Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

FDA Reviewer Slams Xarelto for Stroke Prevention in Afib

By Emily P. Walker, Washington Correspondent,
Reviewed by
September 06, 2011

Review

WASHINGTON -- Rivaroxaban (Xarelto) is not as effective as warfarin for preventing strokes in patients with atrial fibrillation and should not be approved for the new indication, according to an FDA reviewer.

That opinion was set forth in briefing documents prepared for the FDA's Cardiovascular and Renal Drugs Advisory Committee meeting Thursday. The committee will review Johnson & Johnson's application to extend marketing approval for its direct oral factor Xa inhibitor rivaroxaban to include prevention of stroke and systemic embolism in patients with nonvalvular approved atrial fibrillation.

But, in its briefing documents the company argued that the "benefits of treatment with rivaroxaban clearly outweigh the risks when compared with warfarin therapy."

Results from the company-sponsored ROCKET-AF study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use. Johnson & Johnson is seeking approval that indicates their drug works better at preventing strokes than warfarin.

But the briefing documents held no joy for J & J as one of the three FDA reviewers concluded that the company failed to prove that rivaroxaban was superior to warfarin for stroke prevention. The reviewer is recommending that the agency issue a complete response letter to the company rather than approve the new indication. Rivaroxaban is approved for prevention of DVT in patients undergoing joint replacement surgery.

The FDA reviewers pored over results from the ROCKET-AF study, which enrolled more than 14,000 adults with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. Patients were evenly randomized to 20 mg of rivaroxaban daily or to warfarin. The primary endpoint was time to a composite endpoint of stroke or systemic embolism.

The time period for the primary efficacy endpoint was any thrombotic events occurring while the patient was "on treatment," which was defined as last dose plus two days. By that standard, rivaroxaban was superior to warfarin (P=0.01).

But there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin. It was, however, shown to work at least as well as warfarin.

After the ROCKET-AF study was completed, the company developed instructions detailing a treatment plan for transitioning patients from rivaroxaban to warfarin, but those instructions haven't been evaluated. A study testing how to transition patients would have to be done before rivaroxaban could be approved, according to the FDA reviewer.

The FDA requires that drugs approved for life-threatening conditions -- such as stroke -- be shown to be at least as effective as other available drugs. But as the FDA reviewer pointed out, the agency "generally prefer[s] an intention-to-treat analysis as the basis of a superiority claim."

Additionally, according to the FDA reviewer, the per-protocol analyses where rivaroxaban came out a winner is "misleading" because improper dosing of warfarin may have been to blame. The company did not show that when warfarin -- which is notoriously tricky to correctly dose -- is used "skillfully" that rivaroxaban would work any better, the reviewer said.

"Thus, the data do not convincingly demonstrate that rivaroxaban is as effective in preventing strokes and systemic emboli as warfarin when warfarin is used skillfully," the reviewer said.

Another warfarin study -- RE-LY -- found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin (and that study did a better job at correctly dosing warfarin, the reviewer said). Last October, dabigatran received marketing approval for prevention of stroke in patients with nonvalvular atrial fibrillation.

The reviewer noted that there are no data available from a rivaroxaban versus dabigatran match-up, and left open the question of whether such a study was in order.

In its briefing documents, the company stressed the ease of use and management of rivaroxaban, which does not require INR monitoring, nor does it require dietary restrictions -- both of which are required with warfarin therapy.

"Additional medications such as rivaroxaban would give the physician a wider range of therapeutic options that can be tailored to the individual patient," the company said.

But the FDA reviewer didn't see approval as a benefit for patients: If rivaroxaban is approved, he wrote, "patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully."

"In the opinion of this reviewer, rivaroxaban should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully or that it is as safe and effective as another approved agent, such as dabigatran," the reviewer said.

Despite the overwhelmingly negative tone of the FDA review, there were no new safety issues uncovered, the reviewers said.

In fact, rivaroxaban-treated patients experienced numerically fewer critical organ bleeds, intracranial hemorrhages, hemorrhagic strokes, and fatal bleeds compared with patients treated with warfarin.

The Cardiovascular and Renal Drugs Advisory Committee will vote Thursday afternoon on whether rivaroxaban should be approved, and, if so, whether its label should state it works better than warfarin at preventing strokes.

[Chevychelov]

Elevated cathepsin S serum levels linked with increased risk for death

Jobs E. JAMA. 2011;doi:10.1001/jama.2011.1246.

Higher serum cathepsin S levels are associated with an increased mortality risk among elderly patients, according to a study.

In a prospective study using two community-based cohorts — the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) — serum samples were used to measure cathepsin S. Both studies took place in Uppsala, Sweden. ULSAM was initiated in 1970 and had 1,009 participants. PIVUS took place between 2001 and 2004 and had 987 participants.

Anthropometrical measurements, BP, blood sampling and questionnaires regarding socioeconomic status, medical history, smoking habits, medication use and physical activity level were investigated by researchers in both studies. Serum levels of cathepsin S, inflammatory markers and cystatin C were all measured by an enzyme-linked immunosorbent assay. Both studies used Cox proportional hazard regression and three multivariable models to find associations of serum level of cathepsin S with total mortality. The ULSAM study included CV and cancer mortality.

When adjusted for age, systolic BP, diabetes, smoking status, BMI, total cholesterol, HDL, antihypertensive treatment, lipid-lowering treatment and history of CVD, Cox regression models showed that higher serum cathepsin S was associated with an increased risk for mortality. Cathepsin S was also associated with an increased mortality risk for CV and cancer mortality in the ULSAM cohort. In a follow-up, 413 participants in the ULSAM cohort died of CVD (131 deaths) and cancer (148 deaths), whereas 100 participants in the PIVUS cohort died. Incidence rate per 1 unit increase of cathepsin S was 0.44/100 person-years at risk in ULSAM, and 0.15/100 person-years at risk in PIVUS. Total mortality after adjustment for age, sex, lifestyle factors and established CV risk factors had an HR of 1.04 in ULSAM and 1.03 for PIVUS. In ULSAM, CV mortality had an HR of 1.05 and cancer mortality had an HR of 1.06.

__________________________________________________ _______________________________

Review: Single cryoballoon ablation procedure in patients with paroxysmal and persistent AF yields mixed results

Andrade J. Heart Rhythm. 2011;doi:10.1016/j.hrthm.2011.03.050.

A single cryoballoon ablation procedure results in high acute and medium-term efficacy rates for paroxysmal atrial fibrillation and lower success rates when used as stand-alone therapy for persistent atrial fibrillation, according to a systematic review.

Researchers conducted a literature search using Medline, Embase and Biosis for abstracts specifically referencing cryoballoon for AF ablation. According to researchers, the search was limited to adults aged at least 19 years and publications dated between January 2000 and January 2011, but the language was not restricted to English. Overall, 23 articles were retained for final analysis: 20 reporting cryoballoon for paroxysmal AF, one reporting cryoballoon ablation for persistent AF, and two reporting cryoballoon ablation for both paroxysmal and persistent AF.

Results show that the ablation procedure was performed exclusively with cryoballoon in nine of 23 studies. Cryoballoon was combined with focal ablation in the remaining 14 studies in up to 17.1% of patients. Of 23 studies, 91.67% to 100% of patients and 94.87% to 100% of targeted veins had acute procedural success. Complete pulmonary vein isolation resulted in 77.81% of patients who underwent ablation with the cryoballoon catheter alone (95% CI, 74.99-80.45) and 92.64% of targets veins (95% CI, 91.76-93.45). In studies with cryoballoon ablation combined with concomitant focal cryoablation, 98.85% of patients (95% CI, 97.69-99.54) and 98.24% of targeted veins (95% CI, 97.69-98.68) achieved complete pulmonary vein isolation.

In 1-year freedom from recurrent AF off antiarrhythmic drug, there was a 73% 3-month blanking period and 60% no blanking period in patients with paroxysmal AF, whereas cryoballoon-based pulmonary vein isolation alone for persistent AF resulted in a 1-year freedom from AF of 45%, according to researchers. Researchers also found evidence that catheter ablation of persistent and permanent AF may require more extensive ablation beyond pulmonary vein isolation vs. paroxysmal AF. Treating paroxysmal AF with focal point-by-point radiofrequency ablation has shown success, but complications that included cardiac perforation with pericardial tamponade, injury to esophagus, phrenic nerve and aorta, and pulmonary vein stenosis were reported in 5% to 6% of patients.

[Chevychelov]

Panel Endorses Xarelto for Stroke Prevention

ADELPHI, Md. -- An FDA advisory committee has voted 9-2, with one abstention, to recommend that the FDA approve the direct oral factor Xa inhibitor rivaroxaban (Xarelto) to prevent stroke in patients with atrial fibrillation.

The overwhelmingly positive endorsement by the FDA's Cardiovascular and Renal Drugs Advisory Committee came just two days after the release of briefing documents prepared by an FDA reviewer -- documents that assailed the efficacy and safety of the drug.

Johnson & Johnson, which partnered with Bayer to develop rivaroxaban, had already secured marketing approval for the direct oral factor Xa inhibitor to prevent deep vein thrombosis in patients undergoing joint replacement surgery. In the application reviewed by the panel Thursday the company sought to extend marketing approval to include the stroke prevention indication.

The advisory committee spent most of the day reviewing J&J's ROCKET-AF study of more than 14,000 patients with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. The study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.

If the FDA approves rivaroxaban, J&J would like to claim that their drug does work better than warfarin because ROCKET-AF showed the drug worked better than warfarin in patients when success was measured two days after the patients stopped taking rivaroxaban. (P=0.01).

However, there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin.

"Clearly it is not superior to warfarin," said panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles

Warfarin, an inexpensive drug, is a mainstay in stroke prevention. But it's notoriously tricky to dose and requires INR testing to get it right as well as dietary restrictions to keep it right, which makes warfarin unpopular with many patients -- and many physicians.

The rivaroxaban, on the other hand, is one 20 mg pill a day, and neither INR monitoring nor dietary restrictions are required.

Panelists voiced concerns about a spike in adverse events seen when patients stopped taking rivaroxaban and were transitioned to warfarin at the end of the study.

Panelist Steven Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic, who was one of the two panel members who voted against recommending approval for rivaroxaban, said it's very common to interrupt anticoagulant treatment.

"Although warfarin is a drug we love to hate, its treatment effects are slow and it's forgiving," he said. By comparison "the first few days you stop rivaroxaban, pretty bad things happen. We haven't studied that. And it makes me concerned."

Most panelists favored requiring J&J to perform a postmarketing study to examine what is the safest way to transition patients off rivaroxaban onto a new drug. Several panelists wanted that study done before the FDA approved the drug.

But physicians who work for J&J said the adverse events observed in the study wouldn't be mirrored in the real world because patients generally don't just stop taking a blood thinner cold-turkey as they did in the study. In the "real world," patients are transitioned more seamlessly onto a different anticoagulant, the company said.

An FDA reviewer and panelists were also concerned that warfarin wasn't administered ideally in the trial, causing rivaroxaban to appear more effective than it may have been had warfarin been dosed properly. Just 56% of patients who received warfarin in the ROCKET-AF were in the ideal INF range of 2 to 3 during the study, which the panel criticized as being way too low.

"INR control in ROCKET was worse than in other recent trials, which might have biased the overall results in favor of rivaroxaban," said FDA reviewer Martin Rose, MD, who authored a highly critical review of rivaroxaban that was released several days before Thursday's meeting.

One of those recent trials is the RE-LY trial, which found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin.

But panel chairman Michael Lincoff, MD, another cardiologist from the Cleveland Clinic, said the spotty warfarin dosing in ROCKET-AF was acceptable because it was similar to how warfarin is used outside of clinical trials.

Dabigatran was a constant topic of conversation at the meeting, with panelists and the FDA making comparisons between rivaroxaban and dabigatran, despite the fact that no trial has yet been conducted pitting the two anticoagulants head-to-head.

"Any current expert will say it's important to do head-to-head clinical trials," said Robert Califf, MD, director of Duke University's Translational Medicine Institute and a principal investigator in the ROCKET-AF trial.

Some panelists questioned the need for another blood thinner that was shown to be noninferior to warfarin, when dabigatran was shown to be superior to warfarin.

But others at the meeting -- including a patient representative -- said more oral anticoagulants are needed because warfarin is not always well-tolerated and dabigatran can cause gastrointestinal side effects.

"All afib patients are aware of the three drugs we need to take," said patient representative Debra McCall of California. "A drug to regulate rhythm, a drug to regulate rate, and a blood thinner. We have options for rate and rhythm, but we don't have many options for blood thinners."

Following the committee vote the American Heart Association released a statement noting it will review its guidelines for anticoagulation therapy in patients with nonvalvular atrial fibrillation if the FDA does decide to approve the drug for stroke prevention in that population.

"For the millions of patients with atrial fibrillation, stroke is a real health threat, and the emerging studies of new anticoagulant drugs like rivaroxaban have been very encouraging," said Gordon Tomaselli, MD president of the American Heart Association.

The FDA is expected to make an approval decision on rivaroxaban by Nov. 4. The agency isn't required to follow the advice of its advisory committees, but it often does.

[Chevychelov]

Statin-Hemorrhage Link Disputed

By Todd Neale, Senior Staff Writer, September 12, 2011

Explain that a new retrospective cohort study found no association between statin use and intracerebral hemorrhage in patients with an ischemic stroke in contrast to other trial results.

Note that the risk of recurrent ischemic stroke was reduced for statin users in all of the recent studies including this one.
Review

Statins do not appear to be associated with a greater risk of intracerebral hemorrhage in patients who have had an ischemic stroke, a retrospective cohort study showed.

In fact, through about four years of follow-up, the rate of intracerebral hemorrhage was slightly lower in the statin users (2.94 versus 3.71 per 1,000 patient-years), according to Daniel Hackam, MD, PhD, of the University of Western Ontario in London, and colleagues.

The difference was not significant (HR 0.87, 95% CI 0.65 to 1.17), they reported online in Archives of Neurology.

The findings contrast with a post hoc analysis of the SPARCL (Stroke Prevention by Aggressive Lowering of Cholesterol Levels) trial, which found that the significant decrease in recurrent ischemic stroke with atorvastatin (Lipitor) was accompanied by a greater risk of hemorrhagic stroke (2.3% versus 1.4%).

The Heart Protection Study also suggested a greater risk of hemorrhagic stroke with statins in patients with a history of cerebrovascular disease (1.3% versus 0.7%).

A recent meta-analysis from the Cholesterol Treatment Trialists' Collaboration, however, showed no significant association between statin use and intracerebral hemorrhage, Hackam and colleagues noted.

In an accompanying editorial, Philip Gorelick, MD, MPH, of the University of Illinois in Chicago, said the discrepancy in findings from the clinical trials and the current observational study could be the result, at least in part, of the different study designs.

"Until we have additional, high-level evidence to clarify the statin-intracerebral hemorrhage risk relationship, I recommend careful control of modifiable risks for brain hemorrhage such as blood pressure in those who are treated with a statin," Gorelick wrote.

"Other statin-associated risks for intracerebral hemorrhage such as history of intracerebral hemorrhage or use of antithrombotic therapy, and possibly the presence of cerebral microbleeds, should be carefully considered in the clinical decision-making process," he wrote.

Hackam and colleagues retrospectively examined data from 17,872 patients with a history of ischemic stroke who lived in Ontario -- half who started on statins within 120 days of discharge and half who did not. The two groups were matched using propensity scores.

Using six healthcare databases, the researchers followed the patients (mean age 78; 54% female) for a median of 4.2 years. During that time, there were 213 intracerebral hemorrhages.

Consistent with previous studies, statin use was associated with a significantly lower risk of ischemic stroke (HR 0.83, 95% CI 0.75 to 0.92).

The rate of hemorrhage, however, did not differ between statin users and nonusers either overall or in analyses looking at the doses of the cholesterol-lowering medications.

After excluding patients who were not adherent to statin treatment and control patients who started taking statins during follow-up, statin use was associated with a significantly lower risk of intracerebral hemorrhage (HR 0.65, 95% CI 0.47 to 0.91).

Statins also appeared to have a protective effect in a multivariate analysis in a larger patient population (HR 0.79, 95% CI 0.63 to 0.99).

The researchers found that statin use was not associated with bone mineral density testing, vitamin D or B12 screening, gastrointestinal endoscopy, or elective knee arthroplasty, which indicates that the results were not due to healthy user bias or differences in quality of care between statin users and nonusers.

"Physicians should continue to adhere to current treatment guidelines recommending statin therapy for most patients with a history of ischemic stroke," Hackam and colleagues concluded.

In his editorial, Gorelick noted that there remains some question about the safety of using statins in patients who have a history of intracerebral hemorrhage, as highlighted by an analysis published earlier this year.

"The clinical decision to administer a statin following intracerebral hemorrhage remains a challenging one with available evidence tilting in the direction of withholding such therapy, especially when there is a history of lobar brain hemorrhage," he wrote.

The researchers acknowledged some limitations of their study, including the lack of information on some characteristics, including blood pressure profile, lipids, leukoaraiosis on neuroimaging, and lifestyle habits, the unknown applicability of the findings to younger patients, the lack of adjudication of the clinical events, and the possible misclassification of statin use.

[Chevychelov]

Control of CV Risks Improves Male Sexual Function

By John Gever, Senior Editor, Published: September 12, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that avoidance of risk factors and the adoption of healthy lifestyle behaviors is associated with reduction of MI, cardiac death, and stroke but few adhere to all of the tenets of a healthy lifestyle.


Point out that these two studies describe benefits of healthy lifestyle on erectile dysfunction and may lead more individuals to adopt these changes and improve health.

Erectile dysfunction (ED) is a cardiovascular risk factor independent of others, even as interventions leading to improvements in such risk factors also appear to alleviate ED, according to two separate meta-analyses.

In one, pooled data from 12 prospective cohort studies indicated that men with ED had increased risks of 35% to 48% for outcomes including cardiovascular disease, coronary heart disease, and stroke, according to Li-Qiang Qin, MD, PhD, and colleagues at Soochow University in Suzhou, China.

The other meta-analysis, with data from six clinical trials, found that successful lifestyle modifications as well as lipid-lowering statin therapy -- intended to improve conventional cardiovascular risk factors -- led to better sexual function, reported Bhanu Gupta, MD, and colleagues at the Mayo Clinic in Rochester, Minn.

The Chinese study appeared in the Sept. 20 issue of the Journal of the American College of Cardiology, while the Mayo review was published online in Archives of Internal Medicine.

As both research groups observed, an association between ED and cardiovascular disease has been noted previously but whether it was causal -- and, if so, in which direction -- remained unclear.

The new studies do not fully resolve these questions. But Qin and colleagues indicated that their analysis points to ED as an independent risk factor for cardiovascular disease.

Gupta and colleagues, meanwhile, concluded that ED is a lifestyle condition that is amenable to the same interventions known to be effective against other lifestyle-related cardiovascular risk factors.

But neither study examined whether drug treatments or other therapies targeting ED specifically -- such as sildenafil (Viagra) and related drugs -- affect cardiovascular risk.

Qin and colleagues searched for prospective cohort studies that looked for associations between ED and risk of fatal and nonfatal cardiac events, heart failure, peripheral artery disease, stroke, sudden death, or all-cause mortality.

Outcomes including acute MI, angina, and other ischemia were lumped together as "coronary heart disease." In turn, these outcomes plus stroke, cardiac arrest, heart failure, peripheral artery disease, and sudden death were all considered "cardiovascular disease."

They found 12 studies meeting their requirements, with a total of more than 36,000 participants.

After adjusting for covariates when possible, Qin and colleagues calculated the following relative risks for adverse outcomes associated with ED, relative to study participants who did not have ED:
Cardiovascular disease, 1.48 (95% CI 1.25 to 1.74)
Coronary heart disease, 1.46 (95% CI 1.31 to 1.63)
Stroke, 1.35 (95% CI 1.19 to 1.54)
All-cause mortality, 1.19 (95% CI 1.05 to 1.34)


In two of the included studies, the reference group was men with minimal to mild ED rather than no ED at all. But excluding them from the meta-analysis did not change the associations substantially, Qin and colleagues indicated.

Other sensitivity analyses also suggested that the relative risks identified in the primary calculations were robust.

However, the researchers noted that ascertainment of ED, enrollment criteria, and other aspects of the included studies varied considerably. Those studies relying on participants' self-reporting of ED may have underestimated its prevalence "because of embarrassment," Qin and colleagues noted.

The Mayo analysis was considerably smaller. Gupta and colleagues drew on a total of six randomized trials conducted since 2004 -- four testing lifestyle modifications and two in which atorvastatin (Lipitor) therapy was the intervention -- with 740 participants, in which effects on ED were measured.

Despite the small number of participants, pooled data from these studies demonstrated that cardiovascular risk-oriented interventions significantly relieved ED.

With ED outcomes standardized to weighted mean differences in International Index of Erectile Function scores, the overall improvement was 2.66 points (95% CI 1.86 to 3.47), Gupta and colleagues reported.

Dropping the two statin studies from the analysis, which had a total of 143 participants, did not affect the result much -- pooled data from the four lifestyle intervention studies showed improvements in ED scores of 2.40 points (95% CI 1.19 to 3.61).

Interventions in those studies included a number of programs, some stressing diet and others emphasizing physical activity.

The statin studies themselves were harder to interpret. One found a significant improvement in ED scores, whereas the other did not -- but with just 12 participants total, its impact on the pooled analysis was minimal.

Gupta and colleagues said the findings could be translated immediately into clinical practice.

Noting that phosphodiesterase-5 (PDE-5) inhibitor drugs such as sildenafil "are the mainstay of therapy for ED," the researchers indicated that physicians would do well to stress diet and exercise as well.

"Adoption of lifestyle modifications and CV risk factor reduction will provide incremental benefit regardless of PDE-5 inhibitor use," they wrote.

To the extent that ED is itself a cardiovascular risk factor, such interventions could also stave off more serious outcomes.

In an invited commentary accompanying the Mayo review, two other researchers concurred.

Militza Moreno, MD, and Thomas A. Pearson, MD, MPH, PhD, of the University of Rochester, noted that acute cardiovascular events and heart failure have serious negative effects on quality of life, as does ED.

"It may be the motivation to prevent one of these other poor outcomes that tips the balance toward lifestyle change," they wrote.

"Both clinicians and public health practitioners should be reassured that the benefits of their lifestyle modification efforts are overwhelmingly positive and continue to grow," they added.

[Chevychelov]

EASD: No Microvascular Benefit With Intense BP, Glucose Control

By Kristina Fiore, Staff Writer, September 15, 2011

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.


Explain that the combination of intensive blood pressure and glucose management did not protect against microvascular endpoint measures compared with standard care in a study of type 2 diabetics.


Note that the combination of intensive therapies also did not affect single markers of microvascular disease compared with either therapy alone.
Review

LISBON -- Aggressively lowering blood pressure and blood glucose together won't provide any microvascular benefits to type 2 diabetes patients, researchers said here.

In an analysis of data from the ACCORD trial, neither intense glycemic management nor intense blood pressure control reduced the risk of a composite of microvascular outcomes, Patrick O'Connor, MD, of HealthPartners Research Foundation in Minneapolis, reported during an oral session at the European Association for the Study of Diabetes meeting here.

There was no interaction between the two treatments on that outcome; nor did the combination have significant effects on a host of individual microvascular outcomes including microalbuminuria, macroalbuminuria, or renal failure.

"None of the prespecified outcomes were further significantly reduced in those intensively treated for both glycemia and blood pressure compared with either regimen alone, signifying the lack of an additional beneficial effect from combined intensive management," O'Connor said.

Some work has shown that lowering blood pressure and blood glucose individually diminish some microvascular complications of type 2 diabetes, but there are few data on the combined effects of these interventions.

O'Connor and colleagues analyzed data from the ACCORD blood pressure trial, totaling 4,733 adults with type 2 diabetes and hypertension.

Patients were randomized to either intensive blood pressure control, with a systolic target of 120 mm Hg or less, or standard control of 140 mm Hg or less. They were also separately randomized to either intense blood glucose management (HbA1c under 6%) or a standard target (HbA1c 7% to 7.9%).

Prespecified outcomes included one composite microvascular outcome measure -- dialysis or renal transplantation, high serum creatinine, and retinal photocoagulation or virectomy -- and nine single measures of kidney, eye, or peripheral nerve function.

The researchers looked at two-way interactions between glycemia and blood pressure treatment.

They found that over a mean of 4.7 years, the primary microvascular outcome occurred in 11.4% of those in the intensive blood pressure arm and 10.9% of those in the standard blood pressure arm.

Overall, neither intensive intervention had any effect on whether patients reached the primary composite outcome of microvascular disease.

Nor were there many significant effects on the nine individual markers of microvascular disease, except those on intensive blood pressure management were less likely to develop microalbuminuria (HR 0.84, P=0.02).

Moreover, those on intensive glycemic management had a reduced risk of three outcomes: macroalbuminuria (HR 0.68, P=0.002), loss of vibratory sensation (HR 0.89, P=0.02), and loss of pressure sensation (HR 0.76, P=0.001).

O'Connor and colleagues found no significant interactions between intensive blood pressure and glycemic management for any of the outcomes.

"The benefits seen on the one hand with blood pressure control, or on the other hand with glucose control, were not amplified by an interaction," he said during the session.

In regression analyses, assignment to either intensive program was not a predictor of renal failure as defined by initiation of dialysis or end-stage renal disease. The only significant predictors were serum creatinine and albuminuria at baseline.

O'Connor noted, however, that the low proportions of patients who achieved the primary endpoint could have reduced the power of the analysis.

"The short duration of the study doesn't permit for the full assessment of the impact of the interventions," he said.

[Chevychelov]

EASD: Biomarkers May Predict CAD, Death in Diabetics

By Kristina Fiore, Staff Writer, September 15, 2011

Action Points
Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that both elevated peroxiredoxin-4 and resistin were associated with cardiovascular events and death in patients with type 2 diabetes in two separate studies.


Note that the association with both new biomarkers remained significant after controlling for a number of variables, but that other markers of oxidative stress or inflammation were not measured.
Review

LISBON -- Two biomarkers may be associated with cardiovascular events and death in type 2 diabetes patients, researchers reported here.

The antioxidant peroxiredoxin-4 (Prx4) and the inflammatory protein resistin were significantly associated with both outcomes in two separate trials reported here at the European Association for the Study of Diabetes meeting.

Esther Gerrits, MD, of the University Medical Center Groningen in the Netherlands, said hyperglycemia induces oxidative stress and endothelial damage, which subsequently leads to both microvascular and macrovascular complications in patients with diabetes.

The antioxidant stress system typically protects against oxidative stress, she said, and circulating levels of Prx4 have been proposed as a novel biomarker of oxidative stress.

It is the only secretable form of the six isoforms of the antioxidant, she added, and has previously been linked with sepsis, type 1 diabetes, and myocardial infarction, as well as other inflammatory markers such as C-reactive protein and interleukin-6.

To investigate, Gerrits and colleagues looked at data from the prospective, observational ZODIAC-28 study of 1,067 Dutch primary care patients with type 2 diabetes. They assessed two cohorts, one starting in 1998 and the other in 2001.

Prx4 was assessed in baseline serum samples, and the median value was 0.86 U/L.

Over a median follow up of 9.8 years, 32.3% of patients died. Of those, 43% were attributable to cardiovascular causes, Gerrits said.

She and colleagues found that increased levels of Prx4 were associated with high rates of both cardiovascular and all-cause death, and remained significant after controlling for numerous confounders, including age, gender, body mass index (BMI), serum creatinine, smoking, diabetes duration, systolic blood pressure, cholesterol-HDL ratio, history of complications, and albuminuria.

These patients had an 80% increased risk of all-cause death (95% CI 1.53 to 2.12), which remained a significant 51% increased risk in controlled analyses (95% CI 1.24 to 1.82).

The results were similar for cardiovascular mortality, with an 83% higher risk for those with elevated Prx4 (95% CI 1.46 to 2.30), which remained a significant 52% greater risk after controlling for confounders (95% CI 1.13 to 2.04).

Gerrits noted that although antioxidants are thought to be protective of oxidative stress, it is clearly a biomarker of mortality in this study.

"We don't know the underlying mechanisms yet, but we can speculate that Prx4 has been upregulated in cases of oxidative stress," she said.

But Lise Tarnow, MD, of the Steno Diabetes Center in Gentofte, Denmark, who moderated the session, noted that the researchers did not add other makers of inflammation to their adjusted model.

In a second study, Claudia Menzaghi, PhD, of the Casa Sollievo della Sofferenza in San Giovanni Rotondo in Italy, and colleagues found that elevated levels of resistin also are tied to cardiovascular events and death in type 2 diabetes patients.

Serum resistin, a pro-inflammatory cysteine-rich protein secreted by macrophages, has been associated with an increased risk of cardiovascular events in the general population, but few studies have looked at associations specifically for type 2 diabetes patients.

So they looked at data from four studies -- two case-control studies and and two prospective trials. The case-control data came from 798 patients in the Gargano Heart Study and 1,050 patients in the Joslin Heart Study.

Prospective data came from the 350 patients in the Gargano Heart Study-Prospective and from the 1,028 patients in the Gargano Mortality Study.

Menzaghi and colleagues found that in the case-control studies, serum resistin was significantly higher in patients with coronary artery disease than in those without, and remained so even after controlling for BMI, diabetes duration, and baseline therapies.

In the prospective studies, those with higher levels had a significantly greater risk of cardiovascular events and all-cause death than those with lower levels, which remained after controlled analyses:
Gargano Heart Study-Prospective: HR 1.35, 95% CI 1.14 to 1.59, P=0.001
Gargano Mortality Study: HR 1.13, 95% CI 1.05 to 1.21, P=0.001


The researchers also found that patients in the prospective studies who had resistin levels greater than the median were significantly more likely to have a major cardiovascular event and were more likely to die (P=0.000023 and P=0.0006, respectively).

Menzaghi said resistin is an independent predictor of major cardiovascular events and all-cause death, and may be useful for "improving the predictability of cardiovascular disease in patients with type 2 diabetes."

Tarnow noted that the researchers in this study also did not control for other well-known markers of inflammation, and that correcting for these factors "is very important in the future, as we are facing more challenges with the increasing number of markers that we are measuring."

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ASBMR: Heart Failure Raises Fracture Risk
By Nancy Walsh, Staff Writer, Published: September 17, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

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.


Explain that heart failure in older adults increases their likelihood of osteoporotic fractures by almost 30%, independent of risk factors and bone mineral density (BMD).

SAN DIEGO -- Heart failure in older adults increases their likelihood of osteoporotic fractures by almost 30%, independent of risk factors and bone mineral density (BMD), Canadian researchers reported here.

Among adults 50 and older in Manitoba who had their first BMD test between 1998 and 2007, 10% of those with heart failure developed a major fracture over a five-year period compared with only 5% of those without heart failure, according to Sumit Majumdar, MD, of the University of Alberta.

The unadjusted hazard ratio (HR) for fracture in patients with heart failure was 2.45 (95% CI 2.11 to 2.85, P<0.001), he reported.

"Both osteoporosis and heart failure are common and costly conditions that are underdiagnosed and undertreated, and they share etiologic features such as older age, smoking, and diabetes," Majumdar said at the annual meeting of the American Society for Bone and Mineral Research.

Several recent studies have suggested an association between osteoporosis and heart failure, but none of them have included measures of BMD.

To further explore the possible evidence of a connection, the researchers analyzed data from administrative sources and an osteoporosis clinical registry. They obtained information on heart failure diagnoses as well as nontraumatic fractures of the vertebrae, hip, distal radius, and humerus. Patients were followed until 2009.

The cohort included 45,509 adults, 1,841 of whom had been diagnosed with heart failure within the previous two years.

The 4% of the population who had heart failure were more often men (17% versus 7%) and older (74 versus 66 years).

In addition, they had lower total hip T scores (−1.3 versus −0.9, P<0.001) and had experienced significantly more previous osteoporotic fractures (21% versus 13%), Majumdar said.

A total of 40% of patients with heart failure had a T score at any site below −2.5, compared with 29% of those without heart failure.

And 60% of the heart failure group were taking loop diuretics, which are known to increase fracture risk, compared with only 4% of the larger population, which was a 15-fold difference, he observed.

There were 2,703 major fractures during a median follow up of five years.

"In terms of fracture-free survival, the Kaplan-Meier survival curves started to separate shortly after the first bone mineral density test and continued to diverge out to ten years. The median time to fracture was 3.6 years," Majumdar reported.

The HR for fracture in patients with heart failure after adjustment for age and sex was 1.64 (95% CI 1.45 to 1.86).

After adjustment for comorbidities, osteoporosis risk factors, and the effects of medications, the HR was 1.33 (95% CI 1.11 to 1.60, and remained elevated even after adjustment for total hip BMD (HR 1.28, 95% CI 1.06 to 1.53).

"This meant that patients with heart failure had a 28% increased fracture risk over five years regardless of risk factors or BMD scores," he said.

Limitations of the study included the absence of radiographic confirmation of fractures and a lack of measures of heart failure severity such as ejection fraction.

"Important implications of the study were that it opens up new avenues for research in terms of mechanisms of the diseases. Clinically, we need to recognize that a diagnosis of heart failure portends an increased risk of fracture, so we should be paying much more attention to bone health in patients with heart failure," Majudar concluded.

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Anti-Nausea Drug Linked to Arrhythmias
By Peggy Peck, Executive Editor, Published: September 15, 2011


WASHINGTON -- A drug used to treat nausea and vomiting caused by chemotherapy may trigger dangerous and possibly lethal changes in heart rhythms, the FDA warned Thursday.

The drug, ondansetron (Zofran), may increase the risk of "developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm, including Torsade de Pointes," the FDA said.

In a warning issued to clinicians, the FDA said that patients at greatest risk include those with "underlying heart conditions, such as congenital long QT syndrome, [and] those who are predisposed to low levels of potassium and magnesium in the blood" as well as patients who are taking other medications also associated with QT prolongation.

Ondansetron is a 5-HT3 serotonin receptor antagonist, commonly prescribed to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, and surgery.

The FDA said it has ordered GlaxoSmithKline, which markets Zofran, to conduct a thorough QT study to determine the degree to which the drug may cause QT interval prolongation. The agency expects the results next summer.

In the interim, the FDA has ordered that the drug's label be changed to include "a warning to avoid use in patients with congenital long QT syndrome because these patients are at particular risk for Torsade."

The label will also recommend ECG monitoring in certain patients including those with hypokalemia or hypomagnesemia, congestive heart failure, bradyarrhythmias, and in patients who are taking other medications that increase the risk of QT prolongation.

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FDA panel recommends approval for rivaroxaban
By

The FDA's Cardiovascular and Renal Drugs Advisory Committee voted 9-2, with one abstention, to approve the use of rivaroxaban for the reduction of stroke and non-CNS systemic embolism in patients with non-valvular atrial fibrillation, according to a press release.

The vote follows a review issued by the FDA which suggests withholding from approval due to a noninferior result of rivaroxaban vs. warfarin and insufficient information on rivaroxaban's safety profile.

The panel based its decision on the results of the ROCKET-AF trial. The study involved 14,264 patients across 1,178 sites in 45 countries. Patients were diagnosed with persistent or paroxysmal AF with additional risk factors for stroke, and were randomly assigned to warfarin (Coumadin, Bristol-Meyers Squibb) or rivaroxaban (Xarelto, Johnson & Johnson). Patients who were assigned to rivaroxaban received a 20mg dose once daily, and warfarin was titrated to a target range of two to three.

Overall, a decreased rate of stroke and non-CNS embolism events were associated with rivaroxaban during treatments vs. warfarin (P=.015). In the intention-to-treat analysis, rivaroxaban was noninferior to warfarin (P=.117). The rate of bleeding and adverse events was similar between the rivaroxaban and warfarin arms, but rivaroxaban was associated with less intercraniall hemorrhage and fatal bleeding.

"No one, I believe, doubts that rivaroxaban is effective in preventing stroke in patients with AF," Norman Stockbridge, MD, director of the division of cardiovascular and renal drug products at FDA , said in the opening remarks of the meeting. "Nor are there safety issues that would cause one to question that the stroke reduction benefit was on the whole worthwhile … By at least one analysis, rivaroxaban was superior to warfarin in the ROCKET AF study. Nevertheless, the clinical reviewers question whether the study can be interpreted as showing that rivaroxaban is even as good as warfarin."

When asked if rivaroxaban merits a superior claim to warfarin, 1 out of 12 voted yes and 9 voted no; a claim as an effective alternative to warfarin, 4 voted yes and 5 voted no; a claim as effective, 7 voted yes and 3 voted no; and a claim for patients failing other anticoagulant therapy, 7 voted yes and 2 voted no.

"What constitutes failure," Sanjay Kaul, MD, director of cardiovascular diseases fellowship training program at the Cedars-Sinai Heart Institute, said, "[is] if patients are, for some reason, not well anticoagulated on warfarin, if they don't want to be on warfarin because of the diet or the medications they are on, or if patients simply refuse to take warfarin because they don't want to be bothered with monitoring anticoagulation. Those will be the types of patients where, I think, rivaroxaban would be an effective alternative to warfarin and other anticoagulants that are approved. So, third line option."

Overall, 4 out of 12 committee members thought it would be beneficial to resolve issues for rivaroxaban pre-market vs. post-market.

"I would really like to see this drug tested in this AF population twice daily because it makes a lot more sense from a pharmacodynamic point of view," Steven Nissen, MD, chair of the department of cardiovascular medicine at the Cleveland Clinic Foundation, said. "And, you know, maybe this drug will have more point estimates and confidence intervals and look more like dabigatran if it's studied in a more optimal dosage regimen."

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. - by Casey Murphy
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Hemodynamic response to LV pacing predictive of need for post-CRT remodeling

Duckett S. J Am Coll Cardiol. 2011;58:1128-1136.
By

Acute hemodynamic response to left ventricular pacing is useful for predicting patients who are likely to remodel after cardiac resynchronization therapy for dilated cardiomyopathy and ischemic cardiomyopathy, according to a study.

Researchers collected information for the study from patients undergoing dilated and ischemic cardiomyopathy for cardiac resynchronization therapy (CRT). Patients underwent echocardiography before CRT, implant hemodynamic evaluation during CRT, an occlusive venogram, and LV volumes were assessed before and after CRT. Optimal coronary sinus LV lead position was determined by the largest percentage rise in the maximum rate of LV pressure to dual-chamber LV pacing. Reverse remolding was determined if there was at least a 15% reduction in LV end-systolic volume, and symptomatic response was evaluated by NYHA functional class and quality-of-life questionnaire every 6 months, according to the study.

Overall, 33 patients underwent CRT; 21 undergoing dilated and 12 ischemic cardiomyopathy. “The maximum rate of LV pressure increased significantly from baseline (P<.001) with dual-chamber LV pacing or the optimal LV lead position,” researchers said.

Reverse remolding was exhibited in 56% of patients. When predicting remolding, a more than 10% improvement in maximum rate of LV pressure from baseline with dual-chamber LV pacing was more sensitive vs. echocardiographic parameters, according to the study. Reverse remolding was experienced in 61% of patients with dilated cardiomyopathy vs. 45% with ischemic cardiomyopathy.

According to the study, there was a strong relationship for acute hemodynamic response and reverse remolding for dilated cardiomyopathy (P=.01) and ischemic cardiomyopathy (P=.04). When it came to patients with dilated cardiomyopathy, reverse remolding had a statistically significant relationship between systolic dyssynchrony index (P=.004) and intraventricular ejection fraction (P=.006). Reverse remolding was only statistically significant with intraventricular ejection fraction (P=.006), when it came to patients with ischemic cardiomyopathy.

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EASD: Gliptin Tx Works Long-Term for Glycemic Control

By Ed Susman, Contributing Writer, September 19, 2011

Action Points
Note that these studies were published as abstracts and were presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that long-term treatment of type 2 diabetes with dipeptidyl peptidase-4 (DPP-4) inhibitors for two years appeared to maintain improvement in glycosylated hemoglobin A1c levels.


Note that the reduction in HbA1c was observed for add-on therapy with metformin and for metformin plus sulfonylurea.
Review
LISBON -- Long-term treatment of type 2 diabetes with dipeptidyl peptidase-4 (DPP-4) inhibitors for two years appeared to maintain improvement in glycosylated hemoglobin A1c levels, researchers reported here.

In one study, treatment with linagliptin (Tradjenta) at the end of a 24-week randomized clinical trial resulted in a mean 0.8% decline in HbA1c after 102 weeks of treatment. In addition, patients still had a 0.8% decline in HbA1c, reported David Owens MD, at the European Association for the Study of Diabetes. Owens is from the Center for Endocrinology and Diabetes Science at Cardiff University in the U.K.

In a second study, Douglas Fleming, MD, an investigator for Bristol-Myers Squibb in Princeton, N.J., said treatment with its DPP-4 inhibitor saxagliptin (Onglyza) showed a similar pattern after 52 weeks of therapy: Patients taking saxagliptin (5 mg) in addition to insulin were able to achieve a 0.37% net decline in HbA1c, regardless of whether the patients were also taking metformin.


"The results seen in these extension studies is what we would have expected to see in treating type 2 diabetes patients over the long term," commented Carolyn Deacon, PhD, senior lecturer at the Panum Institute, University of Copenhagen. Deacon moderated the session during which Owens and Fleming presented their findings.

Linagliptin: Long-Term Glycemic Control

Owens said that in his study, patients were randomized to receive linagliptin or placebo for 24 weeks in four controlled clinical trials aimed at determining the efficacy of linagliptin.

In the open-label extension study, patients initially treated with linagliptin were continued on the drug for an additional 78 weeks. Patients initially started on placebo were switched to linagliptin (5 mg) for 78 weeks. The total follow-up time was two years.

For the pooled results, 1,532 patients were included in the 102-week linagliptin study and 589 patients in the 78-week group. The patients were about 57 years of age and about 52% were men. About 57% of the total group was white; about 42% was Asian.

By the end of 102 weeks, the HbA1c had not changed, which Owens noted met the coefficient of durability of 0.14%, meaning there was no relevant increase in HbA1c from week 24 to week 102 (P<0.0001).

He demonstrated that the maintenance of HbA1c levels was similar for the following:
Patients on linagliptin monotherapy achieved a mean 0.5% decrease from a baseline value of 7.98%.
Patients who had linagliptin added onto metformin achieved a mean 0.74% reduction in HbA1c from a baseline value of 8.06%.
Patients with linagliptin added on to treatment with metformin and a sulfonylurea achieved a mean 0.7% reduction in HbA1c from a baseline value of 8.13%.
Patients with an initial combination with pioglitazone (Actos) achieved a 1.5% reduction in HbA1c from baseline levels of 8.55%.


"Linagliptin provides sustained long-term glycemic control when used as monotherapy or add-on to other glucose-lowering agents over two years," Owens said.

In addition, he said that linagliptin was well tolerated by patients during the study and that there was no clinically relevant increase in hypoglycemia or weight gain.

Sustained Results With Saxagliptin Add-On

The story was similar for patients in the saxagliptin study, Fleming illustrated in his oral presentation.

The researchers tested oral saxagliptin for 24 weeks to assess the short-term efficacy and safety of the molecule and then tested its long-term efficacy for 28 weeks. The 24-week trial results were presented at the American Diabetes Association meeting in June.

The enrollees were about 57-years-old; about 57% were women. More than three-fourths were white. The mean duration of type 2 diabetes was 12 years. The baseline HbA1c at the start of the trial was about 8.7%.

In the 52-week analysis, patients achieved a 0.75% decrease from baseline in HbA1c if they were taking saxagliptin (5 mg) added to insulin. That compared with a 0.38% reduction among the patients taking placebo (P<0.0001).

Initially, 304 patients started the study on saxagliptin and 151 patients were enrolled on placebo. About 18% of patients dropped out of the trial, so that 246 patients finished the trial on saxagliptin and 125 finished the trial on placebo.

Fleming also noted a greater increase from baseline mean daily insulin dose in patients who received placebo compared with patients who received saxagliptin.

The proportion of patients in each treatment group who experienced at least one adverse event over the 52-week treatment period was similar. The most common events included hypoglycemia, urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, and bronchitis.

During the initial 24-week period, patients were advised to maintain stable insulin doses, which could be decreased to reduce the risk of hypoglycemia. Patients with hyperglycemia or with substantially increased insulin had a rescue visit and remained in the study on a flexible insulin regimen.

During the extension period, all patients were able to adopt a flexible insulin regimen. Sixty-nine percent of patients were treated with metformin, and the dose could not be changed during the study.

Fleming reported that 21.3% of patients on saxagliptin achieved a therapeutic glycemic response of HbA1c less than 7%, while 8.7% of patients on placebo achieved that goal.

Mean body weight increase 0.8 kg on saxagliptin and 0.5 kg on placebo. The difference was not statistically significant, Fleming reported.

"Saxagliptin was well tolerated when added to insulin with or without concomitant metformin," Fleming said. "Consistent efficacy results were observed regardless of metformin use."

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ASD: Gestational Diabetes Guidelines Controversial

By Kristina Fiore, Staff Writer, September 14, 2011

Review

LISBON -- International guidelines on screening for gestational diabetes that will likely raise the prevalence of the condition have sparked questions over appropriate diagnostic tools and cost efficacy, researchers said here.

During a press briefing at the European Association for the Study of Diabetes meeting here, some researchers said that recommendations from the International Association of Diabetes and Pregnancy Study Groups released in 2010 are cost-effective.

But others are concerned that the two-step screening process, which could raise the prevalence from about 7% of pregnant women to 16% or more, may be too costly and too demanding.

Ob/Gyns and diabetologists have long recognized a need for more consensus on diagnosis and screening for gestational diabetes, but not all medical associations, including the American Congress of Obstetricians and Gynecologists, have accepted the international guidelines.

The 2010 guideline recommends an initial oral glucose tolerance test (OGTT) at the first prenatal visit, and a follow-up at 24 to 28 weeks' gestation if diabetes is not diagnosed initially.

Disease is diagnosed if the 75-g OGTT readings at 0, 1, and 2 hours exceed 5.1 mmol/L (126 mg/dL), 10.0 mmol/L (180 mg/dL), or 8.5 mmol/L (153 mg/dL), respectively.

Sue Kirkman, MD, senior vice president of medical affairs and community information at the American Diabetes Association, said her organization adopted the recommendations into its standards of care last January.

But some researchers have argued that this type of testing is too demanding -- and much more costly -- for pregnant women, especially when a fasting plasma glucose (FPG) test is simpler and may be more accurate, thus reducing the potential problem of overdiagnosis.

In fact, the World Health Organization (WHO) and recommends using FPG levels to diagnose gestational diabetes, which is diagnosed at an FPG of 4.4 mmol/L or higher.

And ACOG said it has declined to adopt the guidelines because of concerns with a lack of randomized controlled trials for the diagnostic criteria.

But Peter Damm, MD, of the University of Copenhagen in Denmark, who was on the international guideline writing committee, said during a press briefing that the group's conclusions were based on the best evidence available -- the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study.

Robert Fraser, MD, of the University of Sheffield in England, added that several subsequent studies also have vouched for the benefits of screening and treating the condition.

Those include the 2005 ACHOIS study and the 2009 Maternal-Fetal Medicine Units Network Trial, which both found that treatment reduces perinatal complications such as increased rates of cesarean section, increased fetal size, neonatal hypoglycemia, and shoulder dystocia, he said.

As well, a meta-analysis of both studies showed a reduction in preeclampsia, birth weight, and the proportion of large-for-gestational-age infants, though there were no effects on C-section rates or neonatal hypoglycemia, Fraser said.

And a cost-efficacy study published in Diabetologia, based on two treatment trials, found screening with FPG and OGTT in which risk was found to be 1% to 4.2% was "most likely" cost-effective and risk higher than 4.2% was cost-effective for universal glucose tolerance testing, he added.

Treatment typically involves diet and lifestyle modification, with a move to insulin if the diabetes is not controlled, Fraser said. Oral diabetes medications, particularly sulfonylureas or metformin, also have been supported by short-term studies.

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BMI Not Greatest Heart Failure Risk Factor

By Crystal Phend, Senior Staff Writer, Published: September 14, 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

Action Points
Explain that normal-weight individuals with that grouping of metabolic risk factors were 2.33 times more likely to develop heart failure over six years than those without metabolic syndrome, suggesting that metabolic syndrome may be a more important heart failure risk than obesity alone.


Point out that in the absence of metabolic syndrome, obese individuals were at lower risk than individuals of normal weight with metabolic syndrome.

Metabolic syndrome may be a more important heart failure risk than obesity alone, Greek researchers found.

Normal-weight individuals with that grouping of metabolic risk factors were 2.33 times more likely to develop heart failure over six years than those without metabolic syndrome (P=0.007) in a study by Christina Voulgari, MD, PhD, of Athens University Medical School, and colleagues.

But neither overweight nor obesity in the absence of metabolic syndrome had a significant impact on the incidence of heart failure, the group reported in the Sept. 20 issue of the Journal of the American College of Cardiology.

Obese individuals who did not have metabolic syndrome were actually at the lowest heart failure risk in the cohort study.

"Their findings give credence to the existence of a 'metabolically healthy population' and raises concern about those with metabolic syndrome," Eileen Hsich, MD, of the Cleveland Clinic, wrote in an accompanying editorial.

The reason for this obesity paradox may be that each component of metabolic syndrome is a known risk factor for heart failure, making it not surprising that they better predict risk together than a single variable alone, she suggested.

But that's not cause to lay off lifestyle recommendations for obese individuals who don't meet criteria for metabolic syndrome, Hsich noted, pointing out that "At an older age, they probably are no longer healthy."

The better message may be to not overlook metabolic syndrome status regardless of weight, the researchers added.

Their study included 550 individuals without diabetes or baseline macrovascular complications, studied over a median of six years of follow-up within a larger prospective, community-based study.

Among them, 271 met National Cholesterol Education Program Adult Treatment Panel III criteria for metabolic syndrome based on insulin resistance, abdominal obesity, hypertension, high triglycerides, and low HDL cholesterol.

Echocardiographic follow-up pointed to 2.5-fold higher risk of heart failure onset with metabolic syndrome overall (95% confidence interval 1.68 to 3.40).

Higher body mass index (BMI) was linked to higher rates of metabolic syndrome (38.4% at 25 kg/m2 and under to 69% at 30 kg/m2 and over) and of the individual components.

But higher BMI alone wasn't predictive of heart failure.

Heart failure incidence was highest, at 15.6%, in those with a normal BMI, 14.2% among overweight individuals, and lowest -- at 9.3% -- among the obese.

In the absence of metabolic syndrome, obese individuals were at lower risk of heart failure than individuals of normal weight with metabolic syndrome (P<0.001).

With metabolic syndrome, all three groups had relatively similar heart failure risk, with adjusted hazard ratios of 2.33, 2.66, and 2.13 versus no metabolic syndrome in a normal-weight individual.

These patterns persisted through adjustment for age, sex, smoking status, physical inactivity, lipids, glucose levels, and inflammatory marker profile.

The researchers cautioned that the relatively few heart failure cases that developed -- 185 in total, likely because they had excluded patients with diabetes and macrovascular complications -- may have limited the study's statistical power despite its longer-term follow-up.

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Long-QT Syndrome
[Ссылки доступны только зарегистрированным пользователям ]

Predicting mortality and hospital admission in patients with COPD: significance of NT pro-BNP, clinical and echocardiographic assessment
[Ссылки доступны только зарегистрированным пользователям ]

Serum thrombin activatable fibrinolysis inhibitor levels in patients with newly diagnosed multiple myeloma
[Ссылки доступны только зарегистрированным пользователям ]

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HFSA: Statins Tied to Lower Mortality in Afib

By Todd Neale, Senior Staff Writer, September 21, 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.


Explain that among patients with atrial fibrillation, those who are taking a statin may be less likely to die during follow-up than those who are not taking a statin.


Note that statin use was not associated with reductions in all-cause or heart failure hospitalization.
Review
BOSTON -- Among patients with atrial fibrillation, those who are taking a statin may be less likely to die during follow-up than those who are not taking a statin, a retrospective study showed.

Through four years, patients who were admitted to the hospital for atrial fibrillation and were started on a statin had a significantly lower rate of all-cause death (28% versus 42%, P<0.001), according to Jason Salamon, MD, of the Albert Einstein College of Medicine in New York City.

But statin use was not associated with reductions in all-cause or heart failure hospitalization, he reported at the Heart Failure Society of America meeting here.


"The study is an indication of the strong pleiotropic effects of statins," Salamon said in an interview.

"I think it solidifies the fact that there is an inflammatory-mediated process in atrial fibrillation and I think that this may give us a chance to do prospective trials to see if statins, in the future, will decrease mortality in patients with atrial fibrillation and may give us another way of managing the condition."

He noted that increasing evidence points toward inflammation playing a role in the pathogenesis of atrial fibrillation, and that some studies have suggested that statins, which have anti-inflammatory properties separate from their lipid-lowering capabilities, may prevent atrial fibrillation.

That is supported by a 2008 meta-analysis in which statins significantly reduced the risk of atrial fibrillation in patients with a history of the condition and in other high-risk populations, including those undergoing cardiac surgery and those with acute coronary syndromes.

In addition, another study reported in 2008 showed that among women with a history of coronary artery disease, those who took statins had a lower risk of developing atrial fibrillation.

But studies have not looked at whether statins are associated with reduced mortality in patients with atrial fibrillation, Salamon said.

He and his colleagues performed a retrospective cohort analysis of patients treated for atrial fibrillation at Montefiore Medical Center over a 12-year period. The study included adult patients with a normal left ventricular ejection fraction and an LDL cholesterol level of less than 130 mg/dL.

Patients with known coronary artery disease or hyperlipidemia were excluded.

At baseline, there were no significant differences between the patients who were started on a statin and those who were not. The mean age was about 70. The mean LDL cholesterol level was 97 mg/dL in patients who were started on a statin and 92 mg/dL in those who were not.

Statin use was associated with a 40% relative reduction in the risk of dying through four years of follow-up (RR 0.6, 95% CI 0.5 to 0.7).

The reduction was not explained by a difference in LDL cholesterol levels, which were similar after the index hospitalization in the patients who were started on a statin (84 mg/dL) and those who were not (85 mg/dL).

Serum creatine phosphokinase levels -- an indication of muscle injury, a potential side effect of statins -- were not significantly different in the two groups.

Salamon and his colleagues acknowledged some limitations of the study, including the retrospective design, the fact that left ventricular ejection fraction was measured by echocardiogram, and the lack of stratification based on the type of atrial fibrillation.

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HFSA: Longer Look Confirms Nesiritide's Flop

By Todd Neale, Senior Staff Writer, September 22, 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.


Note that this study presenting 180-day follow-up essentially confirms data previously published after 30-day follow-up indicating there was no effect of nesiritide compared with placebo on clinical outcomes of patients presenting with acute decompensated heart failure.
Review

BOSTON -- Six-month follow-up in the ASCEND-HF trial confirmed a lack of significant clinical benefit -- or harm -- from nesiritide (Natrecor) in patients with acute decompensated heart failure, researchers found.

At 180 days, the overall rate of all-cause mortality was 12.5%, with no significant difference between the placebo and nesiritide groups (HR 0.96, P=0.52), according to Randall Starling, MD, MPH, of the Cleveland Clinic.

Mortality was significantly predicted by all-cause rehospitalization during the first 30 days of follow-up (HR 1.87, 95% CI 1.50 to 2.34), he reported at the Heart Failure Society of America meeting here.

"The implications for this, we believe, are that rehospitalization is a meaningful endpoint in heart failure trials," Starling said.

Nesiritide -- a recombinant human B-type natriuretic peptide -- was approved by the FDA in 2001 on the basis of the VMAC trial, which compared IV nesiritide with nitroglycerin or placebo in 489 patients with acute decompensated heart failure. The results showed that nesiritide improved pulmonary capillary wedge pressure versus placebo and nitroglycerin and dyspnea versus placebo at three hours.

Approval was met by enthusiasm in the clinical community, but that was dampened in 2005 after two meta-analyses raised concerns about risks of mortality and worsening renal function.

An independent panel convened by the maker of nesiritide, Scios, and chaired by Eugene Braunwald, MD, of Brigham and Women's Hospital in Boston, recommended that a large clinical trial be conducted to definitively assess the safety and efficacy of IV nesiritide.

The result was the ASCEND-HF trial, which compared nesiritide and placebo added to usual care in about 7,000 patients with acute decompensated heart failure.

The main results -- first reported at the American Heart Association meeting last year and later published in the New England Journal of Medicine -- did not reveal any substantial safety concerns but failed to show a significant benefit for nesiritide in reducing the composite of heart failure hospitalization or all-cause death through day 30 or in improving dyspnea at six or 24 hours.

The 180-day analysis that Starling presented was consistent with those findings, in that there were no significant differences in clinical outcomes between the nesiritide and placebo groups.

Cardiovascular death occurred in 8.2% and 8% of the placebo and intervention arm, respectively, and worsening heart failure occurred in 4.9% and 4.6%, respectively.

"When added to usual treatment in unselected patients with acute decompensated heart failure, nesiritide is as safe as placebo, as Dr. Starling pointed out, it is also as effective as placebo, and in this era of comparative effectiveness it's important to recognize it is more expensive than placebo," William Little, MD, of Wake Forest University in Winston-Salem, N.C., said in comments following the presentation, to laughter from the audience.

So despite the strong physiologic rationale for nesiritide, Little added, the translation of that rationale into proven therapies is going to require more work.
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