The aim of this network meta-analysis was to compare the efficacy of various commonly used drugs in treating patients with hypertrophic cardiomyopathy (HCM). Randomized controlled trials on drugs for HCM treatment were retrieved from PubMed, Embase, Cochrane Library, and Web of Science (search cutoff: January 10, 2024). Quality assessment was performed using the risk of bias tool, and data analysis used R software. Seventeen studies (1,133 patients with HCM) were included. The network meta-analysis indicated that mavacamten and perhexiline improved peak oxygen consumption compared with placebo. Mavacamten reduced N-terminal pro-B-type natriuretic peptide, left ventricular mass index, left atrial volume index, and septal E/e′ ratio. Losartan decreased systolic blood pressure, whereas candesartan, mavacamten, and valsartan reduced maximum wall thickness. Perhexiline had better efficacy in increasing peak oxygen consumption, and candesartan in reducing maximum wall thickness. No drug significantly improved left ventricular ejection fraction compared with placebo. In conclusion, on the basis of current studies, commonly used drugs may effectively improve some of the outcome measures in patients with HCM, whereas the novel drug mavacamten showed significant therapeutic effects in most of the remaining outcome measures except for left ventricular ejection fraction.
Hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiovascular disease, affecting 1 in every 500 subjects. Its potential complications include asymmetric left ventricular (LV) hypertrophy, LV outflow tract (LVOT) obstruction, myocardial ischemia, arrhythmia, sudden cardiac death, diastolic dysfunction, and mitral regurgitation. The clinical diagnosis of HCM is based on the identification of unexplained LV hypertrophy detected through echocardiography or cardiovascular magnetic resonance imaging. Treatment strategies include the use of implantable defibrillators, medications, and surgical myectomy to relieve outflow tract obstruction and symptoms of heart failure. Drug therapy constitutes a pivotal aspect of HCM management, whereas common drug treatments are considered nonspecific treatments. The novel small molecule targeted drug mavacamten has emerged as a promising option for modulating cardiac function at the sarcomere level. However, there is a deficiency in comprehensive evaluations regarding the efficacy of various medication treatment regimens. Therefore, this network meta-analysis (NMA) aims to compare the efficacy of different clinically common drugs, providing beneficial guidance for medication treatments tailored to patients with HCM.
Methods
A search was conducted in the Cochrane, PubMed, Embase, and Web of Science databases for randomized controlled trials comparing the efficacy of currently different commonly used clinical drugs in patients with HCM, with the search cut-off date being January 10, 2024. The search used a combination of Medical Subject Headings “Cardiomyopathy, Hypertrophic” and free-text terms such as “Cardiomyopathies Hypertrophic, Hypertrophic Cardiomyopathies, Hypertrophic Cardiomyopathy, Cardiomyopathy Hypertrophic Obstructive, Cardiomyopathies Hypertrophic Obstructive, Hypertrophic Obstructive Cardiomyopathies, Hypertrophic Obstructive Cardiomyopathy, Obstructive Cardiomyopathies, Hypertrophic, Obstructive Cardiomyopathy, Hypertrophic.” The detailed search strategy is provided in Supplementary Material 1 .
The inclusion criteria were as follows: studies must involve adults diagnosed with HCM. The treatment group received commonly used clinical drugs for treating HCM (mavacamten, perhexiline, ranolazine, spironolactone, trimetazidine, losartan, atorvastatin, candesartan, N-acetylcysteine, and valsartan). The control group should use a placebo. The primary outcome measures included peak oxygen consumption (P V O2), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), systolic blood pressure, LV mass index (LVMI), left atrial volume index (LAVI), maximum wall thickness, LV ejection fraction (LVEF), and septal E/e′ ratio. The study type must be a randomized controlled trial.
The exclusion criteria were as follows: duplicates, animal experiments, case reports, conference abstracts, reviews, reports lacking accessible full texts, and studies involving patients with other organic diseases.
Two authors meticulously screened the literature according to preestablished eligible criteria. Any discrepancies were resolved through deliberation or by seeking a third party’s opinion to achieve consensus. The information extracted from the included studies encompassed key details such as the first author, year of publication, country, sample size, gender, mean age, interventions administered, and outcome measures.
The risk of bias assessment was conducted according to the latest guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions. The tool comprises 5 primary components: bias due to the randomization, bias due to deviations from intended interventions, bias due to missing outcome data, bias due to measurement of the outcome, and bias due to outcome selective reporting. The quality of studies was categorized as either “low risk of bias,” “some concerns,” or “high risk of bias.” The results were independently reviewed by 2 researchers, and any discrepancies were resolved through discussion or consultation with a third party to achieve consensus.
Bayesian NMA was performed using a previous vague random-effects model with R v4.3.2. The Markov Chain Monte Carlo method was used to obtain the best pooled estimate and probabilities of each treatment regimen. Continuous outcomes were reported as the posterior mean difference (MD) along with its corresponding 95% confidence interval (CI). The surface under the cumulative ranking curve (SUCRA) percentages were computed to assess the likelihood of each intervention being the most effective. Network plots and funnel plots were generated using STATA v15.0 (William Gould, James Hardin and Brian P. Poi). In the network plots, each node represented a medication, whereas the edges depicted the available comparisons. The size of each node was proportional to the patient cohort size. Cumulative probability plots were generated using the ggplot2 package.
Results
An initial database search retrieved 2,864 studies. After the elimination of 553 duplicates, 1,341 studies were excluded on the basis of title and abstract screening, with an additional 953 exclusions after full-text review. Ultimately, 17 studies were deemed eligible for analysis ( Figure 1 ).
Seventeen studies, comprising 1,133 patients with HCM, were included in the analysis. The pharmacologic interventions encompassed mavacamten, perhexiline, placebo, ranolazine, spironolactone, trimetazidine, losartan, atorvastatin, candesartan, N-acetylcysteine, and valsartan. Detailed characteristics of the studies are listed in Table 1 . All studies included in this analysis clearly delineated the blinding methods used. The primary risk arose from deviations from the intended interventions. The risk of bias evaluation for the included studies is depicted in Figure 2 .
| Study | Year | Country | Sample size | Mean age (years) | Gender (M/F) | Intervention |
|---|---|---|---|---|---|---|
| Abozguia | 2010 | UK | Perhexiline:24 Placebo:22 | Perhexiline:56 Placebo:54 | 16/30 | Perhexiline:100mg/day |
| Axelsson | 2015 | Denmark | losartan:64 Placebo:69 | losartan:51 Placebo:52 | 86/47 | losartan:50mg/day(2w) to 100mg/day(total:12m) |
| Bauersachs | 2007 | Germany | Atorvastatin:14 Placebo:14 | Atorvastatin:44.2 Placebo:52.0 | — | Atorvastatin:80 mg/day |
| Coats | 2019 | UK | Trimetazidine:27 Placebo:24 | Trimetazidine:49 Placebo:51 | 36/15 | Trimetazidine:20 mg, 3 times daily or placebo (for 3 months) |
| Desai | 2022 | USA | Mavacamten:56 Placebo:56 | Mavacamten:59.8 Placebo:60.9 | 57/55 | Mavacamten:5 mg/day |
| Hegde | 2021 | USA | Mavacamten:123 Placebo:128 | Mavacamten:58.5 Placebo:58.5 | 149/102 | mavacamten (starting dose 5 mg) or placebo for 30 weeks |
| Ho | 2020 | USA | Mavacamten (200 ng/ml):19 (200 ng/ml):21 Placebo:19 | Mavacamten (200 ng/ml):54 (200 ng/ml):54 Placebo:54 | 25/34 | Initial dose was 5 mg daily with 1 dose titration at week 6 |
| Ho | 2021 | USA | Valsartan:88 Placebo:90 | Valsartan:23.1 Placebo:23.5 | 109/69 | target dose (adults, 320 mg daily; children <18 years old weighing ≥35 kg, 160 mg daily; children <18 years old weighing <35 kg, 80 mg daily) |
| Kawano | 2005 | Japan | Valsartan:11 Placebo:12 | Valsartan:65 Placebo:62 | 18/5 | Dose of valsartan (mg) 53±22/day |
| Maron | 2018 | USA | Spironolactone:26 Placebo:27 | Spironolactone:40 Placebo:42 | 38/15 | spironolactone 50 mg daily |
| Marian | 2018 | USA | N-acetylcysteine (NAC):29 Placebo:13 | N-acetylcysteine (NAC):50.7 Placebo:47.6 | 32/10 | 600 mg orally every 12 hours for the first 3 months to 1,200 mg twice per day for an additional 9 months |
| Olivotto | 2018 | Italy | Ranolazine:40 Placebo:40 | Ranolazine:54 Placebo:52 | 46/34 | ranolazine 1000 mg bid for 5 months |
| Penicka | 2009 | Czecb | Candesartan:12 Placebo:12 | Candesartan:41 Placebo:45 | 11/13 | 8mg daily, doubled as tolerated every 2 weeks to 32mg daily |
| Shimada | 2013 | USA | Losartan:11 Placebo:9 | Losartan:49 Placebo:54 | 17/3 | 50 mg once daily to 100mg if the lower dosage was well tolerated after 1 week |
| Tian | 2023 | China | Mavacamten:54 Placebo:27 | Mavacamten:52.4 Placebo:51.0 | 58/23 | starting at 2.5 mg once daily |
| YAMAZAKI | 2007 | Japan | Losartan:9 Placebo:10 | Losartan:55.4 Placebo:58.1 | 19/0 | 50 mg of losartan potassium once daily for one year |
Six studies , , , , , mentioned P V O2 ( Figure 3 ), with the network plot ( Figure 3 ) showing no closed loop. Compared with placebo, mavacamten (MD 1.12, 95% CI 0.440 to 1.80) and perhexiline (MD 3.40, 95% CI 3.27 to 3.53) were able to increase P V O2 in patients with HCM ( Figure 3 ), with the effect: perhexiline>mavacamten (mavacamten vs perhexiline [MD −2.28, 95% CI −2.97 to −1.58]) ( Supplementary Table 1 in Supplementary Material 2 ). According to SUCRA, perhexiline ranked first (99.9%), followed by mavacamten (74.6%), placebo (43.1%), with spironolactone last (15.2%) ( Figure 3 , Table 2 ).
| Treatment | pVO2 (%) | NT-pro-BNP (%) | LVEF (%) | Systolic blood pressure (%) | LVMI (%) | LVAI (%) | Maximum wall thickness (%) | septal E/e’ ratio (%) |
|---|---|---|---|---|---|---|---|---|
| mavacamten | 74.6 | 98.6 | / | / | 95.5 | 97.9 | 54.0 | 93.2 |
| perhexiline | 99.9 | / | 49.4 | / | / | / | / | / |
| placebo | 43.1 | 22.1 | 49.3 | 30.8 | 48.5 | 33.3 | 15.6 | 55.5 |
| ranolazine | 48.5 | 55.3 | / | / | / | / | / | 30.1 |
| spironolactone | 15.2 | / | / | / | 35.2 | / | / | 35.5 |
| trimetazidine | 18.7 | 52.3 | 50.1 | / | / | 23.2 | / | / |
| losartan | / | 21.7 | / | 95.8 | 37.9 | 45.7 | 19.0 | 35.6 |
| atorvastatin | / | / | 32.4 | / | / | / | / | / |
| candesartan | / | / | 50.0 | / | / | / | 98.5 | / |
| N-acetylcysteine | / | / | 65.5 | / | 32.8 | / | 46.8 | / |
| valsartan | / | / | 53.3 | 23.4 | / | / | 66.0 | / |
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