Quality of Life after PCI vs. CABG among Patients with Diabetes and Multivessel CAD: Results from the FREEDOM Trial

Study Design

The design, methods, clinical, and economic results of the FREEDOM trial have been described previously.^4,5,10 Briefly, between April 2005 and April 2010, patients from 18 countries with DM and angiographically confirmed multivessel CAD were randomized on a 1:1 basis to undergo revascularization by either CABG or DES-PCI. All patients had an indication for revascularization and were suitable candidates for both procedures. All procedures were performed using standard techniques. Following revascularization, optimal medical therapy was recommended for both groups including tight control of DM, hypertension, and dyslipidemia. Institutional Review Board approval of the protocol was obtained at all sites, and all patients provided informed consent. The trial is registered at the National Institutes of Health website (www.clinical-trials.gov; NCT00086450).

Health status assessment

Health status assessments were performed by means of standardized, written questionnaires administered to each patient at baseline (prior to randomization), 1, 6 and 12 months post-randomization, and annually thereafter. In general, questionnaires were administered in person at the time of scheduled follow-up visits. If patients did not complete the questionnaire at that time, it was administered by mail. Questionnaires were administered using linguistically and culturally validated translations in each patient's native language (http://cvoutcomes.org/licenses).¹¹

Disease specific health status was assessed using the Seattle Angina Questionnaire (SAQ) and the Rose Dyspnea Scale (RDS).^12-15 The SAQ is a validated and reliable 19-item questionnaire that measures CAD-related health status across 5 domains. Scores range from 0 to 100 for each domain with higher scores denoting better health status and fewer symptoms. The SAQ has undergone extensive reliability and validity testing and has been shown to correlate with long-term survival and hospitalization for an acute coronary syndrome among patients with chronic CAD.^12,13,16 In order to reduce respondent burden and to focus on those aspects of health status most likely to capture treatment-related differences, data were collected for 3 of the 5 SAQ domains: angina frequency (AF), physical limitation (PL), and quality of life (QoL). Previous studies have suggested that differences of 8-10 points are clinically meaningful for each of the SAQ subscales.¹⁰

The RDS is a 4-item questionnaire that assesses a patient's level of breathlessness with common activities. Scores range from 0 to 4, with 0 indicating no dyspnea with activities and a score of 4 points on the RDS indicating that dyspnea occurs with minimal physical activity (e.g., getting dressed). Previous studies among patients with an acute coronary syndrome have demonstrated this scale to have acceptable reliability, responsiveness, and internal validity as a measure of health status.^14,17 In addition, higher RDS scores correlate with a higher risk of rehospitalization and long-term mortality in this population.¹⁸

Statistical Analysis

Unless otherwise specified, the analytic population for our study consisted of all randomized patients with available baseline health status data, analyzed according to intention to treat (ITT). When indicated, secondary analyses were performed using a per protocol approach in which only patients who underwent their assigned revascularization procedure were included. Baseline characteristics were compared between the 2 groups using t-tests for continuous variables and chi square tests for categorical variables. Mean health status scores were compared between groups at each time point by means of longitudinal random-effect growth-curve models. These models incorporate all available health status scores including those for patients who subsequently died, withdrew from the study, or were lost to follow-up, and assume that any missing data is missing at random.¹⁹ Variables included in the growth curve models included the baseline score of the health status domain being assessed, treatment assignment, and follow-up time. Linear, quadratic, and cubic effects of time were considered, as well as all corresponding interactions between treatment and time. The models were optimized using a backward elimination procedure, starting with the highest order of time by treatment interaction.

In addition to analyzing the SAQ scores as continuous variables, we performed secondary analyses in which the SAQ-AF scale was treated as an ordinal variable, with patients classified as being angina free (i.e., SAQ-AF score of 100), or having either monthly (SAQ-AF score of 70-90), weekly (SAQ-AF score of 40-60) or daily angina (SAQ-AF score of ≤ 30). The impact of treatment with CABG vs. DES/PCI on this categorical outcome variable, at each follow-up time point was analyzed using ordinal logistic regression. A similar approach was applied to the RDS. Additional analyses of both the SAQ and RDS were performed using this approach while incorporating death as the worst possible health state on the ordinal scale.

The extent to which the effect of CABG vs. DES-PCI on the SAQ-AF scale differed according to subgroups was examined through the addition of treatment by subgroup by time interaction terms to the longitudinal models. All subgroup analyses were pre-specified and considered the following factors: age (<65 vs. 65-75 vs. >75), sex, number of diseased vessels, involvement of the left anterior descending artery (>70% stenosis), SYNTAX score²⁰ (≤22 vs. 23-32 vs. ≥33), and baseline angina severity (daily/weekly vs. monthly vs. none). These subgroup comparisons were restricted to the 1 and 2 year time points because of increased administrative censoring beyond 2 years and because the greatest overall treatment effect in the main analysis occurred at the 1 and 2 year follow-up time points.

All tests of statistical significance were two tailed, and p values of less than 0.05 were considered to indicate statistical significance without adjustment for multiple comparisons. All analyses were performed with the use of SAS for Windows, version 9.3 (SAS institute, Cary, NC).

Patient population

A total of 1900 patients were randomized to undergo either CABG (n=947) or DES-PCI (n=953) as an initial treatment strategy. Of these, 20 patients (12 CABG, 8 PCI) did not have baseline health status data available and were excluded from the analysis (Figure 1). There were no significant differences in clinical characteristics between patients with vs. without baseline health status data other than in the prevalence of stroke ([3/20] 15.0% vs. [62/1880] 3.3%, p=0.03). Of the 1880 patients in the analytic population, 38 either withdrew from the trial or died prior to revascularization (31 patients randomized to CABG and 7 patients to DES-PCI). Among the patients assigned to CABG, 18 crossed over and underwent initial DES-PCI, while 5 patients assigned to initial DES-PCI underwent CABG instead.

Baseline characteristics including health status measures were well matched between the 2 treatment groups (Table 1). The mean age was 63 years, and 71% were male. More than 80% of the population had 3-vessel CAD, and more than 90% had LAD involvement. At baseline, both groups of patients reported significant health status limitations attributable to CAD. Approximately 35% of patients reported daily or weekly angina prior to randomization, and 25% of patients reported moderate or severe dyspnea at baseline (RDS score ≥3). Median follow-up time was 44 months (interquartile range [IQR]: 30-59 months) and 47 months (IQR: 31-59 months) for the CABG and DES-PCI groups, respectively.

Use of Anti-Anginal Medications

The use of anti-anginal medications at each follow-up timepoint is summarized in eTable 1. Beta-blockers were used in ∼80% of patients at almost all time points and did not differ between the two groups. The use of calcium channel blockers and long-acting nitrates was much less frequent overall, but tended to be higher after DES-PCI than after CABG with absolute differences ranging from 0.7% to 10.3% over time.

Health Status Outcomes

The overall questionnaire response rate was >80% for eligible patients during the first 3 years of follow-up and >70% in years 4 and 5 (eTable 2). Compared with baseline, both groups demonstrated substantial improvement in the SAQ-AF subscale that was apparent by 1 month and sustained throughout the 5-year follow-up period (Figure 2A and eTable 3). Between group comparisons demonstrated that CABG resulted in slightly higher scores than DES-PCI on the SAQ-AF subscale at the 1-year and 2-year follow-up time points (mean difference 1.0 and 1.3 points, respectively; Table 2). By 3 years, however, there was no significant difference in angina relief between the DES-PCI and CABG groups. When analyzed as a categorical variable, the proportion of angina free patients tended to be slightly greater with CABG than with DES-PCI at 6 months (83.7% vs. 78.1%), 12 months (83.5% vs. 79.5), and 24 months (83.3% vs. 81.0%), although the differences were only statistically significant at 6 and 12 months (Figure 3 and eTable 4). When death was included as the worst possible health state in the ordinal analysis, CABG remained superior to PCI at 6 and 12 months, but there were no significant differences at any of the later time points (eTable 5).

The results for the SAQ physical limitation and SAQ QoL subscales are summarized in Figures 2B and 2C, respectively (and in eTable 3). Although both treatment groups demonstrated substantial and sustained improvement in these subscales compared with baseline, the pattern and extent of improvement tended to differ over time. At 1 month, DES-PCI resulted in greater improvement compared with CABG for both the physical limitations (mean difference 8.1 points, 95% CI -9.9 to -6.3, p<0.001) and QoL (mean difference 1.9 points, 95% CI -3.6 to -0.2, p=0.03) subscales. By 6 months, scores for the SAQ QoL subscale were similar for the 2 treatment groups but remained modestly higher with DES-PCI for the physical limitations subscale (mean difference 2.3 points, 95% CI -3.8 to -0.9, p=0.002). By 1 year, however, scores for both the physical limitations and QoL subscales were higher with CABG (mean differences 2.0 [95% CI 0.4 to 3.6, p=0.01] and 1.9 points [95% CI 0.4 to 3.4, p=0.01], respectively). CABG continued to demonstrate better outcomes with respect to these 2 SAQ subscales through 2 and 3 years of follow-up. Beyond year 3, there were no consistent between-group differences for any of the SAQ subscales (although there were significant differences in favor of CABG at 5 years for the physical limitations and QoL subscales).

Results for the RDS are summarized in Figure 4 (and in eTable 6). Both DES-PCI and CABG resulted in substantial reductions in the level of dyspnea over time, but the rate of improvement was more rapid with DES-PCI. At 1 month, DES-PCI patients were more likely to be free of limitations due to dyspnea than patients randomized to CABG (RDS 0: 67.6% vs. 58.0%, p<0.001). These between group differences were no longer apparent by 6 months (65.2% vs. 66.9%, p=0.99). Whereas 25% of patients had moderate to severe dyspnea (RDS 3 or 4) at baseline, by 12 months, these proportions had fallen to 9.1% for both groups, and remained between 10 and 12% throughout the follow-up period.

Subgroup analysis

The estimated impact of CABG vs. DES-PCI on the SAQ-AF scale at 1 and 2 year follow-up within prespecified subgroups is summarized in Figures 5A and 5B, respectively. There was no evidence of significant heterogeneity in terms of the effect of CABG vs. DES-PCI across most of the subgroup categories. However there were significant interactions between treatment assignment and both SYNTAX score and baseline angina frequency. At 1-year follow-up, patients with an intermediate SYNTAX score (23-32) demonstrated significantly greater angina relief with CABG than with DES-PCI (mean adjusted difference = 2.8 points) whereas the benefits were minimal for patients with low or high SYTNAX scores (-0.1 and 0.3 points, respectively). CABG was also associated with greater angina relief among patients with daily or weekly angina at baseline (mean adjusted difference = 1.8 points) as compared with patients with only monthly (mean adjusted difference = 1.3 points) or no angina (mean adjusted difference = -0.9 points). Similar patterns were observed at 2-year follow-up as well.

Sensitivity Analyses

There were no major changes when the SAQ and RDS were analyzed using a per-protocol approach rather than ITT (n=1819, data not shown). Our results were also similar when the analysis was restricted to patients who had angina at baseline (n=1476, eTables 7A and 7B) or patients with daily or weekly angina at baseline (n=710, eTables 8A and 8B). Finally, results were similar when worst case values were imputed to patients with missing health status data who experienced a non-fatal MI or stroke during follow-up (eTable 9)

Comparison with Previous Studies

Several previous studies have compared the impact of CABG vs. PCI on health related quality of life among patients with multivessel CAD. In general, these studies have tended to show that compared with PCI, CABG results in superior angina relief over the first 1-3 years after initial revascularization.²² For example, in the Bypass Angioplasty Revascularization Intervention (BARI) trial, which compared balloon angioplasty with CABG, functional status and angina relief were superior over the first 3 years of follow-up with CABG.²³ Similar findings were noted in the Randomized Intervention Treatment of Angina (RITA) trial.³ Thus, with regard to the timing of benefit, the results of FREEDOM are remarkably similar to previous CABG vs. PCI trials.

On the other hand, the magnitude of benefit provided by CABG over PCI in the FREEDOM trial was substantially smaller than in many previous PCI vs. CABG trials. For example, in the Randomized Intervention Treatment of Angina (RITA) Trial, there was a 9.8% absolute difference in the prevalence of angina at 1-year in favor of CABG vs. balloon angioplasty.³ In the Bypass Angioplasty Revascularization Investigation (BARI), the difference in angina relief was even larger with an absolute 15% difference in the prevalence of angina at 1 year in favor of CABG.²³

With the introduction of bare metal stents and the accompanying reductions in restenosis,^24-26 the health status benefits of CABG over PCI for patients undergoing multivessel revascularization were diminished but remained clinically meaningful. In the Arterial Revascularization Therapies Study (ARTS), the absolute difference in angina prevalence at 1 year was ∼10% in favor of CABG, and decreased to ∼5% at 5 years.^2,27 Finally, in the Stent or Surgery (SOS) trial the difference in the SAQ-AF score between PCI (with bare metal stents) and CABG was ∼6 points at 6-month follow-up and ∼3 points at 1-year—differences that are approximately twice as large as those observed in FREEDOM.²⁸ On the other hand, at least in the short term, the difference in angina relief between CABG and DES-PCI observed in FREEDOM is remarkably similar to that seen in the SYNTAX trial²⁹—the only other randomized trial of multivessel coronary revascularization to use drug-eluting stents exclusively. Our results are also consistent with those of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial in which an indirect comparison demonstrated a slightly greater benefit of CABG than PCI on the Duke Activity Status Index (a measure of functional status) when compared with medical therapy.³⁰

These trends indirectly suggest that at least some of the quality of life benefits of CABG over DES-PCI relate to differences in the durability of revascularization between the 2 techniques. Although the introduction of drug-eluting stents has clearly reduced the need for repeat revascularization compared with both balloon angioplasty and bare metal stents, even with universal use of DES in FREEDOM, the rate of repeat revascularization was more than twice as high after DES-PCI as compared with CABG. Several previous studies have shown an association between repeat revascularization and impaired health status—particularly around the time of the repeat revascularization procedure.^28,31,32 It is possible that the higher rates of repeat revascularization seen after PCI in FREEDOM mitigated any differences in angina frequency and quality of life between the 2 strategies. Whether further improvements in DES technology would eliminate any health status benefit of CABG over DES-PCI in the diabetic population is unknown.

Clinical Implications

The primary results of the FREEDOM trial demonstrated that for diabetic patients with multivessel CAD, CABG led to a significant benefit over DES-PCI for the composite endpoint of death, MI, or stroke—driven by reductions in both all cause mortality and MI.⁴ Nonetheless, given the increased rate of stroke seen as well as the well-recognized longer recovery period with CABG, some patients may still prefer the less invasive DES-PCI strategy.³³ Moreover, owing to the higher early mortality after CABG, the reduced mortality seen with CABG in FREEDOM did not emerge until 4-5 years after randomization. These findings suggest that for patients with limited life expectancy (owing to advanced age or multiple comorbid conditions) or for whom improved quality of life is their primary goal, DES-PCI could be considered a reasonable alternative to CABG. In this light, the results of our study provide reassurance that for patients with DM, the quality of life benefits of DES-PCI combined with contemporary medical therapy are generally comparable to those seen with CABG—particularly for those with less severe angina.

Limitations

Our results should be viewed in light of the following limitations. By design, the FREEDOM trial included only a select group of diabetic patients with multi-vessel disease, such that the results do not necessarily apply to patients who do not meet the trial's inclusion and exclusion criteria. In particular, the results of FREEDOM should not be extrapolated to patients with single vessel or left main disease or unstable coronary disease. A second limitation is that health status data were missing on a modest proportion of patients due to a combination of administrative censoring and non-response—mainly at the 4- and 5-year timepoints and to a greater extent after CABG than DES-PCI. Although our analytic approach accounted for data that were missing at random, results at these later timepoints might still be affected by informative (i.e., non-random) censoring and should be interpreted with caution.

A third limitation is that our health status assessment focused on disease-specific, rather than generic measures. Although disease-specific measures are generally more sensitive than generic measures,¹² by focusing on cardiovascular specific outcomes, it is possible that we underestimated the effect of stroke on patients’ overall health status during follow-up, thus biasing our results somewhat in favor of CABG. However, given that absolute differences in rates of stroke were only 2-3%, it seems unlikely that generic health status measures would have shown a difference in favor of PCI. Indeed, a previously published comparison of health utility scores from the FREEDOM trial showed no significant difference between the 2 groups except at the 1 month timepoint.⁵ The disease specific instruments used in this study were also not designed to detect differences in neurocognitive function between the 2 procedures. Finally, the results of FREEDOM only apply to first generation DES, which were used in the vast majority of PCI procedures in the trial. Although second generation everolimus-eluting stents have shown lower rates of target lesion revascularization compared with first-generation DES designs in the overall population,^34,35 it is less clear that these benefits apply to diabetic patients.³⁶

Conclusions

In summary, these results from the FREEDOM trial demonstrate that for patients with diabetes and multivessel CAD, both DES-PCI and CABG provide substantial and sustained benefits on cardiovascular specific health status and quality of life that are evident within 1 month and sustained through 5 years. Between-group comparisons generally favored CABG between 6 months and 2 years, but the observed differences were small. Beyond 2 years, there were no consistent differences between the 2 treatment strategies.