Notes From a Clinical Pharmacist: Atrial Fibrillation Occurring During Acute Hospitalization: A Scientific Statement From the American Heart Association

美國心臟學會在2023/03/13發表了一篇「Atrial Fibrillation Occurring During Acute Hospitalization」針對住院病人心房顫動的處置建議。(article link)

此篇文章著重在「急性AF在住院」病人，提供早期診斷病人的AF與處置(含抗凝血劑anticoagulant)的建議。文中強調了根據病人特徵和臨床情況制定個體化治療策略的重要性，並處理可能導致 AF 的underlying medical conditions提供了建議。

AHA 2023發佈兩項重要觀念：

1️⃣Acute and long term AF management原則：3A & 2M

3A：Acute triggers, AF management, Anticoagulant
2M：Monitor, Modification (lifestyle, risk factors)

2️⃣New conceptualize of acute AF:

急性心房顫動可以被理解為：急性的外在誘發因子(triggers)挑起(provocate)/促動了敏感的內在substrates。建構在此概念上，急性心房顫動代表著，上述那些外在的誘發因子間接揭開了平時相安無事的vulnerable heart condition，或直接揭開了先前未被診斷的AF。

此Scientific Statement 的key recommendations：

住院病人心房房顫的即時診斷與治療
使用適當的抗凝治療以降低中風風險
根據患者特徵和臨床情況考慮rate control或rhythm control：應考慮病人耐受快速心率的能力(capacity to tolerate rapid rates)或房室不同步的能力(atrioventricular dyssynchrony)。
處理可能導致 AF 的underlying medical conditions，例如心衰竭或敗血症(sepsis)
密切監測 AF 的潛在complications，例如血流動力學不穩定(hemodynamic instability )或血栓(thromboembolism)

此篇文章outline：

Acute AF的定義
Risk stratification: substrates and triggers
Detection of acute AF
Acute management: identify triggers, anticoagulants, rate & rhythm control
Acute management in specific settings

ER
ICU
Hypothyroidism
Stroke
COVID-19
Non-cardiac surgery
Cardiac surgery
Atrial flutter

Long term management

Acute AF的定義

Acute AF 定義為病人住在急性病房或病人於某個acute illness期間，心率監測到的 AF。在先前的文獻中，急性 AF 有時被稱為secondary AF。此文研究團隊屏棄secondary AF 一詞，因為通常不清楚在急性病房環境中檢測到的 AF 是否真的繼發於或歸因於其他急性問題。換句話說，AF 可能在急性疾病之前就已經存在於個體中，但之前未被診斷或檢測到。

至於paroxysmal/persistent, symptomatic/ asymptomatic AF的定義維持與先前指引定義的一樣。

Risk stratification: substrates and triggers

細分為內在(substrates)與外在(triggers)風險：

Substrate的概念為：patient with a vulnerable heart condition. 此病人本身/內在的誘發風險因子。

結構性心臟疾病如心房疤痕、心房電傳導或心房結構重朔都是導致心臟成為AF substrate的原因。

心房疤痕(atrial scars)是由於某些慢性疾病未控制，而導致心臟細胞組織纖維化的過程，疾病會導致心房volume or pressure overload如瓣膜性心臟病、心肌病(cardiomyopathy)、長期高血壓、慢性腎病或myopathic states involving atrial myopathy都是風險因子。疤痕組織是不會導電的。

手術也是導致心臟成為AF substrate的原因，包括了心臟手術與心房切開術(atriotomy)、心肺循環機/體外循環機(cardiopulmonary bypass, CPB)、瓣膜手術、迷宮手術(maze procedure）、胸腔手術(thoracic surgeries)或existing pulmonary disease。

其他導致心臟成為AF substrate包括pericardial fat pad(心包油) 和pulmonary vein automaticity。

Triggers的概念為：指容易引發AF的人體以外的外在風險物質。

誘發acute AF的因子(triggers)包括inflammation、local mechanical stress,
oxidative stress, electrolyte imbalance, and shifts in autonomic tone。潛在的誘因包括infection、pericardial effusion and inflammation, long procedural time, hemodynamic shifts, volume loss or overload, intraprocedural and postprocedural pulmonary complications, and medications, including inotropic agents(強心劑)。

急性心房顫動可以被理解為：急性的外在誘發因子(triggers)挑起(provocate)/促動了敏感的內在substrates。建構在此概念上，急性心房顫動代表著，上述那些外在的誘發因子間接揭開了平時相安無事的vulnerable heart condition，或直接揭開了先前未被診斷的AF。(Building on this concept, acute AF may represent previously unrecognized AF or unmasking of an underlying predisposition to AF in the setting of an acute trigger.)

▲A conceptual model of substrates and triggers of acute AF. (AF indicates atrial fibrillation; and PV, pulmonary vein.)

▲Potential mechanistic pathways of acute AF.

Detection of acute AF

評估病人的臨床表徵和危險因素，如年齡、高血壓和心臟疾病。可利用risk scores(如下述)or 檢驗BNP進行風險評估。
高風險病人在acute illness時進行 12 導程心電圖 (ECG)。
如果心電圖正常但仍懷疑有AF，則持續以動24小時態心電圖監測(eg. Holter monitor)。(Continuity of electrocardiographic monitoring during the hospital stay influences the detection of acute AF, with continuous monitoring with telemetry being more likely to detect acute AF compared with episodic ECG.)

Patient-based risk scores

CHA2DS2- VASc score: initially developed for thromboembolism
ATRIA score: initially developed for thromboembolism
HATCH [hypertension, age, transient ischemic attack or stroke, chronic obstructive pulmonary disease, and heart failure] score initially developed for AF progression.
POAF score for postoperative AF

the CHA2DS2-VASc score has outperformed the HATCH or the POAF score.

Acute management: 先De-bug

處理acute AF 的第一件事是找出淺在誘發因子(underlying triggers)並治療它，因為在急症改善之前，rate and rhythm control不太可能成功。

Acute Rate and Rhythm Management

處理血液動力學穩定的病人時，先以“wait-and-see” approach是合理的。因為急性心房顫動發生時，心律會spontaneously convert to sinus rhythm。

治療血液動力學穩定的acute AF時，rate and rhythm control應該個別化處理。要考慮病人耐受淺在快速心率的能力(capacity to tolerate the potential rapid rates)或房室傳導不同步的能力(atrioventricular dyssynchrony)以及病人接受藥物治療的風險承擔能力。

Rate and rhythm control時應考量病人心臟結構性問題、AF促發的血流動力學改變以及使用心律控制藥物的適當性(eg考量藥物禁忌or副作用)。鑑於 AF 的急性節律控制存在急性血栓栓塞的風險，任何進行節律控制策略的決定還需要考慮卒中的風險以及輔助短期和長期抗凝的需要。

在使用rhythm control策略時，應特別注意中風的栓塞風險(risk of acute thromboembolism)，並且評估是否使用短期或長期的anticoagulation。

Acute Rate Control

Rate control的藥物透過增加房室結(AV node)的不反應期(refractory period)來降低的心室心率(ventricular rate)。(詳細藥物整理表格：link)

Rate control的目標心率：

一般建議<110 bpm。
如果伴隨有deterioration of left ventricular function, symptoms, concomitant cardiac resynchronization therapy, or diagnosis of tachycardia- mediated cardiomyopathy，則建議<80 bpm。
在心臟手術時<100 bpm (some <110) is reasonable for asymptomatic patients。

Acute Rhythm Control

在血液動力學不穩定的病人中，直流電心臟整流 (electrical cardioversion with direct current cardioversion, DCCV) 是首選治療方法。
在血液動力學穩定且不能耐受房室不同步的病人中，Rhythm Control可以透過：心臟整流或抗心律不整藥物控制。
Rhythm Control一般建議用於已使用AVnode–blocking agents或已移除triggers後尚不能恢復心律時才使用。

Antiarrhythmic Medications for Acute Pharmacological Cardioversion or Maintenance of Sinus Rhythm (詳見文章附件, link)

In general, the choice of agent depends on the individual situation and underlying clinical substrate such as cardiac and renal function.

Ibutilide can be a reasonable choice for patients unable to receive anesthesia in the absence of existing QT prolongation. The most important concern is torsade de pointes, so the patient must have a normal QTc interval. Ibutilide effects are short lasting (<4 hours); thus, it is not an ideal drug if recurrence of arrhythmia is expected. (Strongly consider pre-treating with magnesium sulfate 1-4 mg IV)
For patients able to take oral medications and without underlying structural heart disease, either propafenone or flecainide oral bolus is an option, with the advantage that they can be transitioned to ongoing dosing.
Amiodarone also has the advantage of transitioning from intravenous to oral form, but cardioversion with amiodarone takes longer than with the aforementioned drugs. Because amiodarone may prolong the QT interval, the use of amiodarone may limit concomitant and subsequent pharmacological options given concerns for potentiation of QT prolongation.
Procainamide is also an intravenous option for acute conversion of AF. While using intravenous procainamide, the patient needs to be closely monitored for hypotension, QT prolongation, and proarrhythmia.
In the critical ill patient, electrical cardioversion is effective, but relapse is common; similarly, relapse would likely be common after pharmacological cardioversion until the underlying acute illness subsides or adequate drug levels of rhythm control agent have been achieved.

📑各別藥物major side effects：

Amiodarone: Pulmonary toxicity, thyroid dysfunction, liver toxicity, skin discoloration
Dofetilide: QT prolongation, torsades de pointes
Flecainide: Proarrhythmia, heart failure exacerbation, digoxin level ↑, Avoid in structural heart disease
Propafenone: Proarrhythmia, metallic taste
Procainamide: Hypotension, lupus-like syndrome, avoid use in heart failure and other heart disease.
Vernakalant: Hypotension, QT prolongation

Electrical Cardioversion

Electrical cardioversion with DCCV has a high success rate for restoring sinus rhythm. Electrical cardioversion is safe, rapid, and more effective than pharmacological cardioversion alone, with the tradeoff of the need for sedation with electrical cardioversion. A patient’s suitability for anesthesia and the ideal anesthesia regimen to support electrical cardioversion benefit from multidisciplinary considerations.

Monitoring During and After Cardioversion

Postcardioversion monitoring for pharmacological cardioversion is recommended for a duration of time that is equal to half of the therapeutic half-life of the medication, and for electrical cardioversion with anesthesia, the duration of monitoring after electrical cardioversion would be as per usual postanesthesia monitoring for the extent of anesthesia necessary to support the performed electrical cardioversion.
In patients who receive ibutilide, the most important concern is torsade de pointes, which usually occurs within 30 minutes of drug administration
Close monitoring is required with a defibrillator(去顫器) readily available for 4 hours or until QT normalizes.
Bradycardia is common after cardioversion because of sinus node suppression of automaticity. Bradycardia commonly improves after the patient wakes up and the sinus node recovers while in sinus rhythm; it is uncommon for severe bradycardia to require intervention other than drug dose adjustment in the rare instances that bradycardia fails to resolve. It is important to note that sinus node function can eventually normalize if the patient is able to maintain sinus rhythm.

Anticoagulation During Acute Hospitalization

General considerations for anticoagulation for patients with AF are based on substrates, with CHA2DS2-VASc score of ≥2 for men or ≥3 for women as an accepted indication for anticoagulation.

Thromboembolic Risks of Acute Cardioversion

緊急的心臟整流的栓塞風險往往是由於體內本身存在的thrombus。因此在藥物整流和電擊整流時，都需考慮使用anticoagulation。
以往的文獻指出AF>48小時的病人較有機會有thrombus的產生，但Subsequent study found time to cardioversion ≥12 hours to be an independent predictor of thromboembolic complications。
因此，最新建議為：

若病人需要進行心律整流前三週未有抗凝血藥物介入，則在整流以前須先以 transesophageal echocardiogram 去排除有 existing intracardiac thrombus，才能在高栓塞風險病人進行整流處置。
After cardioversion, uninterrupted anticoagulation is recommended for 4 weeks, the putative period for recovery of mechanical. Only in patients with CHA2DS2-VASc of 0 in men or 1 in women with very low associated thromboembolic risks may omission of such uninterrupted postcardioversion anticoagulation be considered.

Acute management in specific settings

In Critically Ill Patients

Aggressive management of acute illnesses and prompt treatment of triggers remain the cornerstone of acute AF management in critically ill patients. It may be appropriate to wait to directly treat the acute AF until further treatment of the acute illness if the rapid heart rate is a compensatory mechanism for the critical illness. In patient whose acute AF is causing hemodynamic compromise, immediate DCCV is the strategy of choice. In the absence of hemodynamic compromise, both rate and rhythm control strategies may be considered. Electrical cardioversion may be successful, but early relapse is common in patients who remain acutely ill. Amiodarone and propafenone have demonstrated efficacy for pharmacological cardioversion in this population. Prior limited studies suggest that for acute AF in the critically ill, metoprolol may provide better rate control compared with diltiazem and that esmolol use may be associated with improved arterial elastance and reduced short-term mortality. Although the reduction of in-hospital mortality with β-blockade was no longer evident after multivariable adjustment reflective of more favorable hemodynamic profile before initiation of β-blockade, when feasible, β-blockade remains a reasonable choice for rate control given its demonstrated efficacy in this regard.

Critically ill patients with new-onset AF have a >2-fold higher risk of in-hospital ischemic stroke compared with those without AF. In patients with sepsis, however, CHA2DS2-VASc alone poorly predicts the risk for ischemic stroke. Parenteral anticoagulation in patients with acute AF and sepsis did not reduce risks for ischemic stroke and was associated with increased clinically significant bleeding in one study. Available evidence does not favor routine acute anticoagulation in patients with sepsis with acute AF. Further research combining risk scores based predominantly on chronic conditions (such as the CHA2DS2-VASc risk score) with considerations of the acute coagulopathic and prothrombotic milieu may be useful to better assess the benefits, risks, and optimal selection of critically ill patients with acute AF for acute anticoagulation.

Hyperthyroidism

Goals for management of acute AF in the setting of hyperthyroidism include efforts to restore the euthyroid state and, if feasible, β-blockade for rate control. Although hyperthyroidism may induce a hematologically prothrombotic state, with an increase in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1, hyperthyroidism is not included in the risk stratification scheme for thromboembolism in patients with AF. Correlation of hyperthyroidism with clinical thromboembolism has been controversial; anticoagulation for patients with thyrotoxicosis and AF is guided by CHA2DS2-VASc risk factors in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline on the management of AF. Recent data noted increased risks of ischemic stroke and systemic embolism in patients with AF with hyperthyroidism in the first year of AF diagnosis but with a reduction of increased risks with treatment of hyperthyroidism. These nuanced data underscore the importance of treating the hyperthyroidism and may prompt additional consideration for anticoagulation while attempting to restore the euthyroid state during the first year of AF diagnosis.

Cardiac Surgery

Prophylaxis for AF After Cardiac Surgery

有鑒於心臟手術後誘發的 AF (postoperative AF)有較差的預後，因此臨床指引建議首選 β-blocker或amiodarone用於預防心臟手術術後之postoperative AF。

In terms of colchicine, although the AF substudy of the COPPS study (Colchicine for the Prevention of the Postpericardiotomy Syndrome) demonstrated a reduction of postoperative AF and length of stay, leading to inclusion in the 2014 American Heart Association/ American College of Cardiology/Heart Rhythm Society guideline as a IIb recommendation, the subsequent COPPS-2 study (Colchicine for Prevention of Postpercardiotomy Syndrome and Postoperative Atrial Fibrillation) and END-AF study (Effect of Colchicine on the Incidence of Atrial Fibrillation in Open Heart Surgery Patients) did not demonstrate statistically significant reductions of postoperative AF during hospitalization after cardiac surgery, and associated diarrhea led to discontinuation of colchicine in more than half of colchicine recipients. Recent comprehensive guidelines noted data for colchicine as pharmacological prophylaxis for postoperative AF in the setting of cardiac surgery not to be robust.
Other agents such as renin-angiotensin system inhibitors, nonsteroidal anti-inflammatory agents, steroids, statins, omega-3 fatty acids in the form of fish oil supplements, calcium channel blockers, digitalis, and angiotensin-converting enzyme inhibitors have been tested in small-scale clinical trials, showing varying efficacy in prophylaxis for AF after cardiac surgery.

Acute Treatment of AF After Cardiac Surgery

Treating hemodynamically stable, asymptomatic, acute AF after cardiac surgery with rate control as the initial strategy is reasonable18 given the similar length of hospitalization, morbidities, and mortality with a rate control target of <100 bpm or rhythm maintenance with amiodarone. When acute pharmacological cardioversion is considered, ibutilide and vernakalant (not approved by the US FDA for use in the United States) have demonstrated specific efficacy in acute pharmacological cardioversion of AF after cardiac surgery.

LONGER-TERM MANAGEMENT

Patients with acute AF in the setting of acute medical illness and noncardiac and cardiac surgeries have high rates of AF recurrence long term. The 5-year AF recurrence rates were 42% to 68%, 39%, and 32% to 76% in patients with acute AF in the setting of acute medical illness, noncardiac surgeries, cardiac surgeries, respectively, with higher detection of recurrence in studies using continuous heart rhythm monitoring.

▲Care pathway for acute AF.

Considerations for Long-Term Anticoagulation

The decision to pursue longer-term anticoagulation is based on patient substrate and thromboembolic risk barring contraindications to anticoagulation. Retrospective registry data suggest similar long-term thromboembolic risks in patients with AF with and without acute triggers precipitating manifestation of AF.

Currently, for patients with acute AF after cardiac surgery, long-term anticoagulation may be considered according to the anticipated net benefit and informed patient preference. Results from the ongoing prospective, randomized PACES will provide some guidance based on results from randomization to oral anticoagulant plus background antiplatelet therapy (versus antiplatelet only) for the protocol duration of 90 days. For patients who underwent surgical AF ablation, oral anticoagulation as soon as feasible during hospitalization and long-term anticoagulation based on CHA2DS2- VASc score are recommended. Follow-up of patients with AF after cardiac surgery with reported left atrial appendage closure warrants evaluation of the left atrial appendage with transesophageal echocardiogram or computed tomography to assess for adequacy of closure and further consideration for anticoagulation based on adequacy of closure as well as additional assessment of the patient's thromboembolic risk.

In patients who developed acute AF after noncardiac surgery, registry data suggest that initiation of oral anticoagulation within 30 days after discharge was associated with a reduced risk of thromboembolic events. The randomized prospective ASPIRE-AF trial (Anticoagulation for Stroke Prevention In Patients With Recent Episodes of Perioperative Atrial Fibrilla- tion After Noncardiac Surgery; NCT03968393) will further inform the optimal long-term oral anticoagulation strategy for patients who develop acute AF after noncardiac surgery.

Longer-Term Rhythm Management

Long-term rhythm management should be individualized as part of a shared decision plan with each patient. The choice of rhythm control method is based on the balance of multiple factors, including patient preference, risk factors, and comorbidities. (詳見table 5, link)

▲Summary of management of acute AF.

Acute AF: 10 Key Implications for Clinical Practice

Acute AF is defined as AF detected in the setting of acute care or acute illness; this includes AF occurring during acute hospitalization. Acute AF may be detected or managed for the first time during acute hospitalization for another condition.
Acute AF is associated with high risk of long-term AF recurrence, warranting clinical attention during acute hospitalization, at transition of care, and over long-term follow-up.
A framework of substrates and triggers can be useful for the evaluation and management of AF occurring during acute hospitalization. AF after cardiac surgery is a distinct type of acute AF.
Acute management of AF occurring during hospitalization requires a multipronged approach. Key components of acute management include identification and treatment of triggers, selection and implementation of rate/rhythm control, and management of anticoagulation.
Acute rate or rhythm control strategy should be individualized with consideration of the patient’s capacity to tolerate the potential rapid rates or atrioventricular dyssynchrony, as well as the patient’s ability to tolerate the risk of either the rate or rhythm control strategy.
In hemodynamically unstable patients, immediate electrical cardioversion with DCCV is the treatment of choice. Rhythm control should also be consid- ered for patients unable to attain clinically adequate rate control despite optimal use of atrioventricular nodal blocking agents and management of acute triggers. Electrical cardioversion is the most effective method to achieve acute rhythm control. Hemodynamic monitoring and considerations for thromboembolic prophylaxis are warranted for both electrical and pharmacological cardioversion.
Indication for anticoagulation is based on substrate, with feasibility and timing for anticoagulation based on patient’s bleeding risk and contextual considerations of the acute conditions.
Given the high risks of AF recurrence in patients with acute AF, clinical follow-up and extended heart rhythm monitoring are warranted to tailor longer-term management. Management of AF and modifications targeting the substrate should be instituted. Long-term management will be heavily tied to the substrate, guiding follow-up, long-term heart rhythm monitoring, and considerations for rhythm management strategies.
Overall management of acute AF addresses substrates and triggers. The 3As of acute management are acute triggers, AF rate/rhythm management, and anticoagulation. The 2As and 2Ms of long-term management are AF rate/rhythm management, anticoagulation, monitoring of heart rhythm, and modification of lifestyle and risk factors.
Patients with acute AF benefit from close interdisciplinary care collaborations, allowing appropriate treatments tailored to patient’s underlying substrates and acute conditions.

Notes From a Clinical Pharmacist

2023年3月17日星期五