PROTECT: Adjust HF Meds to Achieve Natriuretic-Peptide Targets

November 24, 2010

November 23, 2010 (Chicago, Illinois) — A small, single-center, randomized trial supports the strategy of heart-failure medication adjustment guided by assessments of natriuretic-peptide levels, which has been explored in other studies with mixed results [1].

Hopes are that such biomarker-guided HF management may be more effective than standard care at minimizing symptoms and warding off impending decompensation, as suggested by the current study, called Pro-BNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT).

All of the PROTECT trial's 151 patients received standard-of-care heart-failure therapy, with clinically guided changes to medications, while 75 of them also had their meds adjusted so as to push levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) down to a prespecified target of <1000 pg/mL.

Nearly half of patients in the guided-therapy arm actually achieved the target, and as a group they showed a significant reduction in the primary end point (p=0.019) over a mean of 10 months, compared with standard-care patients. Their hazard ratio for the composite of total cardiovascular events (worsening HF, hospitalization for HF, ACS, ventricular arrhythmias, cerebral ischemia, or CV death) was 0.44 (95% CI 0.22–0.84) after adjustment for age, LVEF, NYHA class, and renal function.

Dr. James Januzzi

The results were presented last week by Dr James Januzzi (Massachusetts General Hospital, Boston, MA) at the American Heart Association 2010 Scientific Sessions.

PROTECT distinguishes itself from earlier natriuretic-peptide targeted-therapy studies in part by including only patients with systolic heart failure, Januzzi told heartwire . That helped make treatment more consistent. "In patients with heart failure due to LV systolic dysfunction, there is a very clearly defined series of drug-therapy steps that we may take," he observed, while there is less of an evidence base to guide therapy in heart failure with preserved ejection fraction.

Also, Januzzi said, clinicians in PROTECT were more resolute than in other studies about lowering natriuretic-peptide levels: such levels went further down, and more patients reached the target.

Results of those earlier studies have been inconsistent. Such targeted therapy improved outcomes in, for example, the STARS-BNP trial, but not the PRIMA and TIME-CHF studies. But they varied in patient characteristics, biomarker targets, and adherence to the guided-therapy strategy, as described by heartwire . A recent meta-analysis that did not include PROTECT suggested natriuretic-peptide–guided therapy improves heart-failure survival.

Dr. Gregg C Fonarow

Dr Gregg C Fonarow (University of California, Los Angeles), who comoderated the session in which PROTECT was presented but wasn't involved in the trial, told heartwire that NT-proBNP-guided therapy in the study "was so very impressive" probably because of the vast experience of the investigators.

"It was a single-center study done at an expert center by clinicians who have great insight into heart failure," Fonarow said. "This is a nice advance, but we need replication in a large-scale, multicenter randomized trial." It's unknown whether the same results could be achieved by most other cardiology practices, "so confirmation in a multicenter trial becomes critical if it's to become the standard of care."

Dr. Ileana L Piña

As the assigned discussant following Januzzi's presentation of PROTECT, Dr Ileana L Piña (Case Western Reserve University, Cleveland, OH) pointed out that medication use and outcomes went up in the standard-care group as well, showing "that there's always room for improvement even when we think we're doing a good job."

According to Januzzi, "one of the coolest parts of the study" was the significant drop in use of loop diuretics among patients in the group using NT-proBNP–guided therapy. Diuretics were withdrawn as long as levels of the biomarker remained consistently low, he told heartwire . That's important because the drugs can aggravate neurohormonal activation and promote electrolyte imbalances.

Medication Use and Frequency of Uptitrations in the PROTECT Study Over a Mean 10-Month Follow-Up

Parameter NT-proBNP Guided, n=75 (%) Standard of Care Only, n=76 (%) P
Medication Use by End of Follow-Up      
 Aldosterone Antagonists 62.7 44.7 0.001
 Loop Diuretics 85 96 0.05
 Nitrates 9.3 18.4 0.06
Medication Uptitrated During Follow-Up      
 ACE Inhibitors 25.4 18.1 0.15
 Angiotensin-Receptor Blockers 5.8 22.3 0.01
 Beta Blockers 46 34.5 0.05
 Aldosterone Antagonists 22.7 5.8 <0.001

Loop-diuretic use dropped, said Fonarow, probably because use of drugs that suppress neurohormonal activity--especially aldosterone inhibitors, which are also diuretic--went up significantly.

"We now know that aldosterone antagonists offer benefit in mild, moderate, and severe heart-failure patients," said Fonarow, pointing to the results of the EMPHASIS-HF study reported here at the meeting, as covered by heartwire . The trial showed reductions in cardiovascular death, heart-failure hospitalization, and other major end points with aldosterone antagonist therapy in patients with mild heart failure.

"So [aldosterone antagonists] should be part of the standard-of-care regimen irrespective of natriuretic-peptide levels," he said. "Would the results [of PROTECT] have been the same if background therapy had included not just ACE inhibitors and beta blockers, but also aldosterone antagonists?" he speculated.

PROTECT randomized 151 patients with systolic heart failure (LVEF <40%), in NYHA class 2–4, with a history of at least one "heart-failure event," to receive either standard HF care with or without serial NT-proBNP testing and medications adjusted with the goal of achieving levels <1000 pg/mL. Heart-failure events could include hospital admission for HF or an outpatient diuretic dose increase for heart-failure destabilization in the previous six months.

Age averaged 63 years, the mean LVEF was 27%, about 57% had ischemic heart failure, and about two-thirds had implantable defibrillators, with no significant difference between the groups. Nor did use of medications differ at baseline.

Enrollment into the trial had been stopped at the midway point when a protocol-specified interim analysis showed one group doing significantly better than the other, Januzzi said. The data were unblinded, and it became clear that the gains were in the guided-therapy group.

The natriuretic-peptide target was achieved by 44.3% of patients in the guided-therapy group, according to Januzzi. They also showed a significant reduction in the primary end point of total cardiovascular events, including cardiovascular death, worsening HF, heart-failure hospitalization, acute coronary syndromes, ventricular arrhythmias, and cerebral ischemia over an average follow-up of 10 months.

The primary-end-point benefit was more pronounced among patients >75 years (p=0.005) than among those <75 (p=0.008) and was driven by improvements in worsening heart failure (p=0.001) and heart-failure hospitalization (p=0.002)--both of which were about half in the guided-therapy group compared with those on standard management only.

Primary and Secondary Outcomes in PROTECT

Parameter NT-proBNP Guided, n=75 Standard of Care Only, n=76 P
NT-proBNP Levels (pg/mL)      
Baseline 2344 1946 NS
10-mo follow-up 1125a 1844 0.03
Primary-End-Pointb Events (n) 58 100 0.009
Patients With a Primary Event (%) 29.3 43.4 0.04
Quality of Lifec, Rate of Improvement by 10 Points (%) 61.2 38.8 0.03
a. p=0.01 vs baseline
b. Primary end point=total cardiovascular events (worsening HF, hospitalization for HF, ACS, ventricular arrhythmias (VT/VF), cerebral ischemia, or CV death
c. As measured by the Minnesota Living with Heart Failure Questionnaire

A subgroup of patients, 60 on guided therapy and 56 on standard care, underwent baseline and follow-up echocardiography, which showed mean relative increases in LVEF of 19% and 7% in the two groups, respectively (p=0.01). Guided-therapy patients also showed significantly better improvements in left ventricular end-systolic (p>0.001) and end-diastolic (p=0.008) volumes.

There were no significant differences in prevalence of adverse side effects, including acute renal failure, dizziness, hyperkalemia or hypokalemia, hypotension, or syncope, Januzzi said.

Piña lauded the trial's inclusion of patients >75 years, who make up a large proportion of heart-failure patients but in clinical practice often don't get adequate treatment "because of real or perceived problems such as bradycardia or hypotension." And unlike many of the previous trials of natriuretic-peptide–guided therapy, the older patients benefited significantly, she observed.

Januzzi speculated that elderly patients fared much better in PROTECT than in some earlier studies because its patients in general were assessed by their physicians more often and because uptitrations were carried out more cautiously in older patients.

"We brought elderly patients back more frequently but made smaller incremental changes [in medications], even though those changes over the duration of the study were quite significant," he said. "So I think it's not that guided therapy doesn't work in elderly patients, it's that we need to adjust how we approach them clinically."

PROTECT was partly supported by Roche Diagnostics, which markets a test for NT-proBNP. Januzzi reported receiving research grants from Roche Diagnostics, Siemens, and Critical Diagnostics; being a consultant to Roche Diagnostics and Critical Diagnostics; and speaking for Roche Diagnostics, Siemens, and Ortho Clinical Diagnostics. Piña reported being on advisory committees for General Electric and Normoxsys and a speakers' bureau for Otsuka. Fonarow has previously reported receiving honoraria from and serving as a consultant or on the advisory board for Pfizer, Merck/Schering-Plough, and Bristol-Myers Squibb/Sanofi-Aventis.



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