However, researchers saw higher risks of respiratory failure, longer stays in the intensive care unit, increased hospitalizations, and elevated mortality rates in patients with heart failure with reduced ejection fraction (HFrEF) taking the antihypotensive medication.

The use of midodrine was linked to a decrease in emergency department (ED) visits among patients with heart failure with reduced ejection fraction (HFrEF) in a study published in Frontiers in Pharmacology. However, it was also associated with higher risks of respiratory failure, longer stays in the intensive care unit (ICU), increased hospitalizations, and elevated mortality rates in these patients.

These findings are based off a large-scale study including 11,626 total patients with HFrEF and left ventricular ejection fraction (LVEF) below 50% who did not have malignancy, non-dialysis dependence, or non-orthostatic hypotension. With 10-year enrollment period from 2013 to 2023, half the group (n = 5813) received midodrine while the other half did not receive the intervention.

Doctor using stethoscope on patient's heart | Image credit: joyfotoliakid – stock.adobe.com

Midodrine, a peripheral alpha-1 agonist and antihypotensive medication approved to treat orthostatic hypotension, has historically been well-tolerated with infrequent adverse effects. However, adverse events were reported in 7.9% of 3030 patients in one large-scale study, with common issues including piloerector reactions, gastrointestinal disorders, cardiovascular complaints, and urinary retention. While these issues can often be managed by reducing the dosage of midodrine, its off-label use for conditions like intradialytic hypotension and hypotension related to HF has raised concerns, particularly regarding mortality rates. Studies have shown associations between midodrine use and increased mortality in various clinical settings, challenging previous assumptions about its safety, and its safety level for patients with HFrEF is still unclear.

In the current study, patients with HFrEF who took midodrine had a 21% higher risk of hospitalization, a 16% higher risk of respiratory failure, and a 14% higher risk of ICU admission, compared with those who did not take midodrine. These patients were also 9% more likely to experience all-cause mortality and 5% more likely to go into cardiac arrest. Conversely, midodrine use was linked to a 23% reduced risk of ED visits. The researchers observed similar patterns of risks in most subgroups.

In addition to delayed detection of worsening heart function, increased mortality associated with midodrine use may stem from several other factors, according to the researchers. Excessive consumption of midodrine can lead to severe hypertension and reflex bradycardia, particularly problematic for patients with HF concurrently taking beta blockers, and midodrine's potential to induce peripheral vasoconstriction raises concerns about ischemic events. Additionally, midodrine usage has been linked to the development of supine hypertension, especially at higher doses, which has been associated with increased risk of all-cause mortality and cardiovascular events.

This study has several limitations. First, its retrospective and observational nature may introduce biases, although randomized controlled trials in patients with advanced HFrEF are challenging, according to the researchers. Potential unknown residual confounders could also influence the results, despite efforts to mitigate this through propensity score matching, and the lack of differentiation between inpatients and outpatients when administering midodrine may have impacted the study's comprehensiveness, although the transition to oral midodrine typically occurs before discharge. Further, not all hospitalization-related outcomes may be solely attributed to HFrEF.

“Logically, higher refill frequencies may indicate a more advanced condition, necessitating consultation with a cardiologist,” the researchers said. “Greater emphasis should be placed on monitoring lower refill frequencies to prevent delayed detection of deteriorating heart function. The use of midodrine for hemodynamic support for GDMT [guideline-directed medical therapy] warrants further research to strengthen the available evidence.”

Reference

Wu MJ, Chen CH, Tsai SF. Safety of midodrine in patients with heart failure with reduced ejection fraction: a retrospective cohort study. Front Pharmacol. Published online March 5, 2024. doi:10.3389/fphar.2024.1367790