Alexandra Ward

In a late-breaking poster presented at the 

American Heart Association (AHA) 2019 Scientific Sessions

 in Philadelphia, investigators in Sri Lanka add a randomized controlled trial to the evidence base of mechanistic studies supporting the use of propranolol in hypertension.

The randomized, double-blinded, placebo-controlled clinical APROPRIATE trial evaluated propranolol’s efficacy in patients with resistant hypertension at the National Hospital of Sri Lanka. Patients with a high blood pressure who were on 3 or more antihypertensives and diagnosed by ambulatory blood pressure monitoring (ABPM) were included in the study. Exclusion criteria included whitecoat hypertension.

Over a course of 3 months, a total of 108 patients were screened, with 40 randomized 1:1 to receive either the 40 mg of the study drug 3 times per day or matching placebo.

The primary outcome was systolic and diastolic blood pressure (SBP/DBP) measured in office and on ABPM.

Baseline characteristics were well-balanced between study arms, with a baseline mean SBP of 159.72 mmHg vs 158.00 ± 10.82 mmHg in the propranolol and placebo groups, respectively. Mean baseline DBP was 90.28 mmHg vs 89.00 ± 15.49 mmHg in the propranolol and placebo groups, respectively.

Baseline values upon ABPM were comparative across the propranolol and placebo groups—total mean SBP (148.58 +/- 7.16 vs 153.58 +/- 12.73; p = 0.141), DBP (84.34 +/- 6.83 vs 81.82 +/- 18,74; P = 0.575), mean awake SBP (151.68 +/- 6.28 vs155.77 +/- 12.21; p = 0.192), mean awake DBP (86.54 +/- 6.96 vs 87.85 +/- 7.31; p = 0.565 ), mean sleep SBP values (135.19 +/- 35.22 vs 147.60 +/- 20.01; p = 0.179) and mean sleep DBP (75.72 +/- 19.77 vs 80.05 +/- 10.02; p = 0.387).

After 3 months of either treatment or placebo, patients in the propranolol arm recorded a significantly reduced mean office SBP of 130.00 (+/- 13.24) mmHg vs 139.93 (+/- 14.17) mmHg (p = 0.046). Mean office DBP was 77.83 (+/- 9.65) mmHg compared with 82.66 (+/- 8.58) mmHg in the propranolol and placebo groups, respectively (p = 0.142).

In the propranolol group vs placebo, mean ambulatory SBP was 137.28 +/- 12.55 vs 149.17 +/- 12.51; (p = 0.08) and the DBP 79.40 +/- 5.52 vs 84.08 +/- 8.44 (p = 0.05). Mean change from baseline in DBP was 5.422 +/- 6.14 mmHg in the propranolol group vs -3.48 +/- 15.59 in the placebo (p=0.031).

Investigators found that the treatment arm also displayed reductions in mean ambulatory SBP, awake SBP and DBP, and smaller variations between awake and sleep ABPM, although these results were not statistically significant. Symptomatic sinus bradycardia led to cessation of the drug for 1 patient. 

In conclusion, the study supports the efficacy of propranolol in lowering blood pressure in patients with resistant hypertension compared with placebo. 

The poster, “Addition of Propranolol in Resistant Arterial Hypertension Treatment (APROPRIATE Study) - A Randomized, Double Blinded, Placebo Controlled Clinical Trial,” was presented Saturday, November 16, 2019, at AHA 2019.

Articles

Patients in the propranolol arm recorded a significantly reduced mean office SBP of 130.00 (+/- 13.24) mmHg vs 139.93 (+/- 14.17) mmHg (p = 0.046).

APROPRIATE Study: Propranolol Cuts BP in Patients With Resistant Hypertension

 demonstrated that icosapent ethyl (IPE) has the ability to reduce cardiovascular events by 25%, but investigators have yet to fully explore the mechanism of benefit.

A research team led by Matthew J. Budoff, MD, with LA BioMed, set out to evaluate whether the addition of IPE, along with diet and statin therapy, can lead to a greater change from baseline in plaque volume measured by serial multidetector computed tomography (MDCT) compared with placebo in patients with high triglycerides (TG).

In interim findings presented in a late-breaking session at the 

 in Philadelphia, the EVAPORATE study demonstrated that the addition of IPE significantly slowed coronary plaque progression as compared to placebo over 9 months for 4 of the 5 secondary end points.

However, the mechanistic study’s primary end point of progression rates of low attenuation plaque was not statistically significant as of the 9-month interim mark. The trial will continue to 18 months.

Patients with coronary atherosclerosis, according to MDCT (1 or more angiographic stenoses with ≥20% narrowing), were included in the prospective, randomized, double-blind, placebo-controlled, multicenter study. Inclusion criteria comprised age ≥45 years, fasting TG levels ≥150 mg/dL and <500 mg/dL, LDL-C >40 mg/dL and ≤100 mg/dL, and on stable statin therapy (±ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization.

Exclusion criteria included severe (NYHA class IV) heart failure, contrast allergy, renal insufficiency (eGFR <60), and hypersensitivity to fish and/or shellfish.

Patients had no history of myocardial infarction, stroke, or life-threatening arrhythmia within the prior 6 months, and no history of coronary artery bypass grafting. Baseline characteristics were well-balanced between the treatment and placebo arms.

A total of 80 patients were randomized to receive either IPE 4g/d or placebo.

Investigators performed interim scans at 9 months and are currently following the group for an additional 9 months with MDCT at 0, 9, and 18 months.

The primary end point was progression rates of low attenuation plaque volume as measured by MDCT and defined as -50 to 50 HU, with secondary end points including plaque morphology and composition, markers of inflammation (Lp-PLA2), and LDL-C and HDL-C.

The 9-month interim analysis shows that IPE slowed progression by 21% for low attentuation plaque (p=0.469), 19% for total non-calcified plaque (p=0.010), 42% for total plaque (p=0.0004), 57% for fibrous plaque (p=0.011), and 89% for calcified plaque (p=0.001).

Investigators also demonstrated that progression rates on mineral oil placebo is similar to a non-mineral oil placebo cohort using same the methodology, scanner, and laboratory, showing that the outcomes were benefits of IPE and not a harm of mineral oil.

The study, “Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides (200-499mg/dl) on Statin Therapy (EVAPORATE Study),” was presented Monday, November 18, 2019, at AHA 2019.

The addition of IPE significantly slowed coronary plaque progression as compared to placebo over 9 months for 4 of the 5 secondary end points.

EVAPORATE Interim Analysis: Icosapent Ethyl Plus Statin Therapy Significantly Slowed Plaque Progression

The Fontan operation forges a cavopulmonary connection by diverting venous blood to bypass the heart and flow passively into the pulmonary arteries in patients with forms of congenital heart disease characterized by a functional single ventricle.

But this altered circulation can lead to a breakdown in cardiovascular efficiency over time, which presents as a decline in exercise performance and can lead to increased morbidity and early mortality.

In adolescents who had undergone Fontan, the novel PDE5 inhibitor udenafil has shown in phase 1/2 testing to be associated with the highest average serum concentration, with no dose-limiting adverse events.

 in Philadelphia, investigators of the Fontan Udenafil Exercise Longitudinal (FUEL) trial report that treatment with 87.5 mg of udenafil twice daily was associated with statistically significant improvements in exercise performance at the ventilatory anaerobic threshold (VAT) in adolescent patients who had undergone Fontan palliation.

Treatment with udenafil was generally well-tolerated and safe, but was not associated with a statistically significant improvement in oxygen consumption at peak exercise or changes in myocardial performance index, reactive hyperemia index, or log brain natriuretic peptide, presenter David J. Goldberg, MD, Children's Hospital of Philadelphia, reported.

The National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network initiated this industry-sponsored randomized, placebo-controlled, double-blinded clinical trial, which randomized 400 participants to either the study drug or placebo at 30 clinical sites in North America and the Republic of Korea.

Baseline characteristics between both groups were well-balanced, with a median age of 15.4 ± 2.0 and 15.6 ± 2.0 in the udenafil and placebo groups, respectively. There was a slightly larger proportion of females in the udenafil group (44% vs 36%). Currently on anticoagulation and fluent in English, Spanish, or Korean were inclusion criteria, while participates who had small body size, significant co-morbidities, current therapy with a pulmonary vasodilator, or who had peak VO

 <50% predicted on a recent clinical exercise test were excluded.

The primary efficacy end point was the change in oxygen consumption at peak exercise over 6 months as measured by standardized cardiopulmonary exercise testing. Secondary exercise end points included changes in oxygen consumption, work rate, and ventilatory efficiency at VAT.

(ml/kg/min) was -0.23±4.1 (200) in the udenafil group and -0.89±3.7 (200) in the placebo group (p = 0.092), while the change in VO

 at VAT (ml/min) was 33±185 (155) in the udenafil group and -9.0±193 (162) in the placebo group (p = 0.012).

There was an increased risk of headache (35% vs 25%), facial flushing (16% vs 6%), and increased erection (males only: 12% vs 2%) in the udenafil group. An ongoing open-label extension study is evaluating safety of udenafil over a longer time period.

The study, “Results From the Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal Trial,” was presented Sunday, November 17, 2019, at AHA 2019.

Udenafil positively impacted measures of exercise performance in patients after Fontan, but did not improve peak VO2.

FUEL: Udenafil Improves Exercise Performance, but Not Peak VO2 in Adolescents With Fontan

Immediate coronary angiography after cardiac arrest did not improve survival at 1 year compared with a strategy of delayed procedure in patients successfully resuscitated from out of hospital cardiac arrest (OHCA) in the absence of ST segment elevation (STE), investigators in the Netherlands reported at the 

One-year clinical outcome data from the COronary Angiography after Cardiac arresT (COACT) trial demonstrate that 61.4% of patients in the immediate angiography group and 64.0% of patients in the delayed group were alive 1 year post-cardiac arrest (odds ratio [OR] 0.90; confidence interval [CI], 0.63-1.28).

Additionally, there were no significant differences in the rates of myocardial infarction, revascularization, hospitalization due to heart failure, or ICD shocks between the 2 treatment groups at 1 year, presenter Jorrit Lemkes, MD, Amsterdam University Medical Center, reported at AHA.

COACT is the first randomized study to analyze whether immediate versus delayed invasive strategy improves survival and major adverse cardiac events at 1 year in cardiac arrest patients without ST segment elevation. The investigator-initiated, open-label, multicenter trial enrolled 552 OHCA patients with return of spontaneous circulation (ROSC) and without STE. Patients were randomized 1:1 to receive either immediate angiography (n=264) or delayed angiography (n=258).

To be included in the trial, participants had to be >18 years, comatose (Glasgow coma score <8), with ROSC after OHCA. Patients in the immediate arm were 65.8±12.5 years old and 81.4% male sex, while patients in the delayed group were 65.0±12.2 years old and 76.7% male. The median time from arrest to ROSC was 15 minutes (IQR 8-20) across both groups.

Exclusion criteria included signs of STEMI on the ECG at the emergency department, hemodynamic instability unresponsive to medical therapy, and refractory ventricular arrhythmia, among others.

The primary end point was survival at 90 days, with short-term secondary end points including survival at 90 days with good cerebral performance or moderate disability, Thrombolysis in Myocardial Infarction major bleeding, recurrence of ventricular tachycardia, occurrence of acute kidney injury and need for renal-replacement therapy, time to target temperature, duration of inotropic/catecholamine support, duration of mechanical ventilation, myocardial injury, and markers of shock.

At 1 year, 2 out of 264 (0.8%) patients and 1 out of 258 (0.4%) patients suffered myocardial infarction in the immediate and delayed groups, respectively. The rate of any revascularization since index hospitalization was similar across both groups, as well, with 10/264 (3.8%) and 10/258 (3.9%) in the immediate and delayed groups, respectively.

The study, “One Year Outcomes of Coronary Angiography After Cardiac Arrest,” was presented Sunday, November 17, 2019, at AHA 2019.

A total of 61.4% of patients in the immediate angiography group and 64.0% of patients in the delayed group were alive 1 year post-cardiac arrest.