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Cardiology and Therapy Jun 2021This study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt). (Review)
Review
INTRODUCTION
This study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt).
METHODS
A systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution.
RESULTS
Twenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5-91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% (p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% (p value 0.002) lower male proportion compared to other studies.
CONCLUSIONS
Studies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research.
PubMed: 33315233
DOI: 10.1007/s40119-020-00205-3 -
The Cochrane Database of Systematic... Apr 2020Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on...
BACKGROUND
Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors.
OBJECTIVES
To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs).
SEARCH METHODS
On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites.
SELECTION CRITERIA
We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology.
MAIN RESULTS
The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP.
AUTHORS' CONCLUSIONS
Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Diflunisal; Disease Progression; Humans; Oligonucleotides; Patient Dropouts; Quality of Life; RNA, Small Interfering; Randomized Controlled Trials as Topic
PubMed: 32311072
DOI: 10.1002/14651858.CD012395.pub2 -
JACC. Cardiovascular Imaging Jun 2020This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This study aimed to compare the diagnostic and prognostic performance of native T1 mapping (T1), extracellular volume (ECV) mapping, and late gadolinium enhancement (LGE) imaging for evaluating cardiac amyloidosis (CA).
BACKGROUND
CA is a progressive infiltrative process in the extracellular space that is often underdiagnosed and holds a poor prognosis. Cardiac magnetic resonance (CMR) offers novel techniques for detecting and quantifying the disease burden of CA.
METHODS
We searched PubMed for published studies using native T1, ECV, or LGE to diagnose and prognosticate CA. A total of 18 diagnostic (n = 2,015) and 13 prognostic studies (n = 1,483) were included for analysis. Pooled sensitivities, specificities, diagnostic odds ratios (DORs) of all diagnostic tests were assessed by bivariate analysis. Pooled hazard ratios (HRs) for mortality for the 3 techniques were determined.
RESULTS
Bivariate comparison showed that ECV (DOR: 84.6; 95% confidence interval [CI]: 30.3 to 236.2) had a significantly higher DOR for CA than LGE (DOR: 20.1; 95% CI: 9.1 to 44.1; p = 0.03 vs. ECV). There was no significant difference between LGE and native T1 for sensitivity, specificity, and DOR. HR was significantly higher for ECV (HR: 4.27; 95% CI: 2.87 to 6.37) compared with LGE (HR: 2.60; 95% CI: 1.90 to 3.56; p = 0.03 vs. ECV) and native T1 (HR: 2.04; 95% CI: 1.24 to 3.37; p = 0.01 vs. ECV).
CONCLUSIONS
ECV demonstrates a higher diagnostic OR for assessing cardiac amyloid than LGE and a higher HR for adverse events compared with LGE and native T1. In addition, native T1 showed similar sensitivity and specificity as ECV and LGE without requiring contrast material. Although limited by study heterogeneity, this meta-analysis suggests that ECV provides high diagnostic and prognostic utility for the assessment of cardiac amyloidosis.
Topics: Adult; Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Gadolinium; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Predictive Value of Tests; Reproducibility of Results; Stroke Volume; Ventricular Function, Left
PubMed: 32498919
DOI: 10.1016/j.jcmg.2020.03.010 -
British Journal of Haematology Jul 2023Systemic AL amyloidosis is an incurable condition with various presentations and may cause multiple complications related to organ involvement. As survival has improved,...
Systemic AL amyloidosis is an incurable condition with various presentations and may cause multiple complications related to organ involvement. As survival has improved, disease and therapy-related quality of life (QoL) is becoming an increasingly important treatment endpoint. We review the literature summarising the utilised QoL questionnaires (QLQs) and assess their validity according to COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) standards. Thirteen retrospective observational studies and thirty-two prospective clinical trials were analysed. Most QLQs are generic or only validated in populations with distinct complications of the disease. None meet 'strong evidence' for validation in this context. There is a need to develop a disease-specific QLQ, which could inform treatment choices and facilitate the approval of novel therapies.
Topics: Humans; Quality of Life; Immunoglobulin Light-chain Amyloidosis; Prospective Studies; Retrospective Studies; Patient Reported Outcome Measures; Surveys and Questionnaires
PubMed: 37194132
DOI: 10.1111/bjh.18860 -
European Journal of Internal Medicine Nov 2019The role of bortezomib in the treatment of immunoglobulin light chain (AL) amyloidosis is not well defined. We performed this meta-analysis to evaluate the efficacy and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The role of bortezomib in the treatment of immunoglobulin light chain (AL) amyloidosis is not well defined. We performed this meta-analysis to evaluate the efficacy and safety of bortezomib-based regimens in patients with AL amyloidosis who are not eligible for or refuse autologous stem cell transplantation.
METHODS
A systematic search of Medline, Embase, and the Cochrane Library was conducted to identify related studies.
RESULTS
Twenty-four studies with 1238 patients were included. The pooled overall response rate (ORR) and complete hematological response rate (CHR) were 0.72 (95% CI, 0.67-0.77) and 0.35 (95% CI, 0.30-0.40), respectively. Bortezomib significantly improved the outcome of ORR compared to other regimens (RR 1.28, 95% CI, 1.04-1.57, P = .02). Similar results were observed in CHR (RR 1.90, 95% CI, 1.45-2.50, P < .001) and cardiac response (RR 2.03, 95% CI, 1.31-3.13, P = .002), but not in overall survival (HR 0.82, 95% CI, 0.62-1.09, P = .17). In addition, once-weekly bortezomib was associated with improved overall survival compared with twice-weekly bortezomib (HR 0.52, 95% CI, 0.27-0.99, P = .05). Peripheral neuropathy was the most widely reported adverse event. Incorporation of bortezomib into the standard melphalan + dexamethasone setting showed a trend of increased serious adverse events, though this was not statistically significant (RR 1.29, 95% CI, 0.95-1.75, P = .10).
CONCLUSIONS
Current evidence indicates that bortezomib-based regimens might be effective and safe therapies for patients with AL amyloidosis. There is a great need to conduct more well-designed randomized controlled trials to provide high-quality evidence.
Topics: Antineoplastic Agents; Bortezomib; Humans; Immunoglobulin Light-chain Amyloidosis; Treatment Outcome
PubMed: 31447275
DOI: 10.1016/j.ejim.2019.08.011 -
Frontiers in Pharmacology 2019The present Bayesian network meta-analysis (NMA) was to compare the efficacy of different chemotherapies and autologous stem cell transplantation (ASCT) in...
BACKGROUND/AIMS
The present Bayesian network meta-analysis (NMA) was to compare the efficacy of different chemotherapies and autologous stem cell transplantation (ASCT) in immunoglobulin light-chain (AL) amyloidosis.
METHODS
We systematically searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies compared the rates of hematological response (HR), complete response (CR), renal response, and cardiac response in AL amyloidosis patients.
RESULTS
There were three randomized controlled trials (RCTs) and thirteen observational controlled trials (OCTs) comprising 3,402 participants enrolled for the comparisons of seven treatments: melphalan + dexamethasone (MDex), high-dose melphalan followed by ASCT, bortezomib + melphalan + dexamethasone (BMDex), thalidomide + cyclophosphamide + dexamethasone (CTD), bortezomib + dexamethasone (BDex), bortezomib + cyclophosphamide + dexamethasone (CyBorD), cyclophosphamide + lenalidomide + dexamethasone (CLD). BMDex was ranked first in the aspect of both HR and CR, CTD induced the highest rate of renal response, and BDex was possibly the best treatment for the cardiac response.
CONCLUSION
Although more data about safety and cost are needed, BMDex was recommended as the most efficient treatment for AL amyloidosis patients for enhancing the response rate for HR and CR.
PubMed: 32063846
DOI: 10.3389/fphar.2019.01601 -
Journal of Comparative Effectiveness... Jun 2024The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy... (Review)
Review
The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.
PubMed: 38869839
DOI: 10.57264/cer-2023-0158 -
Hematology (Amsterdam, Netherlands) Dec 2023Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and death. Recent studies suggest that hematologic response may be an important prognostic indicator of overall survival (OS) in AL amyloidosis. The aim of this study was to evaluate the trial-level association between hematologic complete response (CR) or very good partial response or better (≥ VGPR) and OS in newly diagnosed patients.
METHODS
Studies were identified via systematic literature review. Pooled effect estimates were generated by a random-effects model.
RESULTS
Nine observational studies reporting hematologic CR or ≥VGPR and OS hazard ratios (HRs) were included in the meta-analysis. Achieving hematologic CR was associated with improved OS (HR, 0.21; 95% confidence interval [CI] 0.13-0.34). Achieving ≥ VGPR was also associated with improved OS (HR 0.21; 95% CI 0.17-0.26). Results of a sensitivity analysis excluding one outlier study revealed no heterogeneity and a better overall HR estimate. Potential limitations of this meta-analysis include the small number of eligible studies (consistent with the rarity of the disease) and inconsistencies in reporting of results.
CONCLUSIONS
Overall, our findings support the use of deep hematologic response (CR or ≥VGPR) as a clinical trial endpoint in newly diagnosed AL amyloidosis. This study provides evidence that early hematologic response is a strong patient-level surrogate for long-term OS in patients with AL amyloidosis receiving frontline therapy. Structured data collection of depth of response in future trials will further strengthen these observations.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Prognosis; Remission Induction; Proportional Hazards Models
PubMed: 36607151
DOI: 10.1080/16078454.2022.2157581