|CURRICULUM IN CARDIOLOGY - JOURNAL CLUB
|Year : 2018 | Volume
| Issue : 3 | Page : 216-217
Effect of losartan on right ventricle dysfunction in patients with repaired tetralogy of fallot
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||11-Jan-2019|
Dr. Arvind Balaji
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Balaji A. Effect of losartan on right ventricle dysfunction in patients with repaired tetralogy of fallot. J Pract Cardiovasc Sci 2018;4:216-7
|How to cite this URL:|
Balaji A. Effect of losartan on right ventricle dysfunction in patients with repaired tetralogy of fallot. J Pract Cardiovasc Sci [serial online] 2018 [cited 2019 Aug 23];4:216-7. Available from: http://www.j-pcs.org/text.asp?2018/4/3/216/249939
| Citation|| |
Bokma JP, Winter MM, van Dijk AP, Vliegen HW, van Melle JP, Meijboom FJ, et al. Effect of losartan on right ventricular dysfunction: Results from the double-blind, randomized REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in adults with repaired tetralogy of fallot. Circulation 2018;137:1463-71.
| Background|| |
With advances in cardiac surgery, the number of operated patients with congenital heart defects (CHD) has been constantly increasing. Patients with Tetralogy of Fallot (TOF) which is one of the most common CHDs especially are at risk of developing right ventricular (RV) dysfunction, secondary to RV volume and pressure overload, cyanosis, and postsurgical scarring.
After repair, RV dilation and dysfunction may be produced by ischemia-reperfusion injury, surgical scarring, RV volume overload from pulmonary regurgitation, and residual RV outflow obstruction. Although these patients may be asymptomatic for a long time, ultimately, they develop progressive heart failure. There have been no evidence-based medical management strategies of RV dysfunction, in these subsets of patients.
These patients are treated with renin–angiotensin–aldosterone system (RAAS) inhibitors, extrapolating the beneficial effect of these drugs in the management of left ventricular (LV) dysfunction and also after few observational studies have demonstrated neurohormonal activation in patients with RV dysfunction. van der Bom et al. had demonstrated a small benefit of valsartan over placebo in a similar subset.
Jouke P. Bokma et al. had undertaken the REDEFINE trial to evaluate the effect of losartan, an angiotensin II receptor blocker, on the effect of RV dysfunction in patients with repaired TOF (RTOF). Although small, this trial is the largest to be published.
| Methodology|| |
It was a prospective, multicenter, double-blinded placebo-controlled randomized trial. RTOF patients with RV dysfunction (RV ejection fraction [RVEF] <50% as determined with cardiac magnetic resonance imaging) without severe valvular lesions were randomized between losartan (150 mg/day) and placebo. They were followed up for a period of 18–24 months for change in RVEF as the primary outcome. Multiple secondary outcome parameters were looked at including change in RV and LV volumes and mass, LVEF, peak exercise capacity, serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and quality of life. Composite clinical outcome parameters such as supraventricular tachycardia requiring intervention, ventricular tachycardia (≥4 beats), heart failure requiring increase of diuretics, or increase in the New York Heart Association class were also analyzed.
| Results|| |
Ninety-five patients were started on treatment (47 received losartan and 48 received placebo). Both the groups had similar baseline characteristics and were followed up similarly. The analysis was performed on 88 patients (42 in losartan arm and 46 in the placebo arm) since primary outcome data were unavailable in seven patients. Seventeen patients have discontinued medication prematurely. Intention to treat analyses was performed.
There was no change in the RVEF between the two groups (change of 0.77% ± 3.3% in the losartan group and 0.45% ± 3.8% in the placebo group). Losartan did not affect RV end-diastolic volume, LVEF, LV end-diastolic volume, peak exercise capacity, and NT-proBNP. Losartan significantly decreased LV mass (−5.0 g; 95% confidence interval, −9.5 to −0.4; P = 0.034).
Losartan was found to be beneficial in the subgroup with nonrestrictive RV physiology and incomplete remodeling (+2.7% in comparison with placebo P = 0.045). Losartan was also shown to have positive effect on RVEF of symptomatic patients (+2.2%, P = 0.38).Adverse effects (renal toxicity and liver dysfunction) requiring discontinuation of losartan occurred in 4 of the 42 patients (9%). The group, therefore, concluded that losartan should not be routinely prescribed in asymptomatic patients to prevent heart failure.
| Discussion|| |
The study flow was designed and performed appropriately. However, there were many limitations which should be borne in mind before interpreting the results. Although the study was powered for 90 patients, even lower numbers were only treated. Yet, the effect size was very small, that even if greater number were treated, it would be less likely to have obtained different results. The most crucial limitation is that the proportion of symptomatic patients in the study was only 13 (13%), and the mean baseline RVEF was just around 40% and maximum baseline NT-proBNP was just 248 pg/mL, suggesting that the study has been conducted only on mildly symptomatic patients. A reason for the same could be that, at the onset of RV dysfunction, many would have got surgical correction of pulmonary regurgitation, which is the most common cause of RV dysfunction. Hence, it is unclear whether if there could be beneficial effect had more symptomatic patients been treated, which could have been of more relevance in a setting like ours. The authors saw an improvement in RVEF in a subgroup of patients with nonrestrictive physiology together with incomplete remodeling, as defined by QRS fragmentation on ECG. Furthermore, few questions such as (1) whether longer duration of therapy would be beneficial? (2) If used before RV dysfunction had set in, would it delay the onset of the same? are still unanswered.
The recently published American Heart Association guidelines on the management of RV dysfunction also do not recommend the administration of standard heart failure therapy including RAAS inhibitors to CHD patients who are at risk of RV failure. This is in contrast to other causes of RV dysfunction such as those secondary to pulmonary artery hypertension, where afterload reducers (pulmonary vasodilator in this case) show clear benefit and have obtained class 1 recommendation. However, applying the same logic afterload reduction by RAAS inhibition has shown only mixed results and failed to demonstrate clear benefit and is not recommended in patients with systemic RV., RV dysfunction cannot be managed similar to LV dysfunction, in view of the fundamental differences between the two ventricles even starting from the embryogenesis. Further research on elaborating the mechanisms and natural course of deteriorating RV function would help developing RV-specific heart failure therapies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bolger AP, Sharma R, Li W, Leenarts M, Kalra PR, Kemp M, et al.
Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease. Circulation 2002;106:92-9.
van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW, Pieper PG, et al.
Effect of valsartan on systemic right ventricular function: A double-blind, randomized, placebo-controlled pilot trial. Circulation 2013;127:322-30.
Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, Jacob M, Kapur NK, et al.
Evaluation and management of right-sided heart failure: A scientific statement from the American Heart Association. Circulation 2018;137:e578-622.
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
Dore A, Houde C, Chan KL, Ducharme A, Khairy P, Juneau M, et al.
Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: A multicenter, randomized, placebo-controlled clinical trial. Circulation 2005;112:2411-6.
Therrien J, Provost Y, Harrison J, Connelly M, Kaemmerer H, Webb GD, et al.
Effect of angiotensin receptor blockade on systemic right ventricular function and size: A small, randomized, placebo-controlled study. Int J Cardiol 2008;129:187-92.