Pharmacological Reduction of Functional, Ischemic Mitral REgurgitation (PRIME)
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|ClinicalTrials.gov Identifier: NCT02687932|
Recruitment Status : Completed
First Posted : February 22, 2016
Last Update Posted : January 9, 2018
|Condition or disease||Intervention/treatment||Phase|
|Mitral Valve Insufficiency Left Ventricular Dysfunction||Drug: LCZ696 Drug: Valsartan||Phase 4|
Functional ischemic mitral regurgitation (MR) has been reported to occur in up to 40% of patients after myocardial infarction, and the prevalence of functional MR is likely to increase with an aging population and improved survival rates for myocardial infarction. The presence of functional MR is associated with an increased incidence of heart failure and death, and patients with significant functional MR incur about a two-fold increase in the risk of mortality and about a four-fold increase in the risk of heart failure. Functional MR is caused by adverse left ventricular remodeling after myocardial injury with enlargement of the left ventricle (LV), apical and lateral displacement of papillary muscles, leaflet tethering and reduced closing forces. The leaflets are normal in secondary functional MR and the treatment is considerably different between functional and primary MR. Surgery is the only definitive therapy for primary severe MR and primary MR can usually be cured by surgical valve repair. However, surgical indications are unclear in severe functional MR, because outcomes after surgery for functional MR remain suboptimum. Operative mortality, long-term mortality and heart failure rates are still high in patients with severe functional MR despite surgical improvements. According to the current guidelines, mitral valve surgery may be considered only for severely symptomatic patients with severe secondary functional MR who have persistent symptoms despite optimal medical therapy for heart failure.
Because secondary functional MR usually develops as a result of LV dysfunction, diuretics, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), and aldosterone antagonists are given to patients with functional MR in line with the guidelines in the management of heart failure. However, functional MR appears to remain common despite use of these drugs and current medical treatment is usually insufficient for reducing MR or reversing the adverse LV remodeling. Persistence of functional MR due to the insufficient effectiveness of current medical treatment significantly increases morbidity and mortality, and compared with surgical or percutaneous revascularization, significantly higher mortality was observed in patients managed with medical therapy.
Quantitative assessment of MR is strongly recommended in the guidelines and the regurgitant volume and the effective regurgitant orifice area (EROA) of MR can be measured accurately and reproducibly by Doppler echocardiography. The EROA of MR has an important prognostic value in primary and secondary functional MR. Because functional MR carries an adverse prognosis with a graded relationship between MR severity and reduced survival, therapies that induce beneficial reverse remodeling of the LV and reduce MR, may improve survival. ACE inhibitors and ARBs could partially attenuate LV dilatation and remodeling after myocardial injury, but there are no published data from prospective trials regarding whether attenuation of remodeling by ACE inhibitors or ARBs reduces functional MR.
LCZ696 is a dual-acting inhibitor of the renin-angiotensin-aldosterone system (RAAS) and neutral endopeptidase (NEP). As LCZ696 offers the therapeutic advantages of concomitantly blocking both RAAS and NEP, LCZ696 was more effective in reducing the risk of death from cardiovascular causes or hospitalization for heart failure in patients with chronic heart failure than ACE inhibitor. Because NEP is involved in the metabolism of a number of vasoactive peptides such as natriuretic peptides, NEP inhibitor has vasodilating effects, facilitates sodium excretion and has profound effects on LV remodeling. Trials of hypertension and heart failure with a preserved ejection fraction also showed that LCZ696 had greater hemodynamic and neurohormonal effects than ARB alone. To date, there has been no proven pharmacological therapy to improve functional MR, and the development of medical therapy should be at the forefront of research considering the limited role of surgery in managing functional MR. Investigators hypothesize that LCZ696 is superior to ARB alone in improving functional MR in patients with LV dysfunction and functional MR via synergistic effects of NEP and RAAS inhibition on LV remodeling, and try to examine this hypothesis in a multicenter, double-blind, randomized comparison study using echocardiography.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||118 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Multicenter, Randomized, Double-blind, Active-controlled Study to Assess the Efficacy of LCZ696 Compared to Valsartan on Reduction of Mitral Regurgitation in Patients With Left Ventricular Dysfunction and Secondary Functional Mitral Regurgitation of Stage B and C|
|Actual Study Start Date :||March 2016|
|Actual Primary Completion Date :||January 2, 2018|
|Actual Study Completion Date :||January 2, 2018|
LCZ696 for 12 months
Active Comparator: Valsartan
Valsartan for 12 months
- Change of effective regurgitant orifice area (EROA) of functional mitral regurgitation from baseline to 12 months follow-up [ Time Frame: 12 months ]
- Change of regurgitant volume from baseline to 12 months follow-up [ Time Frame: 12 months ]
- Change of left ventricular end-systolic volume from baseline to 12 months follow-up [ Time Frame: 12 months ]
- Change of left ventricular end-diastolic volume from baseline to 12 months follow-up [ Time Frame: 12 months ]
- Change of incomplete mitral leaflet closure area from baseline to 12 months follow-up [ Time Frame: 12 months ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02687932
|Korea, Republic of|
|Inha University Hospital|
|Incheon, Korea, Republic of|
|Asan Medical Center|
|Seoul, Korea, Republic of, 138-736|
|Samsung Medical Center|
|Seoul, Korea, Republic of|
|Yonsei University Medical Center|
|Seoul, Korea, Republic of|
|Principal Investigator:||Duk-Hyun Kang, M.D.||Asan Medical Center|