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Entresto cuts LV mass in hypertensive patients

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High drug cost demands caution

This study produced very interesting and convincing data. The results suggested that treating hypertension with sacubitril plus valsartan produced a significant, incremental improvement in left ventricular mass beyond the formulation’s blood pressure effect. This could potentially have importance when treating patients with hypertension and left ventricular hypertrophy.

Olmesartan was a fair comparator to use. It arguably is the most potent angiotensin receptor blocker for reducing blood pressure. However, in routine practice we generally combine an angiotensin receptor blocker with a diuretic to get maximum blood pressure lowering. In addition, it is not new to show that blood pressure lowering reduces left ventricular size.

Dr. Dan J. Fintel

All treatments that reduce blood pressure will also reverse some amount of left ventricular hypertrophy. The question is whether sacubitril plus valsartan reduces left ventricular size and mass beyond what would be expected based on its blood pressure effect. The results Dr. Schmieder reported suggest it does.

These data are too limited and the cost for prescribing sacubitril plus valsartan is so high, compared with most other antihypertensive drugs, that I would like to see additional study results documenting this effect before I’d be willing to prescribe sacubitril plus valsartan to patients with hypertension but no heart failure.

Dan J. Fintel, MD , a cardiologist and professor of medicine at Northwestern University in Chicago, made these comments in an interview. He has been a speaker on behalf of AstraZeneca, BMS, Daiichi Sankyo, Janssen, Merck, and Pfizer.



– Hypertensive patients without heart failure treated with the heart failure formulation sacubitril plus valsartan had a significantly greater drop in their left ventricular mass than did patients treated with olmesartan in a randomized trial with 114 patients.

Treatment with sacubitril plus valsartan for both 3 and 12 months led to roughly twice as much reduction in left ventricular (LV) mass as did treatment with olmesartan, and this difference persisted after adjustment for between-group differences in blood pressure reduction, Roland E. Schmieder, MD, reported at the American Heart Association Scientific Sessions.

Dr. Roland E. Schmieder Mitchel L. Zoler/Frontline Medical News

Dr. Roland E. Schmieder

Reduced LV mass is potentially a very beneficial added effect from sacubitril plus valsartan, because results from many prior studies showed that reduced LV mass is associated with reductions in cardiovascular death. This new finding “gives another strong argument” for using sacubitril plus valsartan, because the formulation appeared to not only lower blood pressure but also reversed some of the organ damage patients had developed, said Dr. Schmieder, professor and vice chairman of nephrology and hypertension at University Hospital in Erlangen, Germany.

During clinical development of sacubitril plus valsartan (Entresto), the company that owns this compound, Novartis, ran a few small studies using the formulation to treat hypertension, but eventually those studies stopped, he said in an interview. “I hope this pushes development of other neprilysin inhibitor formulations for their blood pressure effects. I think this finding helps us understand why sacubitril plus valsartan was so effective for treating heart failure.” (N Engl J Med. 2014 Sep 11;371[11]:933-1004.)

The study enrolled patients with mild or moderate hypertension; the average blood pressure of enrolled patients was 155/92 mm Hg. They averaged 60 years of age, two-thirds were men, and their average LV mass index at baseline was 72 g/m2. The study excluded patients with heart failure. Patients randomized to receive sacubitril plus valsartan began on a dose of 200 mg/day, and after 2 weeks this rose to 400 mg/day, the maximum recommended dosage in the labeling. Patients randomized to olmesartan began on 20 mg/day, and after 2 weeks their dosage increased to 40 mg/day. Patients in both arms were also eligible to receive amlodipine for additional blood pressure lowering if deemed necessary by the treating physician.

The sacubitril plus valsartan group patients had an average cut in systolic blood pressure of about 26 mm Hg, both 3 and 12 months after the start of treatment. Patients in the olmesartan arm had decreases of 23 mm Hg and 21 mm Hg, respectively, at the two follow-up times. These between-group differences were statistically significant, Dr. Schmieder said.

Measurement of LV mass index using MRI scans showed an average reduction of LV mass index, compared with baseline of 6.4 g/m2 and 6.8 g/m2 after 3 and 12 months of treatment with sacubitril plus valsartan, and average reductions from baseline of 2.3 g/m2 and 3.5 g/m2 at the two follow-up examinations for patients treated with olmesartan. These statistically significant differences remained after adjustment for degree of blood pressure reduction at 3 and 12 months.

Additional measurements showed no between-group differences in aortic distensibility, but central pulse pressure also showed a significantly greater reduction with sacubitril plus valsartan, compared with olmesartan.

The trial was investigator initiated and received funding from Novartis. Dr. Schmieder has received honoraria from Novartis and also from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, and Servier.

On Twitter @mitchelzoler

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