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Pyridostigmine in the treatment of postural orthostatic tachycardia: a singlecenter experiencePyridostigmine in the Treatment of Postural Orthostatic
Tachycardia: A Single-Center Experience
KHALIL KANJWAL, M.D.,* BEVERLY KARABIN, PH.D.,* MUJEEB SHEIKH, M.D.,*
LAWRENCE ELMER, M.D., PH.D.,† YOUSUF KANJWAL, M.D.,* BILAL SAEED, M.D.,*
and BLAIR P. GRUBB, M.D.*
From the *Electrophysiology Section, Division of Cardiology, Department of Medicine, The University of Toledo,
Toledo, Ohio; and †Department of Neurology, The University of Toledo College of Medicine, Health Science
Campus, Toledo, Ohio
Background: The long-term efficacy of pyridostigmine, a reversible acetyl cholinesterase inhibitor, in
the treatment of postural orthostatic tachycardia syndrome (POTS) patients remains unclear. We reportour retrospective, single-center, long-term experience regarding the efficacy and adverse effect profile ofpyridostigmine in the treatment of POTS patients. Methods: This retrospective study included an extensive review of electronic charts and data collection
in regards to patient demographics, orthostatic parameters, side-effect profile, subjective response totherapy, as well as laboratory studies recorded at each follow-up visit to our institution’s Syncope andAutonomic Disorders Center. The response to pyridostigmine therapy was considered successful if patienthad both symptom relief in addition to an objective response in orthostatic hemodynamic parameters(heart rate [HR] and blood pressure). Three hundred patients with POTS were screened for evaluation inthis study. Of these 300, 203 patients with POTS who received pyridostigmine therapy were reviewed. Ofthese 203 patients, 168 were able to tolerate the medication after careful dose titration. The mean follow-up duration in this group of patients was 12 ± 3 (9–15) months. Pyridostigmine improved symptoms oforthostatic intolerance in 88 of 203 (43%) of total patients or 88 of 172 (51%) who were able to toleratethe drug. The symptoms that improved the most included fatigue (55%), palpitations (60%), presyncope(60%), and syncope (48%). Symptom reduction correlated with a statistically significant improvement inupright HR and diastolic blood pressure after treatment with pyridostigmine as compared to their baselinehemodynamic parameters (standing HR 94 ± 19 vs 82 ± 16, P < 0.003, standing diastolic blood pressure71 ± 11 vs 74 ± 12, P < 0.02). Gastrointestinal problems were the most common adverse effects (n = 39,19%) reported. The overall efficacy of pyridostigmine in our study was seen in 42% of total patients or52% of patients who could tolerate taking the drug. Conclusion: The subgroup of POTS patients who can tolerate oral pyridostigmine may demonstrate
improvement in their standing HR, standing diastolic blood pressure, and clinical symptoms of orthostaticintolerance. (PACE 2011; 1–6) pyridostigmine, orthostatic intolerance, postural orthostatic tachycardia syndrome
from variety of symptoms such as palpitations, Postural orthostatic tachycardia syndrome exercise intolerance, lightheadedness, cognitive (POTS) is a form of chronic orthostatic intol- impairment, and syncope.1 Many POTS patients erance associated with an excessive increase can be severely limited in daily activities to in heart rate (HR) during upright posture that the point of functional disability with loss of resolves with recumbency. While the exact both educational and employment opportunities.
incidence is unknown, it is currently thought that A number of therapeutic options have been POTS affects more than 500,000 people in the proposed for these patients, including increased United States alone. POTS patients can suffer hydration and sodium intake, reconditioning andstrength training, as well as pharmacotherapysuch as fludrocortisone, midodrine, serotoninand/or norepinephrine reuptake inhibitors, and Address for reprints: Blair P. Grubb, M.D., F.A.C.C., Professor ofMedicine and Pediatrics, Director Electrophysiology Services, octreotide. However, there are patients where Division of Cardiology, Department of Medicine, Health these treatments are ineffective and/or poorly Sciences Campus, The University of Toledo Medical Center, Mail Stop 1118, 3000 Arlington Ave, Toledo, OH 43614. Fax: Pyridostigmine, an acetyl cholinesterase in- 419-383-3041; e-mail: [email protected] hibitor, is a novel treatment option for the patients Received September 13, 2010; revised November 20, 2010; suffering from POTS, presumably acting through facilitation of ganglionic and neural transmission in both the sympathetic and parasympathetic C 2011, The Authors. Journal compilation C 2011 Wiley Periodicals, Inc.
nerves.3 A study by Raj et al. demonstrated that If these were ineffective, pharmacotherapy was pyridostigmine improved both the tachycardia initiated in a sequence generally consisting of and other symptoms in a group of 17 patients fludrocortisone, midodrine, and selective sero- suffering from POTS.4 In this paper, we report tonin reuptake inhibitors, either alone or in our experience using pyridostigmine in a clinical combination. A trial of stimulants including setting with a large outpatient group of POTS methylphenidate or dextroamphetamine failed patients refractory to other forms of treatment.
to provide symptomatic relief in any of thesepatients. Being a referral center for POTS patients, our study had a higher number of drug refractory The study was a retrospective study approved patients. As such, these refractory POTS patients by our institutional review board. We screened were on multiple medications upon presentation 300 POTS patients who were being followed at our and pyridostigmine was added in slow escalating institution’s Syncope and Autonomic Disorders doses to assess response and efficacy of pyri- Center. A total of 208 patients were found eligible dostigmine in this group of patients. The idea was to assess the use of the drug as it would beemployed by a clinician in a “real world” setting Criterion for Diagnosis of POTS
as an “add on” to existing therapy. We did not POTS was defined as the presence of chronic employ a formal questionnaire or a composite symptoms of orthostatic intolerance (>6 months autonomic severity score (CASS) to assess the duration) accompanied by a reproducible HR increase of at least 30 beats/min (or a rate that the response to treatment with HUTT testing.
exceeded 120 beats/min) that occurs in the first The information about the current symptoms, side 10 minutes of upright posture or head-up tilt effects of medications, and overall improvement in test (HUTT) occurring in the absence of other symptoms from each patient were collected from chronic debilitating disorders. Symptoms include the patient charts, physician communications, fatigue, orthostatic palpitations, exercise intoler- and direct patient inquiry. We also attempted ance, lightheadedness, diminished concentration, to collect information about the prior trials headache, near syncope, and syncope.5 In a retro- of various medications before initiation of the spective detailed chart review, we collected data pyridostigmine; however, that information was including demographic information, presenting not available in the majority of the patients.
symptoms, laboratory data, tilt-table response, and A treatment was considered successful if the patient reported symptomatic relief and if thehemodynamic parameters showed improvement HUTT Protocol
as compared to previous readings. HR and blood The protocol used for tilt-table testing has pressure were recorded both in supine and after been described elsewhere, but basically consisted 3 minutes of standing during each visit. We used of a 70◦ baseline upright tilt for a period descriptive statistics to report our findings.
of 30 minutes, during which time HR andblood pressure were monitored continually. If no Follow-up
symptoms occurred, the patient was lowered to The mean duration of follow-up was 12 ± 3 the supine position and an intravenous infusion (range 9–15 and median 12) months.
of isoproterenol started with a dose sufficient toraise the HR to 20%–25% above the resting value.
Upright tilt was then repeated for a period of All patients were initially started on pyri- 15 minutes. Patients were included in the study dostigmine 30 mg orally twice daily. After a period if they had a POTS pattern on HUTT (rise in HR of 1 week, if no therapeutic effect was noted and independent of any change in blood pressure).
if the drug was tolerated, the dose was increasedto 60-mg orally three times daily. Again after a 1- Treatment Protocols
to 2-week interval, if the drug was tolerated but The treatment protocols that were initially no therapeutic benefit was noted, the dose was employed were based on our previous experiences increased to a maximum of 90-mg orally three with orthostatic disorders and are described in times daily or 180 mg of the sustained release form.
detail elsewhere. We identified 208 patients withPOTS who were refractory to other commonly used medications. Briefly, a sequence of therapies were employed that included physical counter POTS from our Syncope and Autonomic Dysfunc- maneuvers and aerobic and resistance training tion Clinic and found 208 patients eligible for as well as increased dietary fluids and sodium.
inclusion in the current analysis (Fig. 1). Table I Figure 1. Diagram summarizing the design and response to pyridostigmine in patients suffering
from refractory POTS.
shows the baseline clinical characteristics of the Side Effects from Pyridostigmine
A total of 39 patients developed gastrointesti- nal (GI) symptoms; however, these symptoms were whom were women) were found eligible for this considered severe enough to warrant discontinu- study. Of the 208 patients who were found to be ation of the therapy in 35 patients. These adverse candidates for pyridostigmine only 203 received effects included severe abdominal cramps, severe the medicine. Five patients could not afford the nausea, and diarrhea. Four patients had very mild medication and were excluded from the analysis.
bloating and mild nausea and they continued with Thirty five (17%) patients stopped the medication the therapy. None of the patients had diarrhea to as a result of a variety of reported side effects.
begin with and none had any previous history of A total of 172 patients were able to tolerate the diarrhea-predominant irritable bowel syndrome.
medication through its dose titration and were Other minor side effects included neuromuscular included in final analysis. The majority of our (tremors, twitching, hyperhidrosis) in five (2.4%), patients (80%) received 60 mg of pyridostigmine urinary urgency in two (1%), hypertension in two (1%), chest pain in one (0.5%), and hypotension Effect of Pyridostigmine on Clinical Symptoms
We did not identify any clinical predictors Pyridostigmine improved symptoms of ortho- that would portend a favorable response to static intolerance in 88 of 203 (43%) of total pyridostigmine therapy. In our study, there did patients or 88 of 172 (51%) who were able to not appear to be relationship between dosage and tolerate the drug. The symptoms that improved most included fatigue (55%), palpitations (60%),presyncope (60%), and syncope (48%).
Pyridostigmine is a reversible, peripheral Effect of Pyridostigmine on Hemodynamic
cholinesterase inhibitor, which increases the Parameters
availability of acetylcholine at preganglionic nico- Table II demonstrates effects of pyridostig- tinic receptors (both sympathetic and parasympa- mine on HR and blood pressure before and after thetic) and muscarinic receptors (postganglionic treatment. Pyridostigmine significantly improved parasympathetic). This leads to an enhanced standing HR and standing diastolic blood pres- neural transmission, which improves baroreceptor sure; however, there was no significant increase reflex functions.3 This augmented baroreceptor in standing systolic blood pressure.
sensitivity that occurs with pyridostigmine has Table II.
Baseline Clinical Characteristics of Patients Study Characteristics
Type of POTS
Clinical features in patients
included for analysis
been shown to have a beneficial role in patients suffering from neurogenic orthostatic hypotension (NOH).6 In one open-label study and one placebo- controlled study using pyridostigmine, there was reported to be a statistically significant improvement in standing diastolic blood pressure in patients with NOH.7 Further, improvement in patient satisfaction using CASS questionnaire has Precipitating event
also been seen following chronic pyridostigmine therapy. In an open-label study, 20 of 28 patients with NOH receiving pyridostigmine reported marked improvement using CASS questionnaire at 19 ± 8.9 months of follow-up.8 While there are some data to support the use of pyridostigmine Clinical symptoms of POTS
in NOH, the role of pyridostigmine in POTS is limited to a single study. In this study by Raj et al.,4 17 patients with POTS were randomized to treatment with pyridostigmine (30 mg) and placebo. Baseline blood pressure and HR were recorded and compared with change in blood pressure and HR at 2 and 4 hours. Pyridostigmine use was associated with significant decrease in standing HR at 2 hours (119 ± 16 beats per Response to pyridostigmine
minute [bpm] at baseline vs 2 hours, 104 ± 16 bpm, P < 0.001) and continued at 4 hours (100 ± 16 bpm, P < 0.001). The authors proposed Concomitant medications
that acute pyridostigmine therapy induced a shift in cardiovagal tone that was associated with reduction in upright tachycardia in POTS patients.
Similar effects on parasympathetic tone have been reported in heart failure in patients receiving Despite this, the data on the long-term clinical efficacy of pyridostigmine in POTS patients in a clinical setting has yet to be determined.
POTS is a chronic autonomic disorder, displaying wide fluctuations in both hemodynamics as well as patient symptoms due to factors such asenvironmental conditions, disease progression, resistance to therapy, and other concurrent illness.
followed by neuromuscular and genitourinary In the current analysis, pyridostigmine use was problems, similar to that reported in previous associated with improvement in the clinical studies. The GI symptoms were severe enough in 35 (17%) and pyridostigmine therapy was fatigue, palpitations, presyncope, and syncope subsequently discontinued in this subgroup of showing the greatest response. The improvement patients. Pyridostigmine was used as an add-on in these symptoms was most likely related therapy for the treatment of POTS; however, there to improved hemodynamics observed following was no clear drug-drug interaction observed in our pyridoigmine administration. In addition, the use of pyridostigmine was associated with asignificant and sustained improvement in ortho- Limitations
static tachycardia in our study population. This There are certain important limitations in the is comparable to the findings reported by Raj design of the current study. The study group et al.4 Besides improvement in cardiovagal tone, itself was small, and it was not a randomized sustained improvement in upright tachycardia as controlled trial. Rather, each patient was used seen in our study also suggests the absence of a as his/her own control. Also, our study lacked rapid tachyplaxis with long-term therapy. We did a standardized criterion for evaluating efficacy not identify any clinical characteristics that would of therapy. In addition, the assessment of hemo- predict a favorable response to pyridostigmine dynamic responses was also not standardized.
therapy. This limitation in the current analysis The beneficial effects noted in our study could would require a large prospective randomized represent a spontaneous remission in some of study in the future to help identify the subgroup these patients. However, the refractory nature of of POTS patients who may most benefit from the symptoms in this group of patients would seem to argue against chance improvement. Our Pyridostigime has been postulated to improve patients were highly symptomatic and had not sympathetic vasomotor tone and has favorable responded to multiple therapeutic trials of various effect on hemodynamics in several forms of medications. All patients presented here were autonomic dysfunction. Singer et al. in a double- suffering from unusually severe and refractory blinded, placebo-controlled cross over study in forms of POTS and therefore may not represent 58 patients with neurogenic hypotension, showed the majority of patients with POTS. We hope this that the use of pyridostigmine with midodrine study will lay a foundation for a larger randomized was associated with improvement in standing clinical trial that will effectively evaluate the diastolic blood pressure without any supine role of pyridostigmine in the treatment of POTS.
hypertension.7 In our study, we also observed Also, such a study will help to identify those significant improvement in standing diastolic POTS patients who are likely to benefit from blood pressure in POTS patients. This increase in diastolic blood pressure suggests an increase Pyridostigmine therapy may help ameliorate in peripheral vascular resistance following pyri- the refractory symptoms in patients suffering from dostigmine administration. Similar to previous the severe forms of this disorder. Our study did studies we did not note any significant effects on not evaluate the use of pyridostigmine as a first- upright systolic blood pressure. Further, we did line therapy in POTS, as it was added to existing not observe any increase in supine hypertension The overall efficacy of pyridostigmine in our study was seen in 42% of total patients or Conclusion
51% of patients who could tolerate taking the In a subgroup of POTS patients refractory to drug. However, we did not find any specific other forms of therapy, long-term treatment with characteristic feature that could predict a response pyridostigmine reduces standing HR, improves to pyridostigmine therapy. The possible reasons standing diastolic blood pressure, and ameliorates for lack of improvement were noncompliance, many clinical symptoms in patients who can possible progression of the disease, resistant tolerate taking this medication. The utility of the forms of POTS, and intolerance due to side pyridostigmine as a first-line therapy in POTS effects of therapy. In our patient population, remains unknown from the results of this limited GI distress was the most common side effect References
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