Christian Perzanowski, MD – The Early Career Voice

Sniffing to Stop SVT

August 9, 2018 Christian Perzanowski, MD

“The aim of medicine is to prevent disease and prolong life, the ideal of medicine is to eliminate the need of a physician.”
William J. Mayo

Paroxysmal supraventricular tachycardia (pSVT) is a common arrhythmic condition known to cause sudden breathlessness, weakness and dizziness due to very rapid heart rates. This syndrome is common in younger patients but can appear at any age. The onset is random, and often without warning. As one can surmise, the symptoms can be debilitating and frightening. Annual emergency room visits for pSVT eclipse 50,000 per year according to Murman and cols [1]. So, what exactly is a pSVT? These arrhythmias are “short circuit” mechanisms which depend primarily on conduction through the AV node and lead to the heart to be trapped in a fast-unrelenting loop. Heart rates of greater than 150-200 beats per minute are common, and the duration can be prolonged (e.g. 30 minutes or longer). Treatment modalities aim to slow conduction through the AV node and either terminate, and prevent the pSVT. The AV Node is a structure at the base of the heart which functions as an electrical delay station of sorts, permitting ventricular diastole. One can consider this the “brakes” of the heart. Although there exist a number of arrhythmias that fall into this broad category, the most common entities are atrioventricular nodal reentry tachycardia (AVNRT) and orthodromic reciprocating tachycardia (ORT). A full description of the anatomy and physiology of these conditions is beyond the scope of this discussion.

Although patients with pSVT have at their disposal prescription agents referred to as “AV Nodal blockers,” these agents serve best as preventive measures. For acute termination, intravenous forms of these drugs can be administered, however this is almost always is in an emergency room or hospital setting. Another of these parenteral agents is adenosine. This is a highly effective drug with a very short half-life but requires hemodynamic monitoring. Given the intensity of the symptoms, affected patients will frequently recur to the emergency room. Many times, these patients are hospitalized. Although some patients are able to terminate an episode by evoking vagal maneuvers (e.g. bearing down etc), most will need medical attention. Ultimately, many of these patients are candidates for catheter ablation, which can be curative. Nevertheless, avoiding a hospitalization is highly desirable.

As I mentioned in my previous blogs, there has been minimal progress in the development of antiarrhythmics. There is one exception, which is a novel agent presented at the Heart Rhythm Society conference of 2017 [2]. Etripamil (Milestone Pharmaceuticals, Montreal St.-Laurent, Quebec, Canada), is the newest form of pSVT treatment. This unique calcium channel blocker has a quick onset and is delivered intranasally. This innovative delivery is attractive as it could lead to a quick resolution of the pSVT episode and avoid a trip to the emergency room. Stambler et al recently published the results of the NODE-1 trial (etripamil in escalating doses vs placebo). The median time to conversion was brisk at less than 3 minutes [3]. Overall, the conversion rates were excellent with the higher doses (See Figure).

Central Illustration - Conversion Rate of Induced paroxysmal supraventricular tachycardia within 15 min of study drug administration

The medication which was tested during a diagnostic electrophysiology study proved to be safe as well; abnormal electrocardiographic changes and hypotension were rarely observed.

If follow-up data continues to be favorable, then etripamil may be of help to pSVT patients in avoiding hospitalization. This agent may have a role for patients who are awaiting ablation, or those whose cases are deemed too high risk for sedation or anesthesia. The use of a simple intranasal route would suggest that nearly everyone would be capable of self-administration.

References

Murman DH, McDonald AJ, Pelletier AJ, Camargo CA Jr. U.S. emergency department visits for supraventricular tachycardia, 1993-2003.Acad Emerg Med. 2007;14:578-81
https://www.heartrhythmjournal.com/article/S1547-5271(17)30587-8/pdf
Stambler BS, Dorian P, Sager PT, et al. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm.J Am Coll Cardiol. 2018;72:489-497

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.

CP (Tampa, FL 7/18)

tampa florida

WATCHMAN: An Alternative to Warfarin for the High Risk Patient

July 11, 2018 Christian Perzanowski, MD

“Wisdom consists of the anticipation of consequences”
Norman Cousins

I recently saw Mr. John Doe for atrial fibrillation (AF). Well into his eighties, he enjoys a good quality of life. This elderly gentleman is mostly unaware of his paroxysms of AF. However, he had also suffered a stroke in the past, and as such was managed with warfarin. He was lucky. Recently, he experienced a gastrointestinal hemorrhage, requiring temporary reversal of his anticoagulant in addition to receiving a few pints of blood. There were no apparent clinical triggers for this event. Mr. Doe is not a fictional person but is a typical example of what is a common clinical dilemma: how best to protect against stroke in a patient who is at high risk, yet becomes intolerant to warfarin.

Previously, these patients were commonly switched to aspirin alone as a poor alternative to anticoagulation. Most clinicians would feel apprehensive of taking a gamble switching to novel oral anticoagulants which do not have available reversal agents (at the time this blog was written).

So, what then?

Enter the “Watchman.”

The majority of thromboembolic strokes in patients with AF originate in the left atrial appendage (LAA). The function of this structure is to assist with atrial transport, however during AF, atrial blood flow becomes impaired and stasis can occur in the LAA leading to thrombus formation at this location. Fragmentation and embolization of thrombi can lead to stroke, which is commonly disabling. The presence of comorbid factors such as diabetes, heart failure among other clinical variables can further increase this risk [1].

The last several years has witnessed the development and refinement of procedures referred to as left atrial appendage occlusion. Although there are several of the devices available worldwide, I will refer to the WATCHMAN system which is approved for use in the United States. In brief, the WATCHMAN device resembles a small umbrella (Figure 1). The FDA approved the device for the purpose of preventing embolic stroke with non-valvular AF. The available data that lead to its approval implies a non-inferiority to warfarin [2,3]

the WATCHMAN device resembles a small umbrella

Figure 1. (accessed from www.bostonscientific.com; www.modernhealthcare.com)

The method of device introduction is via a femorally placed venous sheath delivered transseptally (from right to left atrium). The destination of the device is the ostium of the LAA (Figure 2). The ultimate goal of the procedure is to totally exclude the LAA from the chamber, thus preventing flow into and from the LAA, in effect precluding thrombus formation. The procedure is performed with the guidance of transesophageal echocardiography, and typically under general anesthesia. The duration of the implant typically does not exceed an hour. Patients are continued on warfarin during the initial perioperative phase.

the destination of the device is the ostium of the LAA

Figure 2. (Accessed from www.bostonscientific.com; openaccessjournals.com)

Generally, after a forty-five-day period, transesophageal echocardiography is repeated to confirm the absence of peri-device leaks and verify device endothelialization. If the results are favorable, patients can often stop warfarin and switch to antiplatelet therapy. Presently, the available evidence compares WATCHMAN to warfarin, and comparisons to other anticoagulants is lacking.

It appears that enthusiasm for the WATCHMAN appears to be growing. For patients who require long-term warfarin use, but are at risk for hemorrhagic complications, this device appears to be a very good option. Cumulative experience will invariably lead to further improvements in design and greater safety [4,5].

References

Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review. JAMA. 2015;313:1950-62
Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial.J Am Coll Cardiol. 2014;64:1-12
https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=2 81&bc=ACAAAAAAAgAAAA%3d%3d&
Reddy VY1, Doshi SK2, Kar S3, Gibson DN4, Price MJ4, Huber K5, Horton RP6, Buchbinder M7, Neuzil P8, Gordon NT9, Holmes DR Jr10; PREVAIL and PROTECT AF Investigators. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials.J Am Coll Cardiol. 2017;70:2964-2975
Obeyesekere MN.Watchman Device: Left Atrial Appendage Closure For Stroke Prophylaxis In Atrial Fibrillation.J Atr Fibrillation. 2014; 7: 1099

Apollo Beach, FL (05/17, CP)

Deciphering the CABANA trial and what if anything do the results mean to the management of atrial fibrillation?

June 11, 2018 Christian Perzanowski, MD

“The truth is rarely pure and never simple.”
Oscar Wilde

“Facts do not cease to exist because they are ignored.”
Aldous Huxley

As is apparent from my previous blogs, I am very passionate about atrial fibrillation (AF). Undoubtedly, the most common arrhythmia nationally, and likely worldwide, can cause disabling symptoms, lead to a stroke and exacerbate heart failure. In my experience, patients with AF can be categorized as either asymptomatic, or highly affected. Essentially the former are unaware of their diagnosis, and are often found to have AF by serendipity. Life is in fact very easy for them, as well as their clinicians: anticoagulate, rate control and move on.

Now, for those who are symptomatic, there exist management challenges. AF is classified as paroxysmal, which is an intermittent or periodic form of arrhythmia; persistent, which is a sustained form and generally felt to be a progressed state of AF; or permanent, where no interventions are done. There is a paucity of available antiarrhythmic agents to treat and suppress AF. Antiarrhythmic drugs have earned a reputation of not being very effective while causing significant systemic adverse effects. Clinicians who care for symptomatic AF patients have certainly observed them to often experience shortness of breath, chest discomfort, loss of stamina, sensation of tachycardia and in some cases heart failure. Not uncommonly, these symptoms lead to anxiety as well as a compromised quality of life. In short, these patients must be treated.

Over the last decade, the techniques employed to treat AF by catheter-based means have improved in efficacy, even for more advanced forms of persistent AF. Although far from ideal, a number of studies have demonstrated ablation methods (e.g. radiofrequency, referred to colloquially as “heat” or cryoablation, “freezing”) to be superior to attempts at drug suppression. This is no surprise, as ablation addresses the problem directly (e.g. preventing AF from initiating) by calculated tissue destruction. While repeat studies are sometimes needed, the improvement in quality of life and improvement in heart failure class (such as observed with CASTLE-AF, AATAC) are known benefits^1,2.

CABANA (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial) sought to determine whether AF ablation versus antiarrhythmic drug therapy could prevent a composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest¹. This was a large randomized study with over 2,000 patients. The results, which were presented at the annual Heart Rhythm Society last month, yielded a rather disappointing result: ablation was not superior to drugs for preventing the above composite endpoint². That’s a rather dubious final score.

In spite of acknowledging what Wilde and Huxley might say, I would like to reconcile several of CABANA’s limitations:

– Personally, I have a grievance with the use of a “composite score” in the above scenario; stroke and “serious bleeding” are in no way equivalent; mechanistically, how would the investigators theorize that ablation could prevent a cardiac arrest?
– Death, while inevitable is indeed a categorical variable, one is either alive or not. Given that the causes of death are innumerable, it does not seem appropriate to consider that ablation could prevent all causes of death. Rather than try to postulate that ablation, or a potpourri of antiarrhythmics could stave of death, a more appropriate measure would be to ascertain prevention of death from heart failure.
– Approximately 25% of patients assigned to drug therapy crossed to ablation. Notably, some sources cited difficulty in enrollment as patients and referring physicians likely felt that ablation would be more beneficial.
– The ablation techniques used, as were the drugs prescribed, were left to the discretion of the treating physicians. Hence, the methods employed were not uniform, and paroxysmal AF cases were pooled with more advanced forms of persistent AF.
– How about continued drug therapy after ablation? The POWDER-AF investigators were able to show less AF burden with continued antiarrhythmic support following AF ablation. This should be expanded upon with larger studies.

From my perspective, I do not believe that CABANA results will affect my practice. Many of us will be curious to see publications regarding future subanalysis. In my opinion, patients who are very symptomatic with AF and have not responded to antiarrhythmics should be treated with AF ablation, and especially those who have developed cardiomyopathy or worsened heart failure as a result of AF⁶.

References

http://circ.ahajournals.org/content/early/2016/03/30/CIRCULATIONAHA.115.019406
https://www.nejm.org/doi/full/10.1056/NEJMoa1707855
https://clinicaltrials.gov/ct2/show/NCT00911508
https://www.nhlbi.nih.gov/news/2018/atrial-fibrillation-catheter-ablation-or-drug-therapy-results-are
Duytschaever M, Demolder A, Phlips T, Sarkozy A, El Haddad M, Taghji P, Knecht S, Tavernier R, Vandekerckhove Y, De Potter T. 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. 2018;39:1429-1437
https://www.hrsonline.org/Policy-Payment/Clinical-Guidelines-Documents/2017-HRS-EHRA-E CAS-APHRS-SOLAECE-Expert-Consensus-Statement-on-Catheter-and-Surgical-Ablation-of-Atrial-Fibrillation

sunset in tampa, florida

Tampa, FL (8/17 CP)

An Antidote To Factor Xa Inhibitors – Andexanet Alfa

May 9, 2018 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 thrombin^1,2. 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

Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost. 2007;5 Suppl 1:60-4
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
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

Crabtree, NC

Crabtree, NC (1/18 CP)

Can Death Be Cheated? A Different Take On The Results Of The VEST Trial

April 10, 2018 Christian Perzanowski, MD

“It’s tough to make predictions, especially about the future”
Yogi Berra

Sudden death is just that: sudden, fulminant and without warning. This is a reality for some patients with a compromised left systolic ventricular function, in particular those with left ventricular ejection fractions of less than 35%¹. Given the advent of improving acute, and chronic heart failure treatment, many of these patients with see an improvement in the vital metric referred to as “EF.” For patients who fail to improve and continue to be considered a “high risk for sudden death,” a primary implantable cardioverter defibrillator (ICD) implant can be offered to mitigate the risk of a sudden cardiac death. Nevertheless, there exist strict ICD implant guidelines as proposed by ACC/HRS and a waiting period is often necessary to meet implant criteria. With that being said, it is a well-known fact that despite undergoing medical uptitration, and recovering from revascularization, at risk patients may still succumb to fatal ventricular arrhythmia².

How often does this really occur? That is the fundamental question. The logical follow-up is to identify to whom and when exactly is a potentially fatal ventricular tachycardia or fibrillation (VT/VF) event going to occur? Knowing the answers to these questions would imply successfully predicting the future.

Out of these concerns arose the wearable cardiac defibrillator (WCD), or more commonly known as the “lifevest”³. In essence, the device which resembles a military “flak jacket” has the capability to detect and treat sustained VT/VF with an external shock. Presumably, life-saving therapy could be delivered quickly and improve the likelihood of survival. The system also permits the patient to defer therapy if still conscious. The reasoning being that a non-hemodynamically collapsing rhythm may terminate spontaneously forgoing a shock, which is a uniformly painful experience. No system is perfect, and common complaints leading to patients’ refusal to wear the device is the anxiety associated with wearing the system. Additionally, the WCD can be cumbersome to wear, provoke excess warmth and will cause frequent alarming if not well-fitted. In my experience, the alarming has lead patients to discontinue its use.

Over the last several years, I have observed a minority of WCD-prescribed patients successfully resuscitated by the Lifevest. However, I have also observed “no events” in the overwhelming majority who never experience any VT/VF and “graduate” to no device; the remainder will ultimately receive an ICD implant. A common management issue encountered in clinical practice is the “protection” of a post-myocardial infarction patient with an EF of 35% or less. The patient will often be the recipient of a percutaneous intervention, or even surgical

revascularization. Notably, the ICD implant guidelines recommend a “waiting period” of ninety days to permit improvement in the EF while maximal medical therapy is employed. Recently at the ACC in Orlando, the results of VEST were presented. The VEST study posed the question of whether the WCD can improve survival in the aforementioned patients using a randomized controlled trial⁴. Over 13,000 patients were screened, and just over 2300 were enrolled in 2:1 fashion: WCD vs optimal therapy only. The duration of follow-up was ninety days.

The results were underwhelming. In fact, there was no statistical difference in the primary outcome of sudden cardiac death VT/VF death: 1.6% for the study group, and 2.4% for the control group. Would a longer study period have made a difference? Were the subjects who expired too sick and prone to lethal electrical storms? A careful subanalysis may provide clues to these questions. Oddly enough, and perhaps the result of a wishful interpretation, the secondary endpoint of “all-cause mortality” was in favor of the WCD (3.1% vs 4.9%). The device is designed to treat VT/VF, and simply cannot defend against the myriad of other mechanisms of death – motor vehicle accidents, septic shock, cancer, sinkhole, shark attack etc. How these were adjudicated is unclear. Personally, I would interpret these results cautiously. Perhaps it is nothing more than a coin toss as to whether the WCD has any benefit in this population.

Undoubtedly for some patients the WCD has provided life-saving therapy. However, these patients appear to be relatively few and far in between. Rather than a broad use of the Lifevest system, further studies should focus on identifying clinical, imaging or electrophysiological features which better define who truly is at high risk for a sudden arrhythmic death, at least in the short-term. For now, accurately predicting sudden death continues to be elusive.

References

Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013;62(16):e147-239
Zaman S. Kovoor P. Sudden cardiac death early after myocardial infarction: pathogenesis, risk stratification, and primary prevention.Circulation. 2014;129(23):2426-35
https://lifevest.zoll.com/medical-professionals/how-does-lifevest-work/
http://www.acc.org/latest-in-cardiology/clinical-trials/2018/03/09/08/06/vest

Crabtree, NC

Valsartan-Sacubitril: The Next “Best Thing” In Systolic Heart Failure?

March 9, 2018 Christian Perzanowski, MD

“Realists do not fear the results of their study” Fyodor Dostoevsky

Heart failure is a problem. In fact, it is a massive problem¹. Over five million adults in the United States live with heart failure². Mozzafarian et al reported in their 2016 update on heart disease and stroke statistics that nearly half the patients diagnosed with heart failure (HF) will be deceased within five years¹. That is a sobering fact. For today’s article, I will reference a novel agent which is becoming widely adopted for systolic HF. Although the past two decades saw a dramatic improvement in the understanding of HF mechanisms, there have been only a number of new pharmacologic “game changers.” Today, I will succinctly discuss the combination agent valsartan-sacubitril (VS) which is an “angiotensin receptor-neprilysin inhibitor” marketed as Entresto (Novartis).

Briefly, valsartan is an angiotensin II receptor blocker which counters vasoconstriction and aldosterone secretion; sacubitril is a pro-drug which is ultimately modified to an active component which inhibits neprilysin, a neutral endopeptidase responsible for the degradation of natriuretic peptides leading to their increased plasma levels. The end result of these cumulative effects is vasodilatation, prevention of sodium retention and accumulation of extracellular fluid^3-5.

In September 2014, McMurray and colleagues published the result of the industry-sponsored PARADIGM-HF trial which compared VS (at that time known as LCZ696) to enalapril. Subjects with NYHA II-IV heart failure and originally a left ventricular ejection fraction of <40% (then amended to <35%) were randomly assigned to the study drug or the ACE-inhibitor. The study which enrolled over 8,000 patients, was terminated early due to a marked survival advantage of the VS arm with regards to the composite end point of death from cardiovascular causes or hospitalization for HF⁶.

Not only was there a survival advantage in patients assigned to the VS arm, but there was a 21% less risk of hospitalization for decompensated HF. Although the absolute risk reduction for cardiovascular death was only 3.2%, the data which was statistically significant, remained solidly in favor of ARB neprilysin inhibition superiority over ACE-inhibitor therapy⁶. From a clinician’s perspective, VS is being used increasingly to treat systolic HF patients with seemingly good results. Whether or not an indication will be given for a HF population with preserved left ventricular ejection fraction remains to be seen⁷.

There appears to be well-founded science supporting VS use in the vulnerable systolic HF population. Hopefully, insurance carriers and third-party payors will provide coverage for this novel agent.

References

Mozzafarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360
https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm
Hubers SJ, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016;133(11):1115-24
Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther. 2016;41:119-27 5.
Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart. 2016;102:1342-7
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 11;371:993-1004
Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Shi VC, Lefkowitz MP, McMurray JJV. Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial. JACC Heart Fail. 2017;5:471-482

Near Maggie Vallet, NC

Near Maggie Valley, NC 01/18 (CP)

Options To Rat Poison – Other Mousetraps?

February 9, 2018 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

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
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
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
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
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
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 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.

The Lack Of New Drugs For Rhythm Control Of Atrial Fibrillation: A Stagnant Pipeline

January 16, 2018 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 attractive^4,5 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 operations^10,11.

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:

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
Leong-Sit P, Tang AS. Atrial fibrillation and heart failure: a bad combination. Current Opinion in Cardiology. 2015;30:161–167
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]
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
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
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
Preti A. New developments in the pharmacotherapy of cocaine abuse. Addict Biol. 2007;12:133-51
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
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
https://www.xconomy.com/san-diego/2015/12/06/heart-drug-safety-concerns-prompt-shutdown-at-laguna-pharmaceuticals/
https://clinicaltrials.gov/ct2/show/NCT02454283

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.

What I Took Home – “BRUISES” With EP-Devices

December 11, 2017 Christian Perzanowski, MD

This year’s AHA Scientific Sessions in Anaheim, CA provided the cardiology community with a number of important trials. Large clinical studies have the possibility to directly impact clinical practice. In the subspecialty of electrophysiology, there was an important trial with significant relevance to physicians who implant or provide perioperative care for patients with pacemakers/ defibrillators (“EP device procedures”).

A frequent dilemma which implanting physicians face is whether or not to suspend anticoagulation prior to insertion of an EP device. Suspension of anticoagulation raises the risk of stroke for many patients and this cannot be ignored. The obvious postoperative concern is the attendant risk of pocket hematoma which is not only a painful experience for the patient, but can also dramatically increase the risk of infection. The latter is considered a potentially disastrous complication with high morbidity and mortality. In 2013, Birnie et al published the results of BRUISE-CONTROL which was a randomized controlled trial with sought to determine outcomes between continued warfarin use, and suspension of warfarin while bridging with intravenous heparin at the time of surgical implant (NEJM 2013). The results were categorically in favor of continued warfarin use. With that study, patients in the uninterrupted oral anticoagulation arm had a marked reduction of postoperative pocket hematoma (3.5% -16%). For some time, many implanting physicians had observed the benefits of continued oral anticoagulation with warfarin during device implants, however the data from this trial provided validation of this practice.

In the past several years, a group of new oral anticoagulants have emerged (NOACs). While the pharmacological mechanisms vary (e.g. factor ten, direct thrombin inhibition) the clinical effects aim to provide systemic anticoagulation. These agents have increased in popularity as an alternative to warfarin. As experience with these agents (e..g. Apibixan, Rivaroxaban, Dabigatran) grew, a determination of their effects on device implants was needed and to ascertain their risk for postoperative hematoma formation. A new trial was launched: BRUISE CONTROL-2. The clinical question was to determine any difference in the development of a hematoma subsequent to a NOAC’s uninterrupted use versus suspension of the NOAC drug two days prior to the procedure. To further add complexity to the matter, only one of these medications has a commercially available reversal agent (dabigatran), hence there is a natural apprehension of performing a procedure under the influence of anticoagulant whose effects cannot be stopped. BRUISE CONTROL-2 presented by Dr David Birnie on 11/12/17.

Surprisingly, there was no difference in pocket hematoma formation (2.1% vs 2.1%). The study was terminated due to futility. The authors concluded that either approach is reasonable. Since the study was not blinded, one might question whether the implanting physicians modified their surgical approach and perhaps could have used different methods to curtail bleeding (e.g. the use of hemostatic or antithrombotic agents introduced into the pocket).

Overall, there was a low complication rate. A size categorization of the incisional hematomas would be helpful as well: a large tension-creating hematoma clearly does not have the same clinical impact as mild swelling. In my opinion the results further validate the safety of NOAC use perioperatively. A subanalysis of how the individual agents performed would be helpful to further elucidate whether there exists a drug superiority, or better yet a BRUISE CONTROL-3 could help address this.

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.

A Gateway To Better Health With Bariatric Surgery

November 14, 2017 Christian Perzanowski, MD

This year’s AHA Scientific Sessions has already provided the medical community with a number of excellent studies. The “GATEWAY” trial addresses the role of bariatric surgery and its effect on hypertension.¹ Patients with morbid obesity are well known to be at risk for a litany of cardiorespiratory complications such as hypertension, obstructive sleep apnea, atrial fibrillation, among others. For many, dietary and lifestyle changes are insufficient measures to lose weight. The past decade has seen the emergence of bariatric surgery as a valid therapeutic approach. In trained hands and with meticulous follow-up, the results can be life-changing.

There already exists published literature regarding the favorable effects on glycemic control and in some cases resolution of type II diabetes in patients followed after Roux-en-Y bypass.²

GATEWAY (Gastric Bypass to Treat Obese Patients With Steady Hypertension) was a randomized trial comparing the effects of surgery to standard medical therapy in patients with morbid obesity (defined as BMI 30-39.9 Kg/m2) with the purpose of achieving control of hypertension. The surgery technique employed is known as a Roux-en-Y gastric bypass; these patients also received medical treatment.

The primary endpoint was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure <140 mm/90 mm Hg, respectively, at 12 months. Although the study did not enroll patients with diabetes mellitus, and was limited to 100 patients, the results are intriguing. In fact, the surgical arm was six times more likely to require less antihypertensives with more than half achieving remission of hypertension using the above target value. Encouragingly, the surgical complication rate was low.

This is encouraging data which also leads to additional questions:

Are such results also obtainable with other surgical methods (Laparoscopic adjustable gastric banding; Sleeve gastrectomy;
Duodenal switch with biliopancreatic diversion etc)³?
Are the antihypertensive effects durable?

Larger studies will further validate these findings.

References:

Schiavon CA et al. Effects of Bariatric Surgery in Obese Patients With Hypertension The GATEWAY Randomized Trial (Gastric Bypass to Treat Obese Patients With Steady Hypertension). http://circ.ahajournals.org/content/early/2017/11/10/CIRCULATIONAHA.117.032130
Schauer PR Burguera B, Ikramuddin S, Cottam D, Gourash W, Hamad G, Eid GM, Mattar S, Ramanathan R, Barinas-Mitchel E, Rao RH, Kuller L, Kelley D. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg. 2003 Oct;238(4):467-8
Colquitt JL1, Pickett K, Loveman E, Frampton GK. Surgery for weight loss in adults. Cochrane Database Syst Rev. 2014 Aug 8;(8):CD00364

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