Can They Finally Rest in Peace? Clonidine and Hydralazine for Hypertension and More

Let me be upfront: I avoid both clonidine and hydralazine when treating hypertension. In the case of hydralazine, I qualify that decision by explicitly stating that it has been an evidence-based therapy for the management of moderate to severe systolic heart failure in African-Americans. 

That said, I continue to routinely set aside time to review published literature on clonidine and hydralazine to determine if I should change my practice and dogma. This is what a recent search uncovered.

Literature

Nearly all the papers published in the last year or so with clonidine as the search engine subject failed to mention antihypertensive use or efficacy. Clonidine is discussed more for central nervous system/sympathetic benefits during drug withdrawal syndromes or in the augmentation of anesthesia. 

While hydralazine continues to populate heart failure literature, it no longer seems to have a compelling antihypertensive niche. The last Cochrane Database Review of hydralazine as an antihypertensive agent in 2011 noted that there were no prospective, randomized trials that ever measured its efficacy. 

At the 2013 American Society of Hypertension annual meeting, both agents were dismissed. (Note: The Eighth Joint National Committee reticence in this regard is another topic altogether.) When asked if the speaker would ever prescribe clonidine for hypertension, he joked, “only to people that I don’t like.” When hydralazine is prescribed for hospitalized patients with hypertensive urgencies, another speaker noted that the drug was a “nightmare.” It has an unpredictable half-life and can take a patient from hypertension to hypotension without warning. It is a vasodilator and can increase cardiac output thereby leading to cardiac ischemia. Furthermore, in pregnancy, it lowers Apgar scores in babies while at the same time increasing abruption and maternal hypotension in mothers.

New Research

During my recent search, I came across an attempt to resuscitate the central adrenoceptor agonist, clonidine.¹ Since a significant number of people still experience untoward events as a consequence of noncardiac surgery, often times a result of myocardial infarctions, the sympathetic nervous system has become a leading suspect. Beta-blockers have already failed rescue in the same clinical situation so maybe clonidine can decrease heightened sympathetic activity in the perioperative period—and thus be cardioprotective.

A total of 10,010 patients undergoing noncardiac surgery were enrolled in a study.¹ Participants were given 0.2 mg/d of clonidine just prior to surgery and continued for 72 hours versus a placebo control group. The primary outcome measures were death and myocardial infarction during the 30 days following surgery. There were 367 and 339 events reported in the clonidine and placebo groups, respectively; therefore, no benefit was ascribed to clonidine. Further, significantly more patients in the clonidine group had clinically important hypotension. 

Although I had my concerns regarding the effectiveness of clonidine for chronic ambulatory hypertension management, I was left thinking that now it seems to have also failed in an area (ie, decreasing sympathetic activity thereby protecting against acute ischemia) wherein one would conjecture it should have been “more at home.” 

Where are we with these 2 agents? I do still have an occasional patient on clonidine for hypertension. That individual is usually someone older who has been on the medication for years and benefits at bedtime from the sleepiness induced by the drug. People who are hypertensive and need to be alert during the day do not like that particular side effect. Hydralazine is a great drug in African American persons with systolic heart disease. But, its parenteral use for hypertensive hospital urgencies, oral treatment for hypertension, or in cases of pregnancy bothers me. Simply put, where is the data?  ■

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the editorial board of Consultant. Dr Rutecki reports that he has no relevant financial relationships to disclose.

Reference:

1.  Devereaux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing non-cardiac surgery. N Engl J Med. 2014;
370(16):1504-1513.