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Spontaneous Circulation: Rebellions of the Heart The End of Amiodarone

Bruen, Charles MD

doi: 10.1097/01.EEM.0000508283.60267.25
Spontaneous Circulation

Dr. Bruenis a cardiac intensivist and emergency physician at Regions Hospital in St. Paul, MN, and an assistant professor at the University of Minnesota with a special interest in emergency cardiovascular care. He completed a combined emergency medicine/internal medicine residency and fellowships in critical care and emergency cardiology at Hennepin County Medical Center. Visit his website, http://resusreview.com, follow him on Twitter @resusreview, and read his past columns athttp://bit.ly/EMN-SponCirc.

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If the devil himself concocted an antiarrhythmic drug, it would be amiodarone.

He would make it suppress arrhythmias very well (so people would want to use it). It would not have the typical downsides of earlier medications that stopped people from taking them but would have a host of atypical, subtle, and ultimately dangerous side effects with delayed presentations that doctors were likely to overlook. It would also be stored in the body, causing a protracted aftermath.

The khella plant of North Africa was the 17th century version of “take two aspirin and call me in the morning.” It was used for renal colic, kidney stones, bronchial asthma, psoriasis, and vitiligo. A laboratory technician working for physiologist Gleb von Anrep in 1946 took it for stomach indigestion, and noticed it cured him of his angina. This got the attention of Belgium pharmaceutical giant Labaz, which identified the active ingredient khellin and the stable oral derivative amiodarone. It acted by blocking potassium channels, prolonging the action potential and lengthening the depolarization of the atria and ventricles. Its applicability as a new class (III) antiarrhythmic for supraventricular and ventricular arrhythmias was obvious.

Labaz released amiodarone in 1962, though not in the United States because the FDA did not have safety data to approve its use. Doctors were impressed by its early effectiveness in diminishing arrhythmias. With marketing slogans such as “Always works, and no side effects,” use of amiodarone spread throughout the United States even without FDA approval. Tens of thousands of patients were on amiodarone by the 1980s, and doctors and patients went to great lengths to get the medicine from Canada and Europe.

Rigorous studies soon uncovered adverse effects that were“missed” during its early development and rollout. Amiodarone causes sun sensitivity, corneal deposits causing halo vision, thyroid dysfunction, liver damage, and pulmonary toxicity. Its action is also more complicated, having sodium-channel blocking (Class I), beta-blocker (Class II), and calcium channel blocker (Class IV) effects. It dilates blood vessels, and acts to block the effect of thyroid hormone. Clinicians also underestimated the challenges caused by variable absorption, and the need to saturate all the tissues before it becomes effective extended its half-life.

The company had many patients on the hook despite these problems and used its leverage to force the FDA to approve the medication by threatening to cut off the U.S. supply. It had become too big to fail. Two trials of amiodarone in cardiac arrest, one vs. placebo and another against lidocaine (ALIVE trial), showed improved survival to hospital admission but no difference in survival at hospital discharge, and the drug made its way into the guidelines. It also became the default treatment for hemodynamically stable ventricular arrhythmia on its popularity and a paucity of evidence.

But is it clearly better than other antiarrhythmics?

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End of the Hype

When the wife of the Viceroy of Peru fell ill with stomach ailments and fever, he was drawn to a flowering native plant to cure her. He named the plant for her — cinchona. Chewing it stopped the shivering from the bitter cold in the Peruvian mountains, and it made sense to the Jesuit apothecaries in mosquito-surrounded Rome to use it to stop malaria rigors. It proved effective.

Jean-Baptiste de Sénac, the personal physician to Louis XV, noted that the bitter crushed cinchona bark mixed with sweetened tonic water caused “long and rebellious palpitations” to cede to it. Its antiarrhythmic properties were not identified until Karel Wenckebach, MD, saw a man who reported that taking a large dose would stop his arrhythmia attacks in 25 minutes rather than in days.

Two active compounds were isolated from the bark. Quinidine the antiarrhythmic and its mirror image quinine proved such an effective malaria treatment that the Dutch moved to monopolize the production of the plant by smuggling seeds out of Peru to Java (an island of Indonesia). Japan conquered Java during World War II, cutting off the supply. The United States moved some production to Costa Rica, but supplies were inadequate, spurring research for a new malaria treatment and another antiarrhythmic.

The anesthetic procaine proved effective at raising the myocardial threshold for electrical stimulation when it was spread on the skin above the heart. A cardiac surgeon experimenting with grafting pectorals muscle onto the heart to reduce angina (not a successful endeavor) used it to reduce arrhythmias following surgery. It did not prove useful because it was rapidly degraded by enzymes and caused tremors and respiratory depression. Placing an amide group next to ester prolonged its duration and created procainamide, supplanting quinidine.

The hype following the introduction of amiodarone pushed procainamide and other antiarrhythmics aside despite compelling evidence. Two recent trials threaten to finally topple its dominance. Amiodarone and the later-developed lidocaine (the first amino amide-type anesthetic) are the current guideline recommendations for shock-resistant ventricular fibrillation or pulseless ventricular tachycardic arrest. A recent trial comparing these agents against placebo showed that neither improved survival or neurologic function. (New Engl J Med 2016;374[18]:1711.)

Then the PROCAMIO trial tested amiodarone directly against procainamide in hemodynamically stable ventricular tachycardia. (Eur Heart J 2016 Jun 28; pii: ehw230; Epub ahead of print.) This was a prospective trial of 62 randomized patients who received procainamide (10 mg/kg over 20 minutes) or amiodarone (5 mg/kg over 20 minutes). The termination of tachycardia was much more successful with procainamide (67%) compared with amiodarone (38%). Only nine percent of procainamide-treated patients suffered a major cardiac adverse event as compared with 41 percent who received amiodarone, with the most common event being hypotension requiring electrical cardioversion.

These results hold true even for those with structural heart disease. The treatment of both groups required about 20 minutes before resolution of the ventricular tachycardia occurred, demonstrating that these were stable patients. Sedation and immediate electrical cardioversion is more appropriate for unstable patients.

Truth eventually overcomes the devil's plans, but it takes longer to fight against the marketing of our pharmaceutical companies.

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