PARADIGM Drug Dose Reduction Doesn't Cut Benefit

Similar benefit with LCZ696 vs ACE inhibitor across lower achieved doses in trial substudy

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• by Crystal Phend
  Senior Staff Writer, MedPage Today

• This article is a collaboration between MedPage Today® and:
  

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

NATIONAL HARBOR, Md. -- Heart failure drug LCZ696 (Entresto) maintains its effect on hospitalizations and mortality even when the dose must be reduced, a PARADIGM-HF trial substudy showed.
The hazard ratios for the primary composite endpoint of death from cardiovascular causes or heart failure hospitalization remained similar across achieved LCZ696 dose categories:

• 0.79 (95% confidence interval 0.71-0.88) for the full 200 mg target dose versus 10 mg enalapril
• 0.80 (95% CI 0.67-0.94) for a reduced 100-200 mg dose versus 5-10 mg enalapril
• 0.76 (95% CI 0.58-0.99) for doses under 100 mg versus under 5 mg enalapril

The comparative efficacy likewise was similar for the primary outcome censored at dose reduction (HR 0.79) and when looking only at events after dose reduction (HR 0.80), Orly Vardeny, PharmD, of the University of Wisconsin in Madison, and colleagues reported here at the Heart Failure Society of America meeting.
"As one looks at the data and as, say, a physician in Minnesota you look at a patient and see the patient tolerates a lower dose and the dose beats enalapril -- Is this the beginning of rethinking the dose range of this drug?" posited John Burnett, Jr., MD, of the Mayo Clinic in Rochester, Minn., as a moderator at the rapid-fire abstract session.
"In general as clinicians, we really need to target doses that were used in the clinical trials," Vardeny responded. "Even though we're saying the relative benefit remains at a lower dose, it's important to still try to target. That's something we always strive for with all our neurohormonal blockers, whether it be beta-blockers, ACE inhibitors, or MRAs. We should still try to target 200 mg BID for the most part [with LCZ696]."
While the findings are reassuring, "I wouldn't routinely reduce the dose, I would only reduce the dose if one had an adverse side effect or outcome," Matthew Wolf, MD, PhD, of the University of Virginia Health System in Charlottesville, agreed in an interview with MedPage Today.
The most common reasons for dose reduction in the trial were:

• Hyperkalemia (6.2% LCZ696, 7.2% enalapril)
• Hypotension (19.7% LCZ696, 14.6% enalapril)
• Patient request (13.3% LCZ696, 13.2% enalapril)

The single strongest predictor of dose reduction was elevated serum creatinine (OR 2.27, 95% CI 2.27-3.26).
The reduced-dose versus reduced-dose comparison was a reasonable way to look at the outcomes, commented Jean Nappi, PharmD, of the Medical University of South Carolina in Charleston.
"I think it's a fair comparison, because they both cause hyperkalemia, they both cause hypotension," she told MedPage Today, so a patient requiring a reduced dose of the one drug likely wouldn't have tolerated a full dose of the other.
From the American Heart Association:

• AHA Science News: PARADIGM HF Results
• 2013 ACCF/AHA Guideline for the Management of Heart Failure
• State of the Science for Transitions of Care in Heart Failure
• Heart Failure Management in Skilled Nursing Facilities

• Primary Source

  Heart Failure Society of America

  Source Reference: Vardeny O, et al "Efficacy of LCZ696 persists at lower than target doses in the paradigm-HF Trial" HFSA 2015.