Over the last two decades, over 25 000 patients were enrolled in 61 RCTs (63 meta-analysis entries) testing PCI for the treatment of nonacute CAD. While BMS and DES yielded sequential improvements in diminishing the need for revascularization, we found no evidence that serial innovations in PCI technologies yielded detectable improvements in the hard outcomes of death or MI, compared to medical therapy. Overall, these results support current recommendations to optimize medical therapy as an initial management strategy in patients with CAD in the non-acute setting. The broad range of included patients across the spectrum of people with nonacute CAD suggests that these findings are likely applicable to many real-life clinical scenarios where either PCI or medical therapy might be considered.
The geometry of our network of trials suggests that each technological innovation became the de facto standard for trials of future innovations, although no clear advantage in terms of hard clinical outcomes had been demonstrated against medical therapy. Only 4 trials involved head-to-head comparisons between stenting and medical therapy and, as of this writing, there are no trials comparing DES to medical therapy. Perhaps not surprisingly, of the six possible comparisons among the 4 interventions, the majority of RCTs (52/63 = 83% including 18 778/25 388 = 74% of total patients) were focused on comparing 2 types of PCI strategies —testing BMS to PTCA and testing DES against BMS.
For patients whose symptoms cannot be adequately relieved by medical therapy, PCI with stenting (drug eluting or bare metal) is a reasonable option for reducing symptoms and improving quality of life.20
In these cases, our indirect comparison suggests that DES substantially reduces the relative risk for TVR/TLR by approximately 70% compared to balloon angioplasty. However, while some medically-treated patients may eventually require PCI for symptom relief,5
many appear able to avoid the risk and expense associated with procedural management of their disease altogether, without incurring any higher risk of mortality or MI. The one caveat to this is that initial PCI with DES may reduce the need for CABG compared to initial medical therapy; this finding however should be confirmed in a head-to-head comparison.
We found that DES was associated with a significantly lower rate of CABG when compared to BMS. In accordance with previous meta-analyses,21
we found no evidence for differences in CABG rates between BMS and PTCA. Furthermore, indirect comparisons suggest that CABG rates favor DES over PTCA and medical therapy. To our knowledge, the present analysis is the first to suggest favorable effects of DES on CABG rates compared to other PCI interventions or medical treatment. For example, assuming control rates similar to those in COURAGE,22
34 patients (95% CI: 23,117) would have to be treated with DES rather than medical therapy to prevent one CABG, over 48 months of follow-up (Appendix Table 5
). A head-to-head trial between DES and medical therapy may clarify differences in outcome between these therapies that were not apparent in this indirect comparison.
Furthermore, we observed that stents were associated with lower rates of subsequent PCIs, with DES favored over BMS for this outcome. This finding is in agreement with previous meta-analyses, but should be interpreted with several caveats in mind. A prior meta-analysis has shown that in the (necessarily unblinded) comparisons between BMS and PTCA, similar degrees of angiographic restenosis were more likely to be revascularized in the PTCA rather than the BMS arm.5
Secondly, there was a tendency for TVR/TLR outcome rates to be higher in the BMS control arms of BMS vs. DES trials, compared to rates in the experimental arm of PTCA vs. BMS trials.23,24
Lastly, in the BENESTENT II trial, which included randomisation between clinically-based and protocol-driven follow-up angiography, protocol-driven angiography itself doubled TVR/TLR rates.25
Taken together these findings suggest that the true reduction in clinically driven TVR/TLR rates from PTCA to DES may be less than the sum suggested by the sequential improvements.
Nevertheless, it remains curious why these substantial sequential reductions in TVR/TLR with sequential innovations in PCI have not translated into detectable improvements in hard outcomes like death or MI. A likely reason for the apparent failure of PCI to reduce death or MI in nonacute CAD is that PCI remains a local therapy, typically targeted at a few hemodynamically-compromising lesions. CAD though is a diffuse disease process that frequently involves the entire coronary vasculature, making it more likely to respond to systemic treatments like medical therapy.26
Additionally, radiographically detected restenotic lesions that may lead to revascularization in nonacute CAD may often be stable and less prone to cause MI or death.27
As with all null meta-analyses, the absence of a detected difference between therapies does not rule out the possibility of an undetected benefit (or harm), as described by our confidence intervals. Of note, a recent meta-analysis suggested a mortality reduction with PCI-based strategies compared to medical strategies.28
This meta-analysis, however, included data extracted from an erroneous report29
and no longer reached formal statistical significance when the corrected outcome data30
were used. There were important methodological differences between our network meta-analysis and the aforementioned study. The latter considered all catheter-based strategies as a single treatment, included trials with mixed interventions in their PCI arm, as well as trials in which substantial numbers of patients received CABG instead of PCI, and did not use any information from indirect comparisons.
Although many patients with unstable angina were included in this network meta-analysis, these results should be cautiously interpreted with respect to this specific population. Several relevant trials that included patients with unstable angina were excluded from the present analysis because they also enrolled patients with acute MI. In earlier studies, patients with unstable angina may actually have had evidence of myonecrosis by more contemporary markers (e.g., troponin). However, the inadvertent inclusion of patients with acute disease and indications for emergency PCI would presumably have biased this study to finding a treatment effect for intervention compared to medical therapy. In any case, our results are consistent with earlier observations that the benefits of PCI in patients with acute coronary syndromes (including those with unstable angina) may be limited to high-risk patients, with uncertain benefit observed in lower-risk patients with negative cardiac biomarkers (i.e. unstable angina).3,31
It also is important to emphasize that our analysis also excluded patients with ST-elevation MI treated with PCI, a clinical setting in which it has more consistently been demonstrated to be better than medical therapy.32
Several limitations of the present analysis are worth noting. First, indirect evidence is susceptible to confounding,33
and thus should be interpreted with due caution, as it does not always agree with the corresponding direct estimates.34,35
Although in our case direct and indirect evidence agreed for all outcomes except for death, this can be an artifact of the limited interconnections in our network (not all possible comparisons have been performed). For death direct and indirect evidence disagreed in their direction, but were both statistically nonsignificant in all comparisons and their confidence intervals overlapped greatly. Second, medical therapy has substantially evolved over the past two decades, and comparisons to medical treatments in some of the earlier trials may not be directly relevant to current practice. Third, crossover from medical therapy to PCI and from PTCA to stenting with BMS may have biased findings towards a neutral effect on some outcomes, and against PCI in general. Because here we are interested in effectiveness (i.e. in testing initial management strategies) rather than efficacy,36,37
we believe that this concern is only tangentially relevant. As with any meta-analysis, we can only analyse outcomes reported in the original RCTs and do not consider every possible clinically relevant outcome. We could not, for example, evaluate for changes in functional status or late in-stent thrombosis due to a lack of consistently reported data. Furthermore, we cannot fully explore treatment effects in different sub-populations without access to individual patient data. Finally, publication bias is an inherent limitation of meta-analyses, but this is more likely to affect the interpretation of the positive findings on revascularization, rather than the neutral finding on death and MI.
Over the past two decades, sequential innovations in PCI for the management of stable CAD showed no evidence of an impact on death or MI when compared to medical therapy. Technology appeared to develop in advance of data on hard clinical outcomes such as deaths and MI. Comparative effectiveness trials of DES versus medical therapy, examining clinically important outcomes are needed.