In a study of nearly 5000 patients who had heart failure with preserved ejection fraction (HFpEF), the effect size of sacubitril / valsartan vs valsartan to reduce heart failure hospitalizations or cardiovascular death did not reach statistical significance. We know better than to call a trial "negative" or "positive" based on a P value alone, but PARAGON HF confirmed the challenges of treating patients with HFpEF.
This was a global trial [1,2] ] of patients who had well-defined heart failure with left ventricular ejection fraction (LVEF) greater than 45%, elevated brain natriuretic peptide, and documented structural heart disease. The investigators used equal-length run-in periods starting with valsartan, then sacubitril / valsartan, a protocol similar to that of previous HFpEF trials. [3,4,5,6]
Their choice of primary endpoint was unusual. While four previous trials in HFpEF used time to first heart failure hospitalization or cardiovascular (CV) death, the PARAGON-HF authors chose the composite of total heart failure admissions and death from cardiovascular causes.
They offered three reasons for the change: (1
The Main Results
Over a median follow-up of 35 months, there were 894 primary endpoint events in the sacubitril / valsartan arm and 1009 in the valsartan arm (12/8 vs 14.6 per 100 patient-years). This corresponded to a relative risk (RR) reduction of 13% (RR, 0.87; 95% confidence interval [CI]0.75 – 1.01; P = .06).
The numerically lower event rate stemmed mostly from fewer heart failure hospitalizations in the sacubitril / valsartan arm (690 vs 797; RR, 0.85 [95% CI, 0.71 – 1.00]). Death from CV causes was similar in both arms (8.5% vs 8.9% for valsartan alone; hazard ratio, 0.95 [95% CI, 0.79 – 1.16]).
The authors indicated that "if the primary outcome reached significance," further analysis of secondary endpoints looking at functional class was planned. That didn't happen, they couldn't put much weight on the slightly higher number of patients in the sacubitril / valsartan arm who had an improvement in functional class.
Similar numbers of patients in both arms stopped taking their assigned drug, but hypotension, as defined by systolic blood pressure less than 100 mm Hg, occurred in 15.8% of sacubitril / valsartan arm vs 0.8% of valsartan arm. Angioedema occurred rarely but was threefold more common with sacubitril / valsartan (0.6% vs 0.2%). Worsening creatinine and hyperkalemia were slightly higher in the valsartan arm.
Two subgroups looked interesting. Patients with LVEF in the lower range (45% to 57%) and women had lower rates of primary endpoint on sacubitril / valsartan (RR, 24% and 34%, respectively); both of these were significant for a treatment-covariate interaction.
I've learned the hard way that — even with large, well-conducted trials — it's difficult to know the exact treatment effect . In PARAGON-HF, the CIs for the primary endpoint range from a clinically meaningful 25% lower rate of events to no effect. The threshold P value is arbitrary. Truth: there is uncertainty.
There are other clues in the data. In the published supplements, the authors show the results of various analyzes of the primary endpoint. If they used the time-to-first event method, as the four previous trials had done, the hazard ratio was decidedly less impressive at 0.92 (95% CI, 0.81 – 1.03) and sacubitril / valsartan would be added to the ineffective list drugs for HFpEF without much debate.
Another clue pointing to a non-clinically meaningful effect of sacubitril / valsartan is the lack of signal for lower CV and overall death. PARAGON-HF enrolled older patients (mean age, 72 years) with multiple comorbidities. If sacubitril / valsartan is much better than valsartan for reducing hospital admissions, why is there not a clear signal of lower CV death rates
Then there is the question of subgroup effects. HFpEF is a heterogeneous condition; It's tempting to see a signal rather than noise in the observation that women and patients with LVEF in the lower range had more reduction in the primary endpoint. Again, maybe it is real, but the case for a true heterogeneous effect would be much stronger had the overall results shown a clear benefit in both heart failure admissions and survival.
Clinicians deciding to adopt a new therapy must consider adverse effects and cost . Even after careful run-in periods and well-defined selection criteria, hypotension was nearly 20-fold greater with sacubitril / valsartan. Indeed, low blood pressure seems to be the greatest impediment to sacubitril / valsartan use in patients with systolic heart failure.
The significant cost difference in two drug matters. Health systems can't print money. Money spent on one therapy means less for others. Spending for expensive drugs is fine if there are clear net benefits. The results of PARAGON-HF do not clear that bar.
Cardiology in 2019 boasts many excellent therapies. Contemporary medical therapies, such as high-dose valsartan, can be tough to beat in trials. What's more, I can't help but think much of HFpEF is due to the long-term effects of exposure to life — in other words, aging. With that frame of reference, it's easier to understand the challenge of treating patients with this condition.
PARAGON-HF stands out as an example of clinical science done well. But as a clinician caring for older complex patients with HFpEF, I find its results do not persuade me to adopt a new therapy.