Comparing the largest registry of ICD implants in the United States with 2 pivotal primary prevention randomized clinical trials, we demonstrated that the adjusted survival of MADIT-II–like and SCD-HeFT–like patients who received a primary prevention ICD in clinical practice was not significantly different from the survival of patients who received an ICD in the clinical trials but was significantly greater than the survival of trial patients randomized to receive medical therapy only. Importantly, the generalizability of these results held even after limiting the analyses to patients 65 years and older.
Prior work in other fields has demonstrated that it is often challenging to generalize the findings from randomized clinical trials to clinical practice.5–11
Our study found that patients receiving ICDs in clinical practice were significantly older and had more co-morbidities than those enrolled in the randomized clinical trials. The rates of use of cardiac medications were also significantly different between the groups. After adjusting for these differences with propensity score matching and Cox proportional hazards models, we found no significant difference in survival between MADIT-II–like patients in the ICD Registry and patients randomized to ICD therapy in MADIT-II and significantly better survival than patients randomized to medical therapy in MADIT-II.
However, there was an appreciable difference in survival between MADIT-II patients who received medical therapy and MADIT-II–like patients in the ICD Registry that appeared early and continued during follow-up (). Although the improved survival among the MADIT-II–like patients in the registry is likely due to the ICD, other additional factors may have played a role. Such factors include the (slightly) lower blood urea nitrogen and higher rates of β-blocker and statin use at baseline in the registry patients after matching. Although blood urea nitrogen was not significantly different between the 2 groups, it was the strongest (by χ2 statistic) factor in the mortality model, which is why it likely had an appreciable effect on the results.
Similarly, we observed no significant difference in survival between SCD-HeFT–like patients in the ICD Registry and patients randomized to receive ICD therapy in SCD-HeFT and significantly better survival than patients randomized to placebo in SCD-HeFT. Similar results were found when the analysis was limited to patients 65 years and older. This is important because of the potential for a higher risk of complications from implanting this device in older patients and the presence of other competing risks for mortality. These findings underscore the effectiveness of primary prevention ICD therapy in clinical practice.
In this analysis, we focused on the following question: when we restrict the real-world analysis to patients who are similar to trial patients, is their survival different? Although this is a narrower definition of external validity, it is an important one. Patients enrolled in randomized clinical trials of primary prevention ICD therapy were monitored carefully over the course of the trials, and physicians who implanted and followed those devices were highly experienced. This level of care may not occur in real-world practice. A previous report using Medicare Claims data found that only 43% of patients who received an ICD had an initial follow-up visit within the recommended 2- to 12-week window after device implantation, and approximately 20% of surviving patients had no follow-up within a year.16
In another analysis of Medicare Claims data, there was an association between a higher risk of procedural complications and a lower volume of ICD implants.17
Therefore, it is reasonable to question whether the results of the trials can be expected in clinical practice. Through propensity score matching and adjustment for differences between registry patients and patients enrolled in the clinical trials, our matched sample became similar to patients enrolled in the clinical trials. This enabled us to address the concern that the care of patients in the highly controlled and monitored setting of clinical trials compromises the external validity of the results.
One prior retrospective study compared clinical practice patients with an ICD with clinical practice ICD-eligible patients with no ICD, using data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry and the Get With The Guidelines–Heart Failure (GWTG-HF) registry, as well as long-term outcome data from Medicare claims files.18
In the 4685 identified patients (mean age, 75 years), mortality was significantly lower among patients who received an ICD compared with those who did not (adjusted hazard ratio, 0.71; 95% CI, 0.56–0.91).18
Our findings support the results of this study and extend them beyond the Medicare population.
One of the main purposes of the ICD Registry, as specified by the Centers for Medicare & Medicaid Services, was to define how the characteristics and outcomes of Medicare beneficiaries receiving a primary prevention ICD compare with those of patients enrolled in the primary prevention ICD randomized clinical trials. Our analysis provides important data on the survival of trial-eligible patients who receive a primary prevention ICD in routine clinical practice, including patients 65 years and older.
Our study has several limitations. Because of appreciable differences in baseline characteristics between registry and randomized clinical trial patients, we were unable to address the question of how the outcomes of patients receiving an ICD in randomized clinical trials compare with the outcomes of all patients seen in clinical practice. Thus, our results may not apply to registry patients who are significantly different from patients in the clinical trials. The most valid approach for examining the effectiveness of ICDs in clinical practice would be through a clinical trial that randomizes patients of similar age and comorbidities to patients seen in clinical practice to an ICD vs no ICD. Propensity score matching was used to create comparable populations. Because of the exclusion of many patients, our cohort may not resemble a true cohort of patients in real-world practice. We could not adjust for clinical factors not captured by the registry nor for unknown confounders. Data were collected by medical record review that was dependent on the accuracy and completeness of documentation and abstraction. Given the limited follow-up in the clinical trials and the merged ICD Registry with the Death Master File, we were unable to examine longer-term survival.
In addition, excluding recipients of cardiac resynchronization therapy may raise concerns about potential fundamental differences between our patient population and patients enrolled in the trials, as some patients with NYHA class III symptoms who would now be eligible for a cardiac resynchronization therapy device were not excluded from MADIT-II and SCD-HeFT; however, patients with NYHA class III symptoms made up only 23% of the MADIT-II population and 30% of the SCD-HeFT population, and a smaller percentage would have qualified for cardiac resynchronization therapy based on a wide QRS.