A new class of drugs for systolic heart failure: The PARADIGM-HF study

STUDY DESIGN AND OBJECTIVES

PARADIGM-HF was a double-blind, randomized controlled trial comparing sacubitril-valsartan and enalapril in patients with chronic systolic heart failure. As such, it was the first trial in recent years to study a new drug in comparison with a well-established heart failure drug rather than as an add-on strategy.¹

Inclusion criteria

To be included in the PARADIGM-HF trial, patients had to have:

• A left ventricular ejection fraction of 40% or less (later changed to ≤ 35%)
• New York Heart Association class II, III, or IV symptoms
• A B-type natriuretic peptide (BNP) level of at least 150 pg/mL or an N-terminal proBNP (NT-proBNP) level of at least 600 pg/mL; for patients hospitalized for heart failure within the previous 12 months, the cut points were lower (BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL).

End points

The primary end point was the composite of cardiovascular death or first hospitalization for heart failure. Other outcomes assessed were time to death from any cause, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score at 8 months, time to new-onset atrial fibrillation, and the time to decline in renal function (defined as end-stage renal disease or a decrease in estimated glomerular filtration rate of at least 50% from randomization). All end points were blindly adjudicated by a clinical end points committee.

Two run-in periods

The study enrolled 10,521 patients from 1,043 centers in 47 countries, who entered the initial run-in period consisting of 2 weeks of treatment with enalapril at the study dosage (10 mg twice daily) in order to ensure no unacceptable side effects. At this point, 1,102 patients exited the study, leaving 9,419 who entered the second run-in period.

The second run-in period consisted of 4 weeks of treatment with sacubitril-valsartan, initially at half the study regimen (100 mg twice daily) and eventually at the full study dosage (200 mg twice daily). During the second run-in period, 977 participants left the study, leaving a total of 8,442 patients who underwent randomization. Forty-three patients were then excluded (6 because of invalid randomization and 37 because of four sites that closed because of major violations of good clinical practice).

Of those randomized, 4,187 patients were assigned to the sacubitril-valsartan treatment group and 4,212 were assigned to the enalapril group. The investigators used an intention-to-treat analysis for this study.

Most patients had NYHA class II symptoms

The randomized patients had a mean age of 64 years, 75% were men, 66% were white, and 58% were from Europe (only 7% were from North America). The mean left ventricular ejection fraction was about 30%, and 60% of the study participants had an ischemic cause for their cardiomyopathy. Although one of the inclusion criteria was New York Heart Association class II, III, or IV symptoms, about 5% of the patients had class I symptoms. Seventy percent had class II symptoms, 24% had class III, and less than 1% had class IV symptoms.

At the time of randomization, 78% of the patients were taking an ACE inhibitor and 93% were taking a beta-blocker, but only a little more than half were taking a mineralocorticoid antagonist and only about 15% had an implantable cardioverter-defibrillator.

STUDY OUTCOMES

This study was designed to detect a 15% lower risk of cardiovascular death in the sacubitril-valsartan group. It was projected to continue for at least 34 months but was stopped early because of an overwhelming benefit of the new drug at a median follow-up of 27 months.

Major findings

The primary composite outcome (cardiovascular death or first hospitalization for heart failure)¹ occurred in 21.8% of the patients in the sacubitril-valsartan group vs 26.5% of patients in the enalapril group (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.73–0.87, P < .001). The number of patients who needed to be treated to prevent one occurrence of the primary composite outcome (100/absolute risk reduction) was only 21. The benefit was strong and consistent across both of the individual components of the composite outcome:

• Cardiovascular death 13.3% vs 16.5%, HR 0.80 (95% CI 0.71–0.89), P < .001
• First hospitalization for worsening heart failure 12.8% vs 15.6%, HR 0.79 (95% CI 0.71–0.89), P < .001.

Secondary outcomes. The sacubitril-valsartan group had a significantly lower rate of death from any cause (17.0% vs 19.8%, HR 0.84, 95% CI 0.76–0.93, P < .001) and a lower mean decrease in KCCQ clinical summary scores at 8 months (2.99 points vs 4.63 points, mean difference 1.64, 95% CI 0.63–2.65, P = .001). The KCCQ score measures subjective symptoms and physical limitations caused by heart failure; possible scores range from 0 to 100, with a higher score indicating better functional status. Notably, sacubitril-valsartan did not increase the KCCQ score in these patients; rather, sacubitril-valsartan recipients had a lower decrease in their scores than those in the enalapril group.

The incidence of new-onset atrial fibrillation was the same in both groups (3.1% and 3.1%).¹ A decline in renal function (defined as end-stage renal disease, a decrease of 50% or more in estimated glomerular filtration rate from the value at randomization or a decrease in the estimated glomerular filtration rate of more than 30 mL/min/1.73 m² to less than 60 mL/min/1.73 m²) occurred in 2.2% of the valsartan-sacubitril group and 2.6% of the enalapril group (P = .28).

The effects of the study drug on the primary composite outcome and on death from a cardiovascular cause were similar in all prespecified subgroups except for NYHA class: the reduction in the risk of the composite outcome was lower in sacubitril-valsartan recipients with NYHA I or II symptoms than in those with NYHA III or IV symptoms (P for interaction .03). However, there were no differences in the other prespecified subgroups, defined by age, sex, race, region, estimated glomerular filtration rate, diabetes, systolic blood pressure, ejection fraction, atrial fibrillation, NT-proBNP, hypertension, previous use of an ACE inhibitor, previous use of an aldosterone antagonist, previous heart failure hospitalization, and time since diagnosis of heart failure.

SAFETY: ANGIOEDEMA, HYPOTENSION, AND RENAL DYSFUNCTION

Angioedema

As noted above, the combination of neprilysin inhibitors and ACE inhibitors has been associated with an increased risk of angioedema. That was an important consideration before starting this study, which used a combination of a neprilysin inhibitor and an ARB in an attempt to avoid this serious side effect.

As it happened, there was no increased risk of significant angioedema with sacubitril-valsartan use compared with enalapril. Rates were similar to those in other studies, which showed a less than 1% risk of angioedema caused by ACE inhibitors.^20,21 Only 19 patients (0.5%) in the sacubitril-valsartan group and 10 patients (0.2%) in the enalapril group experienced any angioedema. Of these, just three patients in the sacubitril-valsartan group and one patient in the enalapril group experienced angioedema that required hospitalization (P = .31). None of these patients had airway compromise due to angioedema.

Hypotension, cough, renal dysfunction, hyperkalemia

Other safety issues that were assessed included hypotension, worsening renal function, increase in potassium levels, and cough. Patients in the sacubitril-valsartan group were more likely to have symptomatic hypotension than patients in the enalapril group (14.0% vs 9.2%, P < .001); however, the authors noted that this was a rare cause of drug discontinuation.

Patients in the sacubitril-valsartan group were less likely to develop cough (11.3% vs 14.3%, P < .001), a serum creatinine level of 2.5 mg/dL or more (3.3% vs 4.5%, P = .007), or a serum potassium level of more than 6.0 mmol/L (11.3% vs 14.3%, P = .007).¹

During the two run-in periods combined, 12% of the patients in the study withdrew because of adverse events, including cough, renal dysfunction, hyperkalemia, and symptomatic hypotension. During the enalapril run-in period, 591 patients (5.6%) withdrew due to adverse events, and 547 patients (5.8%) withdrew due to these events during the sacubitril-valsartan run-in period. After adjusting for the shorter time on enalapril, there was a higher rate of withdrawal because of adverse events from enalapril than from sacubitril-valsartan.

LOWER RISK OF CLINICAL PROGRESSION

In a separate paper,²² the PARADIGM-HF investigators reported that, among the survivors in the study, those who received sacubitril-valsartan fared better in terms of a number of markers of progression of heart failure, with lower rates of:

• Intensification of medical treatment for heart failure
• Emergency department visits for worsening heart failure
• Hospitalization for worsening heart failure
• Need for intensive care
• Need for intravenous inotropic agents
• Need for cardiac devices or heart transplants
• Worsening symptom scores
• Elevation of biomarkers of myocardial injury.