Minoxidil is an arteriolar vasodilator approved in the 1970s as a treatment of severe refractory hypertension, with standard doses ranging between 10 and 40mg daily (up to 100mg/day).1 Within last years, low-dose oral minoxidil (LDOM) has been increasingly used for the treatment of different types of alopecia, supported by numerous studies describing its effectiveness and favorable safety profile.2,3 One of the largest studies thoroughly described the frequency and chronology of adverse effects (AE) of LDOM treatment in 1404 patients.4 Hypertrichosis is a well-known and most common AE of LDOM, appearing in approximately 15% of patients.4,5 Although uncommon, systemic AE may occur and, in a minority of patients, lead to discontinuation of LDOM treatment. The majority of systemic AE are related with the cardiovascular and hemodynamic effect of minoxidil, including lightheadedness (dizziness, postural hypotension), fluid retention (lower limb or facial edema), tachycardia (palpitations), electrocardiogram alterations (mainly in T-wave), headache, insomnia, nightmares or increased appetite.1,4,6,7 These AE are generally well-tolerated and resolve after discontinuation or dose adjustment of LDOM. Serious AE have been reported with high doses of oral minoxidil when used for severe hypertension or due to compounding errors in hair loss treatment, including hypotensive syncope, pericarditis, pericardial effusion or myocardial infarction.1,8

Systemic AE represent the main concern of LDOM treatment in general population with hair loss, which are mostly healthy middle-aged adults. Considering that LDOM is used as an off-label therapy, these safety concerns become major when prescribing it in special situations such as patients with personal history of arterial hypertension (HT) or arrhythmia. It is still unknown whether LDOM could enhance the hypotensive effect of other antihypertensive drugs or increase the risk of systemic AE in these patients.

The objective of this study was to evaluate the safety of LDOM for the treatment of hair loss in patients with HT or arrhythmia.

This retrospective, descriptive, multicenter study included adult patients with personal history of HT or arrhythmia who were under treatment with LDOM for hair loss of any cause for at least one month, at five centers from Brazil and Spain, from January 2018 to April 2022. This minimum treatment duration of one month was established considering the previously described AE's chronology of LDOM.4 Epidemiological, medical, and safety data were collected from patients’ medical records, including prior treatments for HT, AE, and the need to withdraw or adjust the dose of LDOM or antihypertensive treatments. In some patients, the dose of LDOM was titrated according to response and tolerability, and the above parameters were analyzed for each dose.

Statistical analysis was performed with IBM SPSS Statistics (Version 25.0: IBM Corp., 2017). Continuous variables are expressed as mean (range). Logistic regression was used to identify the variables associated with an increased risk of systemic AEs, withdraw or adjustment of LDOM or antihypertensive treatments, which was considered statistically significant if the P-value was<0.05.

To our knowledge, this represents the first study of the safety of LDOM in patients with HT or arrhythmia. Numerous studies have shown its favorable safety profile in general population,2–4,6 and recent studies have investigated the use of LDOM in special situations such as pediatric,9 adolescent,10 and elderly population,11 but there are scarce data of its use in patients with HT or arrhythmia. The global prevalence of HT in adults is 34%,12 so it seems important to expand knowledge about the management and safety issues of LDOM treatment in these patients.

In our cohort of hypertensive patients treated with LDOM, the global frequency and type of AE were consistent to those found in recent studies.2–4 AE were detected in 21.9% of the cases, and hypertrichosis was the most common one (15.9%), similarly to the data found by Vaño-Galvan et al.4 However, we did find a higher frequency of cardiovascular AE (lightheadedness and fluid retention), and more patients presenting more than 1 AE (Table 2).

Lightheadedness and tachycardia were significantly associated with a higher risk of both adjustment and suspension of LDOM (Table 1). Hypertrichosis was associated with dose adjustment but not with suspension, supporting that this AE is usually well-tolerated. Patients who were treated with three or more antihypertensive drugs had also more risk of lightheadedness and suspension of LDOM. Among all antihypertensive drugs, doxazosin led to a higher risk of lightheadedness, fluid retention and suspension of LDOM. This could be explained by the fact that doxazosin is an alpha-adrenergic blocker that also causes arteriolar vasodilation,13 which might produce a synergistic effect with minoxidil. Although it might be plausible that other vasodilators, such as hydralazine or calcium channel blockers, could increase this synergistic effect with minoxidil, we did not find a statistically significant association.

Lightheadedness (also referred as dizziness or postural hypotension) was the most frequent systemic AE and the most common cause of both adjustment and discontinuation of LDOM (Fig. 1). It was generally mild and reported more frequently in summer and in the morning. There were no cases of serious hypotension or impairment of blood pressure (BP) control. In this regard, two recent studies investigated the variation of BP in male patients treated with 5mg LDOM using 24h ambulatory BP monitoring. They found a slight reduction in BP in the 2h after intake of LDOM14 and at week 24.7 Few additional studies have assessed BP during treatment with LDOM at doses between 0.45 and 5mg, obtaining similar results.15–17 This is consistent with 1970s studies with 2.5mg, 5mg and 10mg minoxidil which found a minimal or no hypotensive effect in normotensive patients.18

Figure 1.

Flowchart describing the type and frequency of adverse effects, dose adjustment and discontinuation of LDOM treatment in hypertensive patients. * Sum of individual frequencies may differ from total frequency because some patients developed more than one adverse effect.

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Fluid retention (mainly pedal edema; only 2 cases of facial edema) was detected in our study in 2.6% of the patients, which is a slightly higher frequency than previous studies in general population,3,4 but much lower than treatment with standard doses (7%).1 We did not find a lower frequency in patients taking diuretics as antihypertensive (thiazides or spironolactone).

Tachycardia was only detected in 0.8% of the patients with hypertension, all of them requiring adjustment or suspension of LDOM. Tachycardia is the result of reflex sympathetic activation induced by the vasodilatory effect of oral minoxidil, and it is traditionally described as a frequent AE with standard doses.1 However, studies with LDOM have shown that palpitations are rather uncommon and transient, usually appearing within the first intakes of LDOM.4,7,15,17

EKG changes are another common AE with standard doses of minoxidil, with changes in direction and magnitude of the T-waves in up to 60% of patients, mainly due to a coronary steal mechanism associated with the reduction of blood pressure in the coronary arteries. They are asymptomatic, and usually disappear despite continuation of the treatment.1 Only a few studies have performed EKG in patients with LDOM. One study from Thailand found asymptomatic T-wave changes in 10–20% of the patients (non-ischemic T wave inversion in one lead).15 Sanabria et al. found a non-significant increasing in the occurrence of supraventricular and ventricular extrasystole after 24 weeks of treatment with 5mg LDOM, with no remarkable alterations in ventricular repolarization in the 24-h Holter monitoring.7

Interestingly, from our cohort of patients with arrhythmia, no patients reported palpitations or worsening of their prior disease. We did not perform routine EKG in these patients, but five of them were referred to their Cardiologist who approved treatment with LDOM. However, extreme caution should be taken in patients with coronary disease or chronic heart failure since tachycardia may limit myocardium oxygenation (Fig. 2).

Figure 2.

Recommendations for the management of LDOM therapy in patients with hypertension or arrhythmia (based on authors’ clinical experience and results of this study). a Cardiologist's comment: dermatologist may consider decreasing the dose or changing the hour intake of prior antihypertensive drug if the patient develops lightheadedness. b Contraindications according to minoxidil product monograph. c Cardiologist's comment: LDOM could be used after a myocardial infarction only once a stable post-infarction state has been achieved (12 months after). Do not use if non-revascularized angina/ischemic event.

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Consistently with previous studies of LDOM, we did not detect any serious cardiovascular AE such as syncope, ischemic heart disease, pericarditis, or pericardial effusion. These AE were described with standard doses of minoxidil, but they occurred mainly in patients with underlying diseases such as systemic lupus erythematous, advanced renal disease or congestive heart failure, and are extremely rare with LDOM.19,20

Based on our results, the clinical experience of the authors in LDOM treatment, and the collaboration of a cardiologist in this study (MR), most patients undergoing treatment for HT may start LDOM without previous referral to cardiologist. However, we suggest some recommendations for the management of LDOM therapy in patients with HT or arrhythmia (Fig. 2).

The limitations of this study were the retrospective design, lack of a control group and lack of objective measurement of blood pressure and EKG.

In conclusion, LDOM treatment showed a favorable safety profile in patients with HT or arrhythmia, similar to general population. Most common systemic AE were lightheadedness and fluid retention, which improved after adjustment or withdrawal of LDOM. Combination of LDOM with 3 or more antihypertensive drugs or with doxazosin was associated with a higher risk of these systemic AE.

The authors declare that they have no conflict of interest.