Clinical trials updates

The TRUE-AHF trial: ularitide shows short, not long-term effects on heart patients

By Alvin Chandra, M.D.
Clinical Fellow, Division of Cardiology 

The TRUE-AHF trial was the first to evaluate the short- and long-term benefits and risks of immediate intervention with an intravenous vasodilator drug in patients with acutely decompensated heart failure, including its long-term effects on mortality. The results follow:

Acute decompensated heart failure continues to be a health care chal­lenge, with readmission rates remaining at 20 percent within 30 days and one-year mortality up to 25 percent. It has been hypothesized that acute ventricular distension during an acute heart failure episode actually causes myocardial microinjury, which in turn accelerates the risk of hospitalization and increases the long-term risk of cardiovascular death. This trial examined whether preventing acute ventricular distension earlier (within 12 hours of presentation) would decrease the risk of cardiovascular death in acute heart failure patients.

For the acute ventricular distension infusion, we used ularitide, a syn­thetic analog of urodilatin, which is a new natriuretic peptide that causes diuresis, natriuresis, systemic and renal vasodilation, and inhibition of the renin-angiotensin system.

The TRUE-AHF trial was a randomized, double-blinded, placebo-con­trolled, parallel-group trial that was driven by event in acute heart failure patients. In all, 2,157 patients were enrolled. Each patient was randomized in 1:1 fashion to receive either a continuous IV infusion of ularitide 15 ng/kg/min for 48 hours or a placebo.

The study’s primary endpoints were hierarchiacal clinical composite endpoints at 48 hours (short-term) and cardiovascular mortality (long-term).

When compared with the placebo group at 48 hours, the ularitide group showed a significant decrease in NT-proBNP (by 47 percent, p<0.001), an increase in hemoglobin (p<0.001), an increase in serum creatinine (p=0.005), and a decrease in hepatic transaminases (p<0.001), all of which were consistent with improved intravascular decongestion. Patients receiv­ing the ularitide therapy also showed a significant decrease in in-hospital heart failure events at 48 hours (p=0.005). However, there was no significant change in high-sensitivity troponin T at 48 hours (p=0.70).

The overall clinical composite endpoint was not significant (p=0.82). More importantly, there was no significant difference in cardiovascular mortality six months after randomization (p=0.75). In the secondary endpoints, there were no significant differences in the 30-day heart failure rehospitalization rate (p=1.00) and all-cause mortality of cardiovascular hospitalization at six months (p=0.10).

In conclusion, the trial showed that early IV vasodilator therapy with ularitide in acute failure patients is associated in the short term with improved intravascular decongestion and a reduced number of in-hospital heart failure events. However, there were no significant differences in the heart failure rehospitalization rate and long-term risk of cardiovascular death. 

The EUCLID trial: examining the efficacy of ticagrelor in peripheral artery disease

By David McNamara, M.D., M.P.H.
Clinical Fellow, Division of Cardiology

The EUCLID trial was designed to test if long-term monotherapy treat­ment with the drug ticagrelor would be superior to clopidogrel at preventing cardiovascular death, myocardial infarction (MI), or isch­emic stroke in patients with symptomatic peripheral artery disease (PAD). 

PAD affects 200 million people worldwide and is associated with both cardiovascular and limb-related morbidity and mortality. The CAPRIE trial in 1996 suggested clopidogrel offered an 8 percent relative risk reduction to aspirin for the composite endpoint of MI, ischemic stroke, and vascular death, with PAD driving these results. Ticagrelor was associated with an improved morbidity and mortality when compared to clopidogrel in acute coronary syndrome patients in the well-known PLATO trial. Subsequently, in patients with a prior MI, ticagrelor reduced cardiovascular death, MI, and stroke in the PEGASUS-TIMI 54 trial. 

With this backdrop, the EUCLID study was a double-blind superior­ity trial presented at this year's American Heart Association meeting and published in the New England Journal of Medicine. The trial tested if taking 90 mg BID of ticagrelor was superior to taking 75 mg of clopidogrel daily in preventing cardiovascular death, MI, or ischemic stroke in patients with stable symptomatic PAD.

The trial’s 13,885 subjects from 28 countries were randomized 1:1 to the two interventions, excluding patients with the CYP2C19 liver enzyme and patients taking dual antiplatelet therapy; patient follow-up was greater than 98 percent. A second endpoint was tested that included the primary end­point in addition to acute limb ischemia (ALI) requiring hos pitalization. The inclusion criteria were individuals with an ankle-brachial index (ABI) ratio of less than 0.8 or prior lower revascularization.

Of the 6,930 participants treated with ticagrelor, the primary endpoint occurred in 751 participants (10.8 percent); of the 6,955 participants treated with clopidogrel, the primary endpoint occurred in 740 participants (10.6 per­cent), resulting in a hazard ratio of 1.02 (confidence interval [CI] of 0.92-1.13). 

No differences were noted in rates of CV death or MI between the two interventions, but ticagrelor was associated with a small reduction in the rates of ischemic stroke, with a hazard ratio of 0.78 (CI of 0.62-0.98). In regard to the secondary efficacy outcome of the primary outcome plus ALI, 839 of the 6,930 ticagrelor patients (12.1 percent) and 833 of the 6,955 clopidogrel patients had a hazard ratio of 1.02 (CI of 0.92-1.12).

Ultimately, ticagrelor was found not to be superior to clopidogrel in preventing cardiovascular death, MI, or ischemic stroke in stable symp­tomatic peripheral artery disease.

The Pioneer AF-PCI trial: strategy found to reduce bleeding in AF patients

By Daniel Bennett, M.D.
Clinical Fellow, Division of Cardiology

The risk of major bleeding in the setting of chronic systemic antico­agulation and the need for dual antiplatelet therapy (DAPT) follow­ing percutaneous coronary intervention (PCI) poses a significant challenge for providers. Current ACC/AHA guidelines recommend the “duration of triple antithrombotic therapy…should be minimized to the extent possible to limit the risk of bleeding.” In addition, the safety and efficacy target-specific oral anticoagulant (TSOAC) therapy in combination with DAPT following PCI remains largely unknown.

The goal of the PIONEER AF-PCI trial was to answer some of these im­portant questions. The trial compared the safety of rivaroxaban to vitamin K antagonists (VKAs) in more than 2,000 patients with nonvalvular atrial fibrillation requiring DAPT following PCI.

Patients were assigned in a 1:1:1 ratio of rivaroxaban 15 mg daily plus a P2Y12 inhibitor (i.e., clopidogrel, ticagrelor, or prasugrel) for 12 months; rivaroxaban 2.5 mg twice daily plus DAPT stratified by one, six, or 12 months (if DAPT continued for only one or six months, patients were continued on rivaroxaban 15 mg and low-dose aspirin for the remainder of the 12-month treatment period); and dose-adjusted VKA therapy plus DAPT stratified by one, six, or 12 months (if DAPT continued for only one or six months, patients were continued on dose-adjusted VKA and low-dose aspirin for the remainder of the 12-month treatment period). 

Overall, there was nearly a 10 percent absolute risk reduction in clini­cally significant bleeding in both of the groups treated with rivaroxaban compared to the group treated with dose-adjusted VKA. Although the trial was not powered to detect differences in efficacy of preventing in-stent thrombosis, cardiovascular death, myocardial infarction, or stroke, there did not appear to be any significant differences in these event rates. 

This trial thus provides evidence of improved safety with reductions in bleeding complications with the use of low-dose rivaroxaban over traditional, dose-adjusted VKA in combination with DAPT following PCI. However, this study does not address the optimal timing of triple therapy discontinuation because duration of DAPT was not randomized and remains largely up to provider discretion. 

ART: 5-year interim results show no gain in BIMA vs. SIMA for coronary artery bypass patients

By Purav Mody, M.D.
Clinical Fellow, Division of Cardiology 

The Arterial Revascularisation Trial (ART) is a multicenter, random­ized clinical trial comparing the use of a single internal mammary artery (SIMA) with bilateral internal mammary arteries (BIMA) in patients with multivessel coronary artery disease undergoing coronary artery bypass surgery (CABG).

Previous studies have demonstrated vastly superior patency rates of arterial bypass conduits at 10 years (in the vicinity of 95 percent) com­pared with venous grafts (about 50 percent). Prior observational analyses have demonstrated approximately 20 percent fewer deaths with the use of BIMA compared to SIMA; however, there was a lack of randomized data supporting this estimate. ART was thus formed, and five-year interim re­sults from the study were presented at the recent AHA Scientific Sessions.

Overall, 3,102 patients were randomized, with 1,548 in the BIMA arm and 1,554 in the SIMA group. The average age of BIMA patients was 64 years; 15 percent were women, 24 percent were diabetic, and 40 percent had prior myocardial infarction. At five years, mortality was 8.7 percent in the BIMA group versus 8.4 percent in the SIMA group (p = 0.77).

Myocardial infarction incidence was 3.4 percent for BIMA patients ver­sus 3.5 percent for SIMA (p = 0.86). Stroke was 2.5 percent for BIMA versus 3.2 percent for SIMA (p = 0.24). Repeat revascularization was 6.5 percent with BIMA versus 6.6 percent with SIMA (p = 0.91). The rate of sternal infection was 3.5 percent in the BIMA group compared to 1.9 percent in the SIMA group (p=0.005).

Among patients with multivessel coronary artery disease, the rates of mortality, stroke, myocardial infarction, and need for repeat revascularization were similar in both arms. The rates of sternal wound complications were significantly higher in the BIMA group.

The reasons for a null result are multiple. First, the benefit of BIMA over SIMA might not be evident given the lower rates of venous graft failure at five years compared to 10 years. Second, the rates of guideline-directed medical therapy were high in both arms (greater than 80 percent), leading to improved patency rates of venous grafts. 

Finally, more patients assigned to BIMA than to SIMA did not receive the assigned procedure (16.4 percent versus 3.9 percent). Given these reasons and limited power in detecting a meaningful difference in treatment effects at the five-year interim period, the ART initiative is currently ongoing, with a 10-year follow-up report planned.

 

Physician Referral Information

UT Southwestern welcomes referrals from providers seeking optimal care for heart patients. Physicians and offices can refer a patient with one easy call to the heart intake coordinator, a registered nurse who is available 24 hours a day, seven days a week. Same-day access is available for patients experiencing chest pain and chest discomfort. To refer a patient to any UT Southwestern clinic or for general inquiries, call Patient and Physician Referral Services at 214-645-8300.

Clinical Heart Center Patient Referrals

Phone: 855-240-0816
Fax: 214-645-7269

Questions or Comments

If you have any questions or would like more information about the Clinical Heart Center or the recent AHA Scientific Sessions, contact Dr. Mark Drazner, Clinical Chief of Cardiology, at mark.drazner@utsouthwestern.edu.

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