July 1, 2008 • www.familypracticenews.com Cardiovascular Medicine 13 Novel Agent Eases Acute Heart Failure Patients Greatly Heart Failure Symptoms Overestimate Life Expectancy

Dyspnea was improved in 53% of the rolofylline BY MARY ANN MOON median of another 13 years. In contrast, the Contributing Writer clinical model predicted a median survival group compared with 37% of the placebo group. of 10 years. The model came close to pre- mbulatory patients with heart failure dicting actual survival rates at 1 and 3 years BY BRUCE JANCIN uresis, adenosine also mediates reduced tend to substantially overestimate of follow-up. Mortality at 3 years was 29%. Denver Bureau renal blood flow and renal function. Atheir life expectancy, especially those The younger the patient, the longer they Rolofylline has the opposite effects. who are younger or who have severe dis- estimated their life expectancies to be. How- C HICAGO — It’s full speed ahead for In the pilot dose-finding study, 301 ease, according to the findings of a survey. ever, the model predicted similar life ex- a pivotal phase III clinical trial of the patients were randomized to intra- Their misperception could “fundamen- pectancies across all age groups. novel drug rolofylline in patients with venous rolofylline at 10, 20, or 30 mg tally influence medical decision making re- Similarly, patients who had advanced acute decompensated heart failure and or to placebo infused daily with loop di- garding medications, devices, transplanta- symptoms gave themselves the same prog- renal dysfunction, on the basis of its uretics over a 4-hour period on the first tion, and end-of-life care,” said Dr. Larry A. nosis, as did patients with minimal symp- impressive performance in a 301-pa- 3 days of hospitalization. Allen of Duke Clinical Research Institute, toms, predicting great longevity despite the tient pilot study. The primary study end point was Durham, N.C., and his associates. objective severity of their disease. In the preliminary round, the selective therapeutic success defined as patient- The researchers There was no dif- adenosine A1 receptor blocker rapidly reported moderate or marked im- surveyed 122 patients ference in the accura- improved acute heart failure symptoms, provement in dyspnea on day 2 or 3. with a broad spec- Patients with cy of patient predic- prevented further worsening of renal The dose-related success rate ranged trum of heart failure advanced disease tions between the 45 function, and reduced the combined from 37% with placebo to 53% with severity to determine might opt for patients who report- rate of death or hospital readmission rolofylline at 30 mg/day. The failure their understanding comfort measures ed they had discussed within 60 days, Dr. Barry M. Massie re- rate (defined as worsening heart failure of their prognoses. over enhanced a prognosis with their ported at the annual meeting of the symptoms or renal function) ranged “Despite advances in survival. clinicians and the 76 American College of Cardiology. from 38% on placebo to 16% with high- care, the prognosis patients who said “This is the first evidence that an in- dose rolofylline. for patients with DR. YANCY they had not. tervention to prevent renal impairment The 60-day combined end point of symptomatic HF re- The study could may positively affect acute symptoms death or rehospitalization for renal or mains poor, with a median life expectancy not address the reasons for the disconnect, and intermediate-term outcomes in pa- cardiovascular causes was 33% with of less than 5 years,” they noted. but it seems likely that inadequate com- tients hospitalized with acute heart fail- placebo, 32% with rolofylline at 10 mg, Most of the study subjects had long- munication between providers and patients ure. These pilot data have important 24% at 20 mg, and 19% at 30 mg. standing chronic heart failure and comorbid plays a role. Also, “individuals’ predictions therapeutic implications. Better treat- Rolofylline’s seizure potential was a conditions such as hypertension and dia- of longer life expectancy for themselves ment of acute heart failure patients with potential concern because the adenosine betes. The sample was racially diverse and may simply reflect hope,” they added. progressive renal dysfunction requiring A1 receptor downregulates electrical ac- included a large number of elderly people. Whatever the reason, patient perception diuresis is a significant unmet medical tivity in the CNS. Patients at high seizure The patient predictions were compared of prognosis warrants further attention, need,” said Dr. Massie, professor of risk because of past history were ex- with those obtained using the Seattle Heart because it “may refine decision making medicine at the University of California, cluded from the trial, and those deemed Failure Model, a prognostic tool that calcu- around resuscitation preferences, adherence San Francisco, and chief of cardiology at intermediate risk received daily pro- lates life expectancy based on clinical char- to medical therapy, and consideration of ad- at the San Francisco VA Medical Center. phylactic lorazepam. No seizures oc- acteristics, medications, device use, and re- vanced HF therapies such as implantable Heart failure is the No. 1 cause of curred in the study. Indeed, rolofylline’s sults of diagnostic testing. cardioverter-defibrillators, cardiac trans- hospitalization in patients aged older side effect profile was essentially the A total of 9% of the subjects believed their plantation, or mechanical cardiac support,” than 65 years. Guidelines call for the same as placebo, according to Dr. Massie. heart failure would be cured, and another Dr. Allen and his associates noted. routine use of diuretics in these acute- The phase III trial, called PROTECT, 51% believed they would always have heart In an editorial accompanying the report, ly decompensated patients. But diuret- is ongoing. To date, roughly 900 of a failure but nevertheless would have a normal Dr. Clyde W. Yancy agreed. “Another reason ics can be associated with worsening re- planned 2,000 patients have been en- life expectancy. Only 36% indicated that precise awareness of survival may be im- nal function, especially in patients with rolled. Only the 30-mg dose of rolo- heart failure would likely shorten their lives. portant is embedded in the ‘time trade-off’ underlying chronic kidney disease. And fylline is being used, and trial end points A total of 63% of patients markedly over- construct,” noted Dr. Yancy of the heart and worsening renal function is itself asso- are the same as in the pilot study. estimated their life expectancy, thinking vascular institute at Baylor University Med- ciated with a worse prognosis. Rolofylline is being developed by they’d survive a median of 40% longer than ical Center, Dallas. “Knowing that survival is Adenosine stimulates sodium reab- Merck & Co. following its purchase of predicted by the clinical prognostic tool, Dr. limited, patients with advanced disease might sorption in the proximal tubule. In the NovaCardia Inc., the drug’s original Allen and his associates said (JAMA opt for comfort measures or an enhanced setting of increased sodium load pre- developer. Dr. Massie is a consultant to 2008;299:2533-42). quality of life, even at the expense of short- sented to the distal tubule during di- the company. ■ Patients also predicted they would live a ened survival” (JAMA 2008;299:2566-7). ■ Atenolol Edged Out Carvedilol for Systolic Heart Failure

BY MITCHEL L. ZOLER other β-blocker, bisoprolol, has also proved to help pa- The mortality rate was lowest, 1.3%, among the 251 Philadelphia Bureau tients with heart failure, but in the United States biso- patients (22%) treated with atenolol. Among the 611 pa- prolol is approved only to treat hypertension. Atenolol, tients (53%) treated with carvedilol, 2.5% died; and C HICAGO — Atenolol may be about as effective as another β-blocker that is often prescribed in the United among the 300 (26%) treated with metoprolol, 6% died. carvedilol for improving survival and reducing hospital- States for treating heart failure, is not approved by the After adjustment by a propensity score analysis, patients izations in patients with systolic heart failure, based on a FDA for treating the indication, noted Dr. Kapoor. treated with atenolol had a slightly reduced risk of death retrospective review of more than 1,000 patients who did The Stanford researchers reviewed 1,385 consecutive compared with patients treated with carvedilol, but the not undergo randomization. patients who had their left ventricular ejection fraction mea- difference between the two drugs was not statistically sig- The finding suggests that atenolol should be tested in sured by echocardiography at the VA Palo Alto Health Care nificant. After propensity score adjustment, patients treat- a prospective, randomized study to definitively test System during 1998 and 2004 and were found to have an ed with metoprolol tartrate were about twice as likely to whether it works as well as carvedilol in patients with ejection fraction of 40% or less. The study then focused on die as were patients treated with atenolol. heart failure, Dr. John R. Kapoor and his associate said the 1,162 patients from this group who were treated with Adjusted analyses were not reported for the secondary in a poster presented at the annual meeting of the Amer- either carvedilol, atenolol, or metoprolol tartrate (an im- end points. But the unadjusted findings showed that the pa- ican College of Cardiology. mediate-release formulation of metoprolol). The primary tients treated with atenolol consistently fared better than Currently, the only β-blockers approved by the Food outcome of the analysis was death within the following 6 did those treated with either carvedilol or metoprolol tar- and Drug Administration for use in patients with heart months; secondary end points were heart-failure hospital- trate for both heart failure hospitalizations and for hospi- failure are carvedilol and metoprolol succinate, an ex- ization, and death plus hospitalization during 6 months of talizations plus deaths. Atenolol treatment was linked with tended-release formulation of metoprolol, said Dr. follow-up. The average age of the patients was 68, and near- superior outcomes at 90 days, 1 year, and 2 years after the Kapoor, a cardiologist at Stanford (Calif.) University. An- ly all were men. start of treatment, Dr. Kapoor reported in his poster. ■