Pharmacologic Treatment Of Patients With Nsvt

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For patients at high risk, the concept of primary prevention of death is valid as long as an effective, proven, prophylactic approach exists. Several methods have been attempted: antiarrhythmic drug suppression and ICD therapy.

ACE inhibitors, spironolactone, and beta-blockers improve survival in "high-risk" patients with NSVT who have CAD, heart failure and/or impaired ventricular function. Even so, death rates in these high-risk groups remain high. Beta-blockers are effective in reducing overall and sudden death mortality among survivors of MI. Whether or not beta-blocker therapy suppresses NSVT or has particular benefit in the NSVT population remains unclear. Nevertheless, beta-blockers improve survival, and should therefore be part of the treatment regimen in post-infarct patients unless contraindications exist.

Antiarrhythmic drugs can suppress NSVT, but they can also increase ectopy and cause sustained VT, torsades de pointes, bradycardia, VF, and death. The empiric use of an antiarrhythmic drug to suppress asymptomatic NSVT is not recommended, and probably never will be. Suppressive antiarrhythmic drug use tested in post-infarct patients has shown no benefit thus far, and in several instances has demonstrated harm (78-82). Antiarrhythmic drug risk is lowest when there is no structural heart disease, and in this setting can be used with more impunity when there is need to suppress symptomatic NSVT ("idiopathic" NSVT).

The Cardiac Arrhythmia Suppression Trial (CAST I) tested the hypothesis that suppression of ventricular arrhythmias after MI with a class I antiarrhythmic drug would improve survival (80,83,84). The trial was terminated early because arrhythmic death and total mortality were substantially higher among those receiving encainide and flecainide compared to those receiving placebo, despite effective suppression of ventricular ectopy. Similarly, CAST II was stopped because of early excess mortality in those receiving moricizine compared with placebo despite arrhythmia suppression. These data support the concept that antiarrhythmic drug suppression of ventricular arrhythmias, including NSVT, can be harmful. As a low mortality rate was present in the placebo group, CAST may have targeted a population at a risk too low to benefit from antiarrhythmic prophylaxis. The sickest patients (e.g., those with NYHA class IV CHF or sustained VT) were excluded from CAST. Despite these limitations, the increased mortality rate in the empirically drug-treated patients focused on the dangers of arrhythmia suppression by an antiarrhythmic drug.

Drug suppression with other antiarrhythmic drugs, and in different patient populations, highlight the global dangers of antiarrhythmic drugs used "empirically" in patients with NSVT. A pure class III drug, D-sotalol, tested in a post-MI population, showed similar results to CAST. The Survival with ORal D-Sotalol (SWORD) trial was designed to test the hypothesis that d-sotalol would reduce all-cause mortality in patients with previous MI and left ventricular dysfunction (79). Many patients in SWORD had NSVT. The trial was terminated prematurely because of a higher mortality among those randomized to d-sotalol. Excess mortality occurred in the "less sick" patients with more preserved left ventricular function, suggesting that the risk of pro-arrhythmia because of D-sotalol was higher than the baseline risks in these patients.

Post-MI studies of empiric amiodarone (BASIS, EMIAT, CAMIAT) and dofetilide (DIAMOND), however, showed a neutral effect on mortality DIAMOND-MI (81,8587). There was no difference in all-cause or cardiac mortality between the amiodarone and placebo. As many of patients in these trials had NSVT, it is likely that amiodarone use is safe for patients with CAD and NSVT (although not necessarily beneficial). The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) enrolled 1,202 post-MI patients with frequent or repetitive ventricular premature depolarizations, and randomly assigned them to amiodarone or placebo. The primary end point was the combination of resuscitated VF and arrhythmic death, which occurred in 6% of the group receiving placebo and 3.3% of the group receiving amiodarone (RR reduction 48.5%, p = 0.016) over a mean follow-up of 1.8 yr. The study lacked power to detect a reduction in all-cause mortality. The European Myocardial Infarct Amiodarone Trial (EMIAT) enrolled 1,486 patients 5-21 d after MI with a LVEF >0.40. The results were nearly identical to those of CAMIAT; there was a decrease in resuscitated cardiac arrest and arrhythmic death, but not total morbidity in patients randomized to amiodarone. In a meta-analysis of these two studies, and several smaller studies evaluating amiodarone in post-infarct and heart-failure patients, total mortality was decreased slightly in patients randomized to amiodarone (87a).

To assess whether beta-blockers used with amiodarone in post-MI patients could improve survival, a post-hoc, intention-to-treat analysis was performed from pooled CAMIAT and EMIAT data. Unadjusted and adjusted relative risks for total mortality, cardiac death, arrhythmic death, non-arrhythmic cardiac death, and resuscitated cardiac arrest or arrhythmic death were lower for patients taking beta-blockers at entry and randomized to amiodarone than for those receiving amiodarone alone. Although these findings require further confirmation, they support the idea that a beta-blocker works synergistically with amiodarone (87b).

The Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT) randomized 674 patients with heart failure, cardiac enlargement, > 10 premature ventricular contractions (PVCs)/h, and a LVEF of < 0.40 to either amiodarone or placebo (47). Overall mortality was the primary end point. Although amiodarone effectively suppressed ventricular ectopy and improved the LVEF, the 2-yr actuarial survival rate was the same in both groups (69.4% amiodarone vs 70.8% placebo, p = 0.6).

An antiarrhythmic drug for NSVT can be a double-edged sword—although the symptoms may be improved, survival may be worsened. No study has shown that empiric suppression of NSVT with an antiarrhythmic drug improves survival. If there is a need to suppress NSVT for symptoms in a high-risk patient or to treat other arrhythmias, amiodarone is the drug of choice.

IMPLANTABLE CARDIOVERTER DEFIBRILLATORS (ICDs) IN NSVT PATIENTS

The ICD is highly effective in terminating life-threatening "malignant" ventricular arrhythmias, and, as such, can lower mortality rates in select populations. As NSVT can be an indicator of risk of arrhythmic death, it has been postulated that ICD implantation may improve survival. The ICD is not meant to treat spontaneously terminating (i.e., nonsustained) VT. An ICD could have a proarrhythmic effect, transforming a benign episode of NSVT into life-threatening VF. Also, ICD shocks may be triggered for a benign arrhythmia (such as AF or sinus tachycardia) or for NSVT that would stop, or does stop, spontaneously, with a negative impact on quality of life. Finally, lead malfunction can cause spurious shocks which detract from quality of life, and may pose risk.

ICD Clinical Trials

To evaluate the survival benefits from ICD implantation, the only end points of importance are all-cause or total mortality. Any other end point ("appropriate shock," treated VT, arrhythmic death, or sudden death) is inadequate and of less importance. As Milton Packer has said: "All deaths are sudden: one minute you are alive. The next you are dead."

Two multicenter primary prevention ("prophylactic") trials have been completed in high-risk patients with NSVT, impaired ventricular function, and ischemic heart disease: the MADIT (Multicenter Automatic Defibrillator Implant Trial) (88) and the MUSTT (Multicenter UnSustained Tachycardia Trial) trials (89). Several important ICD trials are in progress: SCD-HeFT, DEFINITE, COMPANION, MADIT II, and others.

The MADIT trial assessed patients who had CAD and a prior MI. To be enrolled, patients were required to have a LVEF <0.35, asymptomatic NSVT on a Holter recording, and inducible, nonsuppressible (by procainamide) VT or VF induced during electro-physiology testing. Patients with an acute infarction or recent surgery or angioplasty were excluded. Patients were assigned randomly to ICD implant or "conventional" medical therapy. "Conventional" therapy was not specified, but consisted initially of

Electro Physiology
Fig. 7. Data from the MADIT trial—Kaplan-Meier survival curve, depicting total survival in patients randomized to ICD therapy vs conventional therapy. (From: Moss AJ. N Engl J Med 1996;335:1938.)

amiodarone in 74% of the patients (45% of whom were taken off amiodarone within 6 mo). One hundred ninety-six patients (16 women, mean age 63 yr) were enrolled from 32 centers over a 5-yr period (on average, slightly more than one patient enrolled per center per yr) with most patient enrollment concentrated at 2 sites (63 patients, 32% of the study population). The mean ejection fraction was 0.26. Seventy-five percent were randomized >6 mo after an acute MI.

The trial was terminated because of a dramatic decrease in total mortality in the ICD arm (see Fig. 7). The mortality reduction was 54% at 27 mo (p = 0.009). A powerful triangular statistic used to analyze the data in MADIT. Although rarely used in cardiac research, this methodology yielded a statistically significant result with the smallest number of patients enrolled. Most of the benefit of the ICD occurred early after implantation.

The 24-mo mortality in the "conventional arm" was high: 32%. This high mortality may reflect a selection bias, as this mortality was greater than expected based on studies of patients who had survived sustained VT or cardiac arrest (88a). The MADIT population, as a highly selective referral population, was difficult to quantify. These enrolled patients may therefore not represent all patients who could satisfy the enrollment criteria.

Therapy in the non-ICD ("conventional") group was left to the individual investigator to decide. Thus, there was no true control group. Many standard therapies, including beta-blockers, ACE inhibitors, diuretics, and digoxin were relatively underused in the "conventional" group. Drug therapy, dosing, or monitoring were not controlled or even assessed. In the ICD arm, there was more frequent use of beta-blockers (26% vs 8%).

Despite these limitations, electrophysiologists were quick to embrace the results of MADIT, citing its randomized nature and the magnitude of the benefit. The provocative implications of this trial, however, are tempered by several important considerations:

Diuretics Diagrams
Fig. 8. Venn diagram "identifying" the MADIT patient population.

1) NSVT can be a nonspecific marker; 2) Electrophysiology testing was not shown to enhance patient selection for ICD implantation; and 3) The applicability of these results remains questionable, even in patients with CAD. Nevertheless, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines indicate that a class I indication for an ICD is inducible, nonsuppressible, VT in a patient with NSVT and ischemic cardiomyopathy (90).

The common problem of NSVT in patients with structural heart disease can be a highly visible reminder of risk of death. Although MADIT focused attention on this issue, controversy persists. The high mortality in MADIT may simply reflect the patient selection and enrollment specific to this trial and not represent the larger population of patients who appear to satisfy the enrollment criteria (see Fig. 8). Giorgberidze et al. showed that "MADIT-type" patients have a low mortality if they are simply treated with a beta-blocker and no antiarrhythmic therapy (91).

The Multicenter Unsustained Tachycardia Trial (MUSTT), the second important multicenter NSVT trial, tested the hypothesis that electrophysiology-guided anti-arrhythmic therapy would reduce the risk of sudden cardiac death or cardiac arrest (89). A total of 2,202 patients were enrolled from 85 centers. All had CAD, a LVEF <0.40, and asymptomatic NSVT. Of the patients enrolled, thirty-two percent (704) had inducible sustained ventricular tachyarrhythmias, and were randomized to antiarrhythmic therapy (drugs or an ICD) or to no antiarrhythmic therapy. A total of 1,435 patients did not have an inducible sustained tachyarrhythmia and were followed without antiarrhythmic therapy in a registry, as were 63 patients with inducible tachyarrhythmias who refused randomization. Therapy with ACE inhibitors and beta-blockers was recommended for all patients.

Patients designated for no antiarrhythmic therapy had 2-yr and 5-yr rates of cardiac arrest or arrhythmic death of 18% and 32%, respectively. Corresponding rates for patients assigned to electrophysiology test-guided therapy were 12% and 25% (p = 0.04). Overall mortality rates for patients assigned to no antiarrhythmic therapy were 28% at 2 yr and 48% at 5 yr, compared with 22% and 42%, respectively, for those assigned to electrophysiology test-guided therapy (p = 0.06, see Fig. 6B). At 5 yr, the death rate from cardiac causes was significantly higher in the group randomized to no antiarrhythmic therapy, compared with those assigned to electrophysiology test-guided treatment (40% vs 34%, p = 0.05). There was no significant difference in the prevalence of spontaneous, sustained VT between the two groups. Inducibility was not associated with the length of the qualifying run of NSVT (49).

The lower incidence of arrhythmic death and cardiac arrest among patients randomized to electrophysiology-guided therapy was attributable entirely to the ICD. There was no specific randomization to ICD, but among patients assigned to electrophysiology-guided therapy who received an ICD because of drug inefficacy, the 5-yr sudden death or cardiac arrest rate was 9%, compared with 37% among those in the group who were treated with antiarrhythmic drugs (p < 0.001). The total mortality at 5 yr was 24% among the group receiving an ICD vs 55% among those who did not (p < 0.001, see Fig. 6C). Thus, all of the benefit in the EP-guided group was attributable to ICD therapy; patients in the EP-guided group who did not receive ICDs fared worse than patients randomized to conventional therapy.

The results of MUSTT confirmed the results of MADIT: patients with CAD, left ventricular dysfunction, asymptomatic NSVT, and inducible sustained VT have a high arrhythmic and total mortality. MUSTT provided evidence that therapy with an ICD, but not with an antiarrhythmic drug, reduces the risk of death. Lingering questions after these studies center on how best to identify patients that will benefit from prophylactic ICD implantation (see Fig. 8). Questions include: should screening Holter monitors be performed? If so, how often? Can these results be extrapolated to slightly different populations (e.g., patients who have undergone recent revascularization or those with LVEF of 0.45%)? How should patients with NSVT and non-ischemic cardiomyopathy be managed?

Several ongoing trials are attempting to define other high-risk populations. The Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) is evaluating 2,500 patients with class II or III heart failure and a LVEF of <0.35 (91a). This primary prevention placebo-controlled trial is designed to test the hypothesis that an ICD or amiodarone can improve survival in patients already treated with the optimal pharmacologic therapy, including an ACE inhibitor an a beta-blocker. The SCD-HeFT trial has the potential to target a large, less selective high-risk population and with less bias than previous primary prevention trials. While NSVT is not required for enrollment, the actual incidence of NSVT in the study population is likely to be high.

The MADIT II trial is evaluating patients with ischemic cardiomyopathy, New York Heart Association (NYHA) functional class I-III, and LVEF <0.30, to test the hypothesis that these patients will have a lower total mortality with an ICD implant (91b). MADIT II is comparing ICD therapy to no specific additional therapy in this high-risk population. No specific Holter or electrophysiology test criteria are required for enrollment, although device-based EPS is performed at the time of ICD implantation in patients randomized to device therapy. Patients who meet MADIT I ICD implant criteria are excluded from MADIT II.

Another trial which may provide clues to the treatment of high-risk patients with NSVT is the DEFINITE (DEFibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation) trial (91c). This trial tests the hypothesis that an ICD will improve survival in patients with a history of symptomatic CHF non-ischemic dilated cardiomyopathy

(LVEF <0.35), and spontaneous ventricular arrhythmias >10 PVCs/h or NSVT documented on telemetry or Holter monitoring). Exclusion criteria include: CAD, symptomatic ventricular arrhythmias, unexplained syncope within the past 6 mo, prior cardiac arrest, NSVT >15 beats at a rate >120/min, and NYHA functional class IV CHF. All patients will receive standard therapy for CHF, including beta-blockers. One group will receive an ICD. The primary end point is total mortality. Secondary end points include cost-effectiveness, quality-of-life, and cause-specific mortality. There is a 2-yr enrollment with an 18-mo follow-up. The investigators hope to enroll more than 400 patients.

Data from recent clinical trials provide strong evidence that the ICD is useful in patients with NSVT, CAD, impaired ventricular function, and a positive electrophysiol-ogy test. This is the only group of patients that should be considered for a prophylactic ICD based on the present data. There is no other group with asymptomatic NSVT for whom prophylaxis with an antiarrhythmic drug or an ICD has been proven to be beneficial. Ongoing trials will define which other patient groups will benefit from prophylactic ICD implantation.

Guidelines for Prophylactic ICD Implantation

In 1998, the joint ACC/AHA task force deemed the MADIT profile a class I indication (evidence and/or general agreement that the ICD is beneficial, useful, and effective) for ICD implantation: Non-sustained ventricular tachycardia with coronary disease, prior myocardial infarction, left ventricular dysfunction, and inducible ventricular fibrillation or sustsained ventricular tachycardia at electrophysiologic study that is not suppressible by a class I antiarrhythmic drug (90). A class IIb indication (conflicting evidence and/or a divergence of opinion with usefulness of the ICD less well-established) includes nonsustained ventricular tachycardia with CAD, prior MI, and left ventricular dysfunction, and inducible sustained VT or VF at EPS (90). The subgroup, like the MADIT population, differs because an antiarrhythmic drug has not been tested. Many electrophysiologists are now performing EPS in patients who fit the MADIT profile, but are implanting ICDs without testing procainamide. The value of drug testing is questionable. Even if a patient responds beneficially to procainamide during electrophys-iology testing, there are no data indicating that chronic treatment with procainamide will provide a benefit, or that the patient is at a lower risk than patients who do not respond to procainamide.

A number of situations involving NSVT have been deemed class III indications, such as when an ICD is not indicated (90). These include NSVT amenable to surgical or catheter ablation (e.g., idiopathic right ventricular outflow tract (RVOT) or left ventricular septal tachycardias), NSVT caused by a transient or reversible disorder, patients with a terminal illnesses (projected life expectancy <6 mo) and drug-refractory NYHA functional class IV heart failure in patients who are not candidates for cardiac transplantation. Ironically, patients with profound heart failure, cardiomyopathy, and prolonged QRS duration are the focus of studies with biventricular pacing ICDs, to determine whether this device improves survival rates in these high-risk patients.

Caveats Regarding Prophylactic ICD Therapy

A therapy must be evaluated based on its ability to improve longevity and symptoms, but other variables must also be considered: risk, quality of life, and cost. Many patients

Symptoms?

Symptoms?

Algorithm For Icd Management
Fig. 9. Algorithm for the management of patients with NSVT.

do not fit clearly into trial inclusion criteria, and extrapolation of study results can be difficult. For example, is it appropriate to evaluate a 90-yr-old with NSVT for prophylactic ICD implantation? Enthusiasm for ICD use has led to attempts to treat patients with more complex medical problems. In such settings, the ICD may or may not prolong overall survival. In some patients, ICD therapy may impair the quality of remaining life without increasing longevity. In addition, patients with multisystem diseases may have problems that complicate the use of the ICD and increase the risk of device implantation.

Quality-of-Life Issues

Although the ICD clearly has the potential to reduce sudden cardiac death and total morbidity in high-risk patients with NSVT, the impact of the ICD on quality of life is not fully understood. Based on a recent review of published studies that address the psychosocial effects of ICDs, Sears et al. concluded that patients who experience high discharge rates, as well as young ICD recipients, appear to be at highest risk for impaired quality of life (92-94). The incidence of psychological disorders, including depression, appears high. Issues include fear of a shock and/or device malfunction, fear of death, and fear of embarrassment. Between 13% and 38% of ICD recipients experience high levels of anxiety, but these studies are not conclusive, and results vary. Additional investigations concerning the effects of ICD therapy on quality of life are needed.

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Responses

  • adelfo
    Are rvot nsvt tachycardia dangerous?
    8 years ago
  • cristoforo
    Which drugs would be given to treat nsvt?
    8 years ago
  • Ayden
    Does patient with defibrilator needs amiodarone for nsvt?
    8 years ago

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