Meeting Report: American College of Cardiology 2014

American College of Cardiology 2014

Washington, DC, March 29-31, 2014

More than 13,000 physicians and cardiovascular team members attended the ACC 2014 meeting in Washington, DC, to focus on the prevention, diagnosis, and treatment of cardiovascular disease.

Cardiology Review

In this issue of , of the presentations made at ACC 2014 will be highlighted: SYMPLICITY HTN-3, MADIT-CRT, POISE-2, STAMPEDE, CHOICE, STABILITY, and DESCARTES.

Renal Denervation Does Not Reduce BP in Resistant Hypertension

SYMPLICITY HTN-3 principal investigators George Bakris, MD, and Deepak Bhatt, MD, announced at ACC 2014 that the phase III study of catheter-based renal denervation for the treatment of resistant hypertension did not achieve its primary or powered secondary efficacy end points, failing to show that treatment with the investigational procedure resulted in sustained reduction in systolic blood pressure. The trial is the first and only blinded, randomized, sham-controlled study of renal denervation for treatment-resistant hypertension. The study had randomized 535 patients with treatment-resistant hypertension in 87 US medical centers. Patients who received the investigational treatment were compared with a sham-control group that did not receive treatment; all patients continued to take their regular antihypertension medications.

The primary end point of the study was the change in office systolic blood pressure at 6 months, while the 6-month change in the average 24-hour systolic blood pressure assessed by ambulatory blood pressure monitoring was a secondary end point.

Medtronic, the sponsor of the Symplicity renal denervation system, noted that no safety issues arose during the trial. Data showed that the Symplicity system was associated with adverse events in less than 1% of patients, with no cases of renal artery stenosis resulting from the procedure.

The findings were surprising given that findings from the SYMPLICITY 2 study were positive. That study did not include a sham—control arm. The investigators are continuing to analyze the results and will be submitting them for publication.

CORP-2: Colchicine Effective for Recurrent Pericarditis

In addition to conventional therapy, colchicine can reduce pericarditis recurrence, according to Massimo Imazio, MD, of Maria Vittoria Hospital, Turin, Italy. Dr. Imazio and colleagues conducted a multicenter, double-blind, placebo-controlled trial that built on an earlier study (Colchicine for Recurrent Pericarditis [CORP]) that demonstrated significant reductions in pericarditis recurrence in patients developing pericarditis for the first time.

CORP-2 randomized 240 patients who’d experienced multiple episodes of pericarditis to either colchicine or placebo in addition to aspirin, ibuprofen, or indomethacin conventional therapy. At 6 months, 21.6% of the colchicine-treated patients had pericarditis recurrence versus 42.5% of placebo-treated patients (P = .0009).

Patients in the 2 groups experienced similar rates of side effects and discontinuations.

Dr. Imazio speculated that an immune-mediated mechanism may explain the mechanism behind colchicine’s effect. However, the pathogenesis of pericarditis recurrences remains unknown. He said the investigators believe that colchicine should be considered a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications or specific indications.

CORP-2 was published in Lancet.

Cardiac Resynchronization Therapy Can Help Mild HF

A 7-year follow-up study from a major randomized trial suggests that cardiac resynchronization therapy (CRT) can be a longterm solution for patients with mild heart failure (HF) as long as they have left-bundle-branch block (LBBB) along with their reduced left ventricular (LV) ejection fractions and other indications for pacing therapy. The study was published in the New England Journal of Medicine.

The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) long-term follow-up analysis found that patients with LBBB who received CRT with a defibrillator (CRT-D) compared with those who got a defibrillator alone had a 55% reduction in 7-year risk of nonfatal HF events or death from any cause. However, there were no similar benefits from CRT among the patients without LBBB, who experienced an increase in all-cause mortality, investigators said. Lead researcher Ilan Goldenberg, MD, of Sheba Medical Center and Tel Aviv University, Israel, said the finding should be interpreted with caution because it was obtained only after multivariate adjustment and is thus sensitive to covariate selection.

In MADIT-CRT’s primary analysis in 2009, CRT was associated with a 34% drop in the primary end point of death by any cause or HF events over approximately 2.5 years. Most of the CRT benefit was related to a 41% reduction in HF-event risk, which was predominantly found in LBBB patients.

The new analysis followed outcomes for 1820 randomized patients, including 1691 patients who survived the trial study period over a median follow-up of 2.4 years and 854 who were followed longer in a registry for a median of 5.6 years. At 7 years an intention-to-treat analysis showed that 18% of LBBB patients treated by CRT-D had died, compared with 29% of similar patients who were treated with a defibrillator only. All improvements for the composite end point and its components were significant (P < .001).

Jeffrey J. Goldenberger, MD, of Northwestern University noted in an editorial accompanying the study that an equally important finding is the demonstration that patients with a wide QRS complex without LBBB do not benefit from CRT and may even be harmed.

Low-Dose Clonidine, Aspirin Not Protective in Noncardiac Surgery Patients at Risk for ASCVD

Data from the POISE-2 trial suggests that low-dose clonidine increased rates of clinically important hypotension and nonfatal cardiac arrest after noncardiac surgery. A separate POISE-2 trial found that patients who took aspirin after noncardiac surgery had a higher risk of major bleeding than those who did not receive aspirin. Furthermore, aspirin did not reduce the incidence of postoperative myocardial infarction (MI) or mortality.

POISE-2 focused on major cardiovascular (CV) complications of noncardiac surgery, examining the safety and efficacy of low-dose clonidine versus placebo as well as low-dose aspirin versus placebo in over 10,000 patients in 23 countries who have, or are at risk for, atherosclerotic cardiovascular disease (ASCVD). Compared with placebo, clonidine did not improve the primary outcome of mortality and nonfatal MI at 30 days. The clonidine group had a nonsignificant increase in MI. Clinically important hypotension was seen in 48% of clonidine patients versus 37% of placebo patients. Sixteen clonidine patients had nonfatal cardiac arrests, compared with 5 in the placebo group.

Lead study author Daniel I. Sessler, MD, of Cleveland Clinic, concluded that clonidine should not be given to patients having noncardiac surgery as a way to try to reduce perioperative mortality or MI because it worsens the outcome, probably by reducing blood pressure.

The results of the aspirin trial suggest that aspirin should not be used perioperatively in patients with preexisting or without preexisting vascular disease, investigators said. The primary outcome of death or nonfatal MI at 30 days was not different between patients who had taken aspirin prior to surgery and those who took placebo, but major bleeding was significantly higher in aspirin-treated patients than in the placebo group.

Both studies were published in the New England Journal of Medicine (www.nejm.org/doi/full/10.1056/NEJMoa1401106).

Trial of TAVR Devices Favors Balloon-Expandable Over Self-Expanding Device

CHOICE trial investigators, whose results focused on “device success” (the successful vascular access and deployment of the device and retrieval of the delivery system, correct device positioning, and performance of the heart valve without moderate or severe regurgitation) rather than hard clinical outcomes, said that patients who were randomized to treatment with the balloon-expanded Sapien transcatheter aortic valve device had higher device success rates compared with patients randomized to the self-expanding CoreValve device. The CHOICE results were published in the Journal of the American Medical Association.¹

Lead CHOICE investigator Mohamed Abdel-Wahab, MD, of Segeberger Kliniken, Bad Segeberg, Germany, said the driving force in this difference was moderate or severe valvular regurgitation seen in 4.1% of Sapien-treated patients compared with 18.3% of CoreValve patients (P < .001).

A total of 241 patients were randomized to treatment with either the Sapien balloon-expandable device or the self-expanding CoreValve at 5 German centers. At 30 days, device success was observed in 95.5% of 121 patients treated with the balloon-expandable device compared with 77.5% of 120 patients in the self-expanding group (relative risk, 1.24%; 95% confidence interval, 1.12-1.37).

Dr. Abdel-Wahab noted that the evidence linking more than mild aortic regurgitation and consequently device failure with a worse clinical outcome after TAVR means that the findings of the CHOICE trial may have important clinical implications.

New pacemaker use was significantly higher in the CoreValve group (37.6%) versus Sapien (17.3%). Significant differences between the 2 valves became clear in rehospitalizations for HF, more common with the self-expanding CoreValve devices, and in quality-of-life scores, which were slightly higher in the balloon-expandable Sapien.

References

1. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement. The CHOICE randomized clinical trial. JAMA. 2014;doi:10.1001/ jama.2014.3316.

Bariatric Surgery Versus Intensive Medical Therapy for Uncontrolled Type 2 Diabetes Mellitus

Results of the STAMPEDE trial show that gastric bypass and sleeve gastrectomy are each more effective than intensive medical therapy alone in managing uncontrolled type 2 diabetes mellitus in obese patients after 3 years. The study was published in the New England Journal of Medicine (www.nejm.org/doi/full/10.1056/NEJM oa1200225).

In all, 150 patients were randomized into 3 groups: intensive medical therapy only, intensive medical therapy plus Roux-en-Y gastric bypass, or intensive medical therapy plus sleeve gastrectomy. Medical therapy consisted of counseling, lifestyle changes, and insulin sensitizers, glucagon- like peptide-1 (GLP-1) agonists, sulfonylureas, and multiple insulin injections.

The average patient had a baseline glycated hemoglobin of 9.3%, was living with uncontrolled diabetes for 8 or more years, and was taking 3 or more antidiabetes medications and 3 or more antidiabetic medications and 3 or more cardiovascular medications. Patients were 41 to 57 years of age, mildly to moderately obese, and 68% were female.

The primary end point was achieving A1C ≤ 6%. At 3 years, 5% of patients in the medical therapy group met this criterion compared with 37.5% of the gastric bypass patients (P < .001) and 24.5% of sleeve gastrectomy patients (P = 0.01). Greater improvement in metabolic syndrome components such as waist circumference, body mass index, triglycerides, and high-density lipoprotein cholesterol, was seen in the surgical groups versus the patients who received medical therapy alone.

Surgical-group patients also had significant reductions in the use of antihypertensive and lipid-lowering medications. At 3 years, 5% to 10% of them were using insulin compared with 55% of those in the medical therapy group.

Researchers reported improvement in albuminuria in the surgical group even though they had a reduced used of renin-angiotensin system blockers. They hypothesize that bariatric surgery may play a role in preventing further renal parenchymal damage.

No Primary End Point Advantage for Darapladib Over Placebo in Chronic CHD

A new study presented at ACC 2014 and published in the New England Journal of Medicine found that darapladib, a novel inflammation inhibitor, has no primary end point advantage over placebo in patients with chronic coronary heart disease (CHD) with a high level of background care.

Darapladib inhibits Lp-PLA2, a biomarker of inflammation in blood vessels that is generally found on low-density lipoprotein cholesterol (LDL-C). High levels of Lp-PLA2 are an associated risk factor for CHD and linked with vulnerable plaque. Researchers had hoped that darapladib would reduce the likelihood of such plaque resulting in a clot.

In STABILITY, a phase III double-blind trial, nearly 16,000 patients with chronic CHD were randomized to receive a daily 160-mg darapladib tablet or placebo. After a median follow-up of 3.7 years, darapladib demonstrated no significant benefit. There were 769 events (9.7%) in the medication group compared with 819 events (10.4%) for the placebo.

A secondary end point showed a nominally significant reduction in major coronary events (heart attack, urgent angioplasty or bypass, or death). Patients who took daraplabid had a 10% relative risk reduction. Study co-chair Harvey D. White, MD, of the Auckland City Hospital, Auckland, New Zealand, noted that these events are clinically important, with substantial consequences for patients. “The effects on these end points could support the hypothesis that inhibition of Lp-PLA2 with darapladib may alter the composition of atherosclerotic plaques to a less vulnerable state and reduce ischemic events related to coronary artery plaque progression and rupture.” Further study of daraplabid is under way.

DESCARTES: Evolocumab Results in Durable LDL-C Lowering

The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES) demonstrated sustained, substantial lowering of low-density lipoprotein cholesterol (LDL-C) in patients with varying amounts of cardiovascular risk. This randomized, double-blind, placebo-controlled, phase III study compared evolocumab with placebo in 901 patients with hyperlipidemia in 88 centers in 9 countries.

Patients were eligible for DESCARTES if they had LDL-C 75 mg/dL and fasting triglycerides of 400 mg/dL. They were randomized to 1 of 4 background lipid-lowering therapies (diet alone, atorvastatin 10 mg/d, atorvastatin 80 md/d, atorvastatin 80 mg/d with ezetimibe [EZE]). Study subjects with LDL-C ≥75 mg/dL following lipid therapy lead-in were randomized 2:1 to subcutaneous monthly evolocumab 420 mg or placebo.

The study found that evolocumab administered monthly, either alone or in combination with a statin with or without EZE for 52 weeks, lowered LDL-C by 57% compared with placebo (P < .001). Responses varied from 49% to 62% among background therapies. Reduction in LDL-C at week 12 and week 52 were comparable.

Adverse events occurred in 74.8% of patients treated with evolocumab and 74.2% on placebo. The most common adverse event for patients treated with evolocumab was nasopharyngitis.

DESCARTES was published in the New England Journal of Medicine.