Coverage from the American College of Cardiology Meeting

Cardiology Review® Online, April 2006, Volume 23, Issue 4

News from the American College of Cardiology, March 11-14, 2006

Pulmonary vein ablation leads to cure in most AF patients

Atlanta—Circumferential pulmonary artery vein ablation offers a chance at a cure for paroxysmal atrial fibrillation (AF). Almost 90% of patients with AF who underwent the procedure as part of the Ablation for Paroxysmal Atrial Fibrillation (APAF) trial were free of recurrent AF at 9 months without the need for antiarrhythmic drug therapy, said Carlo Pappone, MD, lead investigator of APAF.

The finding came less than 1 month after investigators from the University of Michigan in Ann Arbor reported similarly successful results with pulmonary vein ablation for the treatment of chronic AF in the New England Journal of Medicine (2006;354:934-941).

“It’s possible today to cure AF and maintain sinus rhythm at 9 months in about 90% of patients,” said Dr Pappone, chief of the division of cardiac pacing and electrophysiology, San Raffaele University Hospital, Milan, Italy.

The APAF trial was the first to compare medical therapy with catheter ablation for paroxysmal AF using an appropriately powered, randomized, controlled design. Circumferential pulmonary vein ablation is a radiofrequency procedure used to modify the arrhythmogenic substrate surrounding the pulmonary vein ostia.

In the study, 199 patients who experienced an average of 3 AF episodes per month despite antiarrhythmic drug therapy were randomized to either drug treatment with amiodarone, flecainide, or sotalol, or circumferential pulmonary vein ablation.

Patients in both groups received anticoagulation therapy, which was discontinued if sinus rhythm persisted, positive left-atrial remodeling was documented, or an improvement in delayed transport function occurred.

Preliminary results from the first 150 patients followed for at least 9 months were reported here.

A repeat ablation procedure was performed in 9% of the patients randomized to catheter ablation for recurrent AF or atrial tachycardia. Eighty-seven percent of patients assigned to pulmonary vein catheter ablation were free of recurrent AF or atrial tachycardia at 9 months, compared with only 29% of patients assigned to drug therapy (P < .001).

All 65 of the patients treated with ablation who were in normal sinus rhythm at follow-up had stopped antiarrhythmic drug therapy, and all but 1 discontinued anticoagulation therapy. In this group, AF recurred in 8 patients, 5 of whom were placed on antiarrhythmic drug therapy and 3 of whom underwent another ablation procedure (1 of whom had recurrent AF).

Of the 52 patients randomized to antiarrhythmic drug therapy who had additional recurrent AF, 38 subsequently underwent pulmonary vein ablation, 4 of whom still had recurrent AF.

No serious adverse events occurred in the group undergoing pulmonary vein ablation, including no instances of pulmonary vein stenosis.

Patients older than 70 years and those with an enlarged atrium or ejection fraction <35% were excluded from APAF, noted Paul Armstrong, MD, University of Alberta, Edmonton, making it difficult to generalize the results of APAF to patients typically seen in clinical practice. Patients with AF in the community are often older and have heart failure, he said.

In the study published in the NEJM, 146 patients with chronic AF were randomized to amiodarone and 2 cardioversions alone or in combination with circumferential pulmonary vein ablation.

Of the 77 patients assigned to ablation, 32% required a repeat ablation because of recurrent AF or atypical atrial flutter. On an intent-to-treat basis, 74% of the patients randomized to ablation and 58% of the controls were free of recurrent AF or atrial flutter without antiarrhythmic drug therapy at 1 year.

Atlanta—Intensive statin therapy using 40 mg/day of rosuvastatin leads to regression of coronary atherosclerosis in patients with coronary artery disease (CAD), according to findings from a trial known as ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on In&shy;travascular Ultrasound-Derived Coronary Atheroma Burden).

Regression of atherosclerosis achieved with intensive statin therapy

The study represents the first evidence from intravascular ultrasound (IVUS) that treatment of low-density lipoprotein (LDL) cholesterol to levels significantly below currently accepted guidelines can cause regression of atherosclerotic disease, said Steven Nissen, MD, lead investigator of the study, and president of the American College of Cardiology.

“Prior angiographic and IVUS trials have shown reduced progression of coronary atherosclerosis with statin therapy, but not regression,” he said.

The large LDL cholesterol reduction was accompanied by an increase of almost 15% in high-density lipoprotein (HDL) cholesterol, which may have contributed to the effects observed.

“In ASTEROID…we were able to get the LDL cholesterol down to the lowest level ever achieved in a clinical trial to my knowledge, and that’s 60.8 mg/dL. Also, very surprisingly, we got an increase in the HDL of 14.7%, which is really un&shy;precedented,” said Dr Nissen, medical director of the Cleveland Clinic. “That combination led to really quite large regression of disease. It amounted to about 7% to 9% of the actual volume of plaque in the coronary artery, as measured by IVUS, and this occurred during a 2-year treatment period.”

Final IVUS data were available from 349 patients enrolled in ASTEROID. All patients had CAD, defined as >20% stenosis in any major coronary artery, and were treated with rosuvastatin, 40 mg/day. Their mean LDL cholesterol level at baseline was 130.4 mg/dL, which was lowered 53% by the end of 24 months of treatment. Their mean HDL cholesterol increased from 43.1 mg/dL at baseline to 49.0 mg/dL.

Atheroma volume decreased by a mean of 0.98% and a median of 0.79% from baseline (P < .001), and 63.6% of the study group experienced some regression of their atherosclerosis.

In looking at just the most diseased 10-mm segments of the patients’ arteries, atheroma volume in these segments regressed by a mean of 6.1 mm3 and a median of 5.6 mm3 (P < .001). “This change represents a median reduction of 9.1% in atheroma volume in the 10-mm segment with the greatest disease severity,” according to Dr Nissen.

“We know that plaque be&shy;gins to form often in the 20s and 30s,” he said. “Our average patient was 58 years of age, so think of this as partially re&shy;versing the disease that’s been accumulating for 3 decades.”

Although extrapolating reductions in atheroma volume to reductions in clinical events is speculative, “we’re looking at the disease itself with IVUS,” he said. “I expect that we’ll find that this signalis confirmed with morbidity and mortality benefit.”

Based on the results of ASTEROID, “maximally intensive statin therapy seems warranted in high-risk patients with CAD,” said Dr Nissen.

Despite the success of intensive therapy to reduce LDL cholesterol levels to well below those recommended in current guidelines for the treatment of patients with CAD, “it is by no means sufficient to alter guidelines, and individual physicians will make up their own minds about how compelling an argument can be made for taking LDL lower,” he added. “I wonder if the best standard is not to use target cholesterol levels but to say, let’s get our patients with coronary disease as low an LDL cholesterol as achievable without creating safety problems.”

The results of ASTEROID were published on line in the Journal of the American Medical Association to coincide with the presentation.

Atlanta—Adding clopidogrel to as&shy;pirin provides no further protection against cardiovascular events compared with aspirin alone in stable patients at high risk of cardiovascular events. In fact, in patients without existing cardiovascular disease but several vascular risk factors, the dual antiplatelet strategy in&shy;creases the risk of harm.

Dual antiplatelet strategy of no benefit in stable patients

These findings come from a study known as CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ische&shy;mic Stabilization, Management, and Avoidance), the results of which were announced by Deepak L. Bhatt, MD.

The reporting of the results of CHARISMA in the lay press apparently caused confusion among patients already taking clopidogrel, prompting the American Heart Association (AHA) to issue a statement that patients should continue taking it for approved indications. According to Ralph Sacco, MD, associate chair of neurology at Columbia University, New York City, and a spokesperson for the AHA/American Stroke Association, “… previous trials have documented the benefits of combined treatment with clopidogrel and aspirin for other groups of patients—those with heart attack or unstable angina (also called unstable coronary syndromes) and those who have had coronary angioplasty with stent placement.”

In CHARISMA, 15,603 patients with either documented cardiovascular disease or multiple risk factors for atherosclerosis were randomly assigned to placebo or clopidogrel, 75 mg/day, in addition to low-dose aspirin.

In the overall population of patients, the primary end point—the com&shy;bined rate of car&shy;diovascular death, myo&shy;cardial infarction (MI), or stroke—occurred in 7.3% of the group assigned to placebo and 6.8% as&shy;signed to clopidogrel at a median of 28 months of follow-up, a nonsig&shy;nificant difference.

There was evidence of potential harm by adding clopidogrel to aspirin in patients without qualifying cardiovascular disease. In these patients, dual thera&shy;py increased the risk of cardiovascular death/MI/stroke by 20% compared with aspirin alone (P = .20).

In the primary prevention cohort, severe bleeding was increased by 67% with the addition of clopidogrel to aspirin (P = .07) and moderate bleeding was increased by 60% (P = .08).

The excess deaths in the primary prevention group were not related to the increase in bleeding but rather an in&shy;crease in cardiovascular events, said Dr Bhatt, director of the Cardiovascular Trials Unit and associate director of the Cleveland Clinic Cardiovascular Co&shy;or&shy;dinating Center. “It didn’t appear that the ones who suffered bleeding were the ones who died,” he said.

The rate of death from cardiovascular causes in the primary prevention group was 3.9% among clopidogrel recipients and 2.2% in those assigned to placebo (P = .01).

When the analysis was limited to the 12,153 patients with established cardiovascular disease, clopidogrel reduced occurrence of the primary end point. In this group, the event rate was 7.9% in those assigned to placebo and 6.9% in those assigned to clopidogrel, a statistically significant relative risk reduction of 12.5% (P = .046).

The secon&shy;dary prevention patients had no excess in the risk of severe bleeding but did have a 63% increased risk of moderate bleeding (P < .001) compared with aspirin alone.

“Our hypothesis is that perhaps patients who fall under the secondary prevention umbrella have ‘revved up’ platelets, and adding clopidogrel to aspirin restores them to a steady state,” said Dr Bhatt. “The bleeding risk may be mitigated because their platelets are already revved up, whereas primary prevention patients are exposed to bleeding risk.”

He added, “the bottom line, in primary prevention, is that there is no reason to use clopidogrel based on its lack of efficacy and the excess bleeding seen.”

In responding to the subgroup analysis showing benefit to adding clopidogrel to aspirin for secondary prevention, W. Douglas Weaver, MD, chair of cardiology and co-director of the Heart and Vascular Institute at Henry Ford Hospital in Detroit, said, “The primary end point was negative. I don’t think it’s even fair to look at secondary end points. Our indications for clopidogrel should not change after this study.”

Atlanta—Anemia correction with twice monthly darbepoetin alfa in patients with heart failure improves symptoms, said Dirk J. van Veldhuisen, MD, PhD.

Anemia correction improves heart failure symptoms

Anemia occurs in 20% to 30% of patients with heart failure and is associated with worse symptoms and outcomes. Preliminary studies have shown that treating anemia with erythropoesis-stimulating proteins in patients with heart failure improves cardiac function and exercise capacity.

In a 26-week pilot study, 165 patients with New York Heart Association class II to IV heart failure, an ejection fraction of 40% or less, and anemia defined as a hemoglobin level of 9.0 to 12.5 mg/dL were randomized to placebo or darbepoetin alfa using 1 of 2 dosing strategies. Patients as&shy;signed to darbepoetin were treated subcutaneously every 2 weeks at either a starting dose of 0.75 µg/kg or a fixed dose of 50 µg. The doses of darbepoetin were titrated to achieve and maintain a target hemoglobin of 14 g/dL.

Most patients (95%) had functional class II or III heart failure. The mean hemoglobin level at baseline was 11.5 g/dL.

Both darbepoetin dosing regimens increased hemoglobin levels by 0.05 g/dL per week compared with placebo. “We were able to titrate the hemoglobin perfectly with twice-weekly dosing,” said Dr van Veldhuisen, lead investigator and professor and chairman of cardiology, University Medical Center, Gronin&shy;gen, the Netherlands. “This can be done very well in patients with heart failure.”

Patients assigned to darbepoetin had an improvement in their 6-minute walk distance relative to placebo starting at 14 weeks. By 26 weeks, darbepoetin-treated patients had an improvement of 34.2 m in the 6-minute walk test compared with an improvement of 11.4 m in the placebo recipients, a strong trend that did not quite reach statistical significance (P = .07).

Quality-of-life measures were im&shy;proved in the group treated with darbepoetin. Sixty-five percent of patients receiving darbepoetin showed improvement on the patient Global Assessment scale compared with 49% of placebo patients (P = .057).

On the Kansas City Cardiomyopathy Questionnaire, the total symptom score improved by 8.2 points in the darbepoetin group vs 1.5 points in the placebo group (P = .027). The frequency score, which reflects the frequency of symptoms such as edema, improved by 8.1 points in the darbepoetin group, whereas scores in the placebo group worsened by 2.6 points (P = .003).

Patients with the largest increases in hemoglobin levels had the greatest improvements in these measures.

Six patients in the darbepoetin group and none in the placebo group died, but the study was not adequately powered to detect differences in mortality, Dr van Veldhuisen said.

A larger study comparing darbepoetin alfa and placebo in heart failure patients with anemia produced the opposite effect—fewer deaths in pa&shy;tients randomized to darbepoetin, Dr van Veldhuisen said. (This study was not completed in time to be presented at the American College of Cardiology meeting, he said.) The 2 studies taken together “show a trend toward a reduction in deaths with darbepoetin,” he said.

A Phase III study of 3400 patients with heart failure and anemia, called Re&shy;duction of Events with Darbepoetin alfa in Heart Failure (RED-HF) trial, is evaluating the effect of anemia correction with darbepoetin alfa on morbidity and mortality in patients with symptomatic heart failure. The lead investigator is James B. Young, MD, professor and chairman, division of medicine, Cleve&shy;land Clinic.

“The pilot study found that hemoglobin could be raised safely in patients with heart failure, with some quality-of-life improvements,” he said. “We’re on solid footing to carry on this Phase III study.” The study is being carried out at 620 centers worldwide.

Response to aspirin and clopidogrel is variable; new antiplatelet agent may overcome resistance

Atlanta—Almost 7% of patients who present to the emergency department (ED) with suspected acute coronary syndromes (ACS) show resistance to a high dose of aspirin, and return trips to the ED and repeat hospitalizations are more frequent within 30 days among aspirin-resistant patients compared with those who are not aspirin-resistant.

Furthermore, a considerable number of patients with diabetes who are treated with dual antiplatelet therapy have a suboptimal response to both aspirin and clopidogrel.

Many claim that aspirin resistance may be overcome by increasing the aspirin dose to 325 mg, but this belief was not confirmed in a study by William Peacock, IV, MD, director of clinical operations in the department of emergency medicine, and colleagues at the Cleveland Clinic.

In their study, platelet aspirin resistance was determined in a sample of 200 patients presenting to the ED of a single large tertiary cardiac hospital. Eligible patients had at least 10 minutes of chest pain or an ischemic equivalent within the prior 24 hours. Patients re&shy;ceived 325 mg of aspirin, and after 2 hours their blood was assessed for platelet function using a bedside platelet function assay.

Overall, 13 (6.5%) were aspirin-resistant. Nearly one fourth (23.1%) of pa&shy;tients who were aspirin-resistant were defined as high risk. At 1 month of follow-up, 12.5% of the aspirin-resistant patients had ED revisits compared with only 4.9% who were not aspirin-resistant. Re&shy;hospitalization within 30 days occurred in 12.5% of the aspirin-resistant patients, compared with only 4.3% of those that were not aspirin-resistant.

In another study, investigators at San Carlos University Hospitals in Madrid, Spain, studied 187 patients with diabetes and stable coronary artery disease (CAD) who were on long-term aspirin (100 mg/day) and clopidogrel (75 mg/day). Platelet function testing found that 51% were resistant to aspirin and adenosine diphosphate (ADP)-induced platelet aggregation testing discovered 25% who were resistant to clopidogrel. Thirteen percent were resistant to both drugs, as evidenced by an increase in a battery of platelet biomarkers.

These same investigators performed a similar study in an&shy;other 86 pa&shy;tients with diabetes and known CAD who were on aspirin, 100 mg/day, and clopidogrel, 75 mg/day, for at least 1 month. Twenty-four pa&shy;tients were hy&shy;poresponders to clopidogrel on ADP platelet-induced aggregation testing.

In the hyporesponders, the “combination of clopidogrel and aspirin is not associated with synergistic antiplatelet effects,” said Dominick J. Angiolillo, MD, lead author of the study. “Alternative platelet regimens are warranted in these patients to achi&shy;eve more en&shy;hanced platelet inhibition.”

An alternative antiplatelet in Phase III clinical trials is prasugrel, a novel thienopyridine that blocks the P2Y12 adenosine diphosphate receptor and in&shy;hibits plat&shy;elet activation and aggregation mediated by this receptor.

The active met&shy;abolite of clopidogrel is formed in the liver, and response is variable to this metabolite. In contrast, the metabolic transformation with prasugrel occurs in the blood and the intestinal wall, resulting in a more efficient generation of the active metabolite.

In a study of 81 aspirin-treated pa&shy;tients with stable CAD, loading doses of prasugel (40 or 60 mg) or clopidogrel (300 mg) were administered and platelet aggregation was measured. More than 90% of prasugrel-treated patients achieved a greater than 20% inhibition of platelet aggregation, compared with less than 50% of patients assigned to clopidogrel. Patients with more active platelets at baseline had higher and more consistent platelet aggregation inhibition with prasugrel.

According to Andrew Frelinger, III, PhD, associate director of the Center for Platelet Function Studies at the University of Massachusetts, Worcester, “We hope that the ability of prasugrel to quickly and effectively inhibit platelet aggregation, by mechanisms distinct from and complementary to aspirin, will translate into improved clinical outcomes in future trials.”

Statins are underused in high-risk hypertensive patients

Atlanta—Many high-risk patients with hypertension are not receiving concomitant statin therapy despite the obvious benefit afforded by such therapy, found Richard H. Chapman, PhD.

“While research demonstrates that statin therapy could benefit hypertensive patients who have other cardiac risk factors, the majority of these patients were not receiving cholesterol-lowering statin drugs,” said Dr Chapman, a re&shy;searcher at ValueMedics Research in Falls Church, Va, and lead investigator of a study tracking medication use in high-risk hypertensive subjects.

In the study, medical and pharmaceutical claims from members of more than 75 health plans across the United States were used to identify adults who began treatment for hypertension over a 2.5-year period. Within this group of newly treated hypertensive patients, statin use was evaluated in 142,389 with either hypercholesterolemia, established coronary heart disease (CHD), or diabetes, or those without CHD but 3 or more major vascular risk factors.

Although 30% had documented hypercholesterolemia, only 17.3% were already on a statin when they started their antihypertensive drug therapy. Less than one third (29.4%) began taking statins during the first year. Therefore, more than half of the patients received no statin therapy within the first year of starting antihypertensive therapy.

In the group with hypertension and established coronary artery disease, only 11.5% were already on a statin, and only an additional 30.9% started during the first year.

More than 60% of the patients with diabetes and more than half (53.7%) with 3 or more CHD risk factors did not re&shy;ceive a statin during the first year.

Meanwhile, a new analysis finds that control of both blood pressure and lipids could reduce the number of CHD events over 10 years by more than one third.

Further, even more aggressive cotrol of both risk factors, defined as reducing blood pressure to less than 120/80 mm Hg and low-density lipoprotein cholesterol to less than 100 mg/dL, while increasing high-density lipoprotein cholesterol to more than 60 mg/dL, could prevent 75% of CHD events over 10 years, said Nathan D. Wong, PhD, lead investigator of the analysis, and director of the Heart Disease Prevention Pro&shy;gram at the University of California, Irvine. “The potential to reduce the number of CHD events by up to three fourths could have a tremendous positive effect on the health care system by preventing deaths, reducing suffering, and saving precious health care resources.”

Wong and colleagues examined the database of the National Health and Nutrition Examination Survey 2001-2002 for adults aged 30 to 74 years without CHD for whom blood pressure and blood lipid values were available. Of the 1921 people without CHD, 31% had hypertension, and they were categorized into the following groups: uncomplicated hypertension, moderate-risk hypertension (1 or more additional risk factors for CHD), complicated hypertension (3 or more additional CHD risk factors), hypertension with metabolic syndrome, or hypertension with diabetes.

Using the Framingham risk algorithm, the researchers found that achieving control of both blood pressure and lipids in those with uncomplicated hypertension would prevent almost 26,000 of the 91,000 expected CHD events over 10 years. Three fourths of events could be prevented with aggressive control of each risk factor in the subjects with moderate- or high-risk hypertension.

In the group with metabolic syndrome, aggressive control of both risk factors could prevent about 80% of the expected 1.1 million CHD events over 10 years, and in the patients with diabetes, aggressive control could prevent 346,000 of the expected 486,000 events.