Polypill: Combining three antihypertensives, a statin, and an aspirin in a single, five-drug capsule appears to achieve the same benefit as giving the drugs individually, although the statin in the combination was slightly less effective, researchers said here.
While the combination did appear to blunt the potency of simvastatin -- reducing cholesterol by 27 mg/L (0.70 mmol/L) versus 32 mg/L (0.83 mmol/L) for simvastatin monotherapy (P<0.04) -- the statin still achieved significant reductions in LDL compared with controls (P<0.0001), said Salim Yusuf, D.Phil., F.R.C.P.C., of the Population Health Research Institute at McMaster University and Hamilton Health Sciences in Hamilton, Ontario, Canada.
Dr. Yusuf, co-chair and principal investigator of The Indian Polycap Study (TIPS), reported findings of the phase II trial today at the American College of Cardiology meeting here. The results were simultaneously published online in The Lancet.
Dr. Yusuf said the polypill reduced LDL by about 25%, compared with a 28% reduction with simvastatin monotherapy, "a difference that was statistically significant but clinically not meaningful."
Relaxin: Relaxin, a naturally occurring hormone, appears to be a safe and effective treatment for acute heart failure accompanied by normal-to-high blood pressure, a phase II study showed.
Treatment with a 30-µg/kg dose led to significant improvements in dyspnea in the first 24 hours (P=0.044) and borderline significant improvements through 14 days (P=0.053) compared with placebo, according to John Teerlink, M.D., of the University of California San Francisco, and colleagues.
In addition, the combined endpoint of cardiovascular death or readmission for heart or kidney failure within 60 days occurred less frequently in patients receiving that dose (2.6% versus 17.2%, P=0.053).
Dr. Teerlink reported the findings at the American College of Cardiology meeting here. The results were published simultaneously online in The Lancet.
After 180 days, there were no cardiovascular deaths among patients who received the 30-µg/kg dose, compared with 14.3% of placebo patients (P=0.046).
There were no safety concerns with that dose and no adverse renal affects, the researchers said.
The group called the study exploratory, with the primary objective of determining an optimal dose for a phase III study.
"If established in larger studies, the beneﬁts of relaxin might represent an important advance in the treatment of patients with acute heart failure," they said.
Relaxin is a vasodilator involved in the cardiovascular responses to pregnancy, and a small study suggested that it might have benefits for patients with heart failure.
To explore the safety and optimal dose of the hormone, Dr. Teerlink and colleagues initiated the Pre-RELAX-AHF (Preliminary Study of Relaxin in Acute Heart Failure) study, which enrolled 234 patients from 54 centers in eight countries.
Because up to 80% of patients with heart failure have normal-to-high blood pressure, only patients with a systolic reading greater than 125 mm Hg were included. Those with normal blood pressure were hypothesized to benefit most from the drug as they might have the most vasoconstriction.
All also presented with dyspnea, congestion on chest radiograph, mild-to-moderate renal insufficiency, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP.
Their mean age was 70.3, and 56% were male. The mean systolic blood pressure was 147 mm Hg.
Patients were randomized within 16 hours of presentation (median 6.6 hours) to standard care plus IV infusion of placebo or one of four doses of relaxin: 10, 30, 100, or 250 µg/kg.
The 30-µg/kg dose yielded the most clinical benefit.
In addition to improvements in dyspnea, cardiovascular outcomes, and readmission, there were trends toward fewer days spent in the hospital and more days alive outside the hospital.
The dose had no apparent effect on inhospital worsening of heart failure or persistent renal impairment.
The other doses had few clinical benefits.
Adverse events, including those deemed serious, were distributed equally among the study groups.
However, protocol-specified discontinuation of the study drug because of reduction in blood pressure occurred more frequently in the relaxin groups (10% with the 30-µg/kg dose versus 3% with placebo).
Dr. Teerlink and colleagues concluded, "Evidence from Pre-RELAX-AHF suggests that early administration of this drug in addition to standard therapy might be associated with more rapid, sustained, and complete resolution of acute heart failure, as well as with more favorable long-term outcomes."
They noted, however, that caution should be used when interpreting the findings because of the small sample size, number of treatment groups, and absence of a single primary endpoint.
As a phase II study, the trial was not powered to prove differences in efficacy, they said.
The 30-µg/kg dose will be further evaluated in the phase III RELAX-AHF-1 study.
In an accompanying editorial in The Lancet, Adrian Hernandez, M.D., and Christopher Granger, M.D., of Duke University Medical Center, agreed that the results should be considered in light of study's exploratory nature.
"The results are probably too good to be true, in view of the lack of a dose-dependent effect and the surprising effect of a short treatment on post-discharge outcomes," they said.
But, they added, the findings warrant further study.
Moreover, the hsCRP concentrations were independently predictive of outcome, said Paul M. Ridker, M.D., of Brigham and Women's Hospital in Boston, and principal investigator of the trial.
Dr. Ridker reported results of the two-target JUPITER analysis at the American College of Cardiology meeting and the findings were simultaneously published online in the Lancet.
Compared with those on placebo, participants randomized to rosuvastatin (Crestor) who achieved an LDL of less than 70 mg/L had a 55% reduction in vascular events (P<0.0001), and those who achieved an hsCRP concentration of less than 2.0 mg/L had a 62% reduction in events (P<0.0001).
The greatest reductions -- 79% -- were achieved by the 944 patients who achieved an LDL of less than 70 mg/L and hsCRP less than 1 mg/L (P<0.0001).
And the observed effect remained after adjustment for baseline characteristics, including baseline levels of LDL and hsCRP.
In an editorial that accompanied the Lancet publication, Jean-Pierre Després, M.D., of the Centre de Recherche de L'Institut Universitaire de Cardiologie et de Pneumologie de Québec, in Québec City, pointed out that although guidelines typically focus on LDL as the most important target, "we should pay attention to the additional results of this report, which indicate that irrespective of lipid endpoint used (including the apoliprotein B to apoliprotein A1 ratio) a low concentration of C-reactive protein achieved with rosuvastatin treatment confers the best prognosis."
Last fall Dr. Ridker reported that less than two years of daily rosuvastatin therapy could reduce the relative risk of stroke, MI, and cardiovascular death by 44%, but the results of this prespecified, two-target analysis may dwarf the media frenzy created by that initial report. (See: AHA: JUPITER Results Point to Role of Statins for 'Apparently Healthy' Patients)
"We now know that the large benefit gained is due not only to reduction in cholesterol, but to reduction in hsCRP as well," Dr. Ridker said.
The JUPITER trial randomized 17,802 men and women, mean age 66, with no history of atherosclerosis. And although all participants had baseline cholesterol readings in the normal range, they all had elevated hsCRP, which was defined as 2.0 mg/L or higher.
The population mirrored many baby boomers, a little out-of-shape, with numbers nudging toward frank cardiovascular risk, but not meeting the current threshold for drug therapy.
The median blood pressure was 134/80 mm Hg, LDL 108 mg/dL, HDL 49 mg/dL, and triglycerides 118 mg/dL. Body mass index was 28.3, and 41% met criteria for metabolic syndrome.
Dr. Ridker said it was likely that the benefit seen in the JUPITER trial was a class effect.
But although there are several statins, including a number that are available in generic formulations, only one other statin matches 20 mg rosuvastatin for potency -- 80 mg atorvastatin (Lipitor).
And although it might be tempting to suggest a statins-in-the-water approach, the JUPITER investigators concluded, that for otherwise healthy patients who have raised LDL or hsCRP, the initial intervention should remain "dietary restriction, exercise, and smoking cessation."
But "for people choosing to start pharmacological prophylaxis, reductions in both LDL cholesterol and hsCRP are indicators of the success of treatment with statin therapy."