Anemia in HF: Improvement in HB Linked to Outcomes

Highlights from the 2006 Scientific Sessions of the American Heart Association, Chicago, November 12-15, 2006

Patients with symptomatic heart failure (HF) and anemia who experience at least a 1 mg/dL increase in hemoglobin (Hb) while on treatment with darbepoetin alfa have improved function and fewer clinical events than those not achieving a 1 mg/dL increase in Hb, according to a post hoc analysis of STAMINA-HeFT (Study of Anemia in Heart Failure—Heart Failure Trial).

STAMINA-HeFT was a randomized, double-blind, placebo-controlled study of twice weekly darbepoetin alfa in anemic HF patients. In the study, 319 patients with New York Heart Association (NYHA) class II to IV HF who had Hb levels of 9.0 to 12.5 g/dL were randomized to placebo or darbepoetin alfa for 1 year to achieve a target Hb of 14.0 g/dL. The mean improvement in Hb level in the patients assigned to darbepoetin alfa was 1.8 g/dL.

In the overall study population, there was a trend toward improvement in exercise duration (the primary end point) with darbepoetin alfa that did not reach statistical significance.

The analysis presented here included only those patients enrolled in STAMINA-HeFT who were assigned to darbepoetin alfa. Outcomes were compared among the treated patients who achieved at least a 1 g/dL increase in Hb after week 17 and those who failed to achieve at least a 1 g/dL increase in Hb.

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The adjusted mean change in exercise duration from baseline to 6 months was 66.2 seconds in the patients with ≥1 g/dL increase in Hb, compared with an increase of 14.7 seconds in those with a <1.0 g/dL increase in Hb ( = .037).

“The findings suggest that an increase of 1.0 g/dL or more in hemoglobin is required to achieve benefit,” said lead investigator Jalal Ghali, MD, from Wayne State University Health Center in Detroit.

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Clinical outcomes were also significantly improved in the patients who achieved at least a 1 g/dL increase in Hb. In this group, there was a 71% reduction in the composite of all-cause mortality or heart failure-related hospitalization ( = .001), a 75% decrease in heart failure-related hospitalization alone ( = .002), and a 79% reduction in all-cause mortality ( = .004) relative to the patients with <1 g/dL improvement in Hb concentration.

The outcomes from this analysis strengthen the hypothesis that raising Hb in anemic HF patients may lead to improved outcomes, said James Young, MD. “By no means are these conclusive data but they show that the hypothesis is rational,” he said. “Pilot studies have given us assurance that in a large number of HF patients it’s safe to raise hemoglobin with erythropoietin-stimulating therapies and there is a suggestion that patients improve.”

Recent studies have shown that a target Hb in the normal range may be too high for patients with anemia and renal insufficiency or end-stage renal failure. “In the HF population, the target Hb is very much up in the air,” said Dr Young, professor and chairman, division of medicine, Cleveland Clinic.

He noted that the patients enrolled in STAMINA-HeFT and other pilot studies of anemia correction in patients with HF are different than those with renal insufficiency. “It’s easier to correct Hb in an HF patient than in one with renal insufficiency or on hemodialysis,” he said.

Two large-scale clinical trials that are studying anemia correction with darbepoetin alfa in patients with HF have given no indication of harm with therapy, said Dr Young.

Use of thiazolidinediones (TZDs) appears safe in ambulatory patients with diabetes and heart failure (HF), according to a retrospective analysis of a veterans population. Also, in a randomized study in patients with type 2 diabetes, one particular TZD, pioglitazone, had an antiatherosclerotic effect compared with glimepride.

TZDs may be safe in HF; protect against atherosclerosis progression

• David Aguilar, MD, and colleagues measured the time to first hospitalization and time to death over 2 years in 7147 veterans with HF and diabetes who were treated in ambulatory clinics at Veterans Affairs medical centers. Among these patients, 818 were being treated with TZDs and 4700 were not.

The rate of HF hospitalizations over this period was not significantly different between the TZD users and nonusers (16.4% vs 15.8%, respectively), said Dr Aguilar, assistant professor of medicine at Baylor College of Medicine, Houston.

The incidence of death was lower in the TZD users (20.5%) than the nonusers (25.4%). TZD users tended to be younger with higher ejection fractions, and less likely to be hospitalized for HF in the 2 years preceding the study. When adjusting for these differences, “the benefit with TZD use went away but we still couldn’t find a hazard,” said Dr Aguilar.

“I would use TZDs cautiously in patients with diabetes who have class I or II compensated HF,” he said. He indicated that many clinicians are already using these agents in patients with diabetes and HF without evidence to support that this practice is safe.

TZD use is not recommended for patients with NYHA class III or IV symptoms because they may exacerbate volume status and may worsen HF signs and symptoms.

• Pioglitazone had a beneficial effect on carotid intima media thickness (CIMT) compared with glimepride in patients with type 2 diabetes, said Theodore Mazzone, MD, lead investigator of the CHICAGO (Carotid Intima Media Thickness in Atherosclerosis Using Pioglitazone) study.

CIMT, a surrogate marker for atherosclerosis and cardiovascular risk, was measured at baseline and again at 72 weeks in 462 patients with type 2 diabetes who were randomized to either 15 to 45 mg/day of pioglitazone or 1 to 4 mg/day of glimeperide. To be eligible, patients could not have symptomatic coronary artery disease, cerebrovascular disease, peripheral arterial disease, or cardiac failure at baseline.

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Despite equivalent blood glucose control, posterior wall CIMT increased by .012 mm in the patients assigned to glimepiride and decreased by .001 mm in those randomized to pioglitazone ( = .017). Notably, about 60% of patients were on statins, and the effect of pioglitazone on CIMT was apparent in these patients as well, said Dr Mazzone, chief of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago.

One patient taking pioglitazone was hospitalized for heart failure, which was reversed upon discontinuation of the drug. Although CHICAGO was not powered to detect differences in clinical events, 10 cardiovascular events occurred in the glimepiride group vs 4 in the pioglitazone group.

“Pioglitazone could be part of a novel strategy to manage residual cardiovascular risk in type 2 diabetes,” said Dr Mazzone.

In healthy middle-aged men, a change in resting heart rate over 5 years predicts mortality during the next 2 decades, said Xavier P. Jouven, MD, PhD.

Change in heart rate predicts long-term mortality in men

“Measuring heart rate is not expensive and not invasive,” he said. “The role of and measurement of resting heart rate has been underestimated as a health indicator. We have to devote more scientific attention to resting heart rate.”

Resting heart rate, determined by measuring the radial pulse during a 1-minute recording, was measured in 4320 men between 1967 and 1972. The men were 42 to 53 years old at the time of the initial recording. They were divided into 9 groups according to their baseline heart rate (≤60 bpm, 61 to 75 bpm, and >75 bpm) and the change in heart rate from their first to fifth examination (decrease >7 bpm, change of -7 to +7 bpm, and increase >7 bpm).

After adjusting for standard cardiovascular risk factors, men whose resting heart rates increased by more than 7 bpm had a 47% increase in mortality over the 20-year follow up, whereas those whose resting heart rate decreased by more than 7 bpm had an 18% decrease in mortality. This relationship persisted when using changes in resting heart rate as small as 5 bpm or as great as 10 bpm, said Dr Jouven, of Hôpital Européen Georges Pompidou, INSERM, Paris.

The increased risk of mortality with an increase in heart rate occurred in men regardless of their baseline heart rate, he added.

“We can’t say for sure whether the increase in resting heart rate is only a marker for some other disease process or whether it is directly associated with mortality,” he said.

Heart rate changes could occur as a result of changes in physical activity, medications, or anxiety or other conditions, or may be due to genetic factors. Because his study was initiated before the era of beta blockers, this class of medications could be ruled out as a factor in the finding, he said.

Data from the Physician’s Health Study show that a history of migraine is another cardiovascular risk factor in men, reported Tobias Kurth, MD, ScD. The finding follows previous reports of a similar relationship between migraine and cardiovascular risk in women in the Women’s Health Study.

“We do not know how or why migraines are associated with increased cardiovascular risk,” said Dr Kurth, associate epidemiologist at Brigham and Women’s Hospital, Boston, Mass., and assistant professor of medicine at Harvard Medical School. “Physicians and patients with migraine should pay even more attention to traditional cardiovascular risk factors such as high blood pressure, diabetes, cholesterol, smoking, and obesity,” he said.

In the Physician’s Health Study, men who reported a history of migraine at baseline had a higher prevalence of hypertension and dyslipidemia. After controlling for these risk factors, the men with migraine still had a 24% increased risk of cardiovascular events compared with men with no history of migraine. The excess risk could be attributed to a 42% increased risk of myocardial infarction.

The mechanism behind the association is not clear, he said.