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Above, Monophasic action potential from a ventricular muscle fiber during normal cardiac function, showing rapid depolarization and then repolarization occurring slowly during the plateau stage but rapidly toward the end. Below, Electrocariogram recorded simultaneously

Medical Physiology – Guyton and Hall – Fig 11.3

Propagation of action potentials in both directions along conductive fiber


Action potential (in millivolts) from a purkinje fiber of the heart, showing a “plateau”


The cardiac action potential

Electrophysiologic Testing – Fourth Edition – Blackwell publishing – Fig 1.2

Typical changes in conductance sodium and potassium ion channels when the membrane potential is suddenly increased from the normal resting value of

90 millivolts to a positive value of +10 millivolts for a 2 milliseconds.


Sequence of cardiac activation: a comparison with dominoes, where the first domino topples the one next to it and so on.

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Localized differences in the cardiac action potential


Cardiac action potentials from different locations within the heart have different shapes. These differnces account for the differences seen in electrophysiologic properties in various tissues within the heart

Action potential (in millivolts) from a purkinje fiber of the heart, showing a “plateau”


Rhythmical discharge os a sinus nodal fiber. Also, the sinus nodal action potential is compared with that of a ventricular muscle fiber


Figure 1 Changes in heart rate in the different treatment groups during the double-blind, dose-ranging phase at rest (A) and at peak exercise (B). *p <0.05 vs. placebo in pairwise

comparisons. bid = twice daily.

Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina - J Clin Pract, February 2006, 60, 2, 222–228 – Fig 01

Effect of ivabradine on time to angina sufficient to limit continued bicycle exercise among protocol-compliant patients with coronary artery disease. Measurements were obtained after 2

weeks of double-blind randomised therapy. A dose-response relationship is apparent.

Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina - J Clin Pract, February 2006, 60, 2, 222–228 – Fig 02

Sinus bradycardia

Electrophysiololic Testing – Richard N. Fogoros – Fig 2.1

Three categories of heart block. In first-degree block (top tracing), all atrial impulses are conducted to the ventricles, but conduction is slow (the PR interval is prolonged). In second-degree block (middle tracing), some atrial impulses are conducted and some are not. In third-

degree block (bottom tracing), none of the atrial impulses are conducted to the ventricles

Electrophysiololic Testing – Richard N. Fogoros – Fig 2.2

Prepequisites for reentry


An anatomic circuit must be present in which two portions of the circuit (pathways A and B in the figure) have electrophysiologic properties that differ from one another in a critical way. In this example, pathway A conducts electrical impulses more slowly than pathway B; pathway B has a longer refractory period than pathway A

Initiation of reentry


If the prerequisites in fig 2.5 are present, then an appropriately timed premature impulse can block in pathway B (which has a relatively long refractory period) while conducting down pathway A. Because conduction down pathway A is slow, pathway B has tme to recover, allowing the impulse to conduct retrogradely up pathway B. The impulse can then reenter pathway A. A continuously circulating impulse is thus established

Termination of reentry


An appropriately timed premature impulse can enter the circuit during a reentrant tachycardia, collide with the reentrant impulse as shown, and terminate reentry

Characteristics of the voltage-gated sodium (top) and potassium (bottom) channels, showing successive activation and inactivation of the sodium channels and delayed

activation of the potassium channels when the membrane potential is changed from the normal resting negative value to a positive value


Most relevant ionic currents in automatic (A) and contractile (B) cells suring systole. Contractile cells are characterized by na early and abrupt Na+ inward flow and na initial and

transient K+ outward flow (Ito), wich are not present in automatic cells

Clinical Arrhythmology – Antoni Bayes de Luna – Fig 2.13

Membrane response curve. The response dv/dt depends on the transmembrane diastolic potential (TDP) at each time point


The Vaughan Williams classification of antiarrhythmic drugs.

Antiarrhythmic drugs for the maintenance of sinus rhythm: Risks and benefits - International Journal of Cardiology - IJCA-13587; No of Pages 10– Table 01

Classification of Antiarrhythmic Drugs

Electrophysiologic Testing – Fourth Edition – Blackwell publishing – Table 3.1

Subclassification of Class I Antiarrhythmic Agents

Electrophysiologic Testing – Fourth Edition – Blackwell publishing – Table 3.2

Efficacy, adverse events, and contraindications of antiarrhythmic drugs used for maintenance of sinus rhythm.

Antiarrhythmic drugs for the maintenance of sinus rhythm: Risks and benefits - International Journal of Cardiology - IJCA-13587; No of Pages 10– Table 02

Kaplan–Meier Estimates of Death from Cardiovascular Causes (Primary Outcome).

Among 1376 patients with atrial fibrillation and congestive heart failure who were followed for a mean of 37 months, 182 patients (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 patients (25%) in the rate-control group (hazard ratio, 1.06; 95% confidence

interval, 0.86 to 1.30).

Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure - N Engl J Med 2008;358:2667-77. – Fig 02

Kaplan–Meier Estimates of Secondary Outcomes.

Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure - N Engl J Med 2008;358:2667-77. – Fig 03

Single and pooled OR for all cause mortality of 5 included RCTs with mean age < 65 years.

Rate vs. rhythm control in patients with atrial fibrillation — An updated meta-analysis of 10 randomized controlled trials - International Journal of Cardiology - IJCA-13920; No of Pages 3 – Fig 02

Single and pooled OR for worsening heart failure of 3 included RCTs with mean age < 65 years.

Rate vs. rhythm control in patients with atrial fibrillation — An updated meta-analysis of 10 randomized controlled trials - International Journal of Cardiology - IJCA-13920; No of Pages 3 – Fig 03

Forest plot comparing rate and rhythm control for total mortality in patients with AF and HF.

Rate vs rhythm control in patients with atrial fibrillation and heart failure: A systematic review and meta-analysis of randomised controlled trials European Journal of Internal Medicine 22 (2011) 448–455 – Fig 02

Forest plot comparing rate and rhythm control for hospitalisations in patients with AF and HF.


Forest plot comparing rate and rhythm control for stroke/thromboembolic events in patients with AF and HF.


Rate-control pharmacological agents

Ventricular rate control is generally achieved with the use of beta-blockers and calcium

channel blockers (Ahmad & Dorian, 2006; Martinez, Epstein, & Bass, 2005). Beta-

blockers include propranolol, metroprolol, atenolol, esmolol, and nadolol. Calcium

channel blockers include dilitazem and verapamil. Only with older, sedentary patients

is digoxin recommended as a primary agent for ventricular rate control because its

effectiveness in controlling heart rate during exercise has been questioned (Ahmad &

Dorian, 2006; Korantzopoulos et al., 2005; Reiffel, 2000). Rate control is considered a

reasonable, viable,first-line treatment for many older adults with AF. Rate control in

AF provides some important benefits such as the prevention of "late consequences of

uncontrolled rate (such as tachycardia induced cardiomyopathy)" (Ahmad & Dorian,

2006, p. 88).

Rhythm-control pharmacological agents

Antiarrhythmic drugs used in the treatment of AF include flecainide,

propafenone, amiodarone, sotalol, and dofetilide (Cohen & Naccarelli,

2008). Azimilide is also used in rhythm control but is not currently

available for use in the United States (Dresing & Schweikert, 2002).

Quinidine, procainamide, and disopyramide are no longer prescribed

for patients with AF because serious adverse reactions, proarrhythmic

potential, and inefficacy have been reported (ACC/AHA/ESC, 2006;

Korantzopoulos et al., 2005).

Kaplan-Meier curves for event-free survival of patients maintaining chronic sinus rhythm and patients with permanent AF

Mending the rhythm does not improve prognosis in patients with persistent atrial fibrillation: a subanalysis of the RACE study - European Heart Journal (2006) 27, 357-364 - Fig 02

Pharmacokinetic interactions between antiarrhythmics and

other drugs

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Mean ± standard errors of the mean serum amiodarone concentrations versus time in healthy subjects after a single oral dose of 17 mg/kg ingested in combination with grapefruit juice or water.

Grapefruit juice inhibits the cytochrome P450 3A4 enzyme mediated production of desethylamiodarone, resulting in higher amiodarone concentrations. Amiodarone was given in 300 mL of commercially available grapefruit juice

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Waldo, A. (2006). A perspective on antiarrhythmic drug

therapy to treat atrial fibrillation: There remains an unmet

need. American Heart Journal, 151(4), 771-778.

Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide, and propafenone, for the management of atrial fibrillation - Europace (2011) 13, 329–345 - Fig 01

Diagram flow. *Number of studies that reported the event and at least 1 event was observed during follow-up.

Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on all-cause mortality. Odds ratios and 95% confidence intervals.

Note—odds ratio smaller than 1 indicates a benefit (lower mortality) for the active agent.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on all-cause mortality in studies involving .100 patients in either arm. Odds ratios and 95% confidence intervals. Note—odds

ratio smaller than 1 indicates a benefit (lower mortality) for the active agent.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on stroke. Odds ratios and 95% confidence intervals.

Note-odds ratio lower than 1 describes a lower rate of stroke for the active treatment.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on atrial fibrillation recurrence. Odds ratios and 95% confidence intervals.

Note-odds ratio lower than 1 describes a lower rate of atrial fibrillation recurrence for the active treatment.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on treatment discontinuation. Odds ratios and 95% confidence intervals.

Note-odds ratio smaller than 1 indicates a benefit (lower discontinuation) for the active agent.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on withdrawal due to adverse events. Odds ratios and 95% confidence intervals.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on incidence of serious adverse events. Odds ratios and 95% confidence intervals.

Note-odds ratio lower than 1 describes a lower rate of serious adverse events for the active treatment.


Mixed treatment comparison analysis: effect of anti-arrhythmic drugs on incidence of proarrhythmic events, odds ratio, and 95% confidence intervals.


Cochrane review(2007) found that several class IA, IC, and III drugs maintain sinus rhythm, but are associated with an increase in AEs, including proarrhythmia [15]. Overall, the recurrence of AF was decreased by 20-50% when AAD were used

compared with when AADs were not used. However, none of these drugs have been shown to reduce mortality or any major cardiovascular outcomes. In a study by Flaker et

al., patients receiving antiarrhythmic therapy (quinidine, procainamide, disopyramide, flecainide, encainide, and amiodarone) had an increased risk of cardiac mortality (relative risk [RR] 2.5, confidence interval [CI] 1.3-4.9, p=0.006) and arrhythmic death (RR 2.6, CI 1.2-5.6, p=0.02) compared with those not given antiarrhythmic medications. Among patients with a history of heart failure, risk increased further (cardiac mortality, RR 4.7,

CI 1.9-11.6; p<0.001; arrhythmic death, RR 3.7, CI 1.3-10.4, p=0.01).

Meta-analysis of dabigatran etexilate 150 mg BID versus

placebo, aspirin monotherapy, aspirin plus clopidogrel, and

adjusted-dose vitamin K antagonists.

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when compared with placebo, dabigatran etexilate was estimated to

provide a reduction in risk up to 75% for any stroke, up to 77% for

ischaemic stroke, up to 83% for systemic embolism, and up to 36%

for all-cause death. When compared with aspirin plus clopidogrel

and aspirin monotherapy, use of dabigatran etexilate was estimated

to provide reduction in risk up to 63% for any stroke, 63% for

ischaemic stroke, and up to 79% for systemic embolism

Pharmacological Rate Control During Atrial Fibrillation

RECOMMENDATIONS

Class I

1. Measurement of the heart rate at rest and control of the rate using pharmacological agents (either a beta blocker or nondihydropyridine calcium channel antagonist, in most cases) are recommended for patients with persistent or permanent AF. (Level of Evidence: B)

2. In the absence of preexcitation, intravenous administration of beta blockers (esmolol, metoprolol, or propranolol) or nondihydropyridine calcium channel antagonists (verapamil, diltiazem) is recommended to slow the ventricular response to AF in the acute setting, exercising caution in patients with hypotension or HF. (Level of Evidence: B)

3. Intravenous administration of digoxin or amiodarone is recommended to control the heart rate in patients with AF and HF who do not have an accessory pathway. (Level of Evidence: B)

4. In patients who experience symptoms related to AF during activity, the adequacy of heart rate control should be assessed during exercise, adjusting pharmacological treatment as necessary to keep the rate in the physiological range. (Level of Evidence: C)

5. Digoxin is effective following oral administration to control the heart rate at rest in patients with AF and is indicated for patients with HF, LV dysfunction, or for sedentary individuals. (Level of Evidence: C)


RECOMMENDATIONS

Class IIa

1. A combination of digoxin and either a beta blocker or nondihydropyridine calcium channel antagonist is reasonable to control the heart rate both at rest and during exercise in patients with AF. The choiceof medication should be individualized and the dose modulated to avoid bradycardia. (Level of Evidence: B)

2. It is reasonable to use ablation of the AV node or accessory pathway to control heart rate when pharmacological therapy is insufficient or associated with side effects. (Level of Evidence: B)

3. Intravenous amiodarone can be useful to control the heart rate in patients with AF when other measures are unsuccessful or contraindicated. (Level of Evidence: C)

4. When electrical cardioversion is not necessary in patients with AF and an accessory pathway, intravenous procainamide or ibutilide is a reasonable alternative. (Level of Evidence: C)


RECOMMENDATIONS

Class IIb

1. When the ventricular rate cannot be adequately controlled both at rest and during exercise in patients with AF using a beta blocker, nondihydropyridine calcium channel antagonist, or digoxin, alone or in combination, oral amiodarone may be administered to control the heart rate. (Level of Evidence: C)

2. Intravenous procainamide, disopyramide, ibutilide, or amiodarone may be considered for hemodynamicallystable patients with AF involving conduction over an accessory pathway. (Level of Evidence: B)

3. When the rate cannot be controlled with pharmacological agents or tachycardia-mediated cardiomyopathyis suspected, catheter-directed ablation of the AV node may be considered in patients with AF to control the heart rate. (Level of Evidence: C)


RECOMMENDATIONS

Class III

1. Digitalis should not be used as the sole agent to control the rate of ventricular response in patients with paroxysmal AF. (Level of Evidence: B)

2. Catheter ablation of the AV node should not be attempted without a prior trial of medication to control the ventricular rate in patients with AF. (Level of Evidence: C)

3. In patients with decompensated HF and AF, intravenous administration of a nondihydropyridine calcium channel antagonist may exacerbate hemodynamic compromise and is not recommended. (Level of Evidence: C)

4. Intravenous administration of digitalis glycosides or nondihydropyridine calcium channel antagonists to patients with AF and a preexcitation syndrome may paradoxically accelerate the ventricular response and is not recommended. (Level of Evidence: C)

Effects of propranolol (4-40 mg/day) on lymphocyte ß2-AR density in six male volunteers. Ordinate, left lymphocyte ß2-AR density in ICYP binding sites/cell; right plasma propranolol levels in ng/ml. Solid horizontal line and broken lines mean±SEM of lymphocyte pre-drug ß2-AR density. Abscissa

days of study. *P<0.05 vs pre-drug levels.

ß-adrenoceptor blocker treatment and the cardiac ß-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure – Fig 01

Effect of chronic ß-AR blocker treatment on right atrial and saphenous vein ß-AR in patients undergoing coronary artery bypass surgery.


Effect of long-term ß-AR blocker treatment (with metoprolol or bisoprolol) on right atrial GRK activity in patients with different degrees of heart failure. Ordinate GRK activity in cpm [32 P]

rhodopsin/ mg protein. Numbers at the bottom of the column number of patients studied. Modified from Leineweber et al.


Bisoprolol (10 mg p.o.)-induced attenuation of dobutamine infusion induced increases in heart rate, contractility and plasma renin activity in ten male volunteers homozygous for the Arg389 ß1-AR and

eight male volunteers homozygous for the Gly389 ß1-AR polymorphism.


Comparisons of (a) PFR, (b) FG in sinus rhythm among the severe LV dysfunction group (N=38), mild LV dysfunction group (N=33) and control group (N=5)

Force-frequency relationship as a predictor of long-term prognosis in patients with heart diseases - Heart Vessels (2011) 26:153-59 - Fig 3

Mortality and atrial fibrillation in myocardial infarction patients. CI indicates confidence interval.

Mortality Associated With Atrial Fibrillation in Patients With Myocardial Infarction - American Heart Association. - DOI: 10.1161/CIRCULATIONAHA.110.986661 – Fig 02

Kaplan-Meier estimates (analysis of time to first event) of risk of death during first 180 days after randomisation (based on the intention-to-treat analysis)

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial THE LANCET ?Vol 360 -July 20, 2002 – Fig 4

Diagram of the electroionic changes occurring during cellular depolarization and repolarization of contractile myocardium cells


Cellular excitability phases and refractory periods in cells where excitability recovery is voltage-dependent (rapid response).


Location of refractory periods at atrioventricular (AV) level.


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