Research Spotlight

Posted October 15th 2019

Diagnosis, prognosis, and treatment of leukodystrophies.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

van der Knaap, M. S., R. Schiffmann, F. Mochel and N. I. Wolf (2019). “Diagnosis, prognosis, and treatment of leukodystrophies.” Lancet Neurology 18(10): 962-972.

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Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.


Posted October 15th 2019

Cost-Effectiveness of Transcatheter Mitral Valve Repair versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation: Results from the COAPT Trial.

Michael J. Mack M.D.

Michael J. Mack M.D.

Baron, S. J., K. Wang, S. V. Arnold, E. A. Magnuson, B. Whisenant, A. Brieke, M. Rinaldi, A. W. Asgar, J. Lindenfeld, W. T. Abraham, M. J. Mack, G. W. Stone and D. J. Cohen (2019). “Cost-Effectiveness of Transcatheter Mitral Valve Repair versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation: Results from the COAPT Trial.” Circulation Sep 29. [Epub ahead of print].

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Background: The COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair (TMVr) using the MitraClip resulted in reduced mortality and heart-failure hospitalizations and improved quality of life when compared with maximally-tolerated guideline-directed medical therapy (GDMT) in heart-failure patients with 3-4+ secondary mitral regurgitation (SMR). Whether TMVr is cost-effective compared with GDMT in this population is unknown. Methods: We used data from the COAPT trial to perform a formal, patient-level economic analysis of TMVr + GDMT vs. GDMT alone for patients with heart failure and 3-4+ SMR from the perspective of the US health care system. Costs for the index TMVr hospitalization were assessed using a combination of resource-based accounting and hospital billing data (when available). Follow-up medical care costs were estimated based on medical resource use collected during the COAPT trial. Health utilities were estimated for all patients at baseline, 1, 6, 12 and 24 months using the SF-6D. Results: Initial costs for the TMVr procedure and index hospitalization were $35,755 and $48,198, respectively. Although follow-up costs were significantly lower with TMVr compared with GDMT ($26,654 vs. $38,345; p=0.018), cumulative 2-year costs remained higher with TMVr due to the up-front cost of the index procedure ($73,416 vs. $38,345; p<0.001). When intrial survival, health utilities, and costs were modeled over a lifetime horizon, TMVr was projected to increase life-expectancy by 1.13 years and quality-adjusted life-years (QALYs) by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost-effectiveness ratio of $40,361/life-year gained and $55,600/QALY gained. Conclusions: For symptomatic heart-failure patients with 3-4+ SMR, TMVr increases lifeexpectancy and quality-adjusted life-expectancy compared with GDMT at an incremental cost per QALY gained that represents acceptable economic value based on current U.S. thresholds. Clinical Trial Registration: NCT01626079.


Posted October 15th 2019

Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients with Heart Failure and Reduced Ejection Fraction:PARADIGM-HF.

Milton Packer M.D.

Milton Packer M.D.

Selvaraj, S., B. Claggett, A. Pozzi, J. J. V. McMurray, P. S. Jhund, M. Packer, A. S. Desai, E. F. Lewis, M. Vaduganathan, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, M. R. Zile, K. Swedberg and S. D. Solomon (2019). “Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients with Heart Failure and Reduced Ejection Fraction:PARADIGM-HF.” Circulation Sep 12. [Epub ahead of print].

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Background: The contemporary prognostic value of the physical examination, beyond traditional risk factors including natriuretic peptides (NPs), risk scores, and symptoms, in heart failure with reduced ejection fraction (HFrEF) is unknown. We sought to determine the association between physical signs of congestion at baseline and during study follow up with quality of life (QoL) and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and S3) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up, and whether improvement in congestion is related to changes in clinical outcomes and QoL, assessed by Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-OSS). Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2%. Patients with baseline congestion were older, more often female, had higher Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores and lower KCCQ-OSS (p<0.05). After adjusting for baseline NPs, time-updated MAGGIC score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (p<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (p=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than enalapril (p=0.011). Each 1-sign reduction was independently associated with a 5.1 (95%CI: 4.7-5.5) point improvement in KCCQ-OSS. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (p<0.001). Conclusions: In HFrEF, the physical exam continues to provide significant, independent prognostic value even beyond symptoms, NPs, and MAGGIC risk score. Sacubitril/valsartan improved congestion to a greater extent than enalapril. Reducing congestion in the outpatient setting is independently associated with improved QoL and reduced cardiovascular events, including mortality. Clinical Trial Registration: NCT01035255.


Posted October 15th 2019

The Parable of Schrodinger’s Cat and the Illusion of Statistical Significance in Clinical Trials.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2019). “The Parable of Schrodinger’s Cat and the Illusion of Statistical Significance in Clinical Trials.” Circulation 140(10): 799-800.

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The field of quantum physics offers important lessons for those involved in the interpretation of clinical trials. A key distinction between quantum physics and classical Newtonian physics is that the latter is deterministic; it describes the future state of a system with definitiveness, and it is useful for understanding the behavior of large objects (ie, those encountered on a human scale). However, at a subatomic level, the utility of Newtonian physics breaks down; it is superseded by quantum physics, in which the future state of a system is defined in a probabilistic rather than deterministic manner. The quantification of uncertainty allows quantum physics to resolve issues that classical physics cannot address. In many ways, the evolution of thinking about clinical evidence parallels the evolution of thinking in physics. When the effect size of a drug or device is large, descriptive studies generally suffice in establishing the efficacy of an intervention. If the mortality rate of pneumococcal pneumonia is uniformly 90% and declines to 10% with the advent of penicillin, there is no need for a randomized controlled trial. The response to imatinib in leukemia was so dramatic that the Food and Drug Administration approved the drug based on an open-label uncontrolled trial of <50 patients.1 If the clinical course of a serious event is highly predictable, a substantial benefit after an intervention represents compelling evidence for efficacy. However, just as classical physics loses its applicability when one shifts to very small effects, the usefulness of descriptive studies evaporates when physicians move from drugs with a 90% benefit to agents that reduce risk by only 10% to 20%. Cardiovascular drugs typically exert small treatment effects and are studied in a setting where outcomes cannot be predicted with precision. (Excerpt from text, p. 799.)


Posted September 26th 2019

Fabry disease genotype, phenotype and migalastat amenability: insights from a national cohort.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

Nowak, A., H. D. Uyen, P. A. Krayenbuehl, F. Beuschlein, R. Schiffmann and F. Barbey (2019). “Fabry disease genotype, phenotype and migalastat amenability: insights from a national cohort.” J Inherit Metab Dis Aug 26. [Epub ahead of print].

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A (alpha-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this paper we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and 1 patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113 L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238 N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual alpha-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations. This article is protected by copyright. All rights reserved.