ESC: Rolofylline shows no improvement over placebo, more adverse events

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Despite the promising findings of the PROTECT Pilot study, the larger PROTECT trial found no difference with Merck’s experimental selective adenosine A1 antagonist, rolofylline, versus placebo in heart failure patients with respect to the primary and main secondary end points of the study, according to findings presented Tuesday at the European Society of Cardiology (ESC) Congress in Barcelona, Spain.

Although more rolofylline patients than placebo patients experienced moderate or marked dyspnea improvement at 24 and 48 hours from randomization, this was counterbalanced by a lack of effect on persistent renal impairment, according to Marco Metra, MD, from the University of Brescia in Italy, and colleagues. They also found that the risk of important neurological events was increased in patients on rolofylline.

In the previously published PROTECT-Pilot study, Metra and colleagues found that rolofylline treatment, at the 30 mg dose, was associated with trends toward better symptom improvement, lesser worsening renal function and fewer deaths or readmissions for heart failure (HF) or renal dysfunction over the next 60 days.

PROTECT (Placebo-controlled Randomized study of the selective A1 adenosine receptor antagonist KW for patients hospitalized with acute HF and volume Overload to assess Treatment Effect on Congestion and renal function Trial) was aimed at assessing the effects of rolofylline on symptoms, renal function and short-term morbidity and mortality in 2,033 patients hospitalized for HF within 24 hours with signs of fluid overload, impaired renal function (estimated GFR 20-80 ml/min) and high BNP or NT-proBNP plasma levels (greater than 500 pg/mL or less than 2000 pg/ml, respectively).

The investigators randomized the patients 2:1 to rolofylline 30 mg/day or placebo, administered as a four hours daily infusion repeated for three days. They assessed dyspnea on a seven-point Likert scale daily for the first seven days (or until discharge, if earlier) and then at 14 days, after enrollment. Blood samples for measurements of serum creatinine were collected daily until day seven (or until discharge, if earlier) and at day 14 after enrollment. Deaths were captured to day 180 and rehospitalizations were captured up to day 60 after enrollment.

The primary endpoint of PROTECT was a three-category ordered outcome of treatment success, patient unchanged or treatment failure. The researchers defined treatment success as a moderate to marked better dyspnea at 24 and 48 hours after the start of study drug compared with baseline, in the absence of any criteria for treatment failure. Treatment failure included any of the following criteria:

  • Death or readmission for HF any time through day seven;
  • Worsening symptoms or signs of HF occurring more than 24 hours after the start of study drug to day seven or discharge, whichever occurred first;
  • Persistent renal impairment as defined by a serum creatinine (SCr) increase of at least 0.3 mg/dL from randomization to day seven, confirmed at day 14; and
  • The initiation of hemofiltration or dialysis through day seven.

Also, they categorized patients as unchanged if they did not meet criteria for either treatment success or treatment failure.

According to the authors, secondary endpoints were: time to death or rehospitalization for cardiovascular or renal causes through day 60 and the proportion of subjects with persistent renal impairment defined as a SCr increase of at least 0.3 mg/dL from randomization to day seven, confirmed at day 14, or the initiation of hemofiltration or dialysis or death through day seven.

Enrollment in PROTECT was concluded in January of this year. A cohort of 677 patients were randomized to a placebo and 1,356 patients received rolofylline (placebo to rolofylline 1:2 randomization). The placebo and rolofylline groups were well balanced with respect to the main baseline characteristics. Follow-up was complete in all but one patient at 60 days and four patients at 180 days.

Metra and colleagues found no significant difference was found between rolofylline and placebo with respect to the primary endpoint. Treatment success was achieved by 40.6 percent patients on rolofylline, compared with 36 percent of the patients on placebo. Also, 21.8 percent of the patients were classified as treatment failure with rolofylline compared with 19.8 percent with placebo, the remainder being unchanged.

Also, they reported that there were no significant differences between the treatment groups in either secondary endpoint. Death or rehospitalization for cardiovascular or renal causes at day 60 occurred in 30.7 percent and 31.9 percent of the rolofylline and placebo patients. Persistent renal impairment occurred in 13.7 percent of placebo patients and 15 percent of rolofylline patients, respectively.

With regards to the primary endpoint, the researchers observed moderate or marked better dyspnea at both 24 and 48 hours in 52 percent of patients in the rolofylline treated group versus 45.4 percent of patients in the placebo group. However, this was partially counterbalanced by the higher rate of persistent renal impairment in the rolofylline group.

Serious adverse events (SAE) occurred in 13.8 percent of rolofylline and 14.7 percent placebo patients and cardiac SAEs occurred in 7.2 percent and 9 percent, respectively. The rate of central nervous system SAEs was 1.5 percent in the rolofyline group versus 0.6 percent in placebo, including more patients experiencing seizures (a known adverse effect of A1 receptor antagonists)—0.8 percent of patients in placebo compared with 0 in placebo, and 1.2 percent vs. 0.5 percent of patients with strokes, respectively.

Based on their findings, the authors concluded that the larger PROTECT trial found no difference with rolofylline versus placebo with respect of the primary and main secondary end-points of the study.