Despite advances in medical technology and pharmacology, there have been no new drugs approved by the FDA for the treatment of heart failure for over a decade. Given the public health challenge, it is with no surprise that the results of the PARADIGM-HF trial¹ have been considered a dramatic advancement in heart failure management. While the results are compelling, questions have been raised that may delay regulatory approval and widespread acceptance.

The PARADIGM-HF trial randomized 8,442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to LCZ696, an angiotensin receptor-neprilysin inhibitor, or enalapril. The study consisted of a screening period; a single-blind run-in period during which all patients received enalapril 10 mg twice daily; an additional single-blind run-in period during which all patients who tolerated enalapril were enrolled to receive LCZ696 at 100 mg twice daily and then at 200 mg twice daily; and if tolerated, the patients were then enrolled in the double-blind treatment period. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. The trial was stopped early after a median follow-up of 27 months due to an overwhelming benefit with LCZ696. The primary outcome occurred in 21.8% in the LCZ696 group and 26.5% in the enalapril group (HR 0.80; 95% CI, 0.73 to 0.87; P <0.001). Compared to enalapril, LCZ696 reduced the risk of death from any cause by 16% (P <0.001) and the risk of hospitalization from heart failure by 21% (P <0.001). The number needed to treat for the primary outcome was 21. Symptomatic hypotension occurred more frequently in the LCZ696 group, but renal impairment, hyperkalemia, and cough were more common in the enalapril group.

Despite the favorable findings with LCZ696, some reservations of the trial's methodology have been raised. Pre-randomization run-in periods are controversial in the interpretation of clinical trials. Run-in periods can result in the exclusion of noncompliant patients, placebo responders, or subjects who could not tolerate the drugs.² Initially, 10,513 patients entered the enalapril run-in phase. Patients received enalapril 10 mg twice daily, which was the dose used in the Studies of Left Ventricular Dysfunction (SOLVD)-Treatment trial³ that found a reduction in mortality in patients with chronic systolic heart failure. Prior to the randomization phase, approximately 20% of patients discontinued the study; thus, only patients who were able to tolerate both drugs were enrolled. This run-in effect can lead to larger treatment effects than would ordinarily be seen without a pre-randomization period, which is further confounded by the early termination of the trial which is also associated with overestimation of treatment effects.

Another potential concern with PARADIGM-HF is the drug-dosing regimen. LCZ696 200 mg twice daily is equivalent to valsartan 160 mg twice daily, which is the target daily dose in heart failure. Patients randomized to enalapril received 10 mg twice daily, while the target daily dose in heart failure is 20 mg twice daily.⁴ It can be hypothesized that the reason for the improved outcome with LCZ696 is due to the more aggressive dosing regimen with valsartan, and not an inherent benefit of sacubitril, the neprilysin inhibitor in LCZ696. On the other hand, SOLVD³, the Vasodilator-Heart Failure Trial II (V-HeFT II)⁵, and the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) trial⁶ all used a target dose of enalapril of 10 mg twice daily. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)⁷ is the only trial that targeted a dose of 20 mg twice daily of enalapril and only 22% of patients successfully achieved this dose.

The Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE)⁸ and OVERTURE⁶ trials studied the combination of enalapril and omapatrilat, a neutral endopeptidase and angiotensin converting enzyme inhibitor. Both studies found a significant increase in angioedema, leading to the design of the PARADIGM-HF trial combining sacubitril with an angiotensin receptor blocker (ARB) instead of an angiotensin converting enzyme inhibitor (ACEI). Although the use of an ARB with sacubitril is a reasonable design, using an ARB in the placebo arm would have prevented the confusion surrounding the intervention and control arms using different classes of drugs.

Another question of PARADIGM-HF is the generalizability to all patient populations. Run-in trials reduce generalizability.² Additionally, it has been shown that African Americans are at a significantly higher risk of angioedema than Caucasians.⁹ In PARADIGM-HF, 66% of patients were Caucasian and 5% were African Americans. Although there was no difference in incidence of angioedema between the LCZ696 and enalapril groups, concern remains that this may not be applicable to all patient populations. With fewer than 500 patients in the entire study being African American and only 213 being exposed to LCZ696 chronically, and in light of the known risk of angioedema borne by African Americans exposed to a combination of ACEI and neprilysin inhibitor, the limited data from PARADIGM-HF cannot confirm an absence of risk for this important cohort known to be disproportionately afflicted with heart failure. Further data in a larger at-risk population will be essential in determining if LCZ696 can be safely prescribed for African Americans with heart failure.

Overall, PARADIGM-HF is predominately a trial of class II New York Heart Association patients (72%) with only 7% of subjects enrolled from North America. As in other heart failure trials conducted prominently outside the U.S., the use of implantable cardioverter-defibrilators (ICD) was less than 15% and for cardiac resynchronization therapy (CRT) was only approximately 7%. Both ICD and CRT therapy are associated with a clear survival advantage.^10-12 This raises the question as to whether the PARADIGM-HF results would be replicated in a patient population exposed to a utilization pattern of device therapy as employed in the U.S.

Although we have raised a number of reservations about PARADIGM-HF, the results are encouraging and potentially paradigm-shifting. The question remains as to whether widespread adoption should occur after this single, large, and well-conducted trial. This question will be before regulators in the upcoming months, and one to which patients and their providers anxiously await the answer.

References

1. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
2. Pablos-Mendez A, Barr RG, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice. JAMA 1998;279:222-5.
3. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302.
4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
5. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.
6. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920-6.
7. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429-35.
8. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103-11.
9. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther 1996;60:8-13.
10. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225-37.
11. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329-38.
12. Goldenberg I, Kutyifa V, Moss AJ. Survival with cardiac-resynchronization therapy. N Engl J Med 2014;371:477-8.

Keywords: African Americans, Aminobutyrates, Angioedema, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Cardiac Resynchronization Therapy, Enalapril, Heart Failure, Systolic, Hyperkalemia, Hypotension, Neprilysin, Pyridines, Receptors, Angiotensin, Tetrazoles, Thiazepines, Valine, Vasodilator Agents, Ventricular Dysfunction, Left

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