LCZ696 Recommendations, New Mid-Range HF Classification Debut in ESC Guidelines

Deborah Brauser

June 02, 2016

FLORENCE, ITALY ( updated ) – The new term for heart-failure patients with LVEF between 40% and 49% should be "HF with mid-range EF (HFmrEF)," according to a report released to a standing-room-only crowd here at the European Society of Cardiology (ESC) Heart Failure 2016 Congress.

"It's time to start dealing with the middle child of heart failure," task force chair of the all-new ESC Guidelines for acute and chronic HF Dr Piotr Ponikowski (Wrocław Medical University, Poland) said to meeting attendees.

The guidelines, which were simultaneously published in the European Heart Journal[1], also note that cardiac resynchronization therapy (CRT) should not be used when a patient has a QRS duration <130 ms, replacing the 2012 guideline recommendation of <120 ms; and has first-time inclusion for the angiotensin receptor/neprilysin inhibitor (ARNI) still referred to here as LCZ696 (valsartan-sacubitril, Entresto; Novartis).

"We're recommending that LCZ696 should replace ACE inhibitors in patients who fit the PARADIGM-HF criteria," said Ponikowski. However, he noted that more research is needed before the drug can be recommended for other patients.

Ponikowski later told heartwire from Medscape that although these are currently the best evidence-based recommendations, clinicians should "follow the guidelines—but not slavishly." Instead, they should take them into account while managing their individual patients.

The guidelines were released just 1 day after the joint release of an update to the heart-failure guidelines from the American Heart Association and American College of Cardiology[2]. Dr Mariel Jessup (University of Pennsylvania, Philadelphia) was on the writing committees for the American and European guidelines.

"Both committees separately deliberated and carefully examined evidence. And I think this validates the concepts that are promoted in both guidelines, that we came to the same conclusions," especially around LCZ696, she said to heartwire.

Existing "Gray Area"

During his presentation on the new mid-range classification during the guidelines session, as well as on diagnostic changes overall, task force cochair Dr Adriaan Voors (University Medical Center Groningen, Netherlands) noted that there's been "a gray area" between HF with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF).

"Identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology, and treatment of this group of patients," he said.

In addition, he introduced a new algorithm for diagnosing non–acute HF and to help to define whether HF can be ruled out completely or if further tests are needed.

The next presentation, on management of chronic heart failure with pharmacology, was conducted by Dr Giuseppe MC Rosano (St Georges University of London, UK). He noted that the recommendation of LCZ696 instead of ACE inhibitors is for "ambulatory patients who remain symptomatic despite optimal therapy."

Rosano added that this includes only those who are able to tolerate the inhibitors or angiotensin-receptor blockers (ARBs). But he cautioned that some safety issues remain with the drug, such as symptomatic hypotension and risk of angioedema.

On the other hand, those with symptomatic HFrEF and LVEF <35% and in sinus rhythm with a heart rate >70 bpm should receive ivabradine (Corlanor, Amgen), "which has been shown to improve outcomes and should be considered when appropriate."

Other therapeutic recommendations for patients with NYHA class 2–5 HFrEF include:

  • A combination ACE inhibitor-ARB should be used only in those receiving a beta-blocker who cannot tolerate a mineralocorticoid receptor antagonist (MRA)—and only under strict supervision.

  • Although no clear evidence suggests using a fixed-dose combination of hydralazine and isosorbide dinitrate in this patient population, the combo can be "considered" in those who cannot tolerate an ACE inhibitor or an ARB.

  • Digoxin may be considered in sinus-rhythm patients to reduce hospitalization risk.

  • Digoxin is recommended only for treating those with comorbid atrial fibrillation and a rapid ventricular rate "when other therapeutic options cannot be pursued."

  • Digitalis should be prescribed only under supervision and should be used cautiously in women, the elderly, and those with reduced renal function.

Treatments that are not recommended for this patient group include statins, oral anticoagulants and antiplatelet therapy, and renin inhibitors.

CRT "Sweet Spot"?

During his presentation on devices and interventions for managing CHF, Dr Frank Ruschitzka (University Heart Center, Zurich, Switzerland) noted that CRT now has a 1A recommendation for HF patients with a QRS duration >150 ms "and [left bundle branch block] LBBB QRS morphology in order to improve symptoms and reduced morbidity and mortality" and has a 1B recommendation for those with a QRS duration of 130 to 149 ms.

"It appears that the 'sweet spot' for CRT is somewhere between 130 and 160," said Ruschitzka, who is also the president-elect for the Heart Failure Association of the ESC. The change to not recommending CRT for patient with a QRS duration below 130 ms came about because of negative findings from the EchoCRT trial.

As for implantable cardioverter defibrillators (ICDs) in HF patients, the devices are not recommended within 40 days of an MI "as implantation at this time does not improve prognosis" or in many patients in NYHA class 4. A wearable version of the device can be considered if a patient is at risk for sudden cardiac death or as a bridge to an ICD.

Ruschitzka also noted that HF patients should have multidisciplinary management and monitoring approaches and that left ventricular assist devices (LVADs) were changed to 2aC and 2aB recommendations "because the old guidelines got a bit carried away."

He ended by noting there are several "gaps in evidence" that need to be addressed in future research, including specific subgroup indications for ICDs and how to select optimal candidates and CRT's effect in patients with atrial fibrillation.

Acute HF

As for acute HF, Dr Veli-Pekka Harjola (Helsinki University Central Hospital, Finland) stressed that early initiation of appropriate therapy for this condition should follow the same "time-to-therapy" approach established in ACS. In addition, he noted that the guidelines include a new algorithm that combines diagnosis and treatment.

"Upon presentation, a measurement of plasma natriuretic peptide level is recommended in all patients with acute dyspnea and suspected acute heart failure," said Harjola, noting that they are aware of worries about false positives from elevated concentrations of the peptides.

Regarding pharmacotherapy for these patients, recommendations have now been broken out for each main drug category, including diuretics, vasodilators, and inotropic agents.

"Global View"

During a presentation on "a global view" on the ESC HF guidelines[3], Dr Mandeep Mehra (Harvard Medical School, Boston, MA) called the new recommendations "clear, practical, and concise."

"Gaps in the guidelines continue to outweigh the differences between guidelines," said Mehra, adding that the new recommendations are quite similar with others "with varying levels of conservatism and practical guidance."

However, "health economic and resource considerations may have to be confronted in the near future, especially in the 'mid-category' recommendations." He added that other implementation challenges will include time to change, practice change burden (in the form of new education and authorizations), reactivation of effort for patients, and potentially added costs.

"In my opinion, the next stage in the evolution of guidelines should include specific guidance on contextualizing and adapting them, as well as providing options for effective techniques for implementation in all-income countries," said Mehra.

The ACC and AHA, along with the Heart Failure Society of America, released their new pharmacological therapy update to the 2013 HF guidelines on May 20, 2016 in the Journal of the American College of Cardiology. It also includes the new addition of LCZ696 and ivabradine to the list of treatment options for "stage C heart-failure patients" with reduced EF.

"I think it's great that we ended up at the same place," said Jessup, referencing how well the new ESC and ACC/AHA guidelines work together. "We all want to do the right thing for patients and for clinicians."

Among the few differences between the European and American recommendations was the discussion of HFmrEF. "I think that's a novel approach that they came up with," said Jessup.

She added that the process to initiate a guideline is different between the organizations. "We wouldn't have a reason to talk about mid-range EF at that time because there's no new trial on it," she said. "When we get to the point of writing an entirely new guideline, I certainly think there's been a lot of discussion about this as a separate entity. So I'm glad the ESC brought it up."

"Population Approach" Emphasized in New CVD Prevention Guidelines From the ESC

FLORENCE, ITALY — In addition to new acute and chronic heart failure (HF) guidelines, all-new CVD prevention guidelines were released here at the ESC Heart Failure Congress, in a joint effort from the ESC and nine other societies.

The new recommendations, presented in a 90-minute session[4], include targeting risk factors such as high blood pressure and lipids and give a strong push toward a "population approach" to prevention—especially in regard to changing food patterns, decreasing smoking, and increasing physical activity.

Dr Monica Tiberi (Clinical Diagnostic Center, Pesaro, Italy) noted that health providers can help to add physical activity to daily life by advising appropriate activities and measuring progression, helping the patient to set personal goals, and exploring barriers to exercise and ways to overcome them. In fact, "regular assessment and counseling on physical activity" is now a class 1B recommendation.

Tiberi added that the risk for an adverse cardiac reaction to exercise is very low in healthy adults, is outweighed by health benefits, and is much lower if the activity has light or moderate intensity.

The guidelines go on to further recommend legislating the composition of food to limit portion sizes and decrease salt, saturated fat, and added sugar; taxing foods and beverages high in saturated fat and sugar; and the "elimination of industrially produced trans fats." To decrease smoking, the guidelines suggest a complete ban on all advertising of tobacco products, restrictions on the marketing and sales of e-cigarettes, and banning smoking near child-friendly areas to curb the effect of passive smoking.

Dr Massimo Francesco Piepoli (Guglielmo de Saliceto Hospital, Piacenza, Italy) said that a major new key message is the importance of incorporating a systematic approach to CV risk assessment by targeting those likely to be at higher risk—and to repeat these assessments every 5 years. The new guidelines include information on how best to use risk-estimation charts.

He also noted the importance of recommending cardiac rehab programs for patients with ACS, after revascularization, and with HF.

In further talk about CVD prevention in patients with HF, Dr Arno Hoes (University Medical Center, Utrecht, Netherlands) reported that the recommendation is to screen and treat all HF patients with preserved ejection fraction or the newly classified mid-range ejection fraction for any CV or non-CV comorbidity. In addition, at least 150 minutes per week of moderate physical activity should be recommended for this patient population, as should vaccination against influenza. Statins are not generally recommended—although clinicians should not stop indicated statins once HF occurs.

"Cardiovascular prevention in heart failure is crucial but complicated. And it's a lifelong endeavor," summarized Hoes.

The guidelines were simultaneously published in the European Heart Journal and are available for free download.


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