Обзор американских кардиологических журналов за неделю (ссылки)

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World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease
Los Angeles • November 3 - 5, 2011

Clinicians Greet Early Results for Type 2 Biologic
LOS ANGELES -- In this exclusive video, Yehuda Handelsman, MD, president and organizer of the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease, talks about early results for a new monoclonal antibody for diabetes and other highlights of this year’s meeting.
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Overworked Kidneys May Be Tied to Stroke Risk
LOS ANGELES -- Renal hyperfiltration may be associated with a greater risk of stroke, especially in patients with the metabolic syndrome or diabetes, researchers found.
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One in Four May Have Hidden Prediabetes, Diabetes
LOS ANGELES -- Free screening by trained volunteers can pick up cases of dysglycemia and other diabetic conditions in the general population, researchers found.
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Selective Antibody Ups Insulin Sensitivity in Mouse Model
LOS ANGELES -- A monoclonal antibody selectively stimulated insulin signaling in vitro and improved fasting blood sugar in an animal study, but its effects on humans remain to be seen, researchers reported here.
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Pounds May Creep Back with Low-fat, Low-Carb Diets
LOS ANGELES -- Diets that cut out fats or carbohydrates may not lead to sustained weight reduction, according to a meta-analysis.
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Weight Loss Enriches Diabetics’ Quality of Life
LOS ANGELES -- Shedding excess pounds offers physical and mental health benefits for patients with type 2 diabetes, researchers found.
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Sleep Apnea Complicates Things in Diabetes
LOS ANGELES -- Diabetes patients with obstructive sleep apnea may have more autonomic dysfunction and also may be at greater risk of hypoglycemia, researchers said here.
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Cardiovascular
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Study: Xarelto Cuts Heart Attack Mortality

By Peggy Peck, Executive Editor,
November 13, 2011

Action Points
Explain that adding the oral anticoagulant rivaroxaban (Xarelto) to standard therapy after a myocardial infarction or other acute coronary syndrome episode significantly reduced the risk of death.


Point out that rivaroxaban is the first of the direct oral factor Xa inhibitors to demonstrate a benefit in acute coronary syndromes.


Note that although there were more bleeding incidents in the rivaroxaban group, and the rate of intracranial bleeding was higher than with placebo, there was not a significant increase in fatal bleeding events.
Review

ORLANDO -- Adding the oral anticoagulant rivaroxaban (Xarelto) to standard therapy after a myocardial infarction or unstable angina significantly reduced the risk of death, researchers reported here.

Patients randomized to 2.5 mg twice daily for 13 to 31 months were 34% less likely to die from cardiovascular disease than patients in the placebo group (HR 0.66, 95% CI 0.51 to 0.86 ) and 32% less likely to die from any cause (HR 0.68, 95% CI 0.53-0.87, P =0.002 for both), Jessica L. Mega, MD, MPH, of Brigham and Women's Hospital in Boston and colleagues, reported in a paper published online today by the New England Journal of Medicine.

The findings were also reported at a late-breaking clinical trials session at the American Heart Association meeting.

The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome (ATLAS-ACS 2 TIMI 51) randomized 15,526 patients to rivaroxaban 2.5 mg or 5 mg twice daily or matching placebo.

The 5 mg dose did not reduce the risk of death, but the rivaroxaban group as a whole had a 16% reduced risk of death (HR 0.84, 95% CI 0.74 to 0.96 P=0.008).

"In analysis of the components of the primary efficacy endpoint, rivaroxaban versus placebo had a hazard ratio of 0.80 (P=0.04) for death from cardiovascular causes (included hemorrhage-related deaths), 0.85 (P=0.47) for myocardial infarction, and 1.24 (P=0.25) for stroke (including ischemic hemorrhagic, and stroke of uncertain causes)," they wrote.

As might be expected, there were more bleeding incidents in the rivaroxaban group -- the rates of major bleeding not related to bypass surgery were 2.1% versus 0.6% (P<0.001) and the rate of intracranial bleeding was 0.6% versus 0.2% (P=0.009). But there was not a significant increase in fatal bleeding events, 0.3% versus 0.2% (P=0.66).

Rivaroxaban is a direct factor Xa inhibitor thus this safety finding takes on even greater significance given the history of this class of anticoagulants in this population.

A year ago, a phase III trial of apixaban was halted due to bleeding events, and in September Astellas Pharma discontinued development of darexaban maleate, following a report at the European Society of Cardiology that the drug caused excess bleeding in ACS patients.

The ATLAS-ACS researchers noted the differences in findings between their study and the earlier apixaban study, and they offered an explanation: ATLAS-ACS was specifically designed to exclude patients that proved problematic in the apixaban ACS study, those "who had a history of ischemic stroke or transient ischemic attack who were to be treated with aspirin and a thienopyridine, a group that has not appeared to benefit from greater decrees of antithrombotic therapy."

In a statement released by the trial's sponsor, Johnson & Johnson Pharmaceutical Research & Development, Eugene Braunwald, MD, of Harvard Medical School in Boston, said the addition of rivaroxaban to standard antiplatelet therapy "could lead to significant improvement in the management of patients with acute coronary syndrome." Braunwald is the founding chair of the Thrombolysis In Myocardial Infarction (TIMI) Study Group at Brigham and Women's Hospital.

Another researcher, C. Michael Gibson, MD, principal investigator of the ATLAS-ACS 2 TIMI 51 trial, and a senior TIMI investigator, was even more ebullient.

"If the data from ATLAS ACS 2 TIMI 51 were extrapolated into clinical practice, we could potentially see one life saved for every 56 patients treated with this combination of therapies over a two year period," Gibson said a statement released by Johnson & Johnson.

In an editorial published with the NEJM paper, Matthew T. Roe, MD, and E. Magnus Ohman, MB, from Duke Clinical Research Institute in Durham, N.C., pointed out that the bleeding rates appeared to be dose dependent as they occurred more often at the higher dose. Moreover, bleeding events were more common after 180 days on treatment and there were numerically higher rates of bleeding in "lighter-weight and elderly patients, as well as in those with reduced renal function and those enrolled in North America."

Since many ACS patients are elderly, that observation warrants additional study, Roe and Ohman noted.

And the findings in North America also require careful interpretation because only 5%-6% of the patients were enrolled in North America -- the highest enrollment was at centers in Eastern Europe, where about 40% of patients were enrolled, followed by centers in Asia (21%) and Western Europe (15%).

A similar regional difference was observed in the pivotal PLATO trial of the antiplatelet ticagrelor (Brilinta). That study, which was also headed by the TIMI researchers, compared ticagrelor with clopidogrel in 18,624 ACS patients and it reported overwhelmingly positive results for the study drug -- 9.8% reached the composite endpoint of death, stroke, or MI versus 11.7% of clopidogrel patients, a relative reduction of 16% (P<0.001).

But most of the PLATO patients came from Europe, the Middle East, or Africa. Only 11% of the patients were recruited in North America. In that cohort, ticagrelor-treated patients were 27% more likely to suffer one of the endpoint events, although the difference fell short of statistical significance (HR 1.27, 95% CI 0.92 to 1.75).

Nonetheless, that nonstatistical difference caught the eye of FDA reviewers and the drug's approval was held up for 12 months.

In ATLAS-ACS the average age of patients was 62 and roughly 75% were white males. About half of them had an ST-elevation MI, 25% had non-ST-elevation MI, and 25% had unstable angina. Sixty percent underwent revascularization with either coronary artery bypass graft or stenting.

Background medications included aspirin (99%), thienopyridine (93%), beta-blockers (66%), ACE inhibitor or ARB (40%) statin (84%), and calcium channel blocker (15%).

[Chevychelov]

AHA: Novel Antiplatelet Increases Bleeding in ACS

By Peggy Peck, Executive Editor,
November 13, 2011

Action Points
Explain that giving a novel antiplatelet, vorapaxar, to acute coronary syndrome patients did not reduce mortality or serious cardiovascular events.


Note that the drug was associated with a significant increase in the risk of major bleeding, including a three-fold increase in intracranial hemorrhage.
Review

ORLANDO -- Giving a novel antiplatelet, vorapaxar, to acute coronary syndrome patients did not reduce mortality or serious cardiovascular events, but it did significantly increase the risk of major bleeding, including intracranial hemorrhage, researchers said here.

It was known that the drug, an oral protease-activated-receptor 1 (PAR-1) antagonist had safety issues because the trial was halted last January, after an unplanned safety review of TRACER data, but the magnitude of the problem was not known: A 35% increase in the relative risk of major bleeding events, and more than a three-fold increase in the risk of intracranial hemorrhage (HR 3.39, 95 % CI, 1.78 to 6.45, P<0.001 for both).

Kenneth W. Mahaffey, MD, DrSc, of the Duke Clinical Research Institute in Durham, N.C., and colleagues reported the findings from the 12,944-patient study as a late-breaking clinical trial at the American Heart Association meeting. The findings were also published online by The New England Journal of Medicine.

The primary endpoint of the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial was a composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.

During a mean follow-up of 502 days, 1,031 of the 6,473 patients in the vorapaxar group reached that composite endpoint as did 1,102 of the 6,471 controls (P=0.07).

There was, however, a signal of efficacy when only death from cardiovascular causes, MI, or stroke were considered: 822 vorapaxar patients versus 910 patients in the placebo control group (P=0.02).

Mahaffey noted that the findings were especially disappointing since there was no hint of a safety problem in an earlier phase II study.

In a statement, Robert Harrington, MD, director of the Duke Clinical Research Institute and chair of the TRACER study's steering committee, said that the "lower incidence of cardiovascular death, heart attack, or stroke with vorapaxar while not significant, is promising." He noted that another study, TRA 2P TIMI 50 is planned and he was still hopeful that development of the drug would eventually be fruitful.

The median age of patients in TRACER was 64 and more than 70% were men, most of them white males (85%).

Background medications included clopidogrel (92%) and aspirin (99%) while 21% were taking glycoprotein IIb/IIIa inhibitors.

Patients in the vorapaxar group were given 40 mg of the drug as a loading dose followed by 2.5 mg daily.

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AHA: Extended Apixaban Fails to Beat Enoxaparin for VTE

By Ed Susman, Contributing Writer,
November 13, 2011

Action Points
Explain that medically ill patients at risk for venous thromboembolism (VTE) did not obtain significant benefit from month-long treatment with apixaban (Eliquis) when compared with two weeks of treatment with the enoxaparin (Lovenox).


Point out that treatment with apixaban also was associated with significantly more bleeding episodes.
Review

ORLANDO -- Medically ill patients at risk for venous thromboembolism (VTE) did not obtain significant benefit from month-long treatment with apixaban (Eliquis) when compared with two weeks of treatment with the enoxaparin (Lovenox), researchers reported here.

The primary endpoint of the composite of death caused by VTE, or evidence of VTE, was experienced by 2.71% of the patients on apixaban, an anticoagulant, and by 3.06% of patients enoxaparin, a low molecular-weight heparin (relative risk with apixaban, 0.87; 95% CI 0.62 to 1.23, P=0.44), according to Samuel Z. Goldhaber, MD, from Brigham & Women's Hospital and Harvard Medical School in Boston.

"In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin," Goldhaber and colleagues reported at the annual scientific sessions of the American Heart Association.

The results of the Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial were simultaneously published in the online version of the New England Journal of Medicine. A total of 6,528 subjects underwent randomization and 4,495 could be evaluated for the primary efficacy outcome with 2,211 in the apixaban group and 2,284 in the enoxaparin group.

Goldhaber also noted that without establishing superiority over enoxaparin, treatment with apixaban also was associated with significantly more bleeding episodes. Major bleeding was observed in 15 of 3,184 patients (0.47%) assigned to apixaban in the double-blind, randomized clinical trial, but was seen in just six of 3,217 patients (0.19%) among those who were receiving enoxaparin (P=0.04).

The patients were assigned to receive apixaban (2.5 mg twice a day) for 30 days or enoxaparin (40 mg once daily) subcutaneously for six to 14 days. The participants in the trial were acutely ill patients with congestive heart failure or respiratory failure, with one additional risk factor for venous thromboembolism.

The primary endpoint was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis or asymptomatic proximal-leg deep-vein thrombosis as detected with the use of systemic bilateral compression untrasonography on day 30.

The mean age of the patients in the international trial was about 67 years. The patients were evenly stratified by sex. About three-quarters of the patients were white, about 10% were Asian and about 9% were black. About three-quarters of the patients were hospitalized for congestive heart failure or respiratory failure; another 21.5% were hospitalized for infections.

Goldhaber suggested that the strategy of extended prophylaxis with apixaban may have promise, despite the negative results of the trial. "This trial was underpowered," he explained. He noted there was a 13% reduction in primary outcome events with apixaban.

Among evaluable patients, the researchers recorded 60 events in patients on apixaban therapy and 70 events in patients taking enoxaparin.

"The ADOPT trial does not provide evidence to justify a policy of extended prophylaxis in a broad population of medically ill patients after hospital discharge," Goldhaber said.

"However, with event rates of venous thromboembolism at 30 days that range from 3% in the ADOPT trial to 5% and 6% in the EXCLAIM and MAGELLAN trials, respectively, it is clear that the risk of venous thromboembolism increases beyond the time of hospital discharge," he explained.

"More precise risk-stratification methods are needed to identify a narrower spectrum of medically-ill patients who may benefit from extended prophylaxis," he said.

Goldhaber told MedPage Today that the study hints that apixaban might be successful in treating patients after they have been discharged from the hospital and are sent home. "In today's world, patients are being sent home from the hospital earlier and there is still an incidence of venous thromboembolism after they go home," he said.

Goldhaber also said the study's requirement that patients return for ultrasound testing cost the trial its statistical power. "We lost nearly 1,000 patients in each arm of the trial because patients did not return for that additional test, which looked for asymptomatic VTE," he explained.

He suggested that longer treatment with apixaban -- perhaps for 40 days or more after hospital discharge -- might make a significant difference in outcomes.

He suggested that one legacy of ADOPT would be a more specific trial aimed at prophylaxis following hospitals discharge.

"This is an important public health problem that we need to address," said May Cushman, MD, professor of medicine at the University of Vermont, Burlington. "The problem is we don't really understand which of these patients are at the highest risk for venous thromboembolism." She said that scores developed by various sources to assess risks have not been validated.

Cushman said that in most studies of venous thromboembolism, therapy does not extend beyond hospital discharge -- and yet evidence indicates that events continue to occur three months after discharge and about half the events occur after hospital discharge. "The 10-day or 30-day follow-up in this trial is not long enough to detect events in this high risk population," she said.

She said the study emphasizes the "urgent need" to develop valid risk detection models; to use therapies with the lowest bleeding risk, to continue follow-up after treatment and to perform more studies of post-discharge treatment.

Apixaban is currently approved in Europe for short-term use in Europe. Bristol-Myers Squibb and Pfizer are seeking approval in the U.S. and Europe for stroke-prevention in atrial-fibrillation patients.

[Chevychelov]

AHA: Afib Onset in Sepsis May Be Prognostic for Stroke

By Crystal Phend, Senior Staff Writer,
November 13, 2011

Action Points
Note that this was a retrospective, population-based cohort study to investigate the relationship between severe sepsis, atrial fibrillation, and stroke/death.


Note that new onset atrial fibrillation occurred in 5.9% of patients with severe sepsis, and that atrial fibrillation was associated with an increased odds of both ischemic stroke and death.


This study, which was based on administrative claims data, had several significant limitations. However, the findings were robust across a range of sensitivity analyses.
Review

ORLANDO -- Atrial fibrillation that develops during severe sepsis predicts high mortality and stroke risk, an observational study found.

Fully 56% of severe sepsis patients with new-onset atrial fibrillation died in the hospital compared with 39% mortality among other severe sepsis patient, reported Allan J. Walkey, MD, MSc, of Boston University, at the American Heart Association meeting.

After adjustment for other factors, the excess risk from developing the arrhythmia during hospitalization for severe sepsis was only 7%, but remained significant at P<0.001 in the population-based study, released simultaneously online in the Journal of the American Medical Association.

Incident atrial fibrillation also more than doubled the risk of having a stroke during hospitalization for severe sepsis, with a rate of 2.6% compared with 0.6% among other severe sepsis patients (adjusted odds ratio 2.70, P<0.001).

If causal links are found, these results could be important for intensivists, noted Christopher H. Goss, MD, MSc, of the University of Washington in Seattle, and Shannon S. Carson, MD, of the University of North Carolina at Chapel Hill, in a JAMA editorial accompanying the paper.

Acute cardioversion, anticoagulation, or both might help prevent stroke complications but can be challenging in this population, they observed.

"It is difficult to maintain successful cardioversion as long as severe sepsis persists, perhaps because acute risk factors such as high catecholamine states have not yet resolved," Goss and Carson pointed out.

"Anticoagulation presents additional risks for patients with severe sepsis due to coagulation abnormalities and frequent invasive procedures," they added.

A causal association is plausible, they noted, pointing to key sensitivity analyses in the study.

There were more than 49,000 severe sepsis cases recorded in the California State Inpatient Database of administrative claims from nonfederal acute care hospitals across the state during 2007. Among those cases, 5.9% developed new-onset atrial fibrillation.

Patients who appeared to have developed atrial fibrillation during their severe sepsis hospitalization had 3.63-fold higher adjusted ischemic stroke risk than those with preexisting atrial fibrillation (P<0.001), which itself didn't predict higher in-hospital stroke risk compared with the severe sepsis population who did not develop atrial fibrillation (P=0.054).

Restricting the analysis to only patients without atrial fibrillation at admission, such that sepsis likely predated the arrhythmia, didn't attenuate the association with stroke, the researchers reported.

Another finding supporting causality was that patients with new-onset atrial fibrillation during their severe sepsis hospitalization tended to be more likely than those without atrial fibrillation to be rehospitalized later with an incident ischemic stroke (adjusted hazard ratio 1.51, P=0.06).

The results also remained significant across increasingly stringent definitions of ischemic stroke, while the mortality link with incident atrial fibrillation also persisted across a range of multivariate adjustments.

Nevertheless, the study's retrospective analysis of administrative claims code couldn't rule out alternative explanations for the associations, the editorialists warned.

For example, an ICU patient admitted for surgery might experience postoperative atrial fibrillation as a complication, and then a stroke that leads to aspiration pneumonia and severe sepsis, they noted.

Residual confounding was possible as well. These included different doses and types of vasopressors used to treat septic shock, which predisposed to atrial fibrillation, but also indicated more severe shock, cerebral hypoperfusion, and higher risk of death.

Another limitation noted by the researchers was that atrial fibrillation episodes may have been more likely to have been coded in claims if clinicians thought it was linked to a stroke, than if deemed clinically insignificant.

"Given the limitations of these observational data, current practice should not change in favor of interventions that could involve additional risk," Goss and Carson concluded.

[Chevychelov]

ATLAS ACS: Adding rivaroxaban to antiplatelet therapy reduced death rates in ACS
By

AHA Scientific Sessions 2011

ORLANDO — Rivaroxaban added to standard treatment reduced the risk for CV death, MI and stroke among patients with acute coronary syndrome, but was associated with an increase in TIMI major bleeding, according to C. Michael Gibson, MS, MD, who presented results of the ATLAS ACS 2-TIMI 51 trial.

Both “very low” and “low” doses of the drug (2.5 mg and 5.0 mg twice daily) were superior to placebo. However, the twice-daily 2.5-mg dose may be the more effective option to reduce CV events in patient with recent ACS.

“Rivaroxaban did reduce the risk for CV death, MI or stroke across a full spectrum of ACS, [from] low risk to high risk,” Gibson, an interventional cardiologist and chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center, Boston, said during a press conference. “The risk for major bleeding was higher with the rivaroxaban arm; however, there was no excess risk for fatal [intracranial hemorrhage] or fatal bleeding, particularly in the 2.5-mg arm. One death would be prevented if 56 patients on current antiplatelet therapies were treated for 2 years with ‘very low’ dose rivaroxaban.”

The study, simultaneously published in the New England Journal of Medicine, included 15,526 patients with recent ACS. All participants were randomly assigned to 2.5 mg or 5 mg rivaroxaban (Xarelto, Johnson & Johnson) twice daily or placebo for up to 31 months. The primary endpoint was a composite of CV death, MI or stroke.

Two-year Kaplan Meier estimates demonstrated that, together, both doses of rivaroxaban reduced the risk for CV death, MI and stroke as compared with placebo (8.9% vs. 10.7%; HR=0.84; 95% CI, 0.74-0.96). Additionally, rivaroxaban at both doses was associated with a reduced risk for stent thrombosis (2.3% vs. 2.9%; HR=0.69; 95% CI, 0.51-0.93).

Compared with placebo, the 5-mg dose was associated with an improvement in the primary endpoint (10.7% vs. 8.8%; P=.03), as was the 2.5-mg dose (10.7% vs. 9.1%; P=.02). The 2.5-mg dose was also associated with a decrease in the rate of death from CV causes (2.7% vs. 4.1%; P=.002) and from any cause (2.9% vs. 4.5%; P=.002). This was not seen, however, with the 5-mg dose.

The risk for non-CABG major bleeding was increased in the rivaroxaban group vs. placebo (2.1% vs. 0.6%; P<.001); this was significant for both doses (P<.001). Compared with placebo, rates of TIMI minor bleeding (0.5% vs. 1.3%; P=.003), TIMI bleeding requiring medical attention (7.5% vs. 14.5%; P<.001) and intracranial hemorrhage (0.6% vs. 0.2%; P=.009) were higher in the combined rivaroxaban group. However, there was no significant increase in fatal bleeding with rivaroxaban (0.3 vs. 0.2%; P=.66).

Compared with the 5-mg dose, the 2.5-mg dose was associated with fewer fatal bleeding events (0.4% vs. 0.1%; P=.04).

“We believe that the results of this study are an important development for relatively young and healthy patients with an ACS,” Matthew T. Roe, MD, and E. Magnus Ohman, MB, FRCPI, wrote in an accompanying editorial published in NEJM. “However, there is much work still to be done, since a large proportion of patients with an ACS who are treated in routine practice are elderly with multiple coexisting illnesses.”

According to Roe and Ohman, based on the balance between ischemic benefit and bleeding risk, a better understanding of the role of rivaroxaban in higher-risk must be ascertained. – by Stacey L. Fisher

[Chevychelov]

ASH: Aspirin Lowers Clot Risk After Anticoagulant Tx

By Kurt Ullman, Contributing Writer,
Reviewed by
November 14, 2011

Review

SAN DIEGO -- Aspirin greatly reduces the risk of venous thromboembolism (VTE) when given up to a year after anticoagulant treatment, with no increase in bleeding, Italian researchers reported.

VTE risk was reduced by nearly 40% when given after six to 12 months of oral anticoagulant treatment, reported Cecilia Becattini, MD, from the University of Perugia, Italy, and colleagues, in a study to be presented next month at the American Society of Hypertension annual meeting.

"Recurrence occurs in 15% to 20% of patients with unprovoked VTE in the two years after withdrawal of oral anticoagulant treatment," the authors noted. "Extending anticoagulant is effective but associated with increased bleeding risk."

To further clarify the issue, the investigators initiated the Warfarin and ASA Study (Warfasa), a double-blind, randomized, placebo-controlled event-driven study. A total of 402 patients with a first-ever unprovoked VTE who had completed six to 12 months of oral anticoagulation treatment were randomized to receive either 100 mg of aspirin daily or placebo. They were followed for at least two years.

VTE recurrence was seen in 27 of the 205 patients receiving aspirin and 42 of the 197 patients who were given placebo (6.3% versus 11.0% patient-years; HR 0.57; 95% CI 0.35 to 0.93).

While on study treatment, 22 patients who received aspirin and 38 patients given placebo had a recurrence (5.7% versus 10.7% patient-years; HR 0.54; 95% CI 0.32 to 0.91).

The mean on-study treatment period was 22 months.

One patient in each group had a major bleeding episode. There was a similar occurrence of clinically relevant non-major bleeding.

"For its safety, practicality, and low cost, aspirin is a valid alternative to oral anticoagulants in the extended treatment of VTE," the investigators concluded.

[Chevychelov]

AHA: Abciximab Straight to Heart No Help in PCI

By Crystal Phend, Senior Staff Writer,
November 14, 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 large, randomized trial indicates that the intracoronary administration of abciximab, although safe, is not associated with measurable outcome benefits compared to the standard IV bolus.
Review

ORLANDO -- Injecting the glycoprotein IIb/IIIa inhibitor abciximab (ReoPro) directly into the heart during percutaneous coronary intervention (PCI) doesn't boost the agent's benefits, researchers found.

The intracoronary approach to bolus administration appeared safe for myocardial infarction (MI) patients in the AIDA STEMI trial, Holger Thiele, MD, of the University of Leipzig Heart Center in Leipzig, Germany, reported here at the American Heart Association meeting.

But the rate of death, reinfarction, and new onset congestive heart failure was similar for intracoronary and intravenous administration at 7% compared with 7.6% (P=0.58).

The only significant advantage of intracoronary administration was lower incidence of heart failure as an individual outcome (2.4% versus 4.1%, P=0.04).

"However, this might be an effect of chance," Thiele said at an AHA press conference where he presented the late-breaking clinical trial results.

The heart failure curves diverged rapidly and maintained their separation for the duration of the trial.

But Thiele noted that his group could not confirm that ST-segment MI resolution or infarct size, as assessed indirectly by the release of creatine kinase, was any different between groups (P=0.37 and P=0.74, respectively).

While guidelines from the AHA and other organizations suggest the intracoronary route may be reasonable, IV administration should remain the standard of care for abciximab, said study discussant Alice Jacobs, MD, of Boston Medical Center.

"There should be no change in clinical practice," she said.

The study included 2,065 patients in Germany undergoing PCI for suspected STEMI, who were randomized to receive a 0.25 mg/kg bolus of abciximab via IV or intracoronary infusion, both followed by a 12 hour IV infusion at 0.125 μg/kg per minute.

But a lower than expected event rate meant the trial was somewhat underpowered and could not exclude a small to moderate difference in outcome between the two arms, although that was unlikely looking just at the absolute numbers, Jacobs noted.

Mortality rates were 4.5% in the intracoronary group versus 3.6% in the IV group (P=0.36). Reinfarction rates were 1.8% in both groups.

The only subgroup that appeared to derive greater benefit from abciximab when given as an intracoronary infusion was women.

"Whether the lack of difference in outcome is due to the lower risk patients with lower event rate; a more rapid distribution of IV abciximab, which we know does occur; or the background of dual-antiplatelet therapy remains unclear," Thiele said.

The safety too was similar between intracoronary and IV groups:
In-hospital stroke (0.5% versus 0.7%, P=0.70)
Stent thrombosis (1.7% versus 2%, P=0.65)
Severe, moderate, and mild bleeding events by GUSTO trial criteria (2.6% versus 1.8%, 2.6% for both, and 8% versus 8.5%, respectively; P=0.63)
Hemodynamic compromise during abciximab bolus (0.1% versus 0.6%, P=0.06)
Life-threatening arrhythmia during PCI (1.7% versus 2.1%, P=0.22)


Further studies might still look at intracoronary abciximab for patients with large infarcts and thrombus burden or no reflow, Jacobs suggested.

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AHA: Sexual Abuse Tied to Greater Heart Disease Risk

By Todd Neale, Senior Staff Writer,
November 14, 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 in this study, severe physical and sexual abuse in childhood and adolescence -- but not less severe abuse -- were significant risk factors for increased cardiovascular event risks in adult women, mediated, at least in part, by increased adult risk factors for cardiovascular disease.
Review
ORLANDO -- Women who were forced to have sex as children or teens appear to carry a higher risk of cardiovascular disease in adulthood, researchers found.

Even after accounting for traditional cardiovascular risk factors, a history of forced sexual activity was associated with a 34% increased relative risk of myocardial infarction (MI) or stroke, according to Janet Rich-Edwards, ScD, MPH, of Brigham and Women's Hospital in Boston.

There was a similar trend for victims of severe physical abuse, although adjustment for adult body mass index, smoking, alcohol use, hypertension, and diabetes rendered the association nonsignificant, Rich-Edwards reported at the American Heart Association meeting.


The findings related to sexual abuse are consistent with two previous epidemiological studies, which "suggests that we continue our abuse prevention efforts in childhood and that we also develop specific cardiovascular disease prevention therapies tailored to the needs of women who experienced abuse in childhood," she said.

In the mid-1990s, the National Violence Against Women Survey of 8,000 women showed that about half of the respondents reported being physically assaulted at some point in their lives, and 18% had been the victims of completed or attempted rape.

Most of the rapes occurred before the women turned 18. Overall, 9% of girls younger than 18 were raped.

Two previous studies have shown an association between childhood abuse and a greater risk of cardiovascular disease.

The Adverse Childhood Experiences study of more than 17,000 men and women found an association with both physical and sexual abuse, whereas the National Comorbidity Study of nearly 6,000 men and women showed a relationship with sexual abuse in women only.

To further explore the issue, Rich-Edwards and colleagues examined data from the Nurses' Health Study II, which surveyed female nurses from 14 states. The women were between the ages of 25 and 42 at baseline in 1989 and between 43 and 60 at the end of follow-up in 2007.

Every other year, the women filled out a questionnaire, and in 2001, they completed an assessment of previous experiences with violence.

The current analysis included 67,315 women who were free from cardiovascular disease and cancer at baseline who completed the violence questionnaire.

Spanking for discipline was not counted as physical violence. The assessment of sexual abuse included both unwanted sexual touching and forced sexual activity.

Overall, 54% of the women said they experienced at least mild physical abuse when they were younger than 18, including 9% who said it was severe.

One-third of women said they had been sexually abused before age 18, including 22% who said it involved unwanted touching and 11% who said it involved forced sexual activity.

During follow up, just 0.8% of women reporting having an MI or stroke, the definition used for cardiovascular disease.

After adjustment for age, race, parental history of cardiovascular disease, body type at age 5, and parental education, both severe physical abuse and forced sexual activity were significantly associated with an increased risk of cardiovascular disease (HRs 1.46 and 1.56, respectively), compared with women who reported no sexual or physical abuse.

Further adjustment for adult BMI, smoking, alcohol use, hypertension, and diabetes, eliminated the association with severe physical abuse and attenuated the relationship with forced sexual activity. Those additional risk factors explained 47% and 38% of each association, respectively.

This suggests that some of the burden of adult cardiovascular disease in women with a history of abuse could be prevented by addressing those risk factors, but there is still much that is unexplained, Rich-Edwards said.

The findings have implications for adult primary care practice, she said.

Physicians should be able to raise the issue, "and point out for women that, though they may have had their bodies disrespected as children, there's a lot they can do as adults to take good care of themselves, including all of our standard cardiovascular [disease] prevention efforts," she said, noting that those efforts probably should be undertaken earlier than usual.

Rich-Edwards said further research is needed to explain the possible mechanisms linking childhood abuse and adult cardiovascular disease beyond traditional risk factors.

"What is clear is that this association is strong; that [sexual abuse is] also associated with these other cardiovascular risk factors; and that we need to do a better job of screening and identifying childhood sexual abuse at an early age," commented Donna Arnett, PhD, an epidemiologist at the University of Alabama at Birmingham and president-elect of the AHA.

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Hypertension Before Pregnancy Tied to Depression During

By Judith Groch, Contributing Writer,
November 14, 2011

Action Points
Note that depression in pregnancy has an adverse effect on outcomes and has been associated with a higher risk of preterm birth and low birth weight as well as postpartum depression.


Point out that in this prospective study, pregnant women with preexisting hypertension, but not pregnancy-induced hypertension, were found to have a higher risk of depression and suggesting that they should be screened for depression.
Review

Women with a pre-pregnancy history of hypertension may be at a higher risk for depression than women who develop hypertension during pregnancy, a single-center study found.

Pregnant women with pre-existing hypertension, with or without superimposed preeclampsia, were 55% to 65% more likely to have significant depressive symptoms or to be taking antidepressants.

No relationship, however, was found between depression and pregnancy-related hypertension, Wayne J. Katon, MD, of the University of Washington School of Medicine in Seattle and colleagues reported General Hospital Psychiatry.

Prior studies had suggested a link between depression and pregnancy-induced hypertension, but have not examined a possible relationship with pre-existing hypertension. Thus the researchers decided to examine the association of minor and major depressive disorders, as well as antidepressant use with both pre-existing and pregnancy-related hypertension.

The study included 2,398 women receiving ongoing prenatal care at a university-based obstetrics clinic from January 2004 through January 2009. Depression prevalence was measured using the DSM-IV MD criteria based on the Patient Health Questionnaire-9 and on self-reported use of antidepressant medication. The primary independent variable in the study was hypertension.

Evidence of pre-existing hypertension, pregnancy-induced hypertension and preeclampsia/eclampsia was determined by codes from the International Classification of Diseases. Logistic regression analysis was used to quantify the association between hypertension in pregnancy and antenatal depression.

After adjusting for sociodemographic variables, chronic medical conditions, smoking, and prior pregnancy complications, women with pre-existing hypertension were found to have a 55% increased risk of any depression (minor, major, use of antidepressants [odds ratio 1.55, 95% CI 1.08 to 2.23]) versus women without hypertension.

The increased risk for pre-existing major depression and/or use of antidepressants was 65% (OR 1.65, 95% CI, 1.10 to 2.48).

On the other hand, the researchers reported that compared with those without prior hypertension, pregnancy-related hypertension including preeclampsia was not associated with an increased risk of any depression or major depression.

The researchers emphasized that women with pre-existing hypertension should undergo depression screening. Depression in pregnancy has been associated with a higher risk of pre-term birth and low birth weight, as well as postpartum depression, they said.

In addition, depression in patients with chronic medical illnesses is associated with poor adherence to medical regimens, such as diet and exercise programs and taking medications as prescribed. About 10% to 25% of women with pre-existing hypertension go on to develop superimposed preeclampsia. Understanding high-risk groups is essential for determining treatment, Katon said.

Future studies need to examine whether depression in pregnant women affects adherence to anti-hypertensive medication as well as progression among women with pre-existing hypertension to worsening hypertension and preeclampsia.

Study limitations included the use of data from a single, albeit large, obstetrics clinic in one U.S region. Other limitations included lack of structured psychiatric interviews to confirm diagnoses and the failure to assess body mass index, although the researchers did control for type 2 diabetes.

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SATURN and AIM-HIGH: Back down to planet Earth
by Seth S. Martin, MD and Roger S. Blumenthal, MD
By

Again this year, clinical trials evaluating lipoprotein-modifying therapies are in the spotlight at the American Heart Association Scientific Sessions 2011, with concurrent publications in The New England Journal of Medicine.

SATURN

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) is a prospective, randomized, multicenter, double blind clinical trial led by Stephen J. Nicholls, MD, Steven E. Nissen, MD, and colleagues. These investigators performed serial IVUS at baseline and after 104 weeks of treatment in 1,039 patients with CHD.

Patients were randomly assigned to treatment with atorvastatin (Lipitor, Pfizer) 80 mg daily or rosuvastatin (Crestor, AstraZeneca) 40 mg daily. The rosuvastatin group attained lower LDL levels than the atorvastatin group (63 mg/dL vs. 70 mg/dL; P,.001) and slightly higher levels of HDL (50 mg/dL vs. 49 mg/dL; P=.01); however, the primary efficacy endpoint — percent atheroma volume — did not differ between the groups. Coronary atherosclerosis regressed with both treatment strategies: by 0.99% (95% CI, –1.19 to –0.63) with atorvastatin and by 1.2% (95% CI, –1.52 to –0.90) with rosuvastatin. Both agents induced regression in most patients: 63% with atorvastatin and 68.5% with rosuvastatin.

AIM-HIGH

In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial, 3,414 patients with established CVD were randomly assigned to extended-release niacin 1,500 mg to 2,000 mg daily or matching placebo with 50 mg of niacin per tablet to mask treatment identity. Both groups received simvastatin (Zocor, Merck) 40 mg to 80 mg and ezetimibe (Vytorin, Merck/Schering-Plough) 10 mg daily, as needed, to maintain LDL levels between 40 mg/dL and 80 mg/dL.

The trial was stopped for a lack of efficacy after an average follow-up of 3 years. Despite an improvement in the lipid profile, including a significant increase in median HDL from 35 mg/dL to 42 mg/dL, there was no difference between the groups in the incidence of the primary composite endpoint of CHD death, nonfatal MI, ischemic stroke, hospitalization for an acute coronary syndrome or symptom-driven coronary or cerebral revascularization.

It was clearly a challenge to end the AIM-HIGH trial after a mean follow-up of 3 years. The rise in strokes may have been a chance finding because many of the participants assigned niacin who sustained a stroke had stopped their niacin a number of months before. The Coronary Drug Project did not find an excess rate of stroke with niacin but did report an excess incidence of atrial fibrillation, a major risk factor for stroke. The rate of AF was not reported in the AIM-HIGH participants by treatment group. The other point to consider is that the event curves in the Cholesterol and Recurrent Events (CURE) study did not separate until after 2 years; this trial compared pravastatin (Pravachol, Teva Pharmaceuticals) vs. placebo. The 3-year follow-up may not have been long enough in AIM-HIGH because the trial mandated equal LDL levels that were accomplished by a greater use of ezetimibe in those not receiving niacin. Only HDL and triglyceride levels differed between treatment groups.

Trials viewed in tandem

SATURN and AIM-HIGH address opposite sides of the coin in some respects — SATURN aimed low with potent statin therapy, whereas AIM-HIGH did as its name implies with add-on niacin. The primary endpoint of SATURN was imaging-based and the primary endpoint of AIM-HIGH was clinical outcomes. However, at the core, both trials assessed two competing lipoprotein management strategies for patients with atherosclerotic vascular disease, with modest differential results on patients’ lipid profiles, and found neutral effects on the primary endpoints.

Some may be surprised, and others may not. Either way, as both camps reconvene back down on planet Earth, two key questions are:
How do we reconcile these studies with existing literature?
What is the bottom line when it comes to managing our patients?

Reconciling data with existing literature

Reconciling these studies may have a lot to do with endpoints. Painting with broad strokes, there is a ladder of endpoints, starting with hard clinical points, running down to soft clinical endpoints, to imaging endpoints, on down to biomarker endpoints. Ultimately, we want to be confident that if we see a change in an endpoint in response to a therapy, then this means we are benefiting patients. As it turns out, this is easier said than done. SATURN and AIM-HIGH raise important questions about surrogate imaging endpoints because SATURN employs one and AIM-HIGH was immediately preceded by a positive trial based on one: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER-6-HALTS).

Regarding SATURN, as pioneered by Drs. Nicholls and Nissen, and accepted by the expert community, IVUS quantifies plaque burden by percent atheroma volume, subtracting lumen area from the total area within the external elastic membrane divided by the total area. If different calculations are used, as in the secondary endpoint of SATURN, then a signal is seen for rosuvastatin trumping atorvastatin in atherosclerosis regression, but the clinical significance is unclear. Also unclear is the fact that the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial failed to show plaque regression with high-dose atorvastatin, whereas SATURN showed such an effect.

Moreover, from the perspective of the individual patient, we are left with the question: Why do some patients regress on potent statin therapy, whereas others only stabilize and others even progress? Also, how much does atherosclerosis regression actually have to do with increases in HDL (15% in ASTEROID and 4% in SATURN)? This was highlighted as a possible mechanism in the publication of the A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial, but why was the same magnitude of HDL increase not seen in SATURN?

The limitations of IVUS in assessment of atherosclerosis progression were discussed by Navin Kapur, MD, and Roger Blumenthal, MD, in an editorial on the ASTEROID in the Journal of the American Medical Association in April 2006. Indeed, we simply do not know how reliably an IVUS measurement or serial IVUS measurements track with clinical outcomes.

The same can be said for serial carotid intima-media thickness data. Although ARBITER-6-HALTS showed a 0.014-mm improvement in carotid intima-media thickness with niacin, this did not translate into a clinical outcomes benefit during a 3-year period in AIM-HIGH. This is a disappointing result, but there were a number of reasons for tempered enthusiasm after ARBITER-6-HALTS, including its premature termination and the small number of patients studied, as laid out in an editorial by Erin Michos, MD, and Blumenthal accompanying publication of the original manuscript in NEJM. The discordance between ARBITER-6-HALTS and AIM-HIGH implies that we should not be relying on serial carotid intima-media thickness testing to determine the best therapies.

Rather, we should rely on clinical outcomes data. Although AIM-HIGH did not show benefit, this does not mean that the HDL hypothesis is dead. Indeed, several clinical trials of novel agents that raise HDL are undergoing investigation. AIM-HIGH also does not mean that niacin itself should dig an early grave.

It remains to be seen whether a modest incremental benefit can be detected in the much larger ongoing niacin trial, Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2-THRIVE), with results expected in 2013. Although a clinical outcomes trial, it is notable that AIM-HIGH patients were not the highest risk, and events were less than expected, so the original primary composite endpoint was amended to include hospitalization for an ACS (softened from “high-risk ACS”) or symptom-driven coronary or cerebral revascularization, which ended up accounting for most of the primary endpoints in the trial.

In some respects, the inclusiveness of the composite endpoint is a good thing because doctors, patients and payers care about hospitalizations and revascularizations; however, in other respects, it is a bad thing because it is a “softer” or less reliable endpoint because more subjectivity enters the equation.

It is not unrealistic to think that HPS-2-THRIVE could show a benefit. Even if it does, we must point out that it does not necessarily follow that the benefit is from HDL raising. Although niacin is associated with increased HDL concentrations, this does not tell us about reverse cholesterol transport and HDL functionality.

Niacin also lowers LDL or, perhaps more importantly, atherogenic lipoprotein particles. Through the particle lens, a clinical effect of niacin may be more clearly understood because the impact on atherogenic particles is modest, so a very large trial may be needed to detect an effect, especially in patients who are already aggressively treated.

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HOOPS: Pharmacist consultation did not reduce HF mortality, hospitalization
By

AHA Scientific Sessions 2011

ORLANDO — A low-intensity, pharmacist-led, collaborative intervention in primary care resulted in modest improvements in prescribing of disease-modifying medications, but did not improve clinical outcomes in a population of well-treated patients with heart failure, Richard Lowrie, MSc, MPC, said here.

Researchers for the Heart Failure and Optimal Outcomes from Pharmacy Study (HOOPS) randomly assigned 87 centers and 1,090 patients in Scotland to receive additional attention from a pharmacist who was collaborating with physicians. Pharmacists met with the patients to review medications and write prescriptions for recommended medications. At another 87 centers, 1,074 patients received routine family physician care without additional pharmacist input.

After almost 5 years, both groups had the same rate of death and HF hospitalizations, approximately 35% (HR=0.97; 95% CI, 0.83-1.14).

However, consultation with a pharmacist did increase the number of patients who received recommended HF medications at recommended doses. At the start of the study, 86% of patients were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. In those not receiving ACE inhibitors or ARBs or who received less than the recommended dose, treatment was started or the dose was increased in 33.1% of patients in the pharmacist consultation group and in 18.5% in the usual-care group (OR=2.26; 95% CI, 1.64-3.10). At baseline, 62% of patients were treated with a beta-blocker; the proportions of starting or having an increase in dose were 17.9% in the pharmacist consultation group and 11.1% in the usual-care group (OR=1.76l 95% CI, 1.31-2.35).

“While our results show that the nonspecialist pharmacist intervention is not that effective in reducing hospitalization or death rates, we did demonstrate the impact pharmacists have on getting patients on recommended HF drugs,” Lowrie, lead Long Term Conditions/Research pharmacist at Greater Glasgow and Clyde Health Service, Scotland, U.K. “This could be an important intervention in health systems with a low number of patients receiving recommended HF drugs.”

A potential mechanism behind the high rate of prescribing of ACE and ARBs reported in this study may be related to pay-for-performance contracts introduced for U.K. family physicians in 2004, which was close to the start of this study, Lowrie said.

The researchers encouraged long-term studies of different collaborative interventions involving different subsets of patients, such as those with severe HF.

For more information:
Lowrie R. LBCT.02. Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16, 2011; Orlando.

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Annual International Scientific Assembly of the American College of Chest Physicians
Honolulu • October 22 - 26, 2011

Oral Prostanoid Shows Promise in PAH
HONOLULU -- When given as first-line therapy by itself, oral treprostinil -- an investigational formulation -- improved exercise capacity in patients with pulmonary arterial hypertension, the phase III FREEDOM-M trial showed.
[Ссылки доступны только зарегистрированным пользователям ]

Asthma Combo Works for COPD
HONOLULU -- An inhaled corticosteroid/long-acting beta-agonist combination approved for asthma improves lung function in patients with moderate to very severe chronic obstructive pulmonary disease, two randomized trials showed.
[Ссылки доступны только зарегистрированным пользователям ]

Risk Factors Vary Among Lung Cancer Types
HONOLULU -- Although the risk for various types of lung cancer depends on demographic and lifestyle factors, smoking remains the great unifier, researchers found.
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Severe PAH May Be Undertreated
HONOLULU -- Many of the sickest patients with pulmonary arterial hypertension may not be receiving recommended treatment, researchers found.
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Sildenafil May Work for Kids’ Pulmonary Hypertension
HONOLULU -- Sildenafil (Revatio), already approved for pulmonary arterial hypertension on the basis of studies in adults, appears to have some benefits for pediatric patients, a randomized trial showed.
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X-Rays No Help in Cutting Lung Cancer Deaths
HONOLULU -- Screening for lung cancer with chest x-rays annually for four years does not reduce deaths from the disease compared with usual care, a large trial confirmed.
[Ссылки доступны только зарегистрированным пользователям ]

Poor Quality of Life, Asthma Flares Linked
HONOLULU -- For patients with severe or difficult-to-treat asthma, as exacerbation severity increased, quality of life suffered, researchers found.
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Combat Vets’ Sleep Problems Tied to Injury Type
HONOLULU -- The type of injury sustained by U.S. military personnel in the Middle East appears to be related to the types of sleep disturbances they experience when they return home, researchers found.
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Airway Anomaly Linked to Autism
HONOLULU -- A specific airway abnormality may be an objective marker for autism spectrum disorders in children, a small study showed.
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Aerobic Exercise Good for Asthma Patients
HONOLULU -- Physical training programs involving aerobic exercise have a range of benefits for patients with asthma, an updated Cochrane review showed.
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Low Platelet Count Does Not Lessen DVT Risk
HONOLULU -- Low platelet counts do not appear to protect critically ill patients with cancer from deep vein thrombosis, a retrospective study showed.
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[Chevychelov]

AHA: Niacin 'AIM's-HIGH but Falls Flat

By Crystal Phend, Senior Staff Writer,
November 15, 2011

Action Points
Explain that niacin boosts high-density lipoprotein (HDL) cholesterol without benefit for clinical outcomes in otherwise well-treated patients.


Point out that there was no difference in rates of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization in patients who received niacin compared with placebo.
Review
ORLANDO -- Niacin boosts high-density lipoprotein (HDL) cholesterol without benefit for clinical outcomes in otherwise well-treated patients, according to a results of a halted, and perhaps inconclusive, clinical trial.

Extended-release niacin (Niaspan) was associated with a clinical event rate of 16.4% compared with 16.2% in the control group, for a slim 2% relative risk reduction that was not significant at P=0.79 in the AIM-HIGH trial.

That primary trial endpoint encompassed coronary heart disease death, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.


None of the individual outcomes differed significantly between groups either, William E. Boden, MD, of the State University of New York at Buffalo, and colleagues reported here at the American Heart Association meeting and simultaneously online in the New England Journal of Medicine.

"If you are able, as a patient with stable, nonacute cardiac disease, to maintain the levels of [low-density lipoprotein; LDL] control that we did in the study, i.e. in the low 60s, then there is not evidence from this trial to support continued use of niacin for the purpose of reducing further clinical events," Boden said at a press conference.

However, the evidence from this trial is far from a definitive answer on niacin, others warned.

"Whatever conclusions are drawn from this trial, it cannot be emphasized too much that it has not tested the HDL hypothesis, nor was it powered sufficiently to test the potential benefits of niacin," argued study discussant Philip Barter, MD, of the University of Sydney, who called the trial "appalling."

Trial Troubles

The trial was halted earlier this year for futility and a small excess of ischemic strokes in the niacin group, which turned out to be not statistically significant in the final analysis (1.1% versus 1.7%, P=0.11).

But the study may have been doomed from the start because of an overly optimistic 25% effect size expected from niacin, further compounded by the early termination hundreds short of the planned 800 events, Barter noted.

Moreover, the study was able to achieve only a 4 mg/dL separation in HDL between treatment groups, though the increase from baseline was greater with niacin as expected (up 25.0% versus 9.8%, P<0.001).

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes trial (AIM-HIGH) randomized 4,414 patients to simvastatin (Zocor, 40 to 80 mg) in combination with high-dose niacin (1,500 to 2,000 mg) or a placebo spiked with 50 mg niacin per tablet to cause flushing to maintain blinding.

Most of the patients were in a secondary prevention population with controlled LDL (under 180 mg/dL) at baseline but low HDL (under 40 mg/dL for men or 50 mg/dL for women). They had already been on a statin for more than a year.

Switching to simvastatin for patients previously on another statin may at least partially have accounted for the HDL boost in the placebo group, Boden suggested.

Because of the active management of LDL, the non-niacin group got more concomitant therapy, noted Steven Nissen, MD, of the Cleveland Clinic, who called the study poorly designed and poorly executed.

Still a Flush of Hope

Despite the negative results, though, it's not time to retire the drug, Robert P. Giugliano, MD, of Brigham and Women's Hospital and Harvard in Boston, argued in an editorial accompanying the NEJM article.

"It would appear to be more prudent to assign it to occasional part-time work, such as in statin-intolerant patients, while we await the results from the much larger Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events trial (HPS2-THRIVE), which is targeted to be completed in 2013," they wrote.

Some clinicians appear to have already started to cut back, according to a drop-off in Niaspan prescriptions noted even before the AIM-HIGH results were released.

AHA conference program chair Elliott Antman, MD, also of Brigham and Women's Hospital, agreed that he's going to prescribe niacin to patients who can't tolerate the amount of statin needed to get to a low LDL.

Others argued for practice as usual pending HPS2-THRIVE.

"I do not believe our practice should change until we see the results of this much larger trial," Barter told reporters.

Another cholesterol researcher at the press conference, Stephen Nicholls, MD, of the Cleveland Clinic, agreed.

"Don't throw the baby out with the bathwater," he cautioned. "Niacin has a number of metabolic effects; it doesn't just raise HDL, it lowers triglycerides, it lowers lipoprotein A, which we know is a potent atherogenic factor, and we have very few agents that lower that factor."

Boden noted that the study results might apply to other populations with less well-controlled lipids and might have been more favorable with longer follow up, yet he expressed confidence in the negative finding.

"We can quibble about whether the 25% effect size was too generous, but the fact remains that the curves were dead on, spot on, with not even a hint of separation," Boden argued.

This may be an almost insurmountable challenge for niacin because it "suggests no trial would be powered to show a difference," even HPS2-THRIVE, commented Donald M. Lloyd-Jones, MD, ScM, of Northwestern University in Chicago and moderator of the late-breaking clinical trial session.

A negative or even neutral result in HPS2-THRIVE would likely spell the end for niacin, Nissen and Barter noted.

But statin-intolerant patients don't have a lot of options, noted Patricia Maningat, MD, and Jan L. Breslow, MD, of Rockefeller University in New York, in an accompanying perspective article.

They argued for pragmatic trials specifically in that population.