Orthostatic hypotension (OH), a sustained drop in systolic blood pressure of 20 mmHg and/or diastolic blood pressure of 10 mmHg usually within 3 minutes of standing, is a common issue in patients with heart failure. Neurogenic orthostatic hypotension (n-OH), an autonomic disorder, is a similar condition; however, in n-OH, the orthostatic blood pressure drop occurs without an appropriate increase of heart rate. The change in heart rate is usually <10-15 bpm.
Patients with cardiomyopathy who have OH present an unusual clinical dilemma. Medications to treat OH can result in salt and water retention, exacerbating systolic heart failure. Diuretics may exacerbate postural intolerance and orthostatic symptoms. Beta-blockers may worsen the heart rate response to position. Vasodilators, which help to unload the heart and treat supine hypertension, may worsen orthostatic blood pressure responses. We present a patient with cardiomyopathy who has n-OH, and discuss our approach to treatment.
A 69-year-old male presenting in transfer from another institution had a history of ischemic cardiomyopathy and was status-post remote myocardial infarction. His left ventricular ejection fraction was 30%. He had a single-chamber, primary prevention ICD from which he had not received any therapies. In addition to coronary artery disease, he had insulin-dependent Type I diabetes, hyperlipidemia, prior systemic hypertension, and a recent diagnosis of Parkinson’s disease. He and his wife report that he has been suffering from orthostatic intolerance for years. It was so bad that he often did not get out of bed until the afternoon, and even then, had extreme weakness and dizziness when standing.
Midodrine 5 mg TID and fludrocortisone, 0.2 mg in the morning and 0.1 mg in the evening, failed to improve his symptoms, but did worsen his supine hypertension and fluid retention. His other medications included: gabapentin 300 mg BID, furosemide 60 mg qD, spironolactone 25 mg qD, NovoLog insulin, metoprolol succinate 25 mg qD, memantine 10 mg qD, rosuvastatin 40 mg qD, carbidopa/levodopa 25/100 mg BID, and aspirin 81 mg daily.
On examination, he was pale and lethargic. He ambulated with a walker, but nearly passed out on the way to the exam room. His sitting blood pressure was 68/42 with a pulse of 92. Cardiopulmonary examination was unremarkable; there was no peripheral edema.
Droxidopa was started at 100 mg TID and titrated to the maximum dose of 600 mg TID over two weeks. Furosemide and metoprolol dosages were reduced. His symptoms (i.e., syncope, fatigue, and dizziness) resolved. His wife reported increased alertness and less napping. Systolic blood pressure was consistently in the low 100s while standing.
Eighteen months later, he presented with a non-ST segment elevation myocardial infarction and acute on chronic systolic heart failure. He elected conservative management. An echocardiogram revealed a stable left ventricular ejection fraction of 32% without other abnormalities. He was treated with IV diuretics and clopidogrel, and the fludrocortisone dose was reduced to 0.1 mg daily.
In follow-up after his myocardial infarction, the patient reported increased dizziness and near syncope, and had systolic blood pressures in the 70s-80s. His decompensated heart failure resolved, and he appeared euvolemic on examination. A workup for adrenal insufficiency was unremarkable. Midodrine was increased to 10 mg three times a day, and daily furosemide was stopped. He remains on maximal dose droxidopa.
This patient suffers from n-OH likely related to peripheral autonomic dysfunction from longstanding diabetes and/or Parkinson’s disease. Patients with n-OH tend to be older, more often men, and may have comorbidities including cardiovascular disease (Figure 1).
Droxidopa has been proven to be a safe and effective drug for reducing symptoms in patients with n-OH.1 Thus far, there have not been adverse cardiac outcomes reported with the use of droxidopa, but as the drug, a norepinephrine prodrug, is converted to norepinephrine, there can be concerns. In our patient, the non-ST segment elevation myocardial infarction and congestive heart failure raise concern of the continued use of droxidopa, but as the heart rate and blood pressure were in the normal range, we suspected that heart failure and myocardial infarction were due to progression of the underlying cardiovascular disease rather than an adverse drug effect. Therefore, medical therapy was continued.
Midodrine is a peripheral alpha-1 adrenergic agonist, which results in peripheral vasoconstriction. This increase in afterload could potentially result in further reduction of systolic function. One small study evaluated the concomitant use of midodrine with ACE inhibitors and beta-blockers in patients with systolic heart failure and hypotension.2 In this small group of patients, the use of midodrine allowed for increased doses of beta-blockers, and ACE inhibitors improved hemodynamics. The average systolic blood pressure at baseline was 79 mmHg, improving to 99 mmHg after 6 months of treatment. There were no adverse effects reported and no decline in renal function.
As patients with n-OH can develop progressive autonomic dysfunction, in addition to their other comorbidities, it is imperative to frequently assess their clinical response and hemodynamics. While theoretical risks exist using droxidopa in patients with cardiovascular disease, the data available to date do not support major concern unless there are marked changes in heart rate or blood pressure.3 It is also important to recognize the level of debility that may occur in patients with n-OH and the need for effective therapy for this difficult to manage problem in light of other clinical conditions.
Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Dr. Feigofsky reports personal fees as a physician advisory board member for Lundbeck, Inc. Dr. Olshansky reports personal fees as a consultant/speaker for Lundbeck, Inc., as a consultant for On-X Life Technologies/Cryolife, as U.S. Co-Chair of the GLORIA AF Registry at Boehringer Ingelheim, and as a member of the Data and Safety Monitoring Board (DSMB) at Amarin Pharma Inc.
- Elgebaly A, Abdelazeim B, Mattar O, Gadelkarim M, Salah R, Negida A. Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension. Clin Auton Res. 2016;26:
- Zakir RM, Folefack A, Saric M, Berkowitz RL. The use of midodrine in patients with advanced heart failure. Congest Heart Fail. 2009;15:108-111.
- White WB, Hauser RA, Rowse GJ, Ziemann A, Hewitt LA. Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension. Am J Cardiol. 2017;119:1111-1115.