BNP vs Symptom Heart Failure

BNP-Guided vs Symptom-Guided Heart Failure Therapy
The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) Randomized Trial

JAMA Vol. 301 No. 4, January 28, 2009
Matthias Pfisterer, MD; Peter Buser, MD; Hans Rickli, MD; Marc Gutmann, MD; Paul Erne, MD; Peter Rickenbacher, MD; André Vuillomenet, MD; Urs Jeker, MD; Paul Dubach, MD; Hansjürg Beer, MD; Se-Il Yoon, MD; Thomas Suter, MD; Hans H. Osterhues, MD; Michael M. Schieber, MD; Patrick Hilti, MD; Ruth Schindler, RN; Hans-Peter Brunner-La Rocca, MD; for the TIME-CHF Investigators
JAMA. 2009;301(4):383-392.
Context It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy.
Objective To compare 18-month outcomes of N-terminal BNP–guided vs symptom-guided heart failure therapy.
Design, Setting, and Patients Randomized controlled multicenter Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) of 499 patients aged 60 years or older with systolic heart failure (ejection fraction 45%), New York Heart Association (NYHA) class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal. The study had an 18-month follow-up and it was conducted at 15 outpatient centers in Switzerland and Germany between January 2003 and June 2008.
Intervention Uptitration of guideline-based treatments to reduce symptoms to NYHA class of II or less (symptom-guided therapy) and BNP level of 2 times or less the upper limit of normal and symptoms to NYHA class of II or less (BNP-guided therapy).
Main Outcome Measures Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires.
Results Heart failure therapy guided by N-terminal BNP and symptom-guided therapy resulted in similar rates of survival free of all-cause hospitalizations (41% vs 40%, respectively; hazard ratio [HR], 0.91 [95% CI, 0.72-1.14]; P = .39). Patients' quality-of-life metrics improved over 18 months of follow-up but these improvements were similar in both the N-terminal BNP–guided and symptom-guided strategies. Compared with the symptom-guided group, survival free of hospitalization for heart failure, a secondary end point, was higher among those in the N-terminal BNP–guided group (72% vs 62%, respectively; HR, 0.68 [95% CI, 0.50-0.92]; P = .01). Heart failure therapy guided by N-terminal BNP improved outcomes in patients aged 60 to 75 years but not in those aged 75 years or older (P < .02 for interaction)
Conclusion Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment.
Trial Registration isrctn.org Identifier: ISRCTN43596477
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VADT

VADT published: Intensive glucose control fails to reduce cardiovascular eventsDecember 18, 2008 Michael O'Riordan
Phoenix, AZ - Results of the Veterans Affairs Diabetes Trial (VADT), a long-term study of US veterans with type 2 diabetes receiving intensive blood glucose control, is now published online December 17, 2008 in the New England Journal of Medicine [1].
First presented at the American Diabetes Association (ADA) 2008 Scientific Sessions in San Francisco, CA and reported by heartwire at that time, the VADT showed that intensive blood glucose lowering in patients with elevated glycated hemoglobin A1c (HbA1c) levels despite medical treatment had no significant effect on the rates of cardiovascular events, death, or microvascular complications.
"We picked the toughest group of patients we could find because we figured if we could do some good there the benefit would be pretty obvious," lead VADT investigator Dr William Duckworth (Phoenix Veterans Affairs Health Care Center, AZ) told heartwire. "As the results show, though, we weren't able to do any good."
The results of the study are in line with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease (ADVANCE) studies. The ADVANCE trial showed a reduction in the progression of albuminuria with intensive glucose control but no effect on cardiovascular event rates. ACCORD, on the other hand, was stopped early because of an increased risk of death in patients who underwent intensive blood glucose lowering.Tough-to-treat patients
Speaking with heartwire, Duckworth said that when the VADT was initiated nearly five years ago, there was little to no evidence that glucose control altered the risk of cardiovascular events. Some studies, including the United Kingdom Prospective Diabetes Study (UKPDS), suggested improvements in microvascular end points, but there were no effects on hard clinical end points such as mortality or MI.
In VADT, investigators randomized 1791 military veterans with diabetes, mean age 60 years, who had a suboptimal response to medical therapy to intensive glucose control or standard glucose control. At the time of randomization, median HbA1c levels were 9.4%. In addition, nearly 75% of patients had hypertension, 40% had a previous cardiovascular event, and patients had been diagnosed with diabetes for a mean 11.5 years.
In both study groups, obese patients were started on two drugs, metformin and rosiglitazone, whereas nonobese patients were started with glimepiride plus rosiglitazone. Patients in the intensive arm started on maximal doses. Insulin was added to most participants to achieve HbA1c levels less than 6.0% in the intensive-treatment arm and less than 9.0% in the standard-therapy arm.
After a median follow-up of 6.5 years, median HbA1c levels were reduced to 8.4% in the standard-lowering arm and to 6.9% in the intensive-glucose-control arm. During this time, 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group experienced a major cardiovascular event, the composite primary end point consisting of MI, stroke, death from cardiovascular causes, congestive heart failure, vascular surgery, inoperable coronary disease, and amputation for ischemic gangrene.
"One of the things we wanted to do was reduce or eliminate as many controllable risk factors as we possibly could," said Duckworth. "We treated blood pressure and lipids very intensely and got those down to very good numbers. We also had the patients on aspirin and encouraged diet and exercise—all the things that you're supposed to do—and once that was done, I was not surprised that glucose lowering had no additional effect. Maybe a little disappointed, but not particularly surprised."
Commenting on the results for heartwire, Dr Roger Blumenthal (Johns Hopkins, Baltimore, MD) pointed out that tight glycemic control earlier in the disease process—ACCORD, ADVANCE, and VADT were carried out in individuals with established disease for a mean duration of eight to 11 years—might have been more successful.
Dr Sherita Golden (Johns Hopkins) echoed Blumenthal's sentiments.
"We all do still wonder if tight control earlier after diagnosis is most beneficial. After an individual has had diabetes for a prolonged time, the horse is out of the barn, so to speak, and tight glucose control is not as effective," said Golden.
She added that getting HbA1c levels down to 7% is still effective in preventing macrovascular complications, "so tight control to this level is still beneficial." In addition, tight control of blood pressure and cholesterol are proven strategies for primary and secondary prevention of cardiovascular disease in diabetes, she said.
Position statement on intensive glycemic control issued
With the publication of VADT and the earlier publications of ACCORD and ADVANCE, the ADA, American Heart Association (AHA), and American College of Cardiology (ACC) issued a position and scientific statement on intensive glycemic control and the prevention of cardiovascular events [2].
"The lack of significant reduction in cardiovascular disease events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1c less than 7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications," write first author Dr Jay Skyler (University of Miami, FL) and colleagues in the statement, published online December 17, 2008 in Circulation.
The report emphasizes the importance of controlling nonglycemic risk factors, such as blood pressure and lipids (using statins), as well as using aspirin and lifestyle modifications as the primary strategies for reducing the burden of cardiovascular disease in people with diabetes.
The group states that based on ACCORD, ADVANCE, and VADT, there is no need for major changes in glycemic-control targets but does offer some "clarification of the language that has consistently stressed individualization."
Lowering HbA1c levels to <7% to reduce microvascular and neuropathic complications in type 1 and 2 diabetes remains a class I recommendation. Less than 7% is also a reasonable target for reducing the risk of macrovascular complications, a class IIb recommendation, at least until more evidence becomes available, they add.
The scientific statement is also published in the Journal of the American College of Cardiology and Diabetes Care.Treat the cardiovascular risk factors
Regarding the clinical implications of the study, Duckworth, like the ADA, AHA, and ACC, emphasized the importance of treating blood pressure and lipid abnormalities to reduce the risk of cardiovascular and microvascular complications from diabetes. He added that VADT, as well as ACCORD and ADVANCE, included older patients and that younger patients might be treated differently.
"I have a practice with my elderly patients, those older than 60 years or 65 years, to not try to get their A1c down to very low levels," he said. "If I have a 45-year-old patient, then I'm considerably more aggressive—again, we don't have any evidence that it makes difference, but these patients have much longer to live and have much more time to develop complications. It's reasonable to think they might benefit from lower glucose levels. It's one of those patient-specific things: we really should be treating patients and not numbers."
The ADA, AHA, and ACC also emphasize the importance of individualizing treatment. In its statement, the group notes that for those with a short duration of disease, long life expectancy, and no significant cardiovascular disease, a more aggressive HbA1c goal might be appropriate, whereas for older patients, those with advanced microvascular and macrovascular disease, less stringent targets are recommended. These last two recommendations have weak evidence supporting them and are based on consensus opinion of experts, case studies, or standards of care.
In their paper, the VADT investigators suggest that one possibility for the lack of observed effect of intensive therapy could be that the cardiovascular benefit is delayed. Ten-year data from UKPDS showed that early intensive glucose lowering, either with a sulfonylurea or metformin, reduced the risk of MI or all-cause mortality. Long-term follow-up from the Diabetes Control and Complications Trial—Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) study also showed a reduction in cardiovascular events in patients whose blood sugar was lowered most.
"If you can manage to get glucose down without risking severe hypoglycemia, then I think it's a good thing to do regardless," said Duckworth. "It might make a difference long term, even though we don't have definite proof of it."
Duckworth reports consulting fees from Novo Nordisk, GlaxoSmithKline, and Caremark and lecture fees from Sanofi-Aventis.
Sources
Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; DOI: 10.1056/NEJMoa0808431. Available at: http://www.nejm.org.
Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation 2008; DOI: 10.1161/CIRCULATIONAHA.108.191305. Available at: http://circ.ahajournals.org.

FDA e prasugrel

FDA asks panel of heart doctors for help reviewing blood-thinning drug prasugrel.
The Wall Street Journal (1/2, Rockoff, subscription required) reports that the Food and Drug Administration's (FDA) Cardiovascular and Renal Drugs Advisory Committee is set to meet on Feb. 3, and while details of the panel's agenda were not available, Eli Lilly and partner Daiichi Sankyo say that the body will discuss "whether to finally approve prasugrel," the company's "powerful anti-clotting drug and would-be competitor to blockbuster Plavix. ... Early this year, lots of folks were brimming with anticipation for prasugrel, a more powerful clot-fighter than Plavix. But the Lilly medicine also carried a higher risk for life-threatening bleeding. Perhaps no surprise then that there was a three-month delay in FDA's review earlier this year, then another with a less clear timetable for action, as the agency weighed what to do." The Journal predicts that the drug will soon be on the market in Europe, but expressed doubt that the FDA will automatically follow suit.
The AP (1/2) also reports on the upcoming meeting, noting that prasugrel is "a potential blockbuster drug that has been plagued by regulatory delays." Prasugrel "is considered crucial to Lilly as it faces a wave of patent expirations in the next few years. Lilly previously told investors it expects to begin selling prasugrel in the first half of 2009, but declined to set a specific date for FDA approval."