Valsartan/sacubitril, formerly known as LCZ696 – but now bearing the brand name Entresto since it won FDA approval for heart failure – may also be a potent treatment for isolated systolic hypertension, the number one driver of stroke, researchers said here.
Bryan Williams, MD, the study’s principal investigator, and chair of medicine at University College London, said the findings from the 454-patient PARAMETER study suggest that “this drug may prove to be extremely useful in treating hypertension.”
Williams reported the results from the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin Receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) trial as a Hot Line study at the European Society of Cardiology meeting.
A year ago PARADIGM, the pivotal trial that led to the FDA approval of LCZ696 for treatment of heart failure, was reported at ESC 2014, and Milton Packer, MD, the principal investigator for PARADIGM served as discussant for PARAMETER.
Packer opened his comments stating that he was surprised to have been invited as discussant since he was the “most conflicted person in this room,” recalling his support from Novartis and his role as PI for PARADIGM. He also noted that he knew nothing about hypertension, and suggested that the reduction in BP demonstrated by LCZ696 probably was not as meaningful as the core issue of neprilysin inhibition, which he said benefits the failing heart.
PARAMETER assessed LCZ696 (400 mg daily) at two time points: 12 weeks and 52 weeks in comparison with optimally dosed olmesartan (40 mg). It recruited elderly patients (mean age 68) and who had both systolic hypertension (≥ 150 mmHg) and wide pulse pressure (>60 mmHg).
Williams said an especially encouraging finding from PARAMETER was that a single dose of the drug in the morning – it is given twice daily for heart failure – provided 24-hour blood pressure reduction. He said this nighttime effect suggested the drug may also be beneficial for patients whose blood pressure does not “dip” while sleeping, a symptom that increases risk of stroke.
At 12 weeks, central arterial systolic pressure decreased by 12.6 mm Hg in the LCZ696 group versus a reduction of 8.9 mm Hg in the olmesartan group. Central aortic pulse pressure decreased by 6.4 mm Hg in the LCZ696 arm versus 4.0 in controls and in both comparisons the difference was significant. (P=o.o1 and 0.012 respectively).
Change in brachial SBP at 12 weeks was a reduction of 13.7 mm Hg at 12 weeks in the LCZ696 patients and 9.9 mm Hg in the olmesartan arm. At 1 year the respective reductions were 7.7 and 4.9 mm Hg and again both reductions were statistically significant.
During the extension study patients were permitted to add on other antihypertensive medicine, but Williams noted that fewer add-on medications were needed in the LCZ696 group.
Blood pressure (brachial and central aortic pressure) was monitored round the clock using the Mobil-O-Graph device.
At 12 weeks 89% of patients were evaluable and at 52 weeks 80% of patients were available for evaluation.
“As arteries stiffen, the pressure in the aorta (close to the heart) rises faster than the pressure measured in the arm, and that is the reason we were interested to see if LCZ696 was more effective at reducing this pressure compared to an ARB alone,” Williams said in a prepared statement.
“The fact that the ARB-neprilysin inhibitor is an effective BP lowering medication is gaining recognition in the hypertension community,” said Randall M. Zusman, MD, of Massachusetts General Hospital in Boston. “However, it is reputed that the drug will not be submitted to the FDA for use in hypertension. It will still be available ‘off-label’ but whether the insurers will cover its use remains to be seen. I would encourage Novartis to pursue a formal approval.”
The study was an investigator-led study funded by Novartis Pharma AG, Basel, Switzerland.
Williams said he received honoraria for lectures on hypertension from Novartis Pharma.
Packer disclosed support from Novartis.
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine
European Society of Cardiology