A 2023 review article provides a comprehensive summary of the existing literature on the use of midodrine in heart failure (HF) patients. While guideline-directed medical therapy (GDMT) plays a crucial role in managing heart failure, the potential for hypotension to hinder its initiation or up-titration is recognized. Midodrine demonstrates potential in addressing various causes of symptomatic hypotension, including vasovagal syncope, orthostatic hypotension in geriatric patients, neuro-cardiogenic syncope, autonomic nervous system dysfunction, and hypotension induced by hemodialysis. In advanced heart failure cases, a recent trial explored using midodrine to elevate blood pressure levels sufficiently for the prescription of disease-modifying therapies, but the approach remains somewhat contentious. The utilization of midodrine in HF has undergone multiple studies and investigations. The current evidence regarding the use of midodrine in HF is outlined in Table 1. [1]
Research indicates that midodrine can enhance blood pressure, diminish the necessity for vasopressor support, and facilitate GDMT prescription for patients who experience intolerance due to hypotension. However, concerns arise from reported increases in all-cause mortality in select studies, limited sample sizes, and the nonrandomized nature of certain study designs. To gain a comprehensive understanding of the risks and benefits associated with midodrine use in HF patients, additional investigations, including extensive randomized controlled trials and prolonged follow-up studies are warranted. Clinicians must carefully balance the potential benefits of midodrine in HF against the limited evidence and potential risks before considering its use. [1]
A 2021 retrospective cohort study evaluated the prevalence of midodrine prescription in hospitalized patients with decompensated heart failure with reduced ejection fraction (HFrEF) between January and December 2019, in which a total of 3,640 patients met inclusion criteria. Among included subjects, 9.3% (n= 340; mean left ventricular ejection fraction [LVEF] 25%) were prescribed midodrine as opposed to 90.7% (n= 3,330; mean LVEF 35%) who were not given midodrine. The results showed that all-cause mortality at 6 months from hospitalization was significantly higher in the midodrine group compared to those without (26.4% vs. 3.9%; p<0.001, relative risk [RR] 6.7, 95% confidence interval [CI] 5.2%-8.5%). Additionally, the patients on midodrine were more likely to be prescribed beta blockers, mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor neprilysin inhibitors (ARNIs) when compared to those without (85% vs. 75%, 53% vs. 31%, 29% vs. 17%, respectively; p<0.001). The authors discuss the high prevalence of midodrine use in the systolic heart failure population, particularly in those with severely reduced LVEF likely due to treatment-induced hypotension, yet suggest a worse prognosis despite the adjustment for comorbidities and increased use of GDMT. Nonetheless, it should be noted that these findings are merely presented as a poster abstract, lacking further details on methodology and results, and the study specifically excluded diagnoses of end-stage renal disease, orthostatic hypotension, and LVEF > 50%. [2]
A prospective study, published in 2009, evaluated the effectiveness of midodrine in the optimization of heart failure therapy for patients encountering challenges due to pre-existing or treatment-induced hypotension. A total of 10 patients with heart failure due to systolic dysfunction and symptomatic hypotension hindering optimal therapy were enrolled. The exclusion criteria comprised severe valvular dysfunction, low heart rates (<40 beats per minute), liver failure, or patients undergoing hemodialysis. The study protocol involved initiating midodrine 5 mg PO every 6 hours, which was titrated up to a maximum of 10 mg every 6 hours. The patient’s blood pressure, B-type natriuretic peptide (BNP) levels, echocardiography, and medical therapy were closely monitored for 6 months. Background diuretic therapy was tailored based on individual volume status, and renal function was assessed using the Modification in Diet in Renal Disease formula. The results revealed notable improvements, with a higher percentage of patients achieving optimal heart failure therapy, supported by increased dosing percentages of ACE inhibitors/ARBs (20% vs. 57.5%; p<0.001), beta-blockers (37.5% vs. 75%; p<0.001), and spironolactone/eplerenone (43.7% vs. 95%; p<0.001). These adjustments corresponded with enhanced LVEF (baseline 24 ± 9.4 vs. 32.2 ± 9.9; p<0.001) and significant clinical improvements. The findings also revealed a major reduction in total hospital admissions (32 vs.12; p= 0.02) and total hospital days (150 vs. 58; p= 0.02) following midodrine treatment. Moreover, patients experienced improved blood pressure, functional class, reduced BNP levels, decreased left ventricular end-diastolic diameter (LVEDD), and increased LVEF at the six-month mark. It was also noted that midodrine was well tolerated among the included patients, with no reported side effects. However, experiences from non-study patients with concurrent benign prostatic hypertrophy occasionally developed prostatism, which was mitigated by adjusting the midodrine dosage. Based on these findings, it was concluded that midodrine was well-tolerated and aided in the up-titration of neurohormonal-blocking agents, resulting in reverse remodeling and enhanced clinical outcomes. However, due to the small cohort size, larger-scale investigations are needed to further validate these findings. [3]
A 2006 prospective study evaluated 10 consecutive patients with HF due to systolic dysfunction and symptomatic hypotension interfering with optimal medical therapy. Patients began midodrine at 5 mg orally every 6 hours, with the option to escalate to a maximum of 10 mg every 6 hours. Systolic blood pressure (SBP) rose from a baseline of 79.2 ± 4.6 to 99.0 ± 11 mmHg (p <0.0004), while BNP decreased from 1402 ± 1559 to 706 ± 592 (p <0.0001). NYHA class was reduced from 3.5 to 2.4 at six months. The utilization of ACE inhibitors/ARBs increased from 54 to 81%, beta-blockers from 82 to 100%, and spironolactone/eplerenone from 72.7 to 91% of the optimal dose. LVEF improved from a baseline of 24 ± 9.44 to 32.2 ± 9.9 % (p<0.001), and LVEDD decreased from a baseline of 6.2 cm to 5.9 cm (p = 0.04). It was suggested that the use of midodrine is safe in patients with heart failure due to systolic dysfunction with hypotension despite concerns regarding vasoconstriction. Additionally, it allowed patients to receive optimal medical therapy with neurohormonal antagonists leading to significant improvements in reverse modeling manifested by increases in LVEF, reduction in LVEDD, and improved outcomes. It should be noted that these results were only presented as an abstract and may not be comprehensive. [4]
Two case reports describe the feasibility of midodrine use in patients with HFrEF and hypotension. Case 1 presents an 81-year-old female with a number of comorbidities being repeatedly admitted for the exacerbation of right-sided heart failure and associated hypotension. Despite optimized intravenous (IV) noradrenaline infusion and diuretic therapy, she required hemofiltration sessions due to deteriorated kidney function. Following 21 days of efforts to wean the patient off of IV noradrenaline, midodrine was initiated, starting 5 mg TID on off-dialysis and 7.5 mg TID on dialysis days. IV support was successfully weaned off and completely discontinued after an increased dose of midodrine 10 mg TID both on- and off-dialysis days. No major adverse events (AEs) were noted during the treatment, and subsequent hemodialysis was performed without the need for further IV support. Case 2 presents a 79-year-old male patient, frequently admitted due to symptoms of heart failure and hypotension, which limit optimal drug titration and initiation of GDMT for class 1 heart failure. The patient’s blood pressure remained low with deterioration of renal function and volume overload despite both IV inotropic (dobutamine and levosimendan) and vasopressor (noradrenaline) support. Hemofiltration was initiated, and in an attempt to wean the patient off IV noradrenaline and possible initiation of GDMT, oral midodrine 2.5 mg TID was started, with a gradual dose increase to 10 mg TID. Subsequently, the patient was successfully weaned off over 3 weeks, tolerated hemodialysis sessions without the need for IV support, and started on small, gradual doses of GDMT administration. The authors acknowledge the struggles with proper initiation and up-titration of GDMT for class I indication in patients with HFrEF due to hypotension. The authors suggest that midodrine may be used off-label to help wean hypotensive patients off of IV vasopressors and allow initiation and possible up-titration of GDMT. [5]