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An Antidote To Factor Xa Inhibitors – Andexanet Alfa

Christian Perzanowski, MD

“Success consists of going from failure to failure without loss of enthusiasm.” Winston Churchill

Treatment options for systemic anticoagulation (AC) have grown substantially during the last several years. One of the most common indications for AC is to reduce the risk of embolic stroke secondary to atrial fibrillation (AF). Although there are multiple reasons to anticoagulate, my column today references stroke prevention for AF. The major concern to both patients and clinicians is the risk of significant bleeding or hemorrhage. The ideal anticoagulant would effectively prevent stroke, hopefully at a low risk for bleeding and interact minimally with other agents. If required, the “perfect” agent could be easily reversed. That last caveat to perfection has proven elusive until recently.

In clinical practice, many patients will refuse AC based upon perceptions of death by uncontrollable bleeding. Notwithstanding the sensational television commercials paid for by legal firms waging lawsuits against pharmaceutical manufacturers, the thought of “bleeding out” understandably makes a reluctant patient even more apprehensive to initiate or continue AC. Nowadays, it is quite common to encounter patients who have studied the different drug options. In my experience, a common motive for rejection of AC is the absence of an antidote. Perhaps this can be better expressed in the words of one my patients… “I don’t want to bleed internally and die because they can’t stop the bleeding …”

Historically, warfarin (e.g. Coumadin) a Vitamin-K antagonist was the most commonly used agent. Widely available, the principal agent used to reverse warfarin effect is Vitamin-K itself. In 2010, the Federal Drug Administration approved Dabigatran, a direct thrombin inhibitor, as an option for stroke prevention for non-valvular AF. This agent became a popular alternative to warfarin. Strengthening its popularity, the ability to reverse and nullify its clinical effects became a reality. In the past few years, idarucizumab was developed as an antidote to dabigatran.

Further research lead to the development of Factor Xa inhibitors: rivaroxaban (Xarelto), Apibixan (Eliquis), and Edoxaban (Savaysa). Factor Xa is an important step in the coagulation cascade. In fact, it is at the convergence of both intrinsic and extrinsic pathways prior to the production of thrombin1,2. Although these AC drugs share desirable clinical characteristics such as convenient dosing, the lack of any significant drug-drug interactions, this class of drugs was saddled with the potential shortcoming of being available clinically without a means to reliably counter the effects.

Andexanet Alfa has been undergoing clinical studies evaluating its role a reversal agent to the class of Factor Xa class inhibitors. Simplistically, this antidote functions as a decoy receptor3. Given the favorable data, the FDA very recently approved its use4. The presence of such an antidote has potentially broad implications: giving patients and practitioners a certain level of comfort to prescribe a novel anticoagulant knowing there exists treatment means to stop hemorrhage related to AC therapy. How much Andexanet’s presence will be able to convince an apprehensive patient to start AC remains to be seen.

References

  1. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5 Suppl 1:60-4
  2. Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov. 2011;10:61-75
  3. Connolly SJ1, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G1, Conley PB1, Verhamme P1, Schmidt J, Middeldorp S1, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J1, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.N Engl J Med. 2016;375:1131-41 4.https://www.thepharmaletter.com/article/fda-approves-andexxa-first-antidote-for-the-reversal-o f-factor-xa-inhibitors

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure. He reports no conflicts of interests.

Crabtree, NC

Crabtree, NC (1/18 CP)
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Options To Rat Poison – Other Mousetraps?

Christian Perzanowski, MD

“The policy of being too cautious is the greatest risk of all.” Jawaharlal Nehru

Of all the potential complications associated with atrial fibrillation (AF), stroke is the most feared. Attempting to predict a stroke has proven to be a daunting task. The mechanism by which AF leads to a stroke is undoubtedly due to the formation of a thrombus within the left atrium, in particular the left atrial appendage (LAA). The latter structure serves to enhance the atrial contribution to ventricular diastolic filling. When AF sets in, effective atrial contractions are greatly minimized, and blood can become stagnant within the LAA and form a thrombus. Should parts of the thrombus embolize, a stroke can result. Such cerebrovascular events can be devastating.

My thoughts today will focus not on the symptoms caused by AF, and their treatments but to summarize medical options in stroke prevention. The mainstay of stroke prevention with this arrhythmia is the use of an anticoagulant. For many years, warfarin was the only anticoagulant available. Although this agent can be a forgiving drug if a dose is missed, it can also be the most fickle. Not uncommonly, patients often perceive this agent to be “rat poison.” Historically, this was its previous use. The drug’s notoriety can be appreciated by the numerous interactions with certain foods (particularly ingredients which have a high content of vitamin K which inhibit its actions), or with other medications such as antibiotics. Additionally, excessive anticoagulation may result with ceratin cardiac medications such as the widely used antiarrhythmic amiodarone. Unfortunately, when the anticoagulant level, colloquially known as the INR, increases above the desired clinical range, bleeding may occur1. Frequent, at least monthly office monitoring is recommended. As such, the quality of life may be impacted for many patients.

In my practice, I have encountered numerous patients that were very determined to avoid warfarin despite facing a risk of stroke. The anticoagulation landscape changed with the introduction of the “novel oral anticoagulants” (NOACs) which exert their effects at different levels of the coagulation cascade. The development of the direct thrombin inhibitor dabigatran (marketed as Pradaxa) was a welcome option to warfarin. However, true to the nature of the class of drugs with which it belongs to, bleeding complications still occur. Since its approval approximately seven years ago, dabigatran is no longer the only NOAC2. The last several years saw the emergence of the factor Xa inhibitors rivaroxaban (Xarelto), apibixan (Eliquis) and most recently edoxoban (Savaysa)3-5.

With that being said, the clinical studies used to obtain FDA approval for use in the United States concluded that collectively these agents have relatively low rates of bleeding. However, the post-marketing experience may be very different than what is observed in the safe confines of a clinical trial. It is vital that there exists medically equivalent options to prevent an AF-related stroke. In general, The NOACs have the clinical advantage of not commonly interacting with other medications, and typically do not require any change in dietary habits or such constraints. Frequent monitoring is not universally required, and other than adjusting for renal function, dosing is often straightforward. With the exception of dabigatran, the other NOACs do not have any readily available reversal agent to counter an acute bleeding event or hemorrhage. This is potentially a serious limitation, and a clinically relevant factor which must be discussed with patients when counseling them on anticoagulation. The ideal “drug” would be completely effective at preventing an atrial thrombus from occurring, and yet lead to no bleeding6. Neither of those objectives are tangible options yet. At the end of the day, both the clinician and patient need to decide which medicine is most likely to be protective and be an acceptable risk.
 
References

  1. Seet RC, Rabinstein AA, Christianson TJ, Petty GW, Brown RD. Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study. J Stroke Cerebrovasc Dis. 2013;22:561-9
  2. Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264-73
  3. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91
  4. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92
  5. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104
  6. Deshpande CG1, Kogut S, Laforge R, Willey C. Impact of medication adherence on risk of ischemic stroke, major bleeding, and deep vein thrombosis in atrial fibrillation patients using novel oral anticoagulants. Curr Med Res Opin. 2018 Jan 16:1-17. doi: 10.1080/03007995.2018.1428543. [Epub ahead of print]

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure.

Apollo beach fl

Apollo Beach, FL 01/18 CP.
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Killing Cardiac Cells

Anberitha Matthews, PhD

chambers of the heart imageI was in the mall one day and the saleswoman started talking about her health issues. For starters, I am not sure why she entrusted me with this information, but okay. So why is that conversation interesting enough to write about? Well, the lady was 20 years of age and she had undergone several cardiovascular challenges, including a cardiac ablation. I had heard of other people having this procedure done but I had not thought much about it (I looked it up but not in much detail), until I met this young lady. So, I started wondering:

  1. What is the underlying pathology that causes one to need to have the procedure?
  2. What is the average age of patients undergoing the procedure?
  3. What is cardiac ablation?
  4. How commonly is this procedure done?

Cardiac ablation is the use of catheters to target and kill off specific cells within the heart, generally in the atrium. The adult mammalian myocardium has a negligible ability to regenerate once damage has occurred. Thus, rather than undergoing cardiomyogenesis (the formation of myocardium/heart muscles), fibrous tissue is instead formed. This phenomenon raised more questions for me, so I did literature searches…then more literature searches…then read more literature. The more I read, the more I felt I needed to read to understand why cardiologist would choose this procedure. Following a myocardial infarction (heart attack) a significant number of cardiomyocytes die leading to an enhanced inflammatory reaction. This cardiac event results in dead myocardial tissue being replaced with interstitial and perivascular collagen deposition. The presence of fibrosis can lead to pressure overload, increased blood pressure or potentially aortic stenosis. However, a patient that has suffered from myocardial infarction would not be a good candidate for cardiac ablation. So, who would be a good fit to undergo such a procedure? Usually it is a patient exhibiting cardiac arrhythmias, including atrial fibrillation (AF or AFib), supraventricular tachycardia (SVT), and Wolff-Parkinson-White Syndrome (WPW). Because this subject is enormous, I will only focus on AF due to the fact that it is the most common cause of arrhythmias treated with catheter ablation.

Pathophysiology of Atrial Fibrillation
AF is characterized by an abnormal heartbeat (quivering or irregular heartbeat) that causes the heart to ineffectively move blood into the ventricles. The onset of AF could be due to family history (genetics), but controllable risk factors are hypertension and valvular heart disease. The cardiovascular consequence of AF includes: 

  1. Coronary artery disease
  2. Mitral stenosis
  3. Mitral regurgitation
  4. Left atrial enlargement
  5. Hypertrophic cardiomyopathy
  6. Congenital Heart Disease
  7. Cerebrovascular Accident

AF is considered the most common arrhythmic disease and it affects about 4% of the population. The prevalence of AF increase with age (<0.2% under 50 year of age (yoa), 4% are 60-70 yoa, and ~15% >80 yoa), with patients suffering from it has an average age between 75-85 yoa. In the U.S., there was a significant number of deaths (>200,000) resulting from AF in 2015, which is reason enough to pursue aggressive therapies to control this heart rhythm disorder.

Treatment
The European Society of Cardiology (ESC) released guidelines that summarized the current evidence that is available to physicians in selecting the best strategy for managing diseases, taking into consideration the risk-benefit ratio of diagnosis and therapeutic means. The recommended guidelines has shifted to focus on the identification of ‘truly low-risk’ patients (<65 with AF alone that does not need antithrombotic therapy) rather than ‘high-risk’ patients. Based on the earlier guidelines for treating AF, a patient of age >20 would not be considered for ablation therapy, so I wondered…what are the alternative treatments? I found they can either be drugs, such as: 1) Novel oral anticoagulants (blood thinners) fall into two categories (Oral direct factor Xa inhibitors or Oral direct thrombin) and 2) Left atrial ablation—introduced by American College of Cardiology Foundation, American Heart Association, and the Heart Rhythm Society.

To read more about these treatment, please be directed to European Heart Journal for the ESC Guidelines. Here I will focus on cardiac ablation.

Cardiac Ablation
Cardiac ablationThe normal mammalian heart is composed of tight layers of myocytes that are separated by small clefts creating a matrix network. The cardiac matrix network is divided into three constituents. The matrix network is collagen-based and serves as a scaffold for various components of the cell as well as transmission of contractive forces that keep the cells in correct timing with neighboring cells. When the heart undergoes damage, the resulting fibrosis disrupts the coordination of this myocardial excitation-contraction leading to hypertension. Subsequently, loss of collagen impair transduction, which causes the uncoordinated contraction of the cardiac muscle bundles (the quivering or fluttering that is felt with AF) or generation of re-entry circuits (irregular heartbeat).

The ablation process will depend on the patient medical condition, past cardiac history, and the ablation technique chosen. There are several types of catheter ablation

a) Radiofrequency ablation-use radiofrequency generators to deliver a current, in a point by point fashion around the pulmonary vein, creating a circular scar around each vein.

b) Cryoablation—uses a single catheter that travels through the femoral vein in the groin to the left atrium. The balloon end (halo) of the catheter has a refrigerant that freezes the tissue it comes in contact with creating a scar.

c) Surgical ablation—generally used when open heart surgery is being conducted.
          i. Mini Maze-use 3-5 incisions on the front and side of the chest to insert the catheter to freeze/heat cardiomyocytes
          ii. Convergent—uses both surgical and catheter based techniques.

Catheter ablation is generally an outpatient procedure, but it should not be taken lightly. As with most consumers, cost comes to mind. How can cardiologist/electrophysiologist conduct such a procedure in so short of a time and charge so much? The answer is simple. The technology used in ablation is extensive; mapping equipment, cardioverter/defibrillator and catheter, recording apparatus, stimulators, and junction boxes. I am overwhelmed just thinking about it all!

Wrap it up…
Cardiovascular disease is a consequence of a lot of factors. Understanding the various procedures that the cardiologists are explaining can be daunting. Even with the expansive literature that is available it is difficult to determine how a procedure will work for each patient, especially with regard to the side effects. For example, in a 2010 study for rhythmic control (294 patients), there was no significant difference between patients that received the catheter ablation compared to those taking antiarrhythmic drugs as a first line of intervention. Catheter ablation is said to be more effective than antiarrhythmic drugs, but the recurrence of AF is significant during long term follow up. Early recurrence of AF is the best predictor of whether one will have a recurrence later. In an observational study conducted at high volume clinics, there was a 39% hospitalization rate post catheter ablation. However, catheter ablation has been deemed reasonable for first line of therapy for AF when patients have paroxysmal AF and low risk for procedures with complications; which is interesting since the majority of studies are inherently biased toward the experienced centers. It is reasonable to speculate that people, such as the saleswoman in the mall, who visit small low volume clinics, contribute to increased rates of hospitalization rates.

I am, furthermore interested in knowing whether there is a decrease in cardiac output post catheter ablation. If this procedure is killing off specific cells in the heart and leaving scar tissue, what are the downstream effects of this cardiac cell death? Especially in patients that have repeated catheter ablations. If there is a decrease in cardiac output, and the kidney filters 20% of the cardiac output daily, then what effect does cardiac ablation have on the renal system? Could this procedure enhance renal failure? I have had conversations with other people who have had cardiac ablations that later suffered from renal failure necessitating dialysis. Since all conditions are patient specific, there is no evidence that catheter ablation is connected to renal failure to my knowledge, but I wonder if anyone else had that observation.

To sum up the conversation I had with the young lady in the mall. She started her cardiac journey at an early age. She has gone through oral anticoagulant drugs, catheter ablation, and open-heart surgery. By the age of 20, that is a lot for one to have gone through. She was in such distress about having to undergo yet another catheter ablation that she was seeking answers to help her understand what she was going through and how to make informed decisions about her care. How can patients be better educated on what is going on with their bodies when visiting medical professionals? People are told to take responsibility for their care, but what if they do not understand enough to know what to ask?

Anberitha Matthews, PhD is a Postdoctoral Fellow at the University of Tennessee Health Science Center in Memphis TN. She is living a dream by researching vascular injury as it pertains to oxidative stress, volunteers with the Mississippi State University Alumni Association, serves as Chapter President and does consulting work with regard to scientific editing.
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The Lack Of New Drugs For Rhythm Control Of Atrial Fibrillation: A Stagnant Pipeline

Christian Perzanowski, MD

“It does not matter how slowly you go as long as you do not stop”
– Confucius
 
Atrial fibrillation (AF) is the most common arrhythmia in the world1. This potentially malignant condition can dramatically raise the risk for stroke. Many patients are symptomatic, and those with congestive heart failure may suffer worse outcomes when afflicted with AF2. Undoubtedly with these patients, avoidance and prevention of AF is desirable. Anticoagulants are a mainstay for stroke prevention, and there are several to choose from. Today my article addresses the rhythm control drugs, or lack of. Here lies the problem: the (few) available oral agents are often not well tolerated, and antiarrhythmic drugs (AAD) are notorious for their potential for adverse effects.
 
Patients nowadays are internet savvy and very commonly will “research” their prescription medications. I cannot even begin to estimate how many patients with highly symptomatic AF I have met who were reluctant or downright refused to take a prescribed antiarrhythmic after reading the potential side effect profile. Amiodarone is one such drug. Largely accepted as effective, many practitioners are wary of long-term use and the development of pulmonary toxicity or hepatic insufficiency although rare. Other agents such as flecainide and propafenone may cause fatigue and dizziness due to bradycardia and ancillary effects. These agents are contraindicated in patient’s structural cardiac abnormalities given concerns for heart failure and risk for ventricular tachycardia.
 
Sotalol, a “potassium” (Ikr) blocker is also a very old drug which needs close monitoring to identify electrocardiographic QT prolongation and the proarrhythmic risk of torsades de pointes, a potentially fatal consequence of inadvertently prolonging ventricular repolarization (more on this below). Dofetilide is another Ikr blocker which functions in similar fashion. The protocol for drug initiation requires mandatory hospitalization for the very same reason I just described.
 
Other agents such as disopyramide and quinidine are rarely used. Dronedarone, a form of “amiodarone light” proved to be largely ineffective and cannot be used in heart failure. Ranolazine, a delayed sodium-blocker is being studied for AF control, but its use outside the treatment for angina is off-label. Unfortunately as a whole, the current available antiarrhythmic arsenal cause electrophysiologic effects on ventricular myocardium. To negate the risks associated with the latter, the ideal AAD would have effects solely on atrial tissue.
 
Catheter ablation for AF has emerged has a viable treatment option for AF. The treatment paradigms generally focus on isolation of the pulmonary veins, and occasionally AF triggers outside these structures. With that being said, AF has proven to be a very formidable problem to treat, and not uncommonly repeat procedures or continued antiarrhythmic therapy is required to achieve a favorable result3. Hence the use of an AAD is done with the purpose of lowering AF burden and frequency.
 
Clinicians who care for AF patients were encouraged when the initial studies of vernakalant were published4. The novel drug prolonged atrial refractoriness by blocking multiple channels, including Ikur. The Ikur channel is found exclusively in the atria which made the availability of such a drug in oral form highly attractive4,5 Finally, an atrial-selective AAD with purportedly a very low risk of torsades de pointes might be available. Unfortunately, during a follow-up trial, ACT V, the trial was stopped due to concerns of drug safety. The FDA required revisions to the study protocol. The sponsor could not agree to those terms, and in March 2012 Merck abandoned development of oral vernakalant. It must be noted that the intravenous form of the drug is available in the European Union6.
 
Vanoxerine, a potent dopamine reuptake inhibitor was being studied in the treatment of cocaine addiction. It also was evaluated for and proved to be unsuccessful in treating Parkinsonism and depression7. However, this agent was observed to prolong ventricular repolarization as evidenced by prolongation of the QT on the surface EKG. This lead to interest as a possible antiarrhythmic. The COR-ART trial published in 2015 suggested a high rate of conversion to sinus rhythm. The medicine was in oral form and generally well tolerated. There were no episodes of torsades de pointes8. However, RESTORE SR, a small randomized trial found the drug to pose a risk for ventricular proarrhythmia in patients with structural heart disease [9]. Out of safety concerns, recruitment was terminated, and the manufacturer, Laguna Pharmaceuticals closed operations10,11.
 
While there continue to be marked improvements in mapping and ablation technologies for AF, clinicians are still left with the same limited medical arsenal. Perhaps greater collaboration and determination among the pharmaceutical industry may lead to finally new medical options for AF.
 
References:

  1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-104
  2. Leong-Sit P, Tang AS. Atrial fibrillation and heart failure: a bad combination. Current Opinion in Cardiology. 2015;30:161–167
  3. Duytschaever M1,2, Demolder A1, Philips T3, Sarkozy A3, El Haddad M1,2, Taghji P1, Knecht S1, Tavernier R1, Vandekerckhove Y1, De Potter T4.PulmOnary vein isolation With vs. without continued antiarrhythmic Drug trEatment in subjects with Recurrent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial. Eur Heart J. 2017 Dec 2. doi: 10.1093/eurheartj/ehx666. [Epub ahead of print]
  4. Torp-Pedersen C, Raev DH, Dickinson G, Butterfield NN, Mangal B, Beatch GN .A randomized, placebo-controlled study of vernakalant (oral) for the prevention of atrial fibrillation recurrence after cardioversion. Circ Arrhythm Electrophysiol. 2011;4:637-43
  5. Camm AJ, Capucci A, Hohnloser SH, Torp-Pedersen C, Van Gelder IC, Mangal B, Beatch GN, AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol. 2011;57:313-21
  6. Camm AJ. The Vernakalant Story: How Did It Come to Approval in Europe and What is the Delay in the U.S.A?Curr Cardiol Rev. 2014; 10:309–314
  7. Preti A. New developments in the pharmacotherapy of cocaine abuse. Addict Biol. 2007;12:133-51
  8. Dittrich HC, Feld GK, Bahnson TD, Camm AJ, Golitsyn S, Katz A, Koontz JI, Kowey PR, Waldo AL, Brown AM. COR-ART: A multicenter, randomized, double-blind, placebo-controlled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flutter to normal sinus rhythm.Heart Rhythm. 2015;12:1105-12
  9. Piccini JP, Pritchett EL, Davison BA, Cotter G, Wiener LE, Koch G, Feld G, Waldo A, van Gelder IC, Camm AJ, Kowey PR, Iwashita J, Dittrich HC. Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR. Heart Rhythm. 2016;13:1777-83
  10. https://www.xconomy.com/san-diego/2015/12/06/heart-drug-safety-concerns-prompt-shutdown-at-laguna-pharmaceuticals/
  11. https://clinicaltrials.gov/ct2/show/NCT02454283

Christian Perzanowski Headshot

Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure.