'Lower Is Better,' Still, for Natriuretic Peptides in Titrating Heart-Failure Drug Therapy

September 27, 2018

NASHVILLE, Tennessee — Pushing down natriuretic-peptide levels by uptitrating guideline-recommended medical therapy in heart failure (HF), even short of a target concentration, likely improves clinical and cardiac-structural outcomes compared with therapy that doesn't lower levels by as much, suggest follow-up analyses of the GUIDE-IT study.

In previously reported primary results, GUIDE-IT failed to show a clinical advantage from titrating HF drugs to a specific biomarker target, an N-terminal pro-brain-type natriuretic peptide (NT-proBNP) concentration of 1000 pg/mL or less, compared with drug therapy based on "usual care" judgment. Patients in the trial all had HF with reduced ejection fraction (HFrEF).

Despite predictions that patients in the biomarker-guided group would be treated more intensively, they and the usual-care patients received a similar degree of guideline-recommended drug management and achieved similar reductions in NT-proBNP.

But in the current report, patients in either group who were biomarker "responders," that is, they reached the biomarker target by 90 days regardless of management strategy, went on to show a 74% decrease (P < .001) in the trial's primary endpoint of cardiovascular (CV) death or HF hospitalization over the median follow-up of 15 months compared to "nonresponders."

In the adjusted analysis, responders also showed a 66% drop (= .009) in all-cause mortality and significantly better Kansas-City Cardiomyopathy Questionnaire (KCCQ) quality-of-life scores, reported James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston, here at the Heart Failure Society of America 2018 Scientific Meeting.

Also, outcomes after more-aggressive guideline-based medical therapy, as tolerated, with resulting declines in the biomarker short of the target, remained significantly better than outcomes of drug therapy that was less intensive for whatever reason.

The analyses of treatment effect on NT-proBNP levels, regardless of any target, suggest that "lower is better," Januzzi explained to theheart.org| Medscape Cardiology. And lower levels, he said, occur in patients able to achieve a more intense degree of guideline-recommended medical therapy.

Clinical Outcome Rates (%) by NT-proBNP Concentrations 90 Days after Baseline Across All GUIDE-IT Patients
End Point


≤1000 pg/mL 1001–2000 pg/mL 2001–3500 pg/mL >3500 pg/mL
Any-cause death 3.1 5.7 12.8 30.9
CV death or HF hospitalization 7.5 25.1 39.4 59.3

In a GUIDE-IT substudy with 269 patients, echocardiographic changes by extent of natriuretic-peptide lowering were consistent with the clinical outcomes achieved by reductions in natriuretic peptide levels, Januzzi observed. They point to significant positive myocardial structural remodeling with greater NT-proBNP declines, with improvement in left ventricular (LV) ejection fractions and end-diastolic and end-systolic volumes.

Change in Echocardiographic Measures (Absolute Units) by Change in NT-proBNP Concentrations at 1 Year*
End Point –1000 pg/mL –2000 pg/mL –3000 pg/mL –4000 pg/mL –5000 pg/mL
LVEF (absolute % points) +6.69 +8.35 +10.2 +11.68 +13.35
EDVi (mL/m2) –15.68 –19.24 –22.80 –26.36 –29.92
ESVi (mL/m2) –17.34 –21.03 –24.71 –28.40 –32.09
*Unpublished numbers for echocardiographic substudy, as previously presented live by GUIDE-IT investigators.
LVEF= left ventricular ejection fraction; EDVi= end-diastolic volume index; ESVi=end-systolic volume index

"Patients that are at the lower range of non-response actually have relatively low event rates, whereas those in the higher range really are heading in a bad direction," Januzzi said during the discussion following his formal presentation. "Those are the patients who in my clinical practice I more intensively monitor."


Clinical Context of GUIDE-IT

The current analysis "affirms the prognostic meaning of changes in natriuretic peptides during therapy," contrary to some concerns that measuring NT-proBNP isn't likely to be fruitful in this setting based on the trial's primary results, Januzzi said.

"I think it actually tells you an awful lot, both in terms of the clinical course, but also mechanistically — what's going on with the left ventricle," for example, he said.

Optimal guideline-recommended medical therapy should be the management goal, "achieving as good therapy as is possible, which by the way, also causes more significant lowering in NT-proBNP."

Then Januzzi said to the HFSA session attendees, "If anyone outside of this room believes that caregivers, giving heart failure therapy, are achieving that goal in the real world, I think that's a reality check that everyone needs. What we have shown is that in the hands of HFSA-level clinicians, you may not need a biomarker to guide therapy. But, in other hands it might actually be somewhat more useful."

Also during the discussion, panelist Nancy K. Sweitzer, MD, PhD, observed that throughout the study, those who went on to be classified as NT-proBNP nonresponders had not been as intensively treated with ACE inhibitors, where as the intensity of beta-blocker therapy climbed over time.

That may be telling us something about the nonresponders, said Sweitzer, of the University of Arizona College of Medicine, Tucson, who was not involved in GUIDE-IT. Perhaps those patients were thought to be less tolerant of ACE inhibitors. "We all struggle with people stopping ACE inhibitors for bumps in creatinine, things like that."

Jannuzzi agreed with that take. "The nonresponders were much more medically complicated, so there is no question that they had a lot of the baggage that patients with complex advanced HFrEF come with," he said. "I think you're seeing the effects of a trade-off decision," for example, preferring beta blockers for patients who might be able to tolerate only limited medication.

Hazard Ratio* for 90-Day Clinical Outcomes, NT-proBNP Responders vs Nonresponders
End Point HR (95% CI) P Value
Death from any cause 0.34 (0.15–0.77) .009
CV Death or HF Hospitalization 0.26 (0.15–0.46) .001
*Adjustments include clinical history, baseline clinical features, comorbidities, and functional measures.

Although the analysis controlled for most baseline differences, the 188 patients who achieved or went below the natriuretic-peptide treatment target by 90 days and the 388 who remained above the target were broadly different.

Ventricular function was similar in responders and nonresponders, but the nonresponder group was sicker, older, and in other ways higher-risk at baseline. The lower-risk patients who became responders were apparently more able to tolerate aggressive medical therapy for the trial's three months, Januzzi proposed.

To measure the intensity of guideline-recommended medical therapy by NT-proBNP status at 90 days in the two groups, the GUIDE-IT team developed a scoring system based on the degree to which patients received beta blockers, ACE inhibitors, angiotensin receptor blockers (ARB), or aldosterone antagonists.

Natriuretic peptide responders and nonresponders had not differed in medical therapy intensity at baseline, but that changed by 90 days when the intensity was significantly greater in responders. That is, guideline-recommended therapy appeared to be less often upwardly titrated in those who became nonresponders, Januzzi said.

Guideline-Recommended Drug Therapy Scores* at Baseline and 90 Days by Natriuretic Peptide Response Status
End Point Responders, n=188 Nonresponders, n=388 P Value
Baseline score 7.0 6.8 0.37
90-day score 8.5 7.7 0.01
*Points given for degree of treatment with beta blockers (in carvedilol equivalents), either ACE inhibitors (in lisinopril equivalents) or ARBs (in losartan equivalents), and MRAs (in spironolactone equivalents); plus 2 points for any of ivabradine, hydralazine/nitrates, and/or sacubitril/valsartan (Entresto, Novartis).

In an adjusted analysis, every 5 mg beta blocker dose increment was associated with a 38% increase (= .005) in the likelihood the patient would be a natriuretic peptide responder; the corresponding odds increase for ACE inhibitors was only 11% (P = .03). There was no such odds increase associated with aldosterone antagonists.

Are There Limits to Upward Titration?

A related topic that occupied discussion after Januzzi's presentation: Whether patients who are destined to be natriuretic-peptide responders, as defined in the study, can be identified early so they, in particular, can receive more aggressive drug therapy.

GUIDE-IT says that "if you can get levels down under 1000, and that's a difficult thing in some patients, it appears that you're going to get a good outcome. You're going to remodel your ventricle, you're going to have better quality of life, and better clinical events," Christopher M. O'Connor, MD, Inova Heart & Vascular Institute, Falls Church, Virginia, told theheart.org | Medscape Cardiology.

"The problem is we can't tell which patients are going to respond to under a 1000 pg/mL or not. There may be innate characteristics of those patients," he said. Conversely, "Those that are sicker or older, more comorbidities, they might not be able to get under 1000."

Clinical and Laboratory Risk Markers at Baseline by Natriuretic Peptide Response Status
End Point Responders, n=188 Nonresponders, n=388 P Value
NT-proBNP (pg/mL) 1241 3308 <.001
Creatinine (mg/dL) 1.1 1.3 <.001
HF Duration (months) 1 21 <.001
KCCQ (mean score) 63 60 .019
6MWD (feet) 343 289 <.001
KCCG= Kansas City Cardiomyopathy Questionnaire; 6MWD= Six Minute Walk Distance

In addition, responders were significantly younger (P < .001) and more likely to be female (P = .009) and with nonischemic heart disease (P < .001), and be in NYHA functional class 2 (P < .001).

Nonresponders were significantly older (P < .001) and more likely to be male (P = .009) with ischemic heart disease (P < .001), diabetes (P < .001), atrial fibrillation (P = .002), jugular venous distension (P = .005), rales (P = .006), and edema (P < .001); and be in NYHA class 3 (P < .001).

A 'blanket strategy' wherein NT-proBNP is suppressed to less than a target in all patients with HFrEF cannot be recommended, said O'Connor, a GUIDE-IT investigator. In the trial, such a strategy "didn't work for a number of reasons," including suboptimal medical therapy, perhaps in both groups. In the natriuretic-peptide-guided therapy group, at least, the rate of "aggressive titration of medicines to optimal doses" was low," he said.

So, if natriuretic peptide levels remain high in HFrEF even through attempts to lower them with guideline-recommended therapy, "should we push more and more, harder and harder? In this trial, they didn't really push that hard. That's one of the tricky, nuanced conclusions from GUIDE-IT."

GUIDE-IT was funded by the National Heart, Lung, and Blood Institute with biomarker assay support from Roche Diagnostics. Januzzi discloses receiving research grants from Roche Diagnostics, Siemens, Singulex, Abbott, and Prevencio; and serving as a consultant or on an advisory board for Boehringer Ingelheim and Janssen. Sweitzer reports that she has no financial disclosures. O'Connor discloses consulting or serving on an advisory board for Merck, Bayer, Bristol-Myers Squibb, and OM1.

Heart Failure Society of America (HFSA) 22nd Annual Scientific Meeting. Late Breaking Insights from Trials and Novel Investigations: The Importance of Natriuretic Peptide Response to Predict Outcomes in Chronic HF with Reduced Ejection Fraction: Insights from the GUIDE-IT Clinical Trial. Presented September 17, 2018

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.


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