Desmopressin In The Treatment of Postural Orthostatic Tachycardia

Transcription

1 The Journal of Innovations in Cardiac Rhythm Management, 6 (2015), DOI: /icrm PHARMACOLOGICAL THERAPY RESEARCH ARTICLE Desmopressin In The Treatment of Postural Orthostatic Tachycardia DAVID GACHOKA, MD 1, KHALIL KANJWAL, MD, FACC, FHRS, CCDS 2 (JOINT FIRST AUTHORS), BEVERLY KARABIN, PhD 1 and BLAIR P. GRUBB, MD, FACC 1 1 Division of Cardiology, Department of Medicine, The University of Toledo Medical Center, OH 2 Michigan Cardiovascular Institute, Central Michigan University, Saginaw, MI ABSTRACT. The long-term efficacy of desmopressin (DDAVP) in treatment of postural orthostatic tachycardia syndrome (POTS) patients remains unclear. We report our retrospective, single-center, long-term experience regarding the efficacy and adverse effect profile of DDAVP in the treatment of POTS patients. In this retrospective analysis, we reviewed the electronic charts for data in regards to patient demographics, orthostatic parameters, side effect profile, subjective response to therapy, and laboratory studies recorded for each clinical follow-up visit at our institution s Syncope and Autonomic Disorder Center. The response to DDAVP therapy was considered successful if the patient had both symptom relief in addition to an objective response in orthostatic hemodynamic parameters including (heart rate (HR) and systolic blood pressure (SBP)). Three hundred and fifty POTS patients were screened for evaluation in this study. Of the 350 patients, 72 patients who received DDAVP therapy were reviewed. Forty-eight patients from this group wereabletotolerate themedication aftercareful dosage titration. Mean follow-up duration in this group of patients was 12±2 months(10 14) months. DDAVP improved symptoms of orthostatic intolerance in 20 of 72 (28%) ofthetotalpatients or20of 48 (42%) ofthosewhowereableto toleratethe drug.symptoms thatimprovedthe mostincluded dizziness (48%), presyncope (38%), fatigue 18%, palpitations(33%), anxiety (42%), and syncope (20%). Symptom reduction correlated with a statistically significant improvement in standing HR after treatment with DDAVP compared with their baseline hemodynamic parameters (standing HR ±12.67 versus 92.10±18.62, po0.03). The most common side effect was hyponatremia n ¼ 9, 20%). In the subgroup of patient with POTS who can tolerate oral DDAVP, there was notable improvement of standing HR, which correlated with improvement inclinicalsymptoms oforthostatic intolerance. ISSN (print) ISSN (online) KEYWORDS. desmopressin, postural orthostatic tachycardia syndrome Innovations in Cardiac Rhythm Management Introduction Postural orthostatic tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance associated with an The authors report no conflicts of interest for the published content. Manuscript received September 14, 2015, final version accepted November 30, Address correspondence to: Blair P. Grubb, MD, FACC, Professor of Medicine, The University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH Blair.Grubb@utoledo.edu *ThispaperisdedicatedtoBarbaraStraus,MD( ).Physician, mother, community leader, dancer, and loving wife (B.P.G.). May her memory be for a blessing. excessive rise in heart rate (HR) during an upright posture that resolves with recumbency. A constellation of symptoms is experienced by patients suffering from POTS, which may include palpitation, dizziness, and fatigue. These symptoms may result in limitation of their daily activities to an extent of functional disability that leads to loss of both educational and employment opportunities. Currently, there is no FDAapproved therapy for patients suffering from this problem. Desmopressin (DDAVP) is a synthetic analogue of arginine vasopressin that has been in use for a long time in the prevention of enuresis in children. It acts by promoting fluid retention by increasing water permeability in the distal tubule of the kidney. Through this mechanism, it promotes 2222 The Journal of Innovations in Cardiac Rhythm Management, December 2015

2 D. Gachoka, K. Kanjwal, B. Karabin, et al. acute blood volume expansion and may reduce orthostatic tachycardia in POTS patients. There is anecdotal evidence on the use of DDAVP as an add-on therapy in management of POTS. We herein present our experience with the use of DDAVP in patients with POTS who were followed at our autonomic center. Methods This was a retrospective study approved by our institutional review board at the University of Toledo medical center. We reviewed 350 electronic medical records (EMRs) of patients with POTS who had been treated at our autonomic center. A total of 72 patients were found to be eligible for inclusion in this study. Criteria for diagnosis of POTS POTS was defined as ongoing symptoms of orthostatic intolerance lasting more than 6 months accompanied by a HR increase of at least 30 bpm or a HR of more than 120 bpm observed during the first 10 min of upright posture or the head-up tilt test (HUTT) occurring in the absence of another chronic debilitating disorder. 1 6 Reported symptoms included fatigue, orthostatic palpitation, exercise intolerance, dizziness or lightheadedness, headache, near syncope, and/or syncope. In a retrospective detailed chart review, we collected data to include presenting symptoms, demographic information, laboratory data, and treatment outcome with DDAVP. Protocol for HUTT The protocol for tilt-table testing has been described extensively elsewhere in our previous work on POTS. 1,5 Treatment protocol Patients treatment protocols were based on our previous experiences with orthostatic disorders as described in detail elsewhere. 3,4 Sequence of therapies employed in this condition included physical counter maneuvers, aerobic and resistance training, as well as increased dietary fluids and sodium. If these therapies were ineffective, pharmacotherapy was initiated in a sequence generally consisting ofb-blockers, central sympatholytic, fludrocortisone, midodrine, and Total patients screened n=350 Elligible patients n= 72 Number that discontinued ddavp due to SE n=14 Lost to follow up n=10 number that complained of hyponatremia n= 9 patients who continued DDAVP through dose titration n=48 Clinical response to DDAVP on 0.1 mg n=5 clinical response to DDAVP on 0.2mg n= 15 patient non responsive to DDAVP n=28 Figure 1: Diagram summarizing the design and response to desmopressin in patients suffering from refractory postural orthostatic tachycardia syndrome. The Journal of Innovations in Cardiac Rhythm Management, December

3 Desmopressin in the Treatment of Postural Orthostatic Tachycardia selective serotonin reuptake inhibitors either alone or in combination. If patients failed to respond to these medications,secondand third-line therapies such as octreotide, erythropoietin, and pyridostigmine were employed. Being a referral center for POTS patients, our study had a higher number of drug refractory patients. As such, these POTS patients were on multiple medications upon presentation, and DDAVP was added on slowly while escalating dosage to assess response and efficacy in patients who failed to respond to the minimum dose. The process was aimed at assessing the usefulness of DDAVP as an adjunct to existing therapy. DDAVP was therefore a third-line add-on therapy in patients who were still symptomatic despite the use of the above agents. We did not employ a formal questionnaire or a composite autonomic severity score (CASS) to assess the response to treatment. The information about the subjective symptoms, overall symptom improvement with treatment, and side effects was collected from the patient s EMR and communication from the physician. Treatment was considered successful if the patient reported symptomatic relief and if the hemodynamic parameters showed improvement compared with previous readings. At each visit, HR and blood pressure (BP) readings were collected in both the supine position and after 10 min of standing. We used descriptive statistics to report our findings. DDAVP was not given to women on oral contraceptives because of the potential for thrombotic complications Follow-up The median length of follow-up was 12±2 months (range months). The study data were collected from patient population seen in our outpatient clinic between 2005 and DDAVP use All patients were initially started on 0.1 mg DDAVP orally once daily. If no significant therapeutic effect was reported and they could still tolerate the medication, the dose was increased to a maximum of 0.2 mg orally once daily. Results A total of 350 patients had visited our clinic with diagnosis of POTS. Of those, 72 were eligible for inclusion in this study (Figure 1). Table 1 shows the population baseline characteristics. Seventy-two patients were eligible, of whom 56 (78%) were women. Ten patients (13%) were lost to follow-up while 14 patients (19%) reported side effects to DDAVP leading them to stop taking the medication. The most common reported side effect was hyponatremia in 12% of the patients, with the lowest sodium level being 125 meq/l. In each of these patients serum sodium levels returned to pretreatment levels within 3 4 weeks after stopping the medication. A total of 48 patients (67%) were able to tolerate DDAVP or go through titration to the maximum dose. DDAVP was initiated at a dose of 0.1 mg daily. If the patient tolerated Table 1: Demographic and clinical feature of the study patients Baseline clinical characteristics of patients in the study Study characteristics Total number of patients screened 350 Number of patients who met inclusion criteria 72 Number of patients that received Desmopressin 72 Number of patient with incomplete follow up 10 Number of patients with side effects 14 Clinical features in patients included in the 48 analysis Age (yrs) 39±18 Females 38 Comorbidities, n (%) Migraine 22 (45.0%) Diabetes 2 (4.0%) Joint hypermobility 1 (2.0%) Hypertension 6 (12.5%) Wolf Parkinson White syndrome 2 (4.0%) Cerebral palsy 1 (2.0%) Delta granules disease 5 (10.4%) Factor 5 Leiden deficiency 2 (4.0%) Precipitating event Viral infection 8 (16.6%) Surgery 5 (10.4%) Trauma 2 (2.0%) pregnancy 3 (6.2%) Clinical symptoms of POTS, n (%) Fatigue 21 (44.0%) Dizziness 31 (65.0%) presyncope 38 (79.0%) Syncope 5 (10.4%) Inability to concentrate 6 (12.5%) Orthostatic palpitation 21 (44.0%) Chest pain 4 (8.3%) Anxiety 7 (14.5%) hypersomnolence 4 (8.3%) Nausea 6 (12.5%) Concomitant medications (n%) b-blocker 16 (33.3%) Midodrine 23 (47.9%) Modafinil 8 (16.6%) Fludrocortisone 25 (52.1%) Octreotide 3 (6.2%) Erythropoietin 5 (10.4%) Norepinephrine reuptake inhibitors 2 (4.0%) Selective serotonin reuptake inhibitor 16 (33.3%) Methylphenidate 2 (4.0%) POTS: postural orthostatic tachycardia syndrome. the medication, symptom improvement was re-evaluated after 6 months. If no subjective change in the symptoms was reported, the dose was increased to 0.2 mg orally once daily. After another 6 months, symptoms and hemodynamic parameters were re-evaluated on the higher dose. Effects of DDAVP on hemodynamic parameters Table 2 provides the effects of DDAVP on hemodynamic parameters between the first and second visit, including improved HR from sitting to standing position without significant effect on the systolic blood pressure (SBP) The Journal of Innovations in Cardiac Rhythm Management, December 2015

4 D. Gachoka, K. Kanjwal, B. Karabin, et al. Table 2: Hemodynamic effects of desmopressin Before treatment After treatment p-value Sitting heart rate 84.04± ±21.53 NS Standing heart rate ± ± Sitting systolic blood pressure ± ±22.89 NS Standing systolic blood pressure ± ±16.90 NS Some of the commonly reported side effects of DDAVP use were hyponatremia, swelling of the arms and digits, headache, and mild confusion. Hyponatremia was the most common reason for discontinuing DDAVP. No patient ith headaches was reported to have signs of increased intracranial pressure such as papilledema. Discussion POTS often affects individuals between 15 and 50 years of age. The ratio of female to male patients is 5:1. 1 Treatment of POTS patients is often very challenging, with nonpharmacological therapy focused on increasing salt and fluid intake, compression stockings, and exercise. 1,7,8 The goal of the therapy is to reduce both the frequency and the severity of their symptoms and improve their quality of life. 9 DDAVP is a synthetic analog of vasopressin, a natural antidiuretic hormone that acts through the principle cells of the collecting duct to reabsorb water into the bloodstream, resulting into increased total effective body volume 2,6 (Figure 2). DDAVP has been used in children to treat enuresis with few side effects noted. In a prospective randomized control study looking at acute effects of DDAVP, a significant reduction in the standing HR was observed when compared with placebo (HR 101.9±14.5 bpm compared with 109.2±17.4 bpm; po0.001). This acute effect on the HR was associated with acute symptomatic improvement; 2 however, the magnitude of HR reduction did not correlate with the degree of symptom resolution. In our analysis, DDAVP use was associatedwithimprovement in the clinical symptoms of POTS. The most notable symptoms that improved included dizziness, fatigue, palpitation, nausea and syncope (Table 3). This improvement was most likely related to the improved hemodynamic changes (particularly HR) observed following DDAVP administration similar to the previous study. There was no significant change in SBP noted to correlate with POTS symptoms improvement. Figure 2: Site of action of desmopressin on the colleting tubules of the nephron (illustration by Helen Grubb). The Journal of Innovations in Cardiac Rhythm Management, December

5 Desmopressin in the Treatment of Postural Orthostatic Tachycardia Table 3: Most common reported improved symptoms Symptoms Number with symptoms before treatment Number with symptoms after treatment Improvement (%) Presyncope Dizziness Fatigue Palpitation Anxiety Syncope The overall efficacy of DDAVP in our study was 28% of the total patients and 42% of the patients who were able to tolerate the drug. We did not find any specific clinical features that predicted a response to DDAVP therapy. Most of the patients who reported no improvement with (or were intolerant of) DDAVP use were also noted to be resistant to or intolerant of other therapeutic regimens as well. Hyponatremia was noted to be the most common adverse effect and the most common reason for discontinuation of this medication; however, the lowest sodium level seen was 125 meq/l and sodium levels returned to normal within weeks of stopping the medication. This side effect was perhaps compounded by the fact that a large volume of fluid intake is one non-pharmacological way to manage POTS symptoms. Other reported side effects though at lesser frequency included headache, nausea, and swelling of digits, which are all related to water retention. We noted a mild drug drug interaction between DDAVP and fludrocortisone leading to enhanced water retention and swelling of the digits. Special attention should be paid to this adverse effect when using these medications concomitantly. Nonetheless, DDAVP appears to be a potentially safe, effective, and inexpensive treatment modality in the treatment of POTS. In light of the expense of other treatment modalities (such as octreotide, erythropoietin, and ivabradine), it seems reasonable to consider DDAVP earlier in the treatment of patients suffering from POTS. Limitations Several limitations were noted during this study. Because of its retrospective nature, randomization of the study population was not possible and each patient served as their own control. The study also lacked standardized criteria for evaluating the efficacy of therapy or assessing the hemodynamic response during treatment. The beneficial effect of DDAVP noted in our study may therefore have been a spontaneous remission of this condition. However, considering that these patients had previously been refractory to other treatment regimens, we can argue their symptomatic improvement was secondary to DDAVP addition. As a referral center, the patients presenting to our clinic were highly symptomatic and had not responded to trials of multiple medication. Conclusion A subgroup of POTS patients who can tolerate DDAVP through dose titration may demonstrate improvement in both standing HR and their clinical symptoms. Overall the agent is safe, inexpensive, and easy to use and should be considered as an additional therapeutic modality in the treatment of POTS. References 1. Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. 2009; 20(3): Coffin ST, Black BK, Biaggioni I, et al. Desmopressin acutely decreases tachycardia and improves symptoms in the postural tachycardia syndrome. Heart Rhythm. 2012;9(9): Grubb B, Dan GA. Syncope due to autonomic insufficiency syndromes associated with orthostatic intolerance. Rom J Intern Med ;38 39: Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: A concise guide to diagnosis and management. JCardiovascElectrophysiol.2006;17(1): Grubb BP, Kosinski D. Tilt table testing: Concepts and limitations. Pacing Clin Electrophysiol. 1997;20(3 Pt 2): Weinstock J. Desmopressin in the postural tachycardia syndrome. Heart Rhythm. 2012;9(9): Grubb BP. Postural tachycardia syndrome. Circulation. 2008; 117(21): Kavi L, Gammage MD, Grubb BP, Karabin BL. Postural tachycardia syndrome: Multiple symptoms, but easily missed. Br J Gen Pract. 2012;62(599): Grubb BP. Clinical practice. Neurocardiogenic syncope. N Engl J Med. 2005;352(10): The Journal of Innovations in Cardiac Rhythm Management, December 2015