Comment
Modulators of the renin-angiotensin system (RAS) have shown promise in animal and pilot human studies in hypertrophic cardiomyopathy.1 The possibility of reversing hypertrophy and improving diastolic function is attractive and certainly deserves further investigation. The investigators of the INHERIT placebo-controlled trial, the results of which are reported in The Lancet Diabetes & Endocrinology,2 set out to investigate the effects of the angiotensin II receptor blocker losartan in patients with hypertrophic cardiomyopathy recruited from a tertiary referral centre in Denmark. The primary outcome measure of left ventricular mass after 12 months of treatment was a sensible choice, and the imaging modalities used—cardiac magnetic resonance imaging (CMR) and CT—are well validated in hypertrophic cardiomyopathy.3,4 The investigators decided to avoid fibrosis as assessed by cardiac MRI as a primary outcome, which would have excluded most patients with an implantable cardioverter defibrillator and hence missed a high-risk patient group. Cardiac fibrosis was, however, measured as a secondary outcome. Change in left ventricular mass after 12 months did not differ significantly between the placebo group and the losartan group (mean difference 1 g/m², 95% CI –3 to 6; p=0·60), although systolic blood pressure in the losartan group was decreased, as expected. Although many readers would label this a negative trial, useful information can still be taken from these findings. The INHERIT results show that losartan does not seem to reduce left ventricular mass or the extent of left ventricular fibrosis in patients with hypertrophic cardiomyopathy. This study is the most comprehensive assessment of angiotensin modulators to date and the results are at odds with earlier work.1 The results also show that losartan is safe in patients with a left ventricular outflow tract gradient. A long-held assumption has been that RAS inhibitors would exacerbate left ventricular outflow tract gradients and lead to syncope. RAS modulators have often been grouped with nitrates as vasodilators and proposed to put patients at risk of syncope; they are therefore largely avoided in patients with hypertrophic obstructive cardiomyopathy. Clinicians
sometimes face the problem of concurrent diagnoses of hypertrophic cardiomyopathy with obstruction and hypertension. Furthermore, results from septal reduction studies have shown that not all of the hypertrophy in hypertrophic cardiomyopathy is genetically determined, since removal of the gradient and afterload results in regression of hypertrophy away from the septum and improves diastolic function.5,6 Any cause of increased afterload must therefore be treated, meaning that hypertension must therefore be controlled. The results of INHERIT show that treatment with losartan is safe and reduces blood pressure in patients with hypertrophic cardiomyopathy. The extent of fibrosis in hypertrophic cardiomyopathy is believed to be a risk factor for sudden cardiac death.10 Studies of fibrosis in patients with hypertrophic cardiomyopathy are often based on a measurement at a single timepoint then monitoring for an outcome such as death or ventricular arrhythmia. With INHERIT, there is the benefit of serial imaging and the observation of change over 12 months. The presence of fibrosis in 83% patients is perhaps slightly higher than in other studies, but the 4 percentage point increase in fibrotic left ventricular mass over the study period is a useful finding. This result provides us with an insight into the natural history of hypertrophic cardiomyopathy, and further serial imaging and clinical monitoring of this group of patients would represent another success for the INHERIT team. This trial represents a rare success in clinical research of hypertrophic cardiomyopathy: a well designed and well executed randomised controlled trial. Few precedents exist of randomised studies on the topic,7–9 and none involved as many patients as were recruited in the INHERIT trial (n=133). The investigators were helped by a solid clinical structure for recruitment, and by choosing an outcome that did not rely on events such as death or cardiac arrest—the Achilles heel for statistical power in many proposed studies into hypertrophic cardiomyopathy. However, the use of surrogate outcomes has its problems and an association with hard clinical outcomes is usually assumed rather than proven beyond doubt. Other issues such as the heterogeneous
www.thelancet.com/diabetes-endocrinology Published online December 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70253-0
Science Photo Library
Can RAS inhibitors affect the course of hypertrophic cardiomyopathy?
Lancet Diabetes Endocrinol 2014 Published Online December 19, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70253-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70241-4
1
Comment
nature of the disease are acknowledged as limitations of this study; hypertrophic cardiomyopathy is a descriptive umbrella term for a group of different genotype mutations with similar clinical phenotypes. The INHERIT investigators attempted to explore different genotypes, but were unfortunately undone by insufficient numbers. Overall, this study is a welcome addition to the evidence base for hypertrophic cardiomyopathy. Although the primary outcome was neutral, we can learn from many useful results obtained, and can at least take heart that that randomised controlled trials are possible in patients with hypertrophic cardiomyopathy. We can hope this model is taken up by other groups to improve the understanding of a complex disease. *Robert M Cooper, Rodney H Stables Institute of Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK [email protected]
2
3
4
5
6
7
8
9
We declare no competing interests. 1
2
Penicka M, Gregor P, Kerekes R, Marek D, Curila K, Krupicka J. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J Mol Diagn 2009; 11: 35–41.
10
Axelsson A, Iversen K, Vejlstrup N, et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; published online Dec 19. http://dx.doi. org/10.1016/S2213-8587(14)70241-4. Hoey ET, Elassaly M, Ganeshan A, Watkin RW, Simpson H. The role of magnetic resonance imaging in hypertrophic cardiomyopathy. Quant Imaging Med Surg 2014; 4: 397–406. Langer C, Both M, Harders H, et al. Late enhanced computed tomography in Hypertrophic Cardiomyopathy enables accurate left-ventricular volumetry. Eur Radiol 2014; published online Oct 15. DOI:10.1007/s00330-014-3434-0. van Dockum WG, ten Cate FJ, ten Berg JM, et al. Myocardial infarction after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: evaluation by contrast-enhanced magnetic resonance imaging. J Am Coll Cardiol 2004; 43: 27–34. Nagueh SF, Lakkis NM, Middleton KJ, et al. Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999; 99: 344–47. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation 1999; 99: 2927–33. Veselka J, Duchonova R, Palenickova J, et al. Impact of ethanol dosing on the long-term outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy: a single-center prospective, and randomized study. Circ J 2006; 70: 1550–52. Abozguia K, Elliott P, McKenna W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010; 122: 1562–69. Ismail TF, Jabbour A, Gulati A, et al. Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy. Heart 2014; 100: 1851–58.
www.thelancet.com/diabetes-endocrinology Published online December 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70253-0
Modulators of the renin-angiotensin system (RAS) have shown promise in animal and pilot human studies in hypertrophic cardiomyopathy.1 The possibility of reversing hypertrophy and improving diastolic function is attractive and certainly deserves further investigation. The investigators of the INHERIT placebo-controlled trial, the results of which are reported in The Lancet Diabetes & Endocrinology,2 set out to investigate the effects of the angiotensin II receptor blocker losartan in patients with hypertrophic cardiomyopathy recruited from a tertiary referral centre in Denmark. The primary outcome measure of left ventricular mass after 12 months of treatment was a sensible choice, and the imaging modalities used—cardiac magnetic resonance imaging (CMR) and CT—are well validated in hypertrophic cardiomyopathy.3,4 The investigators decided to avoid fibrosis as assessed by cardiac MRI as a primary outcome, which would have excluded most patients with an implantable cardioverter defibrillator and hence missed a high-risk patient group. Cardiac fibrosis was, however, measured as a secondary outcome. Change in left ventricular mass after 12 months did not differ significantly between the placebo group and the losartan group (mean difference 1 g/m², 95% CI –3 to 6; p=0·60), although systolic blood pressure in the losartan group was decreased, as expected. Although many readers would label this a negative trial, useful information can still be taken from these findings. The INHERIT results show that losartan does not seem to reduce left ventricular mass or the extent of left ventricular fibrosis in patients with hypertrophic cardiomyopathy. This study is the most comprehensive assessment of angiotensin modulators to date and the results are at odds with earlier work.1 The results also show that losartan is safe in patients with a left ventricular outflow tract gradient. A long-held assumption has been that RAS inhibitors would exacerbate left ventricular outflow tract gradients and lead to syncope. RAS modulators have often been grouped with nitrates as vasodilators and proposed to put patients at risk of syncope; they are therefore largely avoided in patients with hypertrophic obstructive cardiomyopathy. Clinicians
sometimes face the problem of concurrent diagnoses of hypertrophic cardiomyopathy with obstruction and hypertension. Furthermore, results from septal reduction studies have shown that not all of the hypertrophy in hypertrophic cardiomyopathy is genetically determined, since removal of the gradient and afterload results in regression of hypertrophy away from the septum and improves diastolic function.5,6 Any cause of increased afterload must therefore be treated, meaning that hypertension must therefore be controlled. The results of INHERIT show that treatment with losartan is safe and reduces blood pressure in patients with hypertrophic cardiomyopathy. The extent of fibrosis in hypertrophic cardiomyopathy is believed to be a risk factor for sudden cardiac death.10 Studies of fibrosis in patients with hypertrophic cardiomyopathy are often based on a measurement at a single timepoint then monitoring for an outcome such as death or ventricular arrhythmia. With INHERIT, there is the benefit of serial imaging and the observation of change over 12 months. The presence of fibrosis in 83% patients is perhaps slightly higher than in other studies, but the 4 percentage point increase in fibrotic left ventricular mass over the study period is a useful finding. This result provides us with an insight into the natural history of hypertrophic cardiomyopathy, and further serial imaging and clinical monitoring of this group of patients would represent another success for the INHERIT team. This trial represents a rare success in clinical research of hypertrophic cardiomyopathy: a well designed and well executed randomised controlled trial. Few precedents exist of randomised studies on the topic,7–9 and none involved as many patients as were recruited in the INHERIT trial (n=133). The investigators were helped by a solid clinical structure for recruitment, and by choosing an outcome that did not rely on events such as death or cardiac arrest—the Achilles heel for statistical power in many proposed studies into hypertrophic cardiomyopathy. However, the use of surrogate outcomes has its problems and an association with hard clinical outcomes is usually assumed rather than proven beyond doubt. Other issues such as the heterogeneous
www.thelancet.com/diabetes-endocrinology Published online December 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70253-0
Science Photo Library
Can RAS inhibitors affect the course of hypertrophic cardiomyopathy?
Lancet Diabetes Endocrinol 2014 Published Online December 19, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70253-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70241-4
1
Comment
nature of the disease are acknowledged as limitations of this study; hypertrophic cardiomyopathy is a descriptive umbrella term for a group of different genotype mutations with similar clinical phenotypes. The INHERIT investigators attempted to explore different genotypes, but were unfortunately undone by insufficient numbers. Overall, this study is a welcome addition to the evidence base for hypertrophic cardiomyopathy. Although the primary outcome was neutral, we can learn from many useful results obtained, and can at least take heart that that randomised controlled trials are possible in patients with hypertrophic cardiomyopathy. We can hope this model is taken up by other groups to improve the understanding of a complex disease. *Robert M Cooper, Rodney H Stables Institute of Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, Liverpool L14 3PE, UK [email protected]
2
3
4
5
6
7
8
9
We declare no competing interests. 1
2
Penicka M, Gregor P, Kerekes R, Marek D, Curila K, Krupicka J. The effects of candesartan on left ventricular hypertrophy and function in nonobstructive hypertrophic cardiomyopathy: a pilot, randomized study. J Mol Diagn 2009; 11: 35–41.
10
Axelsson A, Iversen K, Vejlstrup N, et al. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; published online Dec 19. http://dx.doi. org/10.1016/S2213-8587(14)70241-4. Hoey ET, Elassaly M, Ganeshan A, Watkin RW, Simpson H. The role of magnetic resonance imaging in hypertrophic cardiomyopathy. Quant Imaging Med Surg 2014; 4: 397–406. Langer C, Both M, Harders H, et al. Late enhanced computed tomography in Hypertrophic Cardiomyopathy enables accurate left-ventricular volumetry. Eur Radiol 2014; published online Oct 15. DOI:10.1007/s00330-014-3434-0. van Dockum WG, ten Cate FJ, ten Berg JM, et al. Myocardial infarction after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: evaluation by contrast-enhanced magnetic resonance imaging. J Am Coll Cardiol 2004; 43: 27–34. Nagueh SF, Lakkis NM, Middleton KJ, et al. Changes in left ventricular diastolic function 6 months after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 1999; 99: 344–47. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation 1999; 99: 2927–33. Veselka J, Duchonova R, Palenickova J, et al. Impact of ethanol dosing on the long-term outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy: a single-center prospective, and randomized study. Circ J 2006; 70: 1550–52. Abozguia K, Elliott P, McKenna W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010; 122: 1562–69. Ismail TF, Jabbour A, Gulati A, et al. Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy. Heart 2014; 100: 1851–58.
www.thelancet.com/diabetes-endocrinology Published online December 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70253-0
