Primary Prophylaxis With the Implantable Cardioverter-Defibrillator: Title and subTitle BreakThe Need for Improved Risk Stratification

Identification of patients at risk for sudden cardiac death (SCD) is a major challenge for the medical community. Although there have been advances in the area of risk stratification, it remains troubling that the majority of individuals who die of SCD are among a population that is not identified by current methods of risk stratification.¹ Nevertheless, several recent trials have attempted to identify groups of patients who may benefit from an implantable cardioverter-defibrillator (ICD).

Current guidelines recommend that survivors of cardiac arrest (occurring after the first 24 hours following myocardial infarction) receive an ICD for secondary prophylaxis of SCD.² However, identifying individuals for primary prophylaxis of SCD with an ICD has proven more difficult. Initial studies identified high-risk patients as those surviving myocardial infarction with significant left ventricular dysfunction and an abnormal electrophysiological study.^{3 - 4} Most recently, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that patients with an ejection fraction (EF) less than 35%, regardless of the nature of the underlying heart disease and irrespective of an electrophysiological study, were high-risk individuals for SCD and would benefit from a prophylactic ICD.⁵

The Center for Medicare & Medicaid Services has updated and expanded its guidelines for coverage of ICD implantation to reflect these findings.⁶ Specifically, prophylactic ICD implantation is approved for patients with New York Heart Association class II or III heart failure and an EF of less than 35%. The effect of this policy has been to expand the number of Medicare beneficiaries eligible for an ICD to more than 500 000. Clearly, the cost to the health care system from this proposal is immense and may ultimately be prohibitive.⁷ In light of the recent ICD recalls, the importance of clearly establishing the need for prophylactic ICD implantation is paramount.⁸

When considering the current guidelines for risk stratification of SCD, it is important to first appreciate that an ideal risk stratification scheme should be reproducible and tailored to the distribution of risk in the population at large. An ideal approach should not only classify patients as high risk or low risk but also have a strategy to further risk stratify patients who are at intermediate risk, so that a large majority of patients could be reliably risk stratified. Remarkably, as the indications for ICD implantation for primary prophylaxis have been extended, the recommended method of risk stratification now relies solely on EF. We question the logic of using a dichotomous EF as the single criterion for ICD implantation for primary prophylaxis.

Although EF has substantial prognostic value for the prediction of SCD, it may not be a reproducible measurement. The echocardiographic measurement of left ventricular dimensions can vary significantly in weekly repeated measurements in an individual patient. The limits of agreement may vary by as much as 8.5% above or below the mean calculated EF in repeated studies.⁹ There may also be differences in the calculated EF for the individual patient, depending on the method used to calculate it. Even using cutting-edge techniques of myocardial imaging, such as contrast echocardiography and cardiac magnetic resonance imaging, there can be a substantial difference in the EF between these studies in an individual patient.¹⁰

Why are there such differences in determining the EF? In addition to methodological variation in calculating EF as well as individual reader differences, biological factors may cause variation in left ventricular dimensions and function. Loading conditions vary on a diurnal basis reflecting changes in intravascular volume and adrenergic drive. Even though small differences in the assessment of EF led to significantly different outcomes in a large clinical trial, there can be large variance in an individual patient.¹¹ In this way, large-scale studies dichotomize patients into high- and low-risk categories even though risk stratification using a cutoff EF alone may not be a clinically robust strategy in the individual patient. Because of the substantial variation in the measurement of EF in an individual, a patient without clinically significant changes in cardiac status may one day “qualify” for an ICD for primary prophylaxis and on another day not qualify at all.

It is unfortunate that current guidelines have reduced risk stratification for SCD to a single, potentially imprecise measurement, with no provision for further risk stratifying of patients who may be at intermediate risk. The risk for SCD appears to be distributed across a spectrum¹ rather than simply high or low. Evidence suggests that EF alone lacks sufficient sensitivity and specificity to be a useful method of risk stratification.^{1 ,12} In a registry of 492 patients who sustained out-of-hospital cardiac arrest, only 19% of patients had an EF less than 30% prior to the event. Most patients enrolled in the largest trials of secondary prophylaxis of sudden cardiac death had an EF of greater than 30%.^{13 - 15} Thus, with the current American College of Cardiology/American Heart Association ICD guidelines,² the majority of patients who die of SCD would never have qualified for an ICD for primary prophylaxis. Moreover, of those patients who are receiving ICDs for primary prophylaxis, most will never use their ICD (81% over 5 years of follow-up in SCD-HeFT).⁵ There is clearly much room for improvement in patient selection and thus more cost-effective management.⁷

Developing a scoring system using readily available, noninvasive methods of risk stratification may be the best approach to defining the spectrum of risk for SCD. Risk scores have helped clinicians tremendously in considering the best course of management for common cardiac problems and pervade many of the guidelines for care of the cardiac patient. For instance, the Framingham Risk Score assists clinicians in appropriately treating hypercholesterolemia.¹⁶ The Congestive Heart Failure, Hypertension, Age, Diabetes and Stroke index (CHADS2) assists clinicians in appropriately treating or withholding systemic anticoagulation therapy to prevent stroke in patients with chronic atrial fibrillation.¹⁷ The Thrombolysis In Myocardial Infarction (TIMI) risk score helps to risk stratify patients presenting with non–ST-elevation myocardial infarction so that the appropriate management strategy can be implemented.¹⁸ With the assistance of a risk score, clinicians faced with an individual patient can reliably withhold potentially expensive or risky therapies in low-risk patients without compromising the quality of care.¹⁹

Although EF is a powerful factor for risk stratification for SCD, several other well-established noninvasive methods of risk stratification, including signal-averaged electrocardiogram, heart rate variability, baroreflex sensitivity, heart rate profile during and after exercise, maximum oxygen consumption during exercise, microvolt T-wave alternans, and serum BNP level, have independent prognostic value.^{20 - 24} By assessing these risk factors in addition to EF in a registry of patients with cardiac disease, whether or not they receive an ICD, it would be possible to develop a risk score to more accurately predict SCD. Similar to other risk scores in cardiac management, a risk score for SCD would provide a strategy to risk-stratify patients who are not clearly high risk or low risk. A risk score would also allow for more cost-effective utilization of resources, which has previously been suggested with the use of baroreflex sensitivity.^{25 - 26} A risk prediction score for SCD that more clearly delineates the spectrum of risk in an individual patient may allow clinicians to withhold implantation of a costly ICD in a low-risk patient with a low EF. A risk prediction score may even allow clinicians to identify high-risk patients following myocardial infarction with a relatively preserved EF, thus making inroads into the large population of at-risk patients who would not otherwise qualify for an ICD by current guidelines.¹

It is extremely important that such studies addressing risk stratification for SCD be conducted both for clinicians who are faced with the difficult decision of ICD implantation and for a health care system that will struggle to remain solvent. Until then, it is important for clinicians to realize that when confronted with an individual patient, risk stratification for prevention of SCD may not be as simple as an absolute EF.