This meta-analysis, involving a patient population of 503, aimed to compare the safety and efficacy of Mavacamten with placebo in recent HCM patients. The study's results indicated a significant association between Mavacamten and achieving a primary endpoint, ≥ 1 New York Heart Association functional class improvement compared to placebo. However, it showcased a non-significant association between both groups regarding ≥ 1 SAE, ≥ 1 TEAE, the incidence of AF, and NSVT rates.

Our analysis revealed a significant association between achieving the primary endpoint and administering Mavacamten instead of a placebo. Mavacamten, effectively reduces excessive myocardial contractility, resulting in enhanced left ventricular diastolic filling, alleviation of LVOT, and improved ventricular lusitropy [22]. This resultant enhancement in the left ventricular compliance reduces symptom severity experienced by HCM patients, both at rest and during exertion. These positive outcomes are reflected in our analysis of the primary composite endpoint. Furthermore, the moderate heterogeneity observed in this outcome indicates that the results maintain a reasonable degree of consistency across the various studies.

In contrast with placebo, the analysis demonstrated a significant difference between Mavacamten and ≥ 1 NYHA-F class. The recent EXPLORER-CN [20], involving 81 participants (Mavacamten n = 54, placebo n = 27), reported that patients in the Mavacamten group had increased improvement in ≥ 1 NYHA-FC-II (82% vs. 68%). Compared to placebo, Mavacamten appears to cause a significant reduction in heart failure symptoms as measured by the NYHA-FC in HCM patients. This is due to its pharmacological mechanism of action, acting as a direct target inhibitor of cardiac myosin, decreasing myosin binding with actin filament, and the excessive contractility that is a feature of HCM [23]. In EXPLORER-HCM [17], too, Mavacamten was superior to placebo in improving patient-centered outcomes. Moreover, the moderate to high heterogeneity observed in this outcome showcases that the results are sufficiently consistent between the studies. However, MAVERICK-HCM [21] acknowledged that their study had relatively small size to notice clinical improvements by pVO2 or NYHA-FC class, urging the need for further randomized control trials to be conducted to draw a conclusive understanding [21]. Lastly, the effect size (RR increased from the initial value to 2.46 when the MAVERICK-HCM [21] was excluded) and heterogeneity (I2 fell from 52 to 25%) significantly changed. This suggests that the MAVERICK-HCM [21] study, having significant differences from other studies pooled, had a major impact on the overall outcomes. Its absence resulted in less heterogeneity among the other trials and a more substantial observed effect.

In oHCM population, Mavacamten was associated with lesser number of SRT and its eligibility compared to placebo, as exhibited by its significant relation. This suggests that Mavacamten has therapeutic benefits that mitigate the progression of oHCM and slow the development of oHCM to the point where invasive therapies like SRT are no longer required. Furthermore, no heterogeneity is observed between the studies. This strengthens the study results and suggests that the findings are similar across investigations, which is advantageous when analyzing the combined findings from meta-analyses.

Our analysis showed no significant associations between Mavacamten and placebo regarding the rates of ≥ 1 SAE and NSVT. A lower risk ratio for ≥ 1 SAE and NSVT indicates that Mavacamten showed decreased risk of these adverse events compared to placebo, underscoring its safety profile as a therapeutic drug. Furthermore, according to a report on Mavacamten-controlled HCM, patients with symptomatic oHCM, when treated with Mavacamten for a median of 62 weeks, maintained the same safety response observed during the first 30 weeks of the drug's pivotal trial [24]. However, the non-significant disparity suggests that these findings could be due to other factors, such as variability in dosage, duration of use, and the characteristics of the study population. Additionally, its insignificant relation with NSVT rates suggests that early detection and treatment of any rhythm abnormalities might be accomplished with routine monitoring, such as through ECGs, which would lessen the likelihood that NSVT would progress. Despite the non-significant association of Mavacamten with NSVT, nullifying its safety, the VALOR-HCM [18] study resulted in no non-sustained ventricular tachycardia found in the Mavacamten group as opposed to 9.1% in the placebo group [25].

Lastly, there was no significant relation between the two groups causing TEAE or increasing the incidence of atrial fibrillation. However, the risk of atrial fibrillation and ≥ 1 TEAE is 5% and 7% higher in the Mavacamten group compared to the placebo group. Notably, the recent EXPLORER-CN [20] study found atrial fibrillation as an adverse outcome in only two out of 54 patients in the Mavacamten group. Still, the pooled analysis presented in Fig. 4 did not yield a significant result. Additionally, an integrated analysis of data from already conducted HCM trials indicates that Mavacamten is generally safe and well-tolerated across various dosages, irrespective of obstruction presence [25]. These results emphasize the need for more extensive and well-powered RCTs to delve deeper into the mechanisms and potential confounding factors linked with Mavacamten-related adverse events.

Our study exhibited several significant limitations. Firstly, the study only includes four RCTs, observed by a small sample size and fewer documented adverse events. Secondly, the analysis combines information from both oHCM and nHCM, which could lead to contradictions. Even though they are both HCM subtypes, their treatments and clinical outcomes vary. Thirdly, on average, the included studies' follow-up periods lasted roughly 23 weeks. To completely comprehend Mavacamten's long-term effects, studies with a long follow-up period are necessary. Fourthly, our research's quality is organically tied to the caliber of the studies it incorporates and is constrained by their constraints, just like any meta-analysis [26].