Unexpected Low Voltage on an ECG

This is a summarized version of the full in-depth article on Relias Media.

By Michael H. Crawford, MD. Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco.

Overview of Inclisiran and Its Mechanism of Action

Inclisiran is a novel small interfering ribonucleic acid (siRNA) therapy designed to reduce low-density lipoprotein (LDL) cholesterol by inhibiting the production of proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 plays a significant role in cholesterol metabolism by reducing the number of LDL receptors on the liver, thereby raising LDL levels in the bloodstream. By inhibiting PCSK9 synthesis, inclisiran increases LDL receptor availability, leading to enhanced clearance of LDL cholesterol. The drug is administered via subcutaneous injections, with dosing starting at day 1, followed by a three-month dose, and then every six months thereafter. This biannual administration schedule offers a potential advantage over more frequent dosing regimens of other LDL-lowering agents.

Long-Term Safety Data from ORION Trials

To assess the long-term safety and tolerability of inclisiran, data from seven clinical trials (ORION-1, 3, 5, 8, 9, 10, and 11) were pooled in a post-hoc analysis, encompassing 5,544 participants (3,576 treated with inclisiran, 1,968 with placebo). The trials included patients with an average age of 64 years, predominantly white (92%), and with a high prevalence of atherosclerotic cardiovascular disease (ASCVD) (84%). Notably, 91% of participants were also on statin therapy. Inclisiran was administered at a dose of 300 mg subcutaneously at the initial visit, on day 90, and subsequently every six months for up to six years. Most subjects were treated for two to four years (72%), with smaller proportions receiving therapy for four to five years (9%) and five to six years (2%).

Primary Outcomes: Safety and Adverse Events

The primary focus of the study was to evaluate serious adverse events, including hepatic, muscle, renal complications, and new-onset diabetes, which could lead to drug discontinuation. After 1.5 years of follow-up, no significant differences in these adverse events were found between the inclisiran and placebo groups. Major adverse cardiovascular events (MACE), while not a primary endpoint, were numerically lower in the inclisiran group (3.8/100 patient years) compared to placebo (6.8/100 patient years), reflecting the potential cardiovascular benefit of LDL-lowering therapy.

Injection site reactions were the most notable adverse events associated with inclisiran, occurring in 9.3% of the inclisiran group versus 1.8% in the placebo group. These reactions were more frequent in women (14% vs. 7% in men) but were generally mild and transient, rarely leading to treatment discontinuation. Furthermore, 4.6% of patients developed treatment-induced anti-drug antibodies, though only 1.4% persisted, and these antibodies were not associated with adverse clinical outcomes.

Implications for Clinical Practice

The study’s findings affirm the safety and tolerability of inclisiran when used in combination with statins and other cholesterol-lowering therapies over a multi-year period. Importantly, inclisiran did not increase the incidence of muscle symptoms, hepatic or renal dysfunction, or diabetes—adverse effects often associated with other lipid-lowering agents such as statins. This makes inclisiran a promising option for patients who may be statin-intolerant or concerned about these potential side effects.

However, there are some limitations. The duration of placebo-controlled data was relatively short (1.5 years), and the majority of participants were followed for fewer than six years. The long-term impact of inclisiran on atherosclerosis progression was not assessed in this analysis, leaving an important question unanswered regarding its effect on plaque burden and long-term cardiovascular outcomes. Furthermore, inclisiran’s impact on reducing LDL cholesterol, though substantial (about 50%), is slightly less than that of monoclonal antibodies targeting PCSK9 (approximately 60%). This difference in efficacy might influence treatment decisions, especially in patients requiring more aggressive LDL reduction.

Commentary: Inclisiran’s Place in Therapy

The commentary on inclisiran highlights the ongoing search for LDL-lowering therapies that are both effective and well-tolerated, particularly in light of patient resistance to statins due to perceived adverse effects. The twice-yearly administration of inclisiran offers a distinct convenience compared to the monthly or bi-monthly dosing of PCSK9 monoclonal antibodies, which may improve adherence in real-world settings. Nevertheless, inclisiran must be administered by a healthcare provider, categorizing it as a medical benefit rather than a pharmacy benefit, which could have implications for cost and access depending on insurance coverage.

While inclisiran’s efficacy in reducing LDL cholesterol is slightly lower than that of monoclonal antibodies, its favorable safety profile and convenient dosing regimen make it an attractive option for long-term management of dyslipidemia, particularly for patients who struggle with adherence to more frequent injections. Ongoing trials focused on cardiovascular outcomes will further clarify its role in preventing major adverse events in high-risk populations.

Summary

Inclisiran represents a promising addition to the arsenal of cholesterol-lowering therapies, particularly for patients who require long-term LDL management but may be intolerant to statins or monoclonal antibody therapies. Its biannual dosing and well-tolerated safety profile make it a convenient option, although more data on its long-term cardiovascular outcomes and comparative efficacy against monoclonal antibodies are needed to fully establish its place in clinical practice.

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