner septum, and younger age alone for the atrial fibrillation severity scale.

Possible explanations for the findings also may have been that symptoms driven more by underlying heart disease or by ventricular irregularity weren't impacted by degree of rate control or that the higher doses of rate control drugs in the strict control group actually adversely affected quality of life.

Van Gelder's group cautioned that the results could not be generalized to patients without permanent atrial fibrillation or who are highly symptomatic.

Other limitations were that strategies to achieve heart rate targets differed between groups and the quality of life questionnaires may not have been sensitive enough, they added.

[Chevychelov]

Diabetes Drug May Have Plaque Benefit


This report is part of a 12-month Clinical Context series.By Todd Neale, Senior Staff Writer, MedPage Today
Published: October 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
for reading medical news

Pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects, a small randomized trial showed.

In patients with impaired glucose tolerance or type 2 diabetes accompanied by carotid atherosclerosis, pioglitazone and glimepiride reduced fasting plasma glucose to a similar extent after four months of treatment, according to Nobuhiro Tahara, MD, PhD, of Kurume University in Japan, and colleagues.

But only pioglitazone reduced atherosclerotic plaque inflammation (P<0.01), as assessed with serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, the researchers reported in the October issue of JACC: Cardiovascular Action Points
Explain that pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects.

Note that the sole independent predictor of a reduction in inflammation was an increase in HDL cholesterol level, which occurred with pioglitazone, but not glimepiride.
Imaging.Action Points
Explain that pioglitazone (Actos) may reduce atherosclerotic plaque inflammation, independent of its glucose-lowering effects.


Note that the sole independent predictor of a reduction in inflammation was an increase in HDL cholesterol level, which occurred with pioglitazone, but not glimepiride.


The sole independent predictor of a reduction in inflammation was an increase in high-density lipid (HDL) cholesterol level, which occurred with pioglitazone, but not glimepiride.

"These findings suggest that HDL-cholesterol-increasing effects of pioglitazone could mainly be involved in the suppression of atherosclerotic plaque inflammation in our patients," Tahara and colleagues wrote, adding that they could not exclude the possibility of some other mechanism.

They noted that previous studies, including AIM-HIGH, have failed to show any benefit from raising HDL cholesterol levels on hard cardiovascular events.

In an accompanying editorial, Ahmed Tawakol, MD, of Massachusetts General Hospital in Boston, and Aloke Finn, MD, of Emory University in Atlanta, added that "it is important to note that it remains unclear whether lowering plaque inflammation is the mechanism by which statins and pioglitazone therapy decrease cardiovascular events or even whether, in general, reductions in inflammation would translate into clinical benefit."

Pioglitazone has been shown to be better than glimepiride for preventing the progression of atherosclerosis in patients with diabetes, and the PROactive trial suggested that the drug might have a plaque-stabilizing effect. But there are no data on whether any specific oral hypoglycemic agent is preferred for preventing atherosclerotic plaque inflammation.

To compare pioglitazone and glimepiride (Amaryl), Tahara and colleagues recruited 52 patients with impaired glucose tolerance or type 2 diabetes. All also had evidence of carotid atherosclerosis.

The patients were randomized to 15 mg to 30 mg of pioglitazone or 0.5 mg to 4 mg of glimepiride for four months, with titration of the doses to maintain a fasting plasma glucose of 110 mg/dL or lower.

Plaque inflammation was measured at baseline and at the completion of the study using FDG-PET. Scans were done on the carotid arteries and the ascending aorta of the aortic arch because those areas are associated with atherothrombotic stroke, according to the researchers.

At baseline, there was no between-group difference in the target-to-background ratio, which is a measure of plaque inflammation.

After four months, both pioglitazone and glimepiride reduced fasting plasma glucose and hemoglobin A1c similarly.

Pioglitazone increased weight and waist circumference and decreased high-sensitivity C-reactive protein (hs-CRP). Glimepiride increased hs-CRP.

There were no significant changes in blood pressure, fasting plasma insulin, low-density lipid cholesterol, or triglycerides in either group.

Pioglitazone significantly decreased atherosclerotic plaque inflammation according to FDG-PET, whereas glimepiride treatment resulted in a nonsignificant increase in inflammation.

Thus, the researchers wrote, "pioglitazone may be a promising strategy for the treatment of atherosclerotic plaque inflammation in impaired glucose tolerant or type 2 diabetic patients."

They acknowledged some limitations of the study, including the small sample size; the possibility of confounding by the use of nonstudy medications; the short duration; and the lack of statistical power to detect differences in cardiovascular endpoints.

The study was supported in part by a grant for the Academic Frontier Project from the Ministry of Education, Science, Sports, Culture, and Technology in Japan.

The study authors reported that they had no conflicts of interest.

Tawakol reported receiving research grants and/or consulting income from Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Roche, VBL Therapeutics, Siemens Medical Systems, and the NIH. Finn reported having sponsored research agreements with Medtronic and St. Jude Medical.

[Chevychelov]

CREST substudy: Carotid artery stenting associated with better quality of life

Cohen D. J Am Coll Cardiol. 2011;58:1557-1565.
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Carotid artery stenting is associated with better health-related quality of life during the early recovery period of carotid revascularization vs. carotid endarterectomy, according to an analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial, or CREST.

Patients undergoing carotid revascularization were randomly assigned to either carotid artery stenting (CAS) or carotid endarterectomy (CEA) groups. Health-related quality of life was measured at baseline, 2 weeks, 1 month and 1 year by using standardized questionnaires and assessed using the Medical Outcomes Study Short-Form 36 (SF-36).

Between December 2000 and July 2008, there were 1,262 patients randomly assigned to CAS and 1,240 to CEA. SF-36 subscale scores were similar at baseline, but by 2 weeks, CAS patients had better scores vs. CEA patients (all P<.01). There were only three of eight subscales with better scores in the CAS group vs. CEA by the 1-month follow-up, and no differences for any SF-36 subscales at 1 year, according to researchers. At 1 year, worse health-related quality-of-life scores were reported in patients who had periprocedural stroke and periprocedural MI vs. patients who had no periprocedural events.

Less difficulty eating or swallowing, less difficulty driving and less impairment from headaches and neck pain, but more walking difficulty and more impairment from leg pain, were reported by CAS patients vs. CEA patients at 2 weeks. These results were similar by the 1-month follow-up. For ratings of overall pain, patients who had CAS and CEA had reported similar scores at baseline (P=.23), and by 2 weeks assessment, CAS patients reported lower pain score vs. CEA patients (P<.01). By 1-month (P=.16) and 12-month (P=.86) assessment, the difference was no longer present. The CAS group also reported less need for pain medication around the 2-week assessment (P<.01), but this difference was also no longer present by 1-month (P=.90) and 12-month (P=.57) evaluation.

“Finding that the choice between these two therapeutic options is a toss-up considering both clinical and quality-of-life outcomes means primarily that, for the clinician, whose primary role is to provide expert advice to the patient, there is no ‘wrong decision,’” Daniel B. Mark, MD, MPH, Manesh R. Patel, MD, and Kevin J. Anstrom, PhD, all of the Duke Clinical Research Institute and the division of cardiology at the Duke University School of Medicine in Durham, N.C., said in an accompanying editorial. “Neither risk can be completely avoided as both events occur after each procedure, but the incremental risks are too low to affect the expected quality-of-life results of either treatment.”

Disclosure: Dr. Cohen received research support from Boston Scientific, Abbott Vascular, Medtronic, Edwards Lifesciences, MedRad, Merck/Shering-Plough,and Eli Lilly-Daiichi Sankyo; is a consultant to Merck/Schering-Plough, Eli Lilly, Medtronic and Cordis; and has served on the speakers’ bureau for Eli Lilly and The Medicines Company. Dr. Mark reports no relevant financial disclosures.





David
Faxon


While carotid stenting patients had better initial quality of life measures by one year there was no difference. This is consistent with the SAPPHIRE trial and not surprising since recover is longer after surgery. It is reassuring since there was a small but significant difference in stroke rate in favor of carotid endarterectomy which might have lead to a lower QoL in the stenting group but this was not seen. It does mean that both techniques are equivalent. Quality of life is often more important to patients than adverse events so this type of study is important in assessing any treatment options.

[Chevychelov]

FDA Device Panel Gives Nod to New Stent for PAD

By Emily P. Walker, Washington Correspondent,
Reviewed by
October 13, 2011

Review

GAITHERSBURG, Md. -- An FDA advisory committee has voted 11-0 to endorse the first-ever drug-eluting stent for treatment of symptomatic peripheral arterial disease, agreeing unanimously that the Zilver PTX stent appears safe and effective.

The vote came at the end of Thursday's meeting of the FDA's Circulatory System Devices Advisory Committee. The FDA does not have to follow the advice of its advisory committees, but it often does.

If approved, the Zilver PTX stent, which was developed by Cook Medical, will be the first drug-eluting stent approved for treatment of peripheral artery disease (PAD), a condition that affects roughly 30 million people annually.

Current treatment options for PAD include percutaneous transluminal balloon angioplasty and bare metal stents, but both methods are associated with high rates of restenosis. About 50% of patients who have bare metal stents implanted in their leg arteries have to have another procedure after a year.

In Cook Medical's randomized clinical trial, 12-month restenosis rates were decreased by 50% in patients with a Zilver stent compared with those who received a bare metal stent.

The FDA panel spent Thursday discussing the company's two Zilver studies, which together included more than 1,000 patients.

The first study was a randomized, controlled trial that enrolled 479 patients and compared treatment of de novo or restenotic lesions of the femoropopliteal artery up to 140 mm in length using the Zilver PTX stent or percutaneous transluminal angioplasty (PTA).

At 12 months, 83% of the Zilver patients achieved primary efficacy versus just 33% of the PTA patients (P<0.01). Almost half of the controlled patients failed PTA on the initial attempt and were then randomized to either Zilver PTX or bare Zilver stents.

Adverse event rates -- including excess deaths, stent thrombosis, or stent fracture -- were about the same between the two groups after one year.

According to two-year follow-up data presented at the International Symposium on Endovascular Therapy last January, nearly 87% of the patients receiving the paclitaxel-eluting stent were still alive and had not needed amputation or another procedure after 24 months of follow-up, compared with just 78% of the patients treated with angioplasty alone who remained event-free (P<0.01).

The second study that the panel reviewed was a global registry of 787 patients treated with de novo or restenotic lesions of the femoropopliteal artery with no restriction on lesion length and was intended to answer the safety question. Patients from 50 centers in Europe, Canada, and Korea treated with the Zilver PTX stent were enrolled and followed for two years.

After one year, about 90% of the patients with the PTX stent had experienced no major adverse events.

Advisory panel chairman Clyde Yancy, MD, chief of cardiology at Northwestern University Feinberg School of Medicine in Chicago, called the new device "a technology that would not just benefit, but greatly benefit, these patients."

Cook Medical is asking the FDA to approve the stent to treat lesions no longer than 140 mm per limb for a total of 280 mm per patient.

"This is going to be a paradigm shift in how we treat the superficial femoral artery," Gary Ansel, MD, co-principal investigator in the Zilver PTX randomized trial, told MedPage Today after the meeting.

Ansel, who is the director of the Center for Critical Limb Care at Riverside Methodist Hospital in Columbus, Ohio, said if the FDA approves the device, endovascular specialists can provide their PAD patients with a treatment option that is less likely to require them to undergo another procedure one year out.

The panel discussed whether the device should be used in patients who can't tolerate antiplatelet therapy, because all patients in the trial took clopidogrel 24 hours prior to the procedure and for 60 days after the procedure. In addition, 90% of the patients in the trial took aspirin for one month to a year after the procedure.

However, panelists did not think being unable to tolerate clopidogrel should necessarily make a patient ineligible for the Zilver PTX.

The Zilver PTX stent is currently used in Asia, Europe, the Middle East/Africa, and South America for treatment of PAD.

[Chevychelov]

VA: Novel Ablation Catheter Tackles Persistent Afib

By Chris Kaiser, Cardiology Editor,
October 13, 2011

Action Points
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


In this clinical trial subjects with persistent atrial fibrillation who were randomized to RF ablation were more likely to achieve a 90% reduction in episodes of atrial fibrillation than those on medical therapy.


Complications occured in 12.3% of subjects, including four periprocedural strokes. The trial was not designed to assess efficacy with respect to long-term stroke prevention.
Review
A radiofrequency ablation catheter system with a multi-electrode design was better at reducing atrial fibrillation (Afib) in patients with persistent or long-standing Afib compared with those on medical management, a randomized trial found.

Of the 138 patients randomized to ablation, 55.8% had an atrial fibrillation and atrial flutter burden reduction of greater than 90% and were free of antiarrhythmic drug therapy at six months, compared with 26.4% of the 72 patients in the medical management arm, according to a study presented at the Venice Arrhythmias 2011 conference this week in Venice, Italy.

The rate of seven-day acute procedural events in the ablation arm was 12.3%, "a rate comparable to other persistent Afib studies," reported Lucas Boersma, MD, PhD, from St. Antonius Ziekenhuis in the Netherlands, and colleagues.


The acute event rate had an upper 95% confidence interval of 19%, which did not meet the prespecified performance goal of 16%. However, the prespecified acute safety endpoint was established in 2006 and was based on patients with paroxysmal atrial fibrillation, John Hummel, MD, director of clinical electrophysiology research at the Ohio State Medical Center in Columbus and an investigator in the trial, told MedPage Today in an interview.

"The patients in this trial were much sicker and had more complex disease than those on whom we modeled our prespecified acute safety endpoint," Hummel said. He also noted that some of the acute events, such as urinary tract infection and pneumonia, had little to do with the catheter system.

"Patients with persistent or long-standing atrial fibrillation, especially those refractory to drug therapy, are particularly challenging, and this new technology holds promise as an option for them," Hummel said.

For the TTOP-AF trial (Tailored Treatment of Persistent Atrial Fibrillation), researchers enrolled 210 patients who were symptomatic and drug refractory. Patients came from 23 sites in the U.S. and one in the Netherlands.

Patients were randomized 2:1 to ablation or medical management. Follow-up was at one, three, and six months in both arms. At three months, those in the ablation arm could be sent for retreatment with ablation if needed. After four months, those in the medical arm could cross over to ablation if needed.

Researchers defined persistent atrial fibrillation as continuous Afib for more than seven days but less than one year, or Afib recurrence within seven days of direct current cardioversion.

They defined long-standing persistent atrial fibrillation as continuous Afib for more than a year but less than four years.

The protocol included the use of three investigational ablation catheters, each designed for specific anatomic targets: pulmonary vein, left atrial septum, and left atrial body. The catheters apply "linear lesions through multiple neighboring electrodes at the same time," Hummel said, as opposed to the conventional point-by-point ablative technique.

The acute safety endpoint involved the use of all three catheters, which included isolating the pulmonary vein, ablating the complex atrial fractionated electrograms, and having the patient in sinus rhythm.

There were no significant differences at baseline between the two arms of the study, including with CHADS2 score, ejection fraction, and number of failed antiarrhythmic drugs.

A total of 93% of patients in the ablation arm had acute success and 35% required retreatment at three months. In the medical arm, 83% received a therapeutic intervention, 78% underwent cardioversion, and 86% had a change in drug dose or type.

The primary effectiveness endpoint included acute safety, chronic safety, and chronic effectiveness. In the intention-to-treat analysis, 55.8% of the ablation patients met the primary effectiveness endpoint at six months versus 26.4% of those being medically managed. The difference was significant at P<0.0001.

"That's a huge difference and a welcome finding because these patients are among the more difficult patients to ablate," Hummel said.

Acute safety events in the ablation arm included four strokes, two cases ofcardiac tamponade, two pseudoaneurysms, and two cases of heart failure with one resulting in death. Hummel noted that the acute stroke rate of 2.7% in TTOP-AF is comparable to other studies.

Chronic safety events in the ablation arm included four asymptomatic pulmonary vein stenoses, one symptomatic pulmonary vein stenosis, one stroke, one persistent atrial septal defect secondary to septal puncture, and one pericardial effusion. The medically managed arm had two cases of gastrointestinal bleeding and one case of atrial fibrillation with rapid ventricular response.

There was "very little difference" in the number of chronic safety adverse events between the two arms when analyzed by cumulative follow-up per patient per month, Hummel said. The ablative arm had 1,243 cumulative follow-up months, whereas the medical arm had 420 months. The number of adverse events per patient per month was 0.008 versus 0.007.

"Prolonged duration atrial fibrillation is a more difficult condition to provide meaningful therapy [for] than patients with shorter episodes of atrial fibrillation," Bruce Wilkoff, MD, president of the Heart Rhythm Society, told MedPage Today. "Medications have not been very effective in this situation, and this new procedure shows significant promise as an alternative."

Medtronic, who sponsored the study, has sent these data to the FDA for review. The catheter system is not available in the U.S, although it has been available in Europe and Canada for several years.

[Chevychelov]

Gut Bacteria May Keep Statin Response in Check

By Todd Neale, Senior Staff Writer,
October 16, 2011

Action Points
Explain that pretreatment levels of secondary bile acids, produced by intestinal bacteria, were found to correlate with the lowering of LDL cholesterol in response to simvastatin.


Note that higher pretreatment levels of these bacterial-derived bile acids were found in good responders to simvastatin but not in poor responders.
Review
Various bacterial-derived bile acids appear to influence the response to statin treatment, researchers found.

Pretreatment levels of several primary and secondary bile acids were strongly associated with the low-density lipoprotein (LDL) cholesterol-lowering ability of simvastatin in healthy individuals, according to Rima Kaddurah-Daouk, PhD, of Duke University, and colleagues.

The findings, reported online in PLoS ONE, "warrant further evaluation of interactions of specific markers for gut microbiota and therapeutic response to statins," the researchers wrote. "Identification of the basis for such interactions may in turn lead to dietary or other interventions that can improve statin efficacy by altering gut microflora."

There is variability among individuals in the therapeutic response to statins, and previous studies have shown that genetics can only account for part of it.


Kaddurah-Daouk and colleagues turned to the field of metabolomics, which incorporates the interactions between a person's genome, microbiome, and environment in explaining response to treatments.

To search for biomarkers that might help predict response to statin therapy, the researchers used two groups of participants from the Cholesterol and Pharmacogenetics Study. The latter was designed to identify factors related to the response to six weeks of treatment with simvastatin 40 mg in healthy, drug-naive volunteers.

One group consisted of 100 randomly selected individuals across the spectrum of LDL cholesterol-lowering response to statin therapy and constituted the full-range group.

The second group was made up of 48 individuals -- 24 from the top 10% and 24 from the bottom 10% in terms of response to statin therapy, who were the good and poor performers, respectively.

In all of these participants, the researchers used a metabolomics platform to measure a panel of metabolites related to cholesterol synthesis, dietary sterol absorption, and bile acid formation.

In the full-range group, there was a correlation between lower pretreatment levels of five primary and secondary bile acids:
Taurocholic acid (TCA)
Glycocholic acid (GCA)
Taurochenodeoxycholic acid (TCDCA)
Glycochenodeoxycholic acid (GCDCA)
Glycoursodeoxycholic acid (GUDCA)


The full-range group had a greater LDL cholesterol-lowering response to simvastatin (P<0.02 for all).

In the good and poor responders, higher pretreatment levels of three secondary bile acids -- lithocholic acid (LCA), taurolithocholic acid (TLCA), and glycolithocholic acid (GLCA) -- were associated with a better response to statin therapy (P<0.05 for all). These secondary bile acids are produced by intestinal bacteria.

Bile acids and statins use the same transporters in the liver and intestine, and the researchers observed that an increased plasma concentration of simvastatin was associated with higher levels of several secondary bile acids in the study groups.

"Bile acids are known to be important endocrine signals, functioning in the systemic control of lipid levels, muscle function, and immune cell regulation," the authors wrote. "It has not escaped our attention that all of these pathways are affected by statins, either as therapeutic targets or side effects, suggesting that bile acids may be important mediators of statin activities."

They concluded that the findings, "along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome, and environmental influences should be considered in the study and management of cardiovascular disease."

The investigators noted that their results could only be applied to simvastatin as metabolites and pathways for other statins might differ.

[Chevychelov]

FDA advisory panel backs drug-eluting stent for PAD

The FDA Circulatory System Devices Panel of the Medical Devices Advisory Committee voted 11-0 today for approval of a new paclitaxel-eluting stent designed for the improvement of luminal diameter for the treatment of de novo or restenotic symptomatic vascular disease of above-the-knee femoral arteries.

The self-expanding nitinol stent (Zilver PTX, Cook Medical) is coated on its outer surface with paclitaxel without any polymer, binder or excipient at a dose density of 3 mcg/mm2. If approved, this device would be the first-ever paclitaxel-eluting stent available in the US for the treatment of symptomatic peripheral arterial disease.

The committee unanimously agreed that the stent is safe for use in patients who meet the proposed indication criteria of maximum lesion length of 140 mm per limb and 280 mm per patient. The 11 panel members further voted that there is reasonable assurance that the stent is effective for patients who meet the aforementioned criteria. Overall, the committee said the benefits of this stent outweigh the risks for use in patients who meet the criteria specified in the proposed indication.

Post-approval trial

Along with the recommended approval, the advisory committee also discussed whether a post-approval study would be necessary for further safety and efficacy data.

The sponsor proposed a long-term follow-up of the randomized control trial that enrolled 479 patients with symptomatic de novo or restenotic superficial femoral artery lesions to be used as a post-approval study. The post-approval study would require 900 patients and would analyze a non-inferiority comparison of the rate of event-free survival between percutaneous transluminal angioplasty and paclitaxel-eluting stent groups at 5 years. The proposed primary endpoint is event-free survival and the rate of stent fracture and late stent thrombosis for patients is the proposed secondary endpoint.

Some panel members questioned whether the post-approval study would require a patient population of 900, or if a cohort that large is necessary. Committee member Richard Lange, MD, from the University of Texas Health Science Center, said finishing the 5-year randomized control trial would provide enough results for the paclitaxel-eluting stent. "I am less convinced that the long-term data will give us any information we don't have already," Lange said during the meeting. "I think the current study going on for 5 years probably tells us enough about stent thrombosis."

John C. Somberg, MD, a panel member from Rush University Medical Center, said a larger study would provide the sponsor with more sufficient data. He suggested continuation of the cohort study, but added that the committee "should advance the idea that there is need for a larger study follow-up that can look for smaller effects, such as stent thrombosis and … whether diabetics are equally benefited from the stent [as are] other populations, such as females.

Other recommended additions for post-approval study included inclusion of bleeding risks and the addition of more women and patients with diabetes.

Although the FDA is not required to follow the recommendations of the advisory committees, it usually does.

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CHD remains leading cause of death in Americans, despite recent decline


Although self-reports of coronary heart disease have declined from 2006 to 2010, CHD remains the leading cause of death in the US, with rates varying from state to state and by race and ethnicity, according to recent data published in the CDC’s Morbidity and Mortality Weekly Report.

“We’re all at risk for heart disease and stroke,” Jing Fang, MD, epidemiologist in the CDC’s Division of Heart Disease and Stroke Prevention, said in a press release. “People of all ages, genders, races and ethnicities are affected. However, certain groups, including American Indians/Alaska natives, African Americans and older adults, are at higher risk than others.”

CDC researchers analyzed data from Behavioral Risk Factor Surveillance System surveys conducted between 2006 and 2010, a state-based, random digit-dialed telephone survey of the US civilian, noninstitutionalized population aged 18 years or older. Administered in all 50 states, the District of Columbia, and the US territories of Guam, Puerto Rico and the US Virgin Islands, the survey estimates state-specific CHD prevalence and recent trends by age, sex, race/ethnicity and education.

Overall, the number of participants who reported being told they have CHD by a health care professional declined from 6.7% to 6%. By 2010, participants aged 65 years and older had a higher CHD prevalence (19.8%) vs. participants aged 45 to 64 years (7.1%) and 18 to 44 years (1.2%). CHD prevalence was also greater in participants with less than a high school education (9.2%) vs. high school graduates (6.7%), participants with some college education (6.2%) and participants with a college degree (4.6%).

Among the states, age-adjusted CHD prevalence from 2006 to 2010 showed the greatest declines in West Virginia (23.1%; from 10.4% to 8%) and Missouri (22.1%; from 7.7% to 6%). By 2010, CHD prevalence by state varied widely, from 3.7% in Hawaii and 3.8% in Washington, D.C. to 8% in West Virginia and 8.2% in Kentucky. Researchers generally observed the greatest regional prevalences in the South.

Declines among racial/ethnic populations from 2006 to 2010 were observed among whites (6.4% to 5.8%) and Hispanics (6.9% to 6.1%). CHD prevalence was greatest among American Indians/Alaska natives (11.6%), followed by blacks (6.5%), Hispanics (6.1%), whites (5.8%), and Asians or native Hawaiians/ Pacific Islanders (3.9%). Analysis of race and sex revealed that in 2010 American Indian/Alaska natives (14.3%) and whites (7.7%) had the greatest CHD prevalence among men, while American Indian/Alaska natives (8.4%) and blacks (5.9%) had the greatest CHD prevalence among women.

Fang J. MMWR. 2011;60:1377-1381.

[Chevychelov]

FDA proposes lower risk classification for external pacemakers

The FDA has issued a proposed rule and draft special controls guidance lowering the risk classification for external pacemaker pulse generators from Class III to Class II.

External pacemaker pulse generators were placed on the market before the Medical Device Amendments Act of 1976, making them a pre-amendment device still being reviewed under premarket notification because the FDA did not issue regulations requiring applications for premarket approval. The FDA has proposed general controls and special controls, making external pacemaker pulse generators safer and more effective for the temporary treatment of regulating heartbeat and controlling irregular heartbeats.

"The FDA has assessed the benefits and risks of external pacemaker pulse generators," Christy Foreman, director of the Office of Device Evaluation at the FDA's Center for Devices and Radiological Health, said in a press release. "The special controls outline in this draft guidance, along with general controls, will assure the safety and efficacy of these devices and provide manufacturers with a more predictable path to market."

The proposed rule and draft special controls guidance provide manufacturers with clarity and specific guidance on what information is needed in a premarket notification for external pacemaker pulse generators, although it will not significantly change the FDA's review of the product.
__________________________________________________ ___________________________
Same-day discharge after PCI not associated with higher risk for death, rehospitalization

Rao S. JAMA. 2011;306:1461-1467.

Among selected low-risk Medicare patients who underwent an elective percutaneous coronary intervention, same-day discharge was rarely implemented, but was not associated with an increased risk for death or rehospitalization at 2 days or at 30 days when compared with patients who remained in the hospital overnight, according to a recent study published in the Journal of the American Medical Association.

“Risks associated with PCI are highest within the first 24 to 48 hours after the procedure,” according to background information in the article. “However, short- and long-term outcomes after PCI have improved because of the evolution in device technology and pharmacotherapy. Despite this improvement, patients are usually observed overnight in the hospital after elective PCI to monitor for PCI-related complications.”

Sunil V. Rao, MD, of the Duke Clinical Research Institute, and colleagues examined the prevalence of same-day discharge among older individuals following PCI and the rates of death or rehospitalization. The study included data from more than 107,000 patients aged 65 years and older who underwent elective PCI procedures at 903 sites participating in the CathPCI Registry between November 2004 and December 2008; these data were linked with Medicare Part A claims. Patients were divided into two groups based on length of stay at the hospital after PCI: same-day discharge or overnight stay.

Overall, the prevalence of same-day discharge was 1.25% (n=1,339), with significant variation across facilities. Rates of procedural success were not significantly different between the two groups. Patient characteristics were similar with same-day discharge vs. overnight stay, although same-day discharge patients underwent shorter procedures with less multivessel intervention. Patients who were discharged the same day as surgery were more often categorized in the lowest quintile of predicted risk for death or rehospitalization, while there were approximately equal proportions of lower- and higher-risk patients observed overnight, according to a JAMA press release.

The researchers found no significant differences in rates of death or rehospitalization at 2 days (same-day discharge 0.37% vs. overnight stay 0.5%) or at 30 days (same-day discharge 9.63% vs. overnight stay 9.7%). Additionally, median time to death or rehospitalization did not differ significantly between the two groups in patients with adverse outcomes (same-day discharge 13 days vs. overnight stay 14 days). When the researchers adjusted for patient and procedure characteristics, same-day discharge was not associated with death or rehospitalization at 30 days.

The researchers noted, however, that despite the apparent safety of same-day discharge for selected patients, this approach is rarely practiced at sites represented in the National Cardiovascular Data Registry. “This may reflect reluctance on the part of clinicians to discharge patients the same day as the PCI procedure because of concerns over early post-PCI complications. Although these concerns are well founded, the rates of vascular or bleeding complications were extremely low (less than 1%) among the patients in our analysis, with no clinically significant differences between groups,” the researchers wrote.

They added, that according to published guidelines, same-day discharge can be considered for patients undergoing PCI who have low-risk clinical features, successful procedures without prolonged postprocedure use of parenteral (by injection) antithrombotic agents, and adequate social support.

[Chevychelov]

Sharp Drop in Heart Failure Admissions, First Ever

By Crystal Phend, Senior Staff Writer,
October 18, 2011

Action Points
Explain that a Medicare claims analysis found admissions for heart failure over the period from 1998 to 2008 decreased significantly, although less in black men than in other groups.


Note that one-year mortality following heart failure hospitalization also decreased significantly during this same period but by a more modest percentage.
Review
Heart failure hospitalizations dropped 29.5% nationally over the past decade, largely because fewer patients were admitted rather than fewer admissions per patient, researchers found.

The risk-adjusted rate of heart failure hospitalization fell from 2,845 to 2,007 per 100,000 person-years from 1998 to 2008 (P<0.001) in a fee-for-service Medicare claims analysis by Jersey Chen, MD, MPH, of Yale University, and colleagues.

That decline -- the first ever documented in the U.S. -- likely saved $4.1 billion in Medicare costs since 1998, they reported in the Oct. 19 issue of the Journal of the American Medical Association.


Lower incidence of heart failure risk factors; modest improvements in blood pressure control; better use of evidence-based therapies; and a shift toward outpatient management of heart failure may have been contributing factors, the group suggested.

The main reason for the drop in hospitalizations was fewer unique patients hospitalized for heart failure, down from 2,014 per 100,000 in 1998 to 1,462 per 100,000 in 2008.

One-year mortality after heart failure hospitalization also dropped modestly by a relative 6.6% over the same period, from a risk-adjusted rate of 31.7% to 29.6% (P<0.001).

That is good news, according to Clyde W. Yancy, MD, of Northwestern University in Chicago and a past president of the American Heart Association.

"Research, implementation of best practices, and quality-focused initiatives, such as Get With The Guidelines, have had a positive return on investment," he said in a statement to MedPage Today.

An accompanying editorial also pointed to the results as a sign of hope, though with plenty of room for improvement.

The "persistently" and "unacceptably" high one-year mortality rates suggested a need for immediate attention to heart failure postdischarge practices, wrote Mihai Gheorghiade, MD, of Northwestern University, and Eugene Braunwald, MD, of Brigham and Women's Hospital and Harvard in Boston.

They suggested the following strategies:
Using more aggressive treatment for subclinical congestion
Taking a mechanistic approach to underlying cardiac abnormalities
Boosting use of digoxin and mineralocorticoid antagonists
Scheduling an early postdischarge visit


"There is more work to be done," agreed Ralph Brindis, MD, immediate past-president of the American College of Cardiology, in a statement. While overall trends are on the right track, not all groups benefited equally, he noted.

When Chen's group analyzed all heart failure hospitalizations nationally in a complete sample of Medicare fee-for-service claims from 1998 to 2008, they found that all sex and race groups showed reductions in heart failure hospitalizations.

But black men had the lowest rate of decline, with heart failure hospitalizations falling from 4,142 to 3,201 per 100,000 person-years over the study period. This improvement was a significant 19% less than other groups after adjusting for age.

The rates didn't fall evenly across states either.

Heart failure hospitalization changes happened significantly slower than the national mean in three states: Connecticut, Rhode Island, and Wyoming. One-year mortality rates actually increased in five states: South Dakota, Arizona, Alaska, Louisiana, and Kentucky.

"We must continue to work to understand the causes of these disparities in outcomes and continue to apply what we learn through research to improve care and prevention across the board," Brindis said in the statement.

The researchers cautioned that the study could not determine causality for any of the findings.

Other limitations were sole inclusion of a Medicare population, which may differ in heart failure hospitalization and mortality trends from a younger population with different insurance, and use of administrative codes not confirmed clinically.

[Chevychelov]

No First Trimester Pregnancy Risk for ACE Inhibitors

By Todd Neale, Senior Staff Writer,
October 18, 2011

Action Points
Explain that it is likely that any teratogenic effects previously attributed to ACE inhibitors taken during the first trimester of pregnancy are the result of the underlying hypertension and not the medications themselves.

Note that untreated hypertension was associated with greater risks of any malformation, congenital heart defects, and neural tube defects.
Review

It is likely that any teratogenic effects previously attributed to ACE inhibitors taken during the first trimester of pregnancy are the result of the underlying hypertension and not the medications themselves, researchers found.

Compared with women who did not have hypertension, use of either ACE inhibitors or other anti-hypertensives in the first trimester was associated with greater odds of any malformation when the child was born (ORs 1.20 and 1.22, respectively), according to De-Kun Li, MD, PhD, of Kaiser Permanente's Division of Research in Oakland, Calif., and colleagues.

However, the presence of hypertension in the absence of drug treatment was also associated with greater odds of any malformation (OR 1.25, 95% CI 1.19 to 1.31), the researchers reported online in BMJ.

Compared with women who had untreated hypertension, those exposed to either ACE inhibitors or other anti-hypertensives were not more likely to give birth to a child with a malformation.

"Our finding suggests that it is likely the underlying hypertension, rather than use of anti-hypertensive drugs in the first trimester, that increases the risk of malformations in offspring," Li and colleagues wrote.

ACE inhibitors have been designated by the FDA as category D drugs -- meaning that they carry known fetal risks -- when used during the second and third trimesters of pregnancy. The effects of ACE inhibitors during the first trimester are not as well known, however.

A 2006 study raised concerns about an increased risk of congenital anomalies when ACE inhibitors, but not other anti-hypertensives, were used during the first trimester, although two subsequent analyses failed to find such an association consistent with the current study.

"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other anti-hypertensives," wrote Allen Mitchell, MD, of Boston University, in an accompanying editorial.

Li and colleagues examined data from 465,754 mothers and their offspring born from 1995 to 2008 within the Kaiser Permanente Northern California region.

During the study period, the prevalence of ACE inhibitor use in the first trimester was only 0.9 per 1,000 pregnancies. The rate for other anti-hypertensives was 2.4 per 1,000.

Among women who did not have hypertension, the rate of congenital malformation was 5.4%. The rate was higher for women who took an ACE inhibitor during the first trimester (8.5%), those who took any other anti-hypertensive (6.9%), and those with untreated hypertension (7.2%).

After adjustment for maternal age, ethnicity, parity, pre-existing diabetes, and overweight, that worked out to a 20% to 25% greater relative risk of birth defects across those three groups. The risk did not differ, however, between the medication groups and the untreated hypertension group.

The researchers then looked into two specific malformations: congenital heart defects and neural tube defects.

The results of the analysis for congenital heart defects mirrored those from the analysis looking at overall malformations, with increased relative risks of 41% to 54% among women taking ACE inhibitors, those taking other anti-hypertensives, and those with untreated hypertension when compared with women without hypertension.

Similarly, when the comparison group was women with untreated hypertension, use of ACE inhibitors or other anti-hypertensives during the first trimester only was not associated with an increased risk of congenital heart defects.

The use of ACE inhibitors or other anti-hypertensives was not associated with neural tube defects, although untreated hypertension carried a higher risk compared with the nonhypertensive controls (1% versus 0.6%; OR 1.43, 95% CI 1.26 to 1.62).

The authors noted some limitations of the study, including unknown compliance to dispensed medications, the inability to track prescriptions filled outside of the Kaiser Permanente system, and the limited information on the characteristics of women with treated and untreated hypertension.

[Chevychelov]

Biomarker Levels May Be Key to Heart Failure Decline

By Chris Kaiser, Cardiology Editor,
October 18, 2011

Action Points
Note that current treatment of chronic CHF due to left ventricular systolic dysfunction consists of the use of beta-adrenergic blockers and vasodilators, with the addition of aldosterone blockade or cardiac resynchronization therapy for those with persistent symptoms. Therapy is guided by ascertainment of clinical stability and volume status.


Note also that persistently elevated levels of NT-proBNP have been shown to be predictive of poor outcomes.


Point out that this study demonstrates that biomonitoring of NP-proBNP levels in combination with aggressive treatment based upon results can lead to significantly improved outcomes in patients with CHF.
Review
Monitoring levels of amino-terminal pro–B-type natriuretic peptide (NT-proBNP) and keeping them below a certain threshold proved to be more beneficial for heart failure patients than the standard of care, the PROTECT study found.

Those in the NT-proBNP monitoring arm had significantly fewer cardiovascular events (58 versus 100, P=0.009) at a mean follow-up of 10 months, James L. Januzzi Jr., MD, from Massachusetts General Hospital in Boston, and colleagues reported.

In addition, patients in the biomarker-monitored arm had fewer events per patient (0.77 versus 1.3, P=0.03) and a longer duration before their first event, according to the study in the Oct. 25 Journal of the American College of Cardiology.


At an interim analysis of the 151 patients thus far enrolled in PROTECT (75 in the NT-proBNP arm), the recommendation was made to stop enrollment because of a statistically significant reduction in the primary endpoint of total cardiovascular events favoring the NT-proBNP arm.

"We found a remarkable reduction in heart failure complications, primarily driven by improvements in worsening heart failure [27 versus 54, P=0.001] and reduced heart failure hospitalizations [11 versus 27, P=0.002]," Januzzi told MedPage Today in an interview.

"NT-proBNP levels are powerfully prognostic and allow therapeutic changes in those at highest risk. This is a very necessary step toward personalized healthcare in the heart failure space," Januzzi said.

The standard drug therapy for patients with chronic heart failure due to left ventricular systolic dysfunction (ejection fraction ≤40%) includes beta-adrenergic blockers and vasodilators, with the addition of an aldosterone blockade or cardiac resynchronization therapy reserved for those with persistent symptoms, Januzzi and colleagues wrote.

They also noted that "ascertainment of clinical stability and volume status in chronic heart failure can be challenging in inexperienced hands," and managing medication dosage is often suboptimal.

With that background, the investigators initiated the PROTECT (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting) study, a single-center randomized controlled trial.

The goal in the interventional arm was to lower NT-proBNP levels to 1,000 pg/mL or below and sustain them there.

The primary clinical endpoint was total cardiovascular events, which was a composite of worsening heart failure, hospitalization for heart failure, clinically significant ventricular arrhythmia, acute coronary syndromes, cerebral ischemia, and cardiac death.

The mean age of patients was 63 years, with 21% older than 75. The older patients averaged slightly more clinic visits than the younger patients (7.5 versus 5.0), and those in the NT-proBNP arm averaged one more clinic visit than those in the standard-of-care arm (6.0 versus 5.0).

Investigators saw a similar average therapy adjustment between the two arms (7 versus 6), but noted that those in the interventional arm had more aggressive dosing changes.

Levels of the biomarker were similar at baseline between the two arms, but declined significantly by the end of the study for those in the NT-proBNP arm (2,344 to 1,125 pg/mL, P=0.01) compared with the standard of care (1,946 to 1,844 pg/mL, P=0.61).

Researchers found a linear relationship between the levels of NT-proBNP and events. Those below 1,000 pg/mL had the lowest mean frequency of events (0.45 events) compared with those between 1,000 and 2,000 pg/mL (1.1 events), between 2,000 and 3,000 pg/mL (1.25 events), and above 3,000 pg/mL (2.0 events) (P<0.001 for trend).

Those in the interventional arm also reported higher quality of life scores. "Not only did they have fewer events, but they also felt better and had favorable reverse cardiac remodeling as seen with echocardiography," Januzzi said.

In an accompanying editorial, Alan Maisel, MD, from the VA San Diego Healthcare System, wrote that PROTECT proves that lowering NT-proBNP levels is "indeed possible, is safe (the kidneys still work, the blood pressure is fine), and may lead to more benefits compared with simple non-biomonitored up-titration of therapies."

Despite the study being single-center and unblinded, it had "strong adherence to study protocol with consistent biomonitoring of NT-proBNP levels, allowing aggressive therapeutic efforts at NT-proBNP lowering," Maisel said.

Because of the relatively small sample size, brief duration of follow-up, and rigorous protocols, these results must be proven in a real-world setting, Maisel said.

In fact, Januzzi said the researchers are readying for a larger multicenter randomized trial. In addition, he and others are researching home-based finger-prick NT-proBNP testing.

[Chevychelov]

Bariatric Surgery Benefits the Whole Family

By Kristina Fiore, Staff Writer,
October 18, 2011

Action Points
Explain that a study found that obese relatives living with a patient who undergoes bariatric surgery had a significant drop in weight a year after the procedure.


Note that adult family members improved their eating habits, with significantly less uncontrollable eating and emotional eating.
Review
When one family member has bariatric surgery, the others lost weight as well, researchers found.

Obese relatives living with the surgery patient had a significant drop in weight a year after the procedure (P=0.01), John Morton, MD, PhD, of Stanford University, and colleagues reported in the October issue of the Archives of Surgery.

Bariatric surgery may be able to "induce weight loss and healthy behaviors in people surrounding the patient," they wrote.

Studies have shown that weight loss is socially contagious, they explained, since spouses who enroll in weight loss programs together tend to shed more pounds, as do those who join a support group.


Thus, if one family member makes lifestyle changes after surgery, it's possible that other family members will do so as well, Morton and colleagues wrote.

They looked at changes in weight and healthy behaviors in 35 patients who had Roux-en-Y gastric bypass, along with 35 adult family members and 15 children, in a single-center, prospective, longitudinal study between Jan. 1, 2007, and Dec. 31, 2009.

Family members were required to attend three patient preoperative educational sessions and all postoperative visits where lifestyle modification was emphasized.

Before the operation, 60% of adult family members and 73% of children were obese.

The researchers found that the mean weight of adult family members fell overall, from 220 lbs. to 198 lbs., but the decline wasn't significant.

However, when family members were divided up based on their level of obesity before the surgery, there was a significant drop in weight for obese adults after one year -- from 234 lbs. to 226 lbs. (P=0.01).

There was also a significant decline in waist circumference for this group, from 119 cm to 111 cm (P=0.03).

As expected, children gained weight in the year after surgery, due to natural growth. Yet their expected one-year mean body mass index (BMI) was higher than the observed one-year BMI, the researchers reported.

In obese children, the expected BMI of 31.2 was higher than the observed BMI of 29.6, but the trend wasn't significant.

In kids who weren't obese, the expected BMI was lower than the observed BMI, they added, and waist circumference remained the same in all children.

Kids did have small but non-significant increases in quality of life, as well as non-significant declines in the number of hours spent in front of the TV.

Similarly, they significantly increased their physical activity levels (P=0.04), as did adult family members (P=0.005).

Adults also improved their eating habits, with significantly less uncontrollable eating (P=0.01) and emotional eating (P=0.04) at one year.

They also drank less alcohol, falling from 11 drinks per month to just one drink per month (P=0.009).

"These data suggest that following surgery, family members were conscious of and attempting to limit maladaptive eating patterns," they wrote.

They concluded that "having a family member undergo weight loss surgery is a powerful reminder for dietary modification."

They added that bariatric surgery programs should encourage family members to participate in patient support groups and education sessions in order to "capitalize on the halo effects" of the procedure.

[Chevychelov]

Obesity, Diabetes and Poverty Share a Common Zip Code

By Kristina Fiore, Staff Writer,
October 19, 2011

Action Points
Explain that helping people move out of poor neighborhoods into those that are better off may help reduce levels of obesity and diabetes.


Note that in a dose-response model, adults who spent more time in lower-poverty housing had greater improvements in diabetes and BMI outcomes.
Review
Helping people move out of poor neighborhoods into those that are better off may help reduce levels of obesity and diabetes, researchers found.

In a large social experiment, people who used vouchers to move to an area with better socioeconomic conditions were significantly less likely to have a high body mass index (BMI) and elevated glycated hemoglobin (HbA1c) levels than those who remained in poor neighborhoods, Jens Ludwig, PhD, of the University of Chicago, and colleagues reported in the Oct. 20 issue of the New England Journal of Medicine.


Moving from high-poverty to low-poverty areas is associated "with modest but potentially important reductions in the prevalence of extreme obesity and diabetes," Ludwig and colleagues wrote.

Researchers have long questioned whether a person's neighborhood directly contributes to the development of obesity and diabetes. Observational studies have shown that neighborhood factors such as poverty or racial separation are associated with greater risks of these conditions.

To look more closely at the association, Ludwig and colleagues looked at data from a Department of Housing and Urban Development (HUD) program conducted between 1994 and 1998.

The department randomly assigned 4,498 women with children who were living in public housing in high-poverty urban areas to one of three groups:
1,788 received rent-subsidy housing vouchers earmarked for a move to a low-poverty area, as well as counseling 'to help with their housing search'
1,312 got rent-subsidy vouchers with no requirement as to where they could live and no special counseling
1,398 were assigned to a control group that wasn't offered either opportunity


The researchers then looked at participants' health outcomes -- including height, weight, and HbA1c levels -- between 2008 and 2010.

Overall, 48% of the families given the vouchers to move to a low-poverty area used them; 63% used the no-restriction vouchers.

Ludwig and colleagues found that using a voucher to move to a low-poverty area was associated with a decreased risk of extreme obesity and diabetes among the female heads-of-households.

Among these women there was a significantly lower prevalence of the following factors than in the control group:
BMI of 35 or higher, absolute difference of 4.61 percentage points (P=0.02), relative reduction of 13%
BMI of 40 or higher, absolute difference of 3.38 percentage points (P=0.03), relative reduction of 19.1%
HbA1c of 6.5% or higher, absolute difference of 4.31 percentage points (P=0.02), relative reduction of 21.6%

There were no significant differences between those in the traditional voucher group and controls.

The difference in outcomes between the two voucher groups wasn't significant for any BMI threshold, but there was a trend toward a significant difference in the prevalence of HbA1c 6.5% or higher at P=0.05, the researchers reported.

This finding suggests that low-poverty vouchers and traditional ones have different associations with neighborhood attributes that may affect health, they wrote.

In a dose-response model, adults who spent more time in lower-poverty housing had greater improvements in diabetes and BMI outcomes, they added.

The study was limited by loss to follow-up, lack of baseline health information, and because subjects volunteered to participate.

Still, the researchers concluded that the results "raise the possibility that clinical or public health interventions that ameliorate the effects of neighborhood environment on obesity and diabetes could generate substantial social benefits."

The mechanisms underlying the associations are unclear and warrant further investigation, they added.