Omapatrilat Provides Long‐Term Control of Hypertension: A Randomized Trial of Treatment Withdrawal

Abstract

Omapatrilat simultaneously inhibits neutral endopeptidase and angiotensin‐converting enzyme, increasing levels of vasodilatory peptides while decreasing production of angiotensin II. This study evaluated the clinical effects of withdrawal of omapatrilat after a patient's hypertension had been controlled (seated diastolic blood pressure <90 mm Hg) on omapatrilat for at least 6 months, with or without adjunctive antihypertensive medications. This double‐blind study randomized 83 patients to receive either their established omapatrilat dose or placebo for 8 weeks; any concomitant antihypertensive medications were kept constant. Patients continuing on omapatrilat had no change in blood pressure. Patients whose chronic omapatrilat treatment was replaced by placebo had clinically important increases in both systolic (+16.5 mm Hg) and diastolic (+9.6 mm Hg) blood pressures (both p<0.001). An increase in blood pressure was also seen in patients who were taking adjunctive antihypertensive medications prior to withdrawal of omapatrilat. This study demonstrates that when compared to withdrawal placebo, omapatrilat maintains clinically and statistically significant blood pressure reductions.

Hypertension is a major risk factor for cardiovascular disease and is poorly controlled worldwide. Both systolic and diastolic blood pressure (SBP/DBP) have been shown to be related to cardiovascular disease leading to morbidity and mortality. ¹ The benefits of treating hypertension and reducing blood pressure (BP) have been documented in numerous clinical trials. ² , ³ , ⁴

Omapatrilat is a new antihypertensive agent with a unique mechanism of action. ⁵ It simultaneously inhibits two key enzymes involved in BP homeostasis: neutral endopeptidase and angiotensin‐converting enzyme (ACE). ⁶ Simultaneous inhibition of neutral endopeptidase and ACE increases vasodilatory peptides, including atrial natriuretic peptide and brain natriuretic peptide and it also increases the half‐life of other vasodilator peptides, including bradykinin and adrenomedullin. ⁷ , ⁸ , ⁹ , ¹⁰ By inhibiting the renin‐angiotensin‐aldosterone system and potentiating the vasodilatory peptides, omapatrilat reduces vasoconstriction and enhances vasodilation, thereby decreasing vascular tone and lowering BP. ¹¹ , ¹² , ¹³ , ¹⁴ Short‐term (8–12 weeks) clinical trials show omapatrilat to be well tolerated and efficacious in hypertensive patients, ¹⁵ , ¹⁶ and data from ongoing long‐term, open‐label studies suggest that patients receive persistent and effective BP control for up to 5 years with omapatrilat given as monotherapy (Bristol‐Myers Squibb Company, data on file, 2002).

While many patients require increasing doses or additional medications to maintain BP control, it is unusual for studies that document the persistence of antihypertensive efficacy to be performed. The primary objective of this study was to compare the change in SBP and DBP, over 8 weeks, in subjects continued on omapatrilat with those whose treatment was replaced by placebo. The safety and tolerability of discontinuation of omapatrilat and continued active treatment were also assessed.

METHODS

The study was conducted under the principles of the Declaration of Helsinki and its amendments and approved by the Institutional Review Boards/Ethics Committees. All subjects were required to give written informed consent before participating.

Study subjects were a subset of a larger group of 1098 subjects enrolled in an ongoing, long‐term, open‐label trial of once‐daily omapatrilat given for ≥6 months with or without adjunctive antihypertensive medications for treatment of mild to moderate hypertension. Subjects were ≥18 years of age, had documented pretreatment seated DBP (SeDBP) 95–110 mm Hg, and had their BP controlled (SeDBP <90 mm Hg) for ≥2 months with a stable dose of omapatrilat ≥20 mg.

Eighty‐three subjects were randomized to receive either placebo (n=41) or their regular once‐daily omapatrilat dosages (n=42). Baseline demographic characteristics, untreated BP, withdrawal baseline BP, and omapatrilat dosage at randomization were similar in both treatment groups (Table). Subjects taking any adjunctive antihypertensive medications at baseline, including hydrochlorothiazide, amlodipine, or atenolol (omapatrilat group, 43%; placebo group, 51%), continued this therapy.

Table.

Baseline Demographic Characteristics/Trough Seated Efficiency Measures

Baseline	Placebo	Omapatriat
	(n=41)	(n=42)
Age, years
Mean (SD)	57.5 (10.5)	56.2 (10.1)
Range	35–77	36–80
Age Group n (%)
<65 years	31 (76)	32 (76)
≥65–74 years	7 (17)	9 (22)
≥75 years	3 (7)	1 (2)
Gender, n (%)
Male	29 (71)	30 (71)
Female	12 (2.9)	12 (2.9)
Race,n (%)
White	37 (90)	38 (90)
Black	3 (7)	3 (7)
Other	1 (2)	1 (2)
Duration of hypertension, years
Mean (SD)	9.4 (7.3)	10.4 (10.8)
Range	1–28	0–57
Short‐term baseline:*
SeDEP, mmHg‐
Mean (SD)	100.4 (3.9)	100.5 (3.8)
Range	95.3–110.0	94.7–110.0
SeSEP, mmHg
Mean (SD)	156.7 (13.3)	154.6 (13.5)
Range	133.3–196.0	132.0–184.7
Withdrawal baseline**
SeDBP mmHg
Mean (SD)	83.6 (5.4)	85.7(3.0)
Range	69.3–92.0	78.7–97.3
SeSEP, mmHg
Mean (SD)	130.7 (9.3)	131.3 (8.6)
Range	101.3–152.0	111.3–151.2
Months treated in long term study prior to withdrawal
Mean (SD)	14.4 (5.3)	15.3 ((6.4)
Range	8–25	7–28
Adjunct use at withdrawal Baseline, n (%)
Yes	21 (51)	18 (43)
No	20 (49)	24 (57)
Omapatrilat dose at withdrawal baseline (mg)
0	2 (5.0)	0 (0)
20	19 (46.0)	23 (55)
40	11 (27.0)	10 (24)
80	9 (22.0)	9 (21)
SeDEP=seated diastolic blood pressure; SeSBP=seated systolic blood pressure; *baseline was the last assessment prior to randomization into the short‐term double‐ blind period; **withdrawal substudy baseline was the last assessment prior to treatment during withdrawal substudy therapy

Subjects were seen at office visits every 2 weeks for 8 weeks after randomization. At each visit, seated BP was measured in triplicate, 24 hours after the preceding dose of study medication, by trained observers using auscultation and a mercury sphygmomanometer, according to a standardized protocol. Compliance with omapatrilat, placebo, and the adjunctive antihypertensive medications was assessed by pill counts at each visit. Safety and tolerability were assessed using open‐ended questions about adverse events, physical examinations, and periodic laboratory testing. Subjects with SeDBP >100 mm Hg confirmed within 1 week were discontinued from the double‐blind study and returned to open‐label treatment with omapatrilat. All subjects resumed long‐term, open‐label treatment with omapatrilat after completion of the study.

RESULTS

At the end of 8 weeks, placebo‐treated subjects had clinically important increases in both seated SBP (SeSBP, +16.5 mm Hg) and SeDBP (+9.6 mm Hg), while omapatrilat‐treated subjects showed no significant changes in SeSBP or SeDBP (Figure). The difference in SeSBP and SeDBP between the two groups was 13.5 and 7.9 mm Hg, respectively (both p<0.001). Most of the increases in BP occurred by 2 weeks. Five subjects (12%) in the placebo group were discontinued for a disqualifying rise in SeDBP (>100 mm Hg). At 8 weeks, increases in BP in subjects receiving placebo plus adjunctive antihypertensive therapy equaled approximately one half of the increases seen in subjects receiving placebo alone (SeSBP, 11.2 mm Hg vs. 20.9 mm Hg; SeDBP, 6.6 mm Hg vs. 12.2 mm Hg). No differences were noted in BP change between subjects receiving omapatrilat plus adjunctive therapy and those receiving omapatrilat alone. While similar studies are unusual, a few have been conducted with diuretics, ACE inhibitors, and calcium channel blockers. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰

Figure.

Mean change from baseline at 2, 4, 6, and 8 weeks in trough seated systolic (SeSBP) and diastolic blood pressure (SeDBP). SeSBP and SeDBP increased significantly after withdrawal to placebo compared with continuation of omapatrilat therapy.

No serious adverse events were reported. The overall adverse event and adverse drug experience incidences were higher in the placebo group than in the omapatrilat group. One placebo‐treated subject discontinued because of an adverse event and was reinitiated on omapatrilat therapy.

New or worsening headaches were reported by nine placebo‐treated subjects (22%) and one omapatrilat‐treated subject (2.4%). Although mild to moderate hypertension is often considered asymptomatic, weak correlations with headache have been observed. ²¹ A reduction in incidence of headache has been shown to follow pharmacologic lowering of BP in subjects with mild to moderate hypertension. ²¹ , ²²

DISCUSSION

In hypertensive subjects with BP that is well controlled with stable doses of omapatrilat, withdrawal of omapatrilat and replacement with placebo was followed by clinically important and statistically significant increases in both SeSBP and SeDBP, occurring primarily within the first 2 weeks. Of the subjects receiving placebo, 12% required discontinuation due to unacceptable increases in BP. This suggests that the actual mean increase in BP would have been greater had these subjects continued on placebo for the full 8 weeks.

In conclusion, this study confirms the clinically significant BP reductions provided by omapatrilat and suggests adverse consequences of discontinuing antihypertensive therapy.

Acknowledgment: Financial support for this study was provided by Bristol‐Myers Squibb Company, Princeton, NJ.