coronary intervention

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The Year in Cardiology 2012

Coronary InterventionSimon R Redwood

Eur Heart J. 2013;34(5):338-344.

IntroductionI am delighted to provide readers of the European Heart Journal with an overview of scientific data relating to Coronary Intervention in 2012. This article aims to summarize the important publications and presentations; it includes a summary of the main interventional meetings (ACC, EuroPCR, ESC, TCT, and AHA) together with a selection of important publications from the major general and specialist journals.

PCI in GeneralThroughout Europe there has been a move towards percutaneous coronary intervention (PCI) being performed in units without on-site cardiac surgery. In the UK, over 60% of units do not have on-site surgery and these units generally perform a lower volume of PCI than those with on-site surgery (median of 435 compared with 1454 procedures, respectively). The need for emergency surgery is now a very uncommon complication. The Atlantic CPORT Investigators randomized, in a non-inferiority design, nearly 19 000 patients undergoing PCI to a hospital with or without on-site surgery in a ratio of 1–3. Six-week mortality was virtually identical (1.0 vs. 0.9%) and 9-month major adverse cardiac events (MACE) were also similar (11.2 vs. 12.1%); however, target vessel revascularization (TVR) was higher without on-site surgery (6.5 vs. 5.4%, P = 0.01). This difference was seen regardless of the definition of TVR and regardless of stent type and may reflect a more conservative approach or a lower initial success rate without on-site surgery. In the USA, a very small proportion of total PCI was performed without on-site surgery and it remains to be seen whether this study will alter that proportion. [1]

Public reporting of patient outcomes following PCI is an important tool to monitor the quality of care; however, it may lead some operators to become 'risk-averse'. Joynt et al. reported a retrospective observational study of patients admitted with an acute coronary syndrome to US hospitals in states that do and in states that do not report outcomes publically between 2002 and 2010. In 2010, ACS patients were less likely to receive PCI in public reporting states than in non-reporting states, and this difference was more marked for STEMI and cardiogenic shock (CS); however, there were no significant differences in mortality. Interestingly, in Massachusetts the odds of undergoing PCI for acute myocardial infarction (MI) fell after the introduction of public reporting. There are, of course, at least two explanations for why public reporting was associated with reduced PCI rates—either operators were more risk-averse or some procedures in non-reporting states are unnecessary and reporting of outcomes improves the appropriateness of PCI.[2]

The SYNTAX study suggested that patients randomized to coronary artery bypass surgery (CABG) had a higher risk of stroke, although the majority of that risk was in fact pre-surgery, implying that it was either a chance finding or related to stopping of anti-platelets pre-op. A meta-analysis of 19 randomized trials of over 10 000 patients found a 30-day rate of stroke of 1.2% after CABG and 0.34% after PCI (P < 0.0001) This equates to an excess of seven strokes for every 1000 patients treated with CABG rather than PCI. Similar results were observed after a median follow-up of 1 year and in an analysis of nearly 34 000 patients from 27 observational studies.[3]

The FREEDOM trial results should be of great importance. This trial randomized 1900 diabetic patients with multi-vessel disease to PCI using drug-eluting stents (DESs) vs. CABG. At 5 years, the primary outcome of death, MI, or cerebrovascular accident (CVA) occurred more commonly in the PCI group (26.6 vs. 18.7%, P = 0.005), driven by excess rates of both MI and death in the PCI arm; however, stroke was higher with CABG (Figure 1). These results serve as a wake-up call to Interventional Cardiologists considering revascularization options for any diabetic with more than single-vessel disease.[4]

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Figure 1.

Kaplan–Meier estimates of the composite primary outcome and death. Shown are rates of the compsite primary outcome of death, myocardial infarction, or stroke. The P-value was calculated by means of the log-rank test on the basis of all available follow-up data (reproduced from Farkouh et al.4).

The management of elective major non-cardiac surgery after coronary stent implantation remains an important issue in peri-operative care. Current guidelines generally recommend delaying surgery for 1 month following bare-metal stents (BMSs) and 1 year following DESs. Registry data were analysed in a cohort study of >8000 patients undergoing non-cardiac surgery and had received stents in the preceding 10 years, with a comparison of patients who had not undergone previous stenting. Although 1-month MACE was 2.1% in patients with coronary stents, if the interval was <45 days, event rates were 6.7% for BMSs and 20% for DESs. Between 45 and 180 days, the event rates were 2.6% for BMSs and nearly 4% for DESs. After 180 days, the rate for DESs was 1.2%. Thus, this analysis supports waiting for at least 45 days for elective non-cardiac surgery following BMSs but at least 180 days following DESs.[5]

Appropriateness of PCIRecently, the ACC and AHA, in conjunction with five other societies, published appropriate use criteria for revascularization. Data from >8000 patients undergoing elective CABG and nearly 34 000 undergoing PCI were analysed to assess appropriateness. Only 1% of those undergoing CABG were deemed inappropriate,

but 14% of PCI patients were inappropriate; furthermore 28% lacked enough non-invasive data to determine appropriateness.[6] Hannan et al.[7] also compared outcomes of patients who did and those who did not undergo elective PCI from the New York database. Using propensity matching and a cohort of 933 matched pairs, outcome was determined; 89% of all patients underwent PCI. Compared with medically treated patients, PCI was associated with lower adverse outcomes at 4 years (for mortality, 10.2 vs. 14.5%; for subsequent revascularization, 24.1 vs. 29.1%).

There are also direct data supporting the use of ischaemia guidance (IG): in a 5000-patient registry, perfusion imaging (MPI) was performed in 42.3% and IG revascularization in 17.3% (12.4% in PCI and 21.8% in CABG). Major adverse cardiac and cerebral events was lower in the IG than in the non-IG group (16.2 vs. 20.7%), driven by lower repeat revascularization.[8]

The ASCERT study analysed elective revascularization strategies in nearly 200 000 over 65-year-old patients with two or three vessel disease undergoing CABG or PCI. One-year mortality was similar but at 4 years, mortality with CABG was lower than PCI (16.5 vs. 20.5%).[9]

The issue of completeness of revascularization following PCI was assessed by several studies. SYNTAX scoring was determined pre- and post-PCI in patients enrolled in the ACUITY study. A residual SYNTAX score of >0 was considered incomplete revascularization (IR). Thirty-day and 1-year ischaemic events were higher in the IR group. Residual SYNTAX score was an independent predictor of ischaemic events at 1 year, including mortality.[10] In a separate analysis of these data, this association was also seen if IR was assessed by quantitative coronary angiography and variably defined according to different diameter stenosis cut-offs.[11]

Physiological Lesion Assessment GuidanceThe use of fractional flow reserve (FFR) to guide PCI is supported by robust clinical data and Pijls et al. [12] published an excellent review. The FAME 2 trial assessed FFR in stable patients and those who had at least one significant lesion (FFR <0.8) were randomized to FFR-guided PCI or optimal medical therapy (OMT). The trial was halted after 880 patients were randomized. The primary endpoint of death, MI, or urgent revascularization was 4.3% in the PCI group and 12.7% in the OMT group (P < 0.001); this difference was due to higher urgent revascularization in the OMT group (Figure 2). There could, of course, have been some bias in recommending revascularization in patients in the OMT group with recurrent angina but these data do further support the routine use of FFR-guided procedures.[13]

Figure 2.

Kaplan–Meier curves for cumulative incidence of the primary endpoint and its components in the group that was randomly assigned to PCI and the best available medical therapy (PCI), the group that was randomly assigned to the best available medical therapy alone (medical therapy), and the group that did not undergo randomization and was enrolled in a registry (registry). After 12 months, a total of two primary end-point events occurred in the PCI group, none in the medical-therapy group, and one in the registry cohort. No deaths occurred after 12 months in any of the groups. Two patients in the PCI group, none in the medical-therapy group, and one in the registry cohort had a myocardial infarction after 12 months. One patient in the registry cohort, and none in the other two groups, had an urgent revascularization performed after 12 months (reproduced from De Bruyne et al. 13).

At Transcatheter Cardiovascular Therapeutics (TCT), data were presented supporting the cost-effectiveness of this approach, although the trial randomized after the FFR measurements were made, so the cost of the wire was not taken into account.

There are now some data emerging for a new method of determining functional significance using a pressure-sensor tipped wire without the need for vasodilatation. Using wave intensity analysis, a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude to FFR was determined, known as the instantaneous wave-free ratio. Early studies suggest that it may be an alternative to FFR determined during vasodilatation,[14] but this new index needs to be validated in larger cohorts of patients.

Haemodynamic SupportThe BCIS-1 trial previously reported no difference in early MACE for high-risk PCI patients randomized to intra-aortic balloon pump placement pre-PCI. However, the long-term mortality data were reported recently. At up to 5-year follow-up, there was a significant mortality advantage favouring upfront IABP insertion [hazard ratio (HR) 0.66, 95% CI: 0.44–0.98, P = 0.039], although the potential mechanisms of this remain unclear.[15]

The outcomes of CS over the time period 1995–2005 were compared in French registries. Over that time period, there was a small reduction in the incidence of CS (6.9–5.7%), and there was a substantial reduction in mortality in these patients, from 70 to 51%; this was associated with an increase in use of PCI from 20 to 50%, which was an independent predictor of survival.[16]

The role of haemodynamic support for CS was determined in the IABP-SHOCK II trial. Patients undergoing revascularization were randomized to IABP support (n = 300) or conventional treatment (n = 300). Thirty-day mortality was very similar in the two groups (39.7 vs. 41.3%, respectively). However, in the IABP group, only 13% were inserted pre-PCI. Thus, although this trial does not support IABP placement after revascularization, this was not a trial of IABP-supported PCI in CS.[17]

StentsA meta-analysis of 72 randomized trials (>117 000 patients) looked at comparative outcomes of different DESs compared with BMSs. Everolimus DESs seemed to have the lowest TVR. Reassuringly, there was no increased risk of any long-term safety outcomes with DESs compared with BMSs; in fact, DESs were associated with reduced MI and sub-acute thrombosis (SAT) rates.[18] At TCT, The XIMA trial was presented. This trial randomized 800 patients over the age of 80 to either BMSs or DESs (Xience). The primary outcome of death, MI, TVR, CVA, or bleeding was non-significantly higher in the BMS group (18.7 vs. 14.5%, P = 0.092), driven by an excess of TVR in that group. Importantly, bleeding was not increased with prolonged dual anti-platelet therapy (DAPT), suggesting that DESs are safe and effective in the elderly.

A report of the SCARR registry of over 94 000 patients found that newer generation DESs are associated with a 38% lower risk of clinical restenosis and a 43% lower risk of SAT compared with first-generation DESs.[19]

The RESET trial compared everolimus with sirolimus DESs in a randomized non-inferiority trial of over 3000 patients. At 1 year, the primary endpoint of TLR occurred in 4.3 vs. 5.0% demonstrating non-inferiority. [20] SORT OUT IV also compared these two stents in a non-inferiority design but with a composite primary endpoint of safety and efficacy. Just over 2700 patients were randomized. The composite endpoint was similar in the two groups at 9 and 18 months, but definite stent thrombosis was higher at 18 months with the sirolimus stent (0.9 vs. 0.2%).[21]

The TWENTE trial randomized 1391 patients to zotarolimus (Resolute) vs. everolimus (Xience) stents in a non-inferiority design. The primary endpoint of target vessel failure (TVF) was similar in the two groups (8.2 vs. 8.1%), and stent thrombosis rates were low and similar.[22]

A further comparison of everolimus and. paclitaxel DESs was reported for left main interventions and again showed reduced 1-year MACE, TVF, and restenosis with everolimus DESs.[23] In addition, at TCT the ISAR-LEFT MAIN-2 trial was presented, and showed similar outcomes with everolimus compared with zotarolimus stents; however, TLR was disappointing at ~10%—I wonder whether that would have been lower if they investigators had mandated the use of intravascular ultrasound (IVUS). An excellent review article on left main interventions was published by Teirstein et al. [24] and is well worth looking at.

In a small mechanistic study, patients with in-stent restenosis (ISR) after DESs were randomized according to lesion length. In those with focal ISR, late lumen loss was higher following cutting balloon that sirolimus DES implantation. In those with diffuse ISR, sirolimus and everolimus stents were comparable.[25]

Late (>10 year) outcomes of the first in man (FIM) non-drug-eluting biodegradable (Igaki-Tamai) stents were reported in 50 patients. All-cause survival was 87% and TLR was 16% and at 1 year and 28% at 10 years. Late thrombosis occurred in two patients. IVUS analysis showed that stent struts had largely disappeared by 3 years. External elastic lamina area did not change suggesting no significant late elastic recoil.

Complications of PCIStent Thrombosis

In the largest head-to-head DESs trial to date, the PROTECT trial compared zotarolimus with sirolimus (Cypher) stents in nearly 9000 patients with duration of DAPT left to the discretion of the operator and showed no difference between the two stents in the primary endpoint of stent thrombosis at 3 years. [26] However, in a prospective cohort study, of over 12 000 patients, the risk of last SAT was assessed and everolimus DESs were associated with a lower very late thrombosis risk than either sirolimus or paclitaxel DESs (hazard ratio: 0.65).[27] In a pooled analysis of ISAR-TEST 3 and 4 and LEADERS trials, the risk of SAT at 4 years with biodegradeable polymer DESs was compared with that with a Cypher stent (a durable polymer); biodegradeable polymer was associated with lower TLR and SAT (hazard ratio: 0.56), driven mainly by a reduction in very late SAT.[28] In a meta-analysis of 50 000 patients, 1-year SAT was lowest with everolimus DESs compared with BMSs, zotarolimus, paclitaxel, or sirolimus DESs.[29]

Duration of DAPT was investigated in several studies. In the 1443 patient EXCELLENT non-inferiority randomized study of 6 months vs. 12-month DAPT after DESs, 1-year TVF occurred in 4.8 vs. 4.3%, respectively. However, this study was not powered to look at death or MI and in the diabetic subset, TVF occurred more frequently in the 6-month group (HR: 3.16; CI: 1.42–7.03, P = 0.005).[30] A further study of 2000 patients compared 3–12-month DAPT following zotarolimus DESs and found no difference in SAT (0.2 vs. 0.3%) at 1 year.[31] The PRODIGY trial randomized 2000 patients to either 6- or 24-month DAPT following a variety of BMSs or DESs. Interestingly, using a composite endpoint of death, MI or stroke, there was no difference between short or prolonged duration DAPT in any group.[32]

Reassuringly, in a study of over 1600 patients, investigators assessed the risks of temporary discontinuation of DAPT within the first year following DESs. Overall, 10.6% interrupted DAPT beyond the first month for a median of 7 days and this was not associated with an increase in MACE.[33]

Thus, second-generation DESs seem to have lower SAT rates and there are now data supporting safety of shorter duration DAPT, at least in non-diabetics.

Acute Kidney Injury

Contrast-induced nephropathy (CIN or AKI) is associated with a significant increase in short- and long-term morbidity and mortality. Various measures have been used to limit its occurrence, including sodium bicarbonate infusion. This was tested in a randomized trial of 258 patients against a similar volume of sodium chloride infusion. Change in glomerular filtration rate was more in the bicarbonate group. Previous studies have failed to conclusively support N-acetyl cysteine.[34] In a separate study, the risk of AKI after cardiac surgery was not found to be influenced by timing between coronary angiography and surgery.[35] At TCT, the POSEIDON trial was presented and showed that LVEDP-guided hydration was superior to standard hydration in preventing AKI in patients with stable renal impairment. Thus, it seems that limitation of contrast volume and adequate hydration, perhaps with the rate guided by weight and LVEDP measurement, are the most-effective strategies for preventing AKI.

Bleeding Post-PCI

Using the CathPCI Registry, post-PCI bleeding was found to reduce by 20% over the years 2005–09, and this seemed largely due to changes in anti-thrombotic strategies with a reduction in GPIIb/IIIa use and an increase in bivalirudin use. Radial access accounted only for 1–2%; in contrast to some previous studies, vascular closure devices seemed to be associated with a small reduction in bleeding.[36]

Varying bleeding definitions make comparisons of different studies troublesome; the Bleeding Academic Research Consortium proposed standardized definitions in order to address this. These were validated in a

pooled analysis of over 12 000 patients from six randomized trials. Bleeding Academic Research Consortium Class >2 was associated with an increase in 1-year mortality, supporting the use of these definitions in outcome trials.[37]

Acute Myocardial InfarctionIntracoronary abciximab but not thrombectomy was found to reduce infarct size in the 450-patient INFUSE-AMI trial.[38] In contrast to this, a retrospective analysis of over 2500 patients found higher TIMI 3 flow rates and better survival in those who had thrombectomy.[39] In a 2000-patient randomized trial, intracoronary, and i.v. abciximab were compared. The primary endpoint of death, recurrent MI, or CCF was similar in the two groups, although there was a small reduction in CCF associated with the intracoronary route and there was no difference in safely. A meta-analysis also supported these results.[40] Thus, abciximab seems to reduce infarct size and the route of administration does not seem to be important. The role of routine thrombectomy remains uncertain.

The use of DESs in acute MI remains controversial, and this year several comparisons were reported. Bare-metal stents were compared with biolimus biodegradable polymer stents in a 1100-patient randomised trial. One-year MACE was lower with the biolimus stent, a difference driven mainly by a reduction in re-infarction and TLR.[41] In a 1500-patient trial, everolimus DESs were compared with BMSs; the primary endpoint of death, recurrent MI, or revascularisation was similar in the two groups. However, TVR rates were lower with the everolimus stent (3.7 vs. 6.8%), as was SAT (0.9 vs. 2.5%).[42] In a meta-analysis of 15 trials with nearly 8000 patients, early-generation DESs reduced TVR compared with BMSs, but this benefit was offset by an increased risk of very late SAT.[43] Finally, a comparison of first-generation (sirolimus) and second-generation (everolimus) stents was reported. In a 625-patient non-inferiority trial, MACE at 1 year was lower with the everolimus stent (4 vs. 7.7%).[44] SAT was also lower with everolimus, although not significantly, and this would need to be confirmed in larger trials. Thus, DESs do reduce restenosis and the newer generation DESs may reduce the increased risk of late SAT.

The issue of access site for STEMI PCI was raised at TCT; the STEMI-RADIAL trial randomized 700 patients to either a radial or femoral approach. Interestingly, the radial approach was associated with less contrast use and shorter ICU stays. The primary endpoint of bleeding or access-site complications was dramatically lower with the radial approach and MACE was equivalent. Although 2b3a use was relatively high, this trial does support the radial approach in experienced hands (excuse the pun!) (Figures 1 and 2).

Conclusions2012 has been a busy and productive year in coronary intervention! It is hoped that this brief summary will help inform the reader and stimulate them to delve more deeply into the publications and presentations highlighted.

References

1. Aversano T, Lemmon CC, Liu L. Outcomes of PCI at hospitals with or without on-site cardiac surgery. N Eng J Med 2012;366:1792–1802.

2. Joynt KE, Blumenthal DM, Orav EJ, Resnie FS, Jha AK. Association of public reporting for percutaneous coronary intervention with utilization and outcomes among medicare beneficiaries with acute myocardial infarction. JAMA 2012;308:1460–1468.

3. Palmerini T, Biondi-Zoccai G, Reggiani LB, Sangiorgi D, Alessi L, De Servi S, Branzi A, Stone GW. Risk of stroke with coronary artery bypass graft surgery compared with percutaneous coronary intervention. J Am Coll Cardiol 2012;60:798–805.

4. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, Yang M, Cohen DJ, Rosenberg Y, Soloman SD, Desai AS, Gersh BJ, Magnuson EA, Lansky A, Boineau R, Weinberger J, Ramanathan K, Sousa E, Rankin J, Bhargava B, Buse J, Hueb W, Smith CR, Muratov V, Bansilal S, King S, Bertrand M, Fuster V. Strategies for multivesssel revascularization in patients with diabetes. N End J Med 2012.pmid:PMID:23121323 Published online ahead of print 4 November 2012

5. Wijeysundera DN, Wijeysundera HC, Yun L, Wąsowicz W, Beattie WS, Velianou JL, Ko DT. Risk of elective major noncardiac surgery after coronary stent insertion: a population-based study. Circulation 2012;126:1355–1362.

6. Hannan EL, Cozzens K, Samadashvili Z, Walford G, Jacobs AK, Holmes DR, Stamato NJ, Sharma S, Venditti FJ, Fergus I, King SB. Appropriateness of coronary revascularization for patients without acute coronary syndromes. J Am Coll Cardiol 2012;59:1870–1876.

7. Hannan EL, Samadashvili Z, Cozzens K, Walford G, Jacobs AK, Holmes DR Jr., Stamato NJ, Gold JP, Sharma S, Venditti FJ, Powell T, King SB. Comparative outcomes for patients who do and do not undergo percutaneous coronary intervention for stable coronary artery disease in New York. Circulation 2012;125:1870–1879.

8. Kim YH, Ahn J-M, Park D-W, Song HG, Lee J-Y, Kim W-J, Yun S-C, Kang S-J, Lee S-W, Lee CW, Moon DH, Chung CH, Lee J-W, Park S-W, Seung-Jung Park S-J. Impact of ischemia-guided revascularization with myocardial perfusion imaging for patients with multivessel coronary disease. J Am Coll Cardiol 2012;60:181–190.

9. Weintraub WS, Grau-Sepulveda MV, Weiss JM, O'Brien SM, Peterson ED, Kolm P, Zhang Z, Klein LW, Shaw RE, McKay C, Ritzenthaler LL, Popma JJ, Messenger JC, Shahian DM, Grover FL, Mayer JE, Shewan CM, Garratt KN, Moussa ID, Dangas GD, Edwards FH. Comparative effectiveness of revascularization strategies. N Eng J Med 2012;366:1467–1476.

10. Philippe Généreux P, Tullio Palmerini T, Adriano Caixeta A, Gregg Rosner G, Philip Green P, Ovidiu Dressler O, Ke Xu K, Helen Parise H, Roxana Mehran R, Patrick W, Serruys PW, Gregg W, Stone GW. The residual SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score. J Am Coll Cardiol 2012;59:2165–2174.

11. Rosner GF, Kirtane AJ, Genereux P, Lansky AJ, Cristea E, Gersh BJ, Weisz G, Parise H, Fahy M, Mehran R, Stone GW. Impact of the presence and extent of incomplete angiographic revascularization after percutaneous coronary intervention in acute coronary syndromes: the acute catheterization and urgent intervention triage strategy (ACUITY) Trial. Circulation 2012;125:2613–2620.

12. Pijls NHJ, Sels J-WEM. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012;59:1045–1057.

13. De Bruyne B, Pijls NHJ, Kalesan B, Barbato E, Tonino PAL, Piroth Z, Jagic N, Mobius-Winckler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engstrom T, Oldroyd KG, Mavromatis K, Manohoran G, Verlee P, Frobert O, Curzen N, Johnson JB, Juni P, Fearon WF; for the FAME 2 Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Eng J Med 2012;367:991–1001.

14. Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, Tarkin J, Petraco R, Broyd C, Jabbour R, Sethi A, Baker CS, Bellamy M, Al-Bustami M, Hackett D, Khan M, Lefroy D, Parker KH, Hughes AD, Francis DP, Di Mario C, Mayet J, Davies JE. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol 2012;59:1392–1402.

15. Perera D, Stables R, Clayton T, DeSilva K, Lumley M, Clack L, Thomas M, Redwood S. Longterm mortality data from the Balloon-pump assisted Coronary Intervention Study (BCIS-1): a randomised controlled trial of elective balloon pump counterpulsation during high-risk PCI. Circulation. doi:10.1161/CIRCULATIONAHA.112.132209. Published online ahead of print 6 December 2012.

16. Aissaoui N, Puymirat E, Tabone X, Charbonnier B, Schiele F, Lefevre T, Durand E, Blanchard D, Simon T, Cambou J-P, Danchin N. Improved outcome of cardiogenic shock at the acute stage of myocardial infarction: a report from the USIK 1995, USIC 2000, and FAST-MI French Nationwide Registries. Eur Heart J 2012;33:2535–2543.

17. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Bohm M, Ebelt H, Schneider S, Schuler G, Werden K; for the IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N End J Med 2012;367:1287–1296.

18. Bangalore S, Kumar S, Fusaro M, Amoroso N, Attubato MJ, Feit F, Bhatt DL, Slater J. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation 2012;125:2873–2891.

19. Sarno G, Lagerqvist B, Frobert O, Nilsson J, Olivecrona G, Omerovic E, Saleh N, Venetzanos D, James S. Lower risk of stent thrombosis and restenosis with unrestricted use of 'new-genration' drug-eluting stents: a report from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33:606–613.

20. Kimura T, Morimoto T, Natsuaki M, Shiomi H, Igarashi K, Kadota K, Tanabe K, Morino Y, Akasaka T, Takatsu Y, Nishikawa H, Yamamoto Y, Nakagawa Y, Hayashi Y, Iwabuchi M, Umeda H, Kawai K, Okada H, Kimura K, Simonton CA, Kozuma K; on behalf of the RESET Investigators. Comparison of everolimus-eluting and sirolimus-eluting coronary stents: 1-year outcomes from the Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial (RESET). Circulation 2012;126:1225–1236.

21. Jensen LO, Thayssen P, Hansen HS, Christiansen EH, Tilsted HH, Krusell LR, Villadsen AB, Junker A, Hansen KN, Kaltoft A, Maeng M, Pedersen KE, Kristensen SD, Bøtker HE, Ravkilde J, Sanchez R, Aarøe J, Madsen M, Sørensen HT, Thuesen L, Lassen JF; for the Scandinavian Organization for Randomized Trials With Clinical Outcome IV (SORT OUT IV) Investigators. Randomized comparison of everolimus-eluting and sirolimus-eluting stents in patients treated with percutaneous coronary intervention: the Scandinavian Organization for Randomized Trials With Clinical Outcome IV (SORT OUT IV). Circulation 2012;125:1246–1255.

22. von Birgelen C, Basalus MWZ, Tandjung K, van Houwelingen KG, Stoel MG, Louwerenburg JHW, Linssen GCM, Saïd SAM, Kleijne MAWJ, Sen H, Löwik MM, van der Palen J, Verhorst PMJ, de Man FHAF. A randomized controlled trial in Second-Generation Zotarolimus-Eluting Resolute Stents Versus Everolimus-Eluting Xience V Stents in Real-World Patients. The TWENTE trial. J Am Coll Cardiol 2012;59:1350–1361.

23. Valenti R, Migliorini A, Parodi G, Carrabba N, Vergara R, Dovellini EV, Antoniucci D. Clinical and angiographic outcomes of patients treated with everolimus-eluting stents or first-generation paclitaxel-eluting stents for unprotected left main disease. J Am Coll Cardiol 2012;60:1217–1222.

24. Teirstein PS, Matthew J, Price MJ. Left main percutaneous coronary intervention. J Am Coll Cardiol 2012;60:1605–1613.

25. Song HG, Park DW, Kim TH, Ahn JM, Kim WJ, Lee JY, Kang SJ, Lee SW, Lee CW, Park SW, Han S, Seong IW, Lee NH, Lee BK, Lee K, Lee SW, Nah DY, Park SJ. Randomized trial of optimal treatment strategies for in-stent restenosis after drug-eluting stent implantation. J Am Coll Cardiol 2012;59:1093–1100.

26. Camenzind Bode C, Greenwood JP, Boersma E, Vranckx P, McFadden E, Werruys PW, O'Neill WW, Jorissen B, Van Leeuwen F, Steg PG; for the PROTECT Steering Committee and Investigators. Stent thrombosis and major clinical events at 3 years after the zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised multicentre open-label controlled trial. Lancet 2012;380:1396–1405.

27. Raeber L, Magro M, Stefanini GG, Kalesan B, van Domburg RT, Onuma Y, Wenaweser P, Daemen J, Meier B, Jüni P, Serruys PW, Windecker S. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study. Circulation 2012;125:1110–1121.

28. Stefanini GG, Byrne RA, Serruys PW, de Waha A, Meier B, Massberg S, Juni P, Schomig A, Windecker S, Kastrati A. Biodegradable polymer drug-eluting stents reduce the risk of stent thrombosis at 4 years in patients undergoing percutaneous coronary intervention: a pooled analysis of individual patient data from the ISAR-TEST 3, ISAR-TEST 4 and LEADERS randomized trials. Eur Heart J 2012;33:1214–1244.

29. Palmerini T, Biondi-Zoccai G, Della Riva D, Stettler C, Sangiorgi D, D'Ascenzo F, Kimura T, Brigouri C, Sabate M, Kim H-S, De Waha A, Kedhi E, Smits PC, Kaiser C, Sardella G, Marullo A, Kirtane AJ, Leon MB, Stone GW. Stent thrombosis with drug-eluting and bare-,metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393–1402.

30. Gwon HC, Hahn JY, Park KW, Song YB, Chae IH, Lim DS, Han KR, Choi JH, Choi SH, Kang HJ, Koo BK, Ahn T, Yoon JH, Jeong MH, Hong TJ, Chung WY, Choi YJ, Hur SH, Kwon HM, Jeon DW, Kim BO, Park SH, Lee NH, Jeon HK, Jang Y, Kim HS. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) Randomized, Multicenter Study. Circulation 2012;125:505–513.

31. Kim B-K, Hong M-K, Shin D-H, Nam C-M, Kim J-S, Ko Y-G, Choi D, Kang T-S, Park B-E, Kang W-C, Lee S-H, Yoon T-S, Hong B-E, Kwon H-M, Jang Y; for the RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy. The RESET trial. J Am Coll Cardiol 2012;60:1340–1348.

32. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, Castriota F, Colombo F, Tebaldi M, Fucà G, Kubbajeh M, Cangiano E, Minarelli M, Scalonen A, Cavazza C, Frangione A, Borghesi M, Marchesini I, Parrinello G, Ferrari R; for the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–2026.

33. Ferreira-González IF, Marsal JR, Ribera A, Permanyer-Miralda MP, Garcia-Del Blanco B, Martí G, Cascant P, Masotti-Centol M, Carrillo X, Mauri J, Batalla N, Larrousse E, Martín E, Serra A, Rumoroso JR, Ruiz-Salmerón R, de la Torre JM, Cequier A, Gómez-Hospital JA, Alfonso F, Martín-Yuste V, Sabatè M, Dorado DG. Double antiplatelet therapy after drug-eluting stent implantation risk associated with discontinuation within the first year. J Am Coll Cardiol 2012;60:1333–1339.

34. Klima T, Christ A, Marana I, Kalbermatter S, Uthoff H, Burri E, Hartwiger S, Schindler C, Breidthardt T, Marenzi G, Mueller C. Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial. Eur Heart J 2012;33:2071–2079.

35. Ko B, Garcia S, Mithani S, Tholakanahalli V, Adabag S. Risk of acute kidney injury in patients who undergo coronary angiography and cardiac surgery in close succession. Eur Heart J 2012;33:2065–2070.

36. Subherwal S, Peterson EP, Dai D, Thomas L, Messenger JC, Xian Y, Brindis RG, Feldman DN, Senter S, Klein LW, Marso SP, Roe MT, Rao SV. Temporal trends in and factors associated with bleeding complications among patients undergoing percutaneous coronary intervention. A report from the National Cardiovascular Data CathPCI Registry. J Am Coll Cardiol 2012;59:1861–1869.

37. Ndrepepa G, Schuster T, Hadamitzky M, Byrne RA, Mehilli J, Neumann FJ, Richardt G, Schulz S, Laugwitz KL, Massberg S, Schömig A, Kastrati A. Validation of the bleeding academic research consortium definition of bleeding in patients with coronary artery disease undergoing percutaneous coronary intervention. Circulation 2012;125:1424–1431.

38. Stone GW, Maehara A, Witzenbichler W, Godlewski J, Parise H, Dambrink J-H, Ochala A, Carlton TW, Cristea E, Wolff SD, Brener SJ, Chowdhary S, El-Omar M, Neunteufl T, Metzger DC, Karowski T, Dizon JM, Mehdan R, Gobson CM; for the INFUSE-AMI Investigators. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction. The INFUSE-AMI Randomized trial. JAMA 2012;307:1817–1260.

39. Noman A, Egred M, Bagnall A, Spyridopolous I, Jamieson S, Ahmed J. Impact of thrombus aspiration during primary percutaneous coronary intervention on mortality in ST-segment elevation myocardial infarction. Eur Heart J 2012;33:3054–3061.

40. Thiele H, Wohrle J, Hambrecht H, Rittger H, Birkemeyer R, Laver B, Neuhaus P, Brosteanu O, Sick P, Wiemer M, Kerber S, Kleinertz K, Eitel I, Desch S, Schuler G. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial. The AIDA-STEMI trial. Lancet 2012;379:923–931.

41. Raber L, Kelbaek H, Ostojie M, Baumbach A, Heg D, Tuller D, von Birgelen C, Roffi M, Moschovitis A, Khattab AA, Wenaweser P, Bonivini R, Pedrazzini G, Kornowski R, Weber K, Trelle S, Lüscher TF, Taniwaki M, Matter CM, Meier B, Juni P, Windecker S. Effect of biolimus-eluting stents with biodegradable polymer vs bare-metal stents on cardiovascular events among patients with acute myocardial infarction: the COMFORTABLE AMI randomized trial. JAMA 2012;308:777–787.

42. Sabate M, Cequier A, Iñiguez A, Serra A, Hernandez-Antolin R, Mainar V, Valgimigli M, Tespili M, den Heijer P, Bethencourt A, Vazquez N, Gómez-Hospital JA, Baz JA, Martin-Yuste V, van Geuns R-J, Alfonso G, Bordes P, Tebaldi M, Masotti M, Silvestro A, Backx B, Brugaletta S, van Es GA, Serruys PW. Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomised controlled trial. Lancet 2012;380:1482–1490.

43. Kalesan B, Pilgrim T, Heinimann K, Raber L, Stefanini GG, Valgimigli M, da Costa BR, Mach F, Lüscher TF, Meier B, Windecker S, Juni P. Comparison of drug-eluting stents with bare metal stents in patients with ST-segment elevation myocardial infarction. Eur Heart J 2012;33:977–987.

44. Hofma SH, Brouwer J, Velders MA, van't Hof AWJ, Smits PC, Queré M, de Vries CJ, van Boven AJ. Second-generation everolimus-eluting stents versus first-generation sirolimus-eluting stents in acute myocardial infarction. 1-year results of the randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. J Am Coll Cardiol 2012;60:381–387.

Eur Heart J. 2013;34(5):338-344. © 2013 Oxford University Press

Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.

www.medscape.com

Drug-eluting Balloon Angioplasty for In-stent Restenosis

A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Andreas Indermuehle, Rahul Bahl, Alexandra J Lansky, Georg M Froehlich, Guido Knapp, Adam Timmis, Pascal Meier

Heart. 2013;99(5):327-333.

Abstract and Introduction

http://www.medscape.com/

Abstract

Context The optimal treatment option for in-stent restenosis is currently unclear.

Objective Systematic review and meta-analysis of the effect of drug-eluting balloons (DEB) to treat in-stent restenosis.

Data sources Trials were identified through a literature search from 2005 through 7 November 2012.

Study selection Randomised clinical trials comparing DEB with a control treatment (plain balloon angioplasty or drug-eluting stents).

Data extraction and synthesis Main endpoints of interest were major adverse cardiac events (MACE), target lesion revascularisation (TLR), binary in-segment restenosis, stent thrombosis (ST), myocardial infarction (MI) and mortality. A random-effects model was used to calculate the pooled relative risks (RR) with 95% CIs.

Results Five studies and a total of 801 patients were included in this analysis. Follow-up duration ranged from 12 to 60months. Most endpoints were significantly reduced for DEB compared with the control groups. For MACE, the relative risk RR was 0.46 (0.31 to 0.70), p<0.001, for TLR it was 0.34 (0.16 to 0.73); p=0.006, for angiographic in-segment restenosis it was 0.28 (0.14 to 0.58); p<0.001. There was a lower mortality for DEB (RR 0.48 (0.24 to 0.95); p=0.034). The incidence of MI was numerically lower, but the differences were not statistically significant (RR 0.68 (0.32 to 1.48); p=0.337). There was no difference in the risk of ST (RR 1.12 (0.23 to 5.50), p=0.891).

Conclusions In-stent restenosis is the bane of coronary angioplasty, and drug-eluting balloon angioplasty is a promising treatment option in this situation. It reduces the risk for MACE compared with plain balloon angioplasty or implantation of a Taxus Liberte drug-eluting stent.

Introduction

Percutaneous coronary intervention (PCI) has evolved to the mainstream revascularisation method, far outnumbering coronary artery bypass grafting (CABG).[1] However, the major drawback of PCI is a higher rate of target lesion revascularisation (TLR) as compared with CABG due to in-stent restenosis (ISR). Even though the restenosis risk has markedly dropped for newer-generation drug-eluting stents (DES), DES have major drawbacks, such as need for prolonged dual antiplatelet therapy (DAPT) and a potentially increased risk for late stent thrombosis (ST) in certain subpopulations.[2 3]

There is currently no optimal treatment option for ISR, neither for bare-metal stent (BMS) restenosis nor for DES. Local application of antiproliferative substances with drug-eluting balloons (DEB) is an emerging approach for the treatment of ISR without the shortfalls of implanting an additional metal scaffold. These devices are increasingly being used by clinicians based on a number of small encouraging studies. However, these studies had limited statistical

power regarding clinical endpoints. We aimed to perform a systematic review and meta-analysis of randomised controlled trials assessing the effectiveness of DEB.

Methods

The study was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines for meta-analyses of randomised trials (see online supplementary file 1).[4 5] Planning and study design were done by two authors (AI, PM) including creation of an electronic database with variables of interest (Microsoft EXCEL). Primary and secondary endpoints, variables of interest and search strategy (databases, sources for unpublished data) were defined in a strategy outline which can be obtained from the study authors on request.

Search Strategy

We searched EMBASE, PubMed, MEDLINE, BIOS and ISI Web of Science from 2005 through 7 November 2012. In addition, abstract lists and conference proceedings from the 2006 to 2011 scientific meetings of the American College of Cardiology, the European Society of Cardiology, the symposium on Transcatheter Cardiovascular Therapeutics, the American Heart Association and the World Congress of Cardiology were searched. We also considered published review articles, editorials and internet-based sources of information ((http://www.tctmd.com, http://www.theheart.org) (http://www.europcronline.com) (http://www.cardiosource.com) and (http://www.crtonline.com)) to assess potential information on studies of interest. Reference lists of selected articles were reviewed for other potentially relevant citations. No language restriction was applied.

The detailed search syntax for the database, Medline, is shown in online supplementary file 2. The syntax for other databases was similar but was adapted where necessary.

Study Selection

In a two-step selection process, the titles and abstracts of all citations were reviewed by two researchers (PM, AI) to identify potentially relevant studies. In a second step, the corresponding publications were reviewed in full text to assess if studies met the following inclusion criteria: drug-eluting balloon versus comparator treatment, randomised controlled trial (figure 1).

Figure 1.

Study selection process. DEB, drug eluting balloons.

Data Extraction and Quality Assessment

http://www.crtonline.com/

http://www.cardiosource.com/

http://www.europcronline.com/

http://www.theheart.org/

http://www.tctmd.com/

Relevant information from the articles, including baseline clinical characteristics of the study population and outcome measures, were extracted using the prepared standardised extraction database (Microsoft EXCEL). We assessed trial quality by evaluating randomisation and allocation concealment, intention-to-treat analysis, blinded assessment of outcome measures, premature stopping of patient enrolment and reporting about dropouts, but without using a quality score given limitations inherent to such an approach (see online supplementary file 3).[6]

Endpoints and Definitions

Baseline variables and clinical and angiographic data were extracted. Variables of interest were a composite of major adverse cardiac events (MACE), TLR, all-cause mortality, myocardial infarction (MI), ISR (≥50% diameter stenosis) and late lumen loss (LLL). For the definition in the individual trials see .

Table 1. Baseline characteristics of included trials

StudyStent type

Drug-eluting balloon

Control SettingClopidogrel (mts)

Follow-up (mts)

MACE TLR

Habara et al 12

DESSequent please

Uncoated balloon

Stable CAD

3 6TLR, MI, death

Symptoms and stenosis >50%

PACCOCATH96% BMS

Paccocath DEB

Uncoated balloon

Stable CAD/ACS

1 60TLR, MI, stroke, death

Symptoms and/or angiographic findings

PEPCAD 2 ISR

BMSSequent please

Taxus Liberte

Stable CAD/ACS

3 (6 for control arm)

12TLR, MI, ST, death

NA

PEPCAD DES DESSequent please

Uncoated balloon

Stable CAD/ACS

6 6TLR, MI, CV death


ISAR-DESIRE DESSequent please

Taxus Liberte, uncoated balloon

Stable CAD/ACS

6 12TLR, death, MI

NA

ACS, acute coronary syndrome; BMS, bare-metal stent; CAD, coronary artery disease; CV, cardiovascular; DES, drug-eluting stent; ISR, in-stent restenosis; MACE, definition of major adverse cardiac events; MI, myocardial infarction; Mts, months; Paccocath DEB, paccocath drug-eluting balloon, paclitaxel eluting, Bayer AG, Leverkusen, Germany; Sequent please, paclitaxel eluting balloon, Bayer, Germany; SES, sirolimus eluting stents; ST, stent thrombosis; TLR, target lesion revascularisation.

Data Synthesis and Analysis

Data of included studies were combined to estimate the pooled impact (risk ratio, RR) of DEB versus a comparator treatment. Calculations were based on a DerSirmonian and Laird random-effects model.[7] This model assumes that the true effects vary between studies for unknown reasons. The primary summary measure usually reported is the estimated average effect across studies.[8] Continuity correction was used when no event occurred in one group to allow calculation of a RR.[9] Heterogeneity among trials was quantified with Higgins' and Thompson's I2.[10] I2 can be interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error. An I2 >50% was considered as at least moderate heterogeneity. We present our primary result estimates of the average effect across studies with 95% CIs in brackets. In addition, we also calculated 95% prediction intervals as described by Higgins et al. [8] These intervals predict the effect that we would potentially expect to see in a new study. These data are presented in the sensitivity analysis paragraph. We did not test for publication bias or small study effects due to the small number of studies included in this analysis.

We have performed subset analyses for the different comparator treatments (plain old balloon angioplasty (POBA) or DES) and for those with bare-metal stent in-stent restenosis (BMS ISR) or DES in-stent restenosis (DES ISR). All analyses were performed with R, V.2.10.1 (package 'meta').[11]

ResultsDescription of Included Studies

A total of 80 articles were reviewed, and five studies including 801 patients satisfied the predetermined inclusion criteria (figure 1).12–,[16] Studies using DEB for de novo stenoses were not considered.[17] All five studies used paclitaxel-eluting balloons.

All study protocols included a routine angiographic follow-up. For the PACCOCATH (Treatment of ISR by Paclitaxel Coated PTCA Balloons) trial, the shorter term and the longer term outcomes (5 years) were reported. For this analysis, we used the 5 years' results.[13]

Three of the five studies compared DEB with conventional POBA, and two trials compared DEB with a first-generation DES (ie, paclitaxel-eluting stent) for the treatment of restenosis.[14]

One study only included patients with stable coronary artery disease (CAD),[12] while the other three included also enrolled patients with an acute coronary syndrome. The PEPCAD 2 ISR trial compared DEB with the paclitaxel-eluting Taxus Liberte stent, whereas the ISAR DESIRE 3 compared DEB with POBA and the paclitaxel-eluting Taxus Liberte stent, respectively.[14]

The ISAR-DESIRE trial is the most recent and largest study in this field.[16] This trial had three arms and compared DEB versus DES (Taxus Liberte) and versus POBA ().


StudyStent type



Follow-up (mts)

MACE TLR

Habara et al 12

DESSequent please

Uncoated balloon

Stable CAD

3 6TLR, MI, death


PACCOCATH96% BMS

Paccocath DEB

Uncoated balloon

Stable CAD/ACS



PEPCAD 2 ISR

BMSSequent please

Taxus Liberte

Stable CAD/ACS



NA


Uncoated balloon

Stable CAD/ACS





Stable CAD/ACS

6 12TLR, death, MI

NA


MACE

For all trials, the primary endpoint was a composite endpoint of MACE. The risk for this primary endpoint was significantly reduced for DEB compared with the control treatments (RR 0.46 (0.31 to 0.70), p<0.001) (figure 2). The definition of MACE differed slightly among the trials ().


StudyStent type



Follow-up (mts)

MACE TLR

Habara et al 12

DESSequent please

Uncoated balloon

Stable CAD

3 6TLR, MI, death


PACCOCATH96% BMS

Paccocath DEB

Uncoated balloon

Stable CAD/ACS



PEPCAD 2 ISR

BMSSequent please

Taxus Liberte

Stable CAD/ACS



NA


Uncoated balloon

Stable CAD/ACS





Stable CAD/ACS

6 12TLR, death, MI

NA


Figure 2.

Forest plot of risk ratios (RR) for major adverse cardiac events. DEB, drug-eluting balloon; MACE, major adverse cardiac events; RR, risk ratio. Markers represent point estimates of risk ratios, marker size represents study weight in random-effects meta-analysis. Horizontal bars indicate 95% CIs.

TLR

The need for TLR was significantly reduced for the DEB group (RR 0.34 (0.16 to 0.73); p=0.006) (figure 3). In most studies, TLR was clinically driven ().


StudyStent type



Follow-up (mts)

MACE TLR

Habara et al 12

DESSequent please

Uncoated balloon

Stable CAD

3 6TLR, MI, death


PACCOCATH96% BMS

Paccocath DEB

Uncoated balloon

Stable CAD/ACS



PEPCAD 2 ISR

BMSSequent please

Taxus Liberte

Stable CAD/ACS



NA


Uncoated balloon

Stable CAD/ACS





Stable CAD/ACS

6 12TLR, death, MI

NA

ACS, acute coronary syndrome; BMS, bare-metal stent; CAD, coronary artery disease; CV, cardiovascular; DES, drug-eluting stent; ISR, in-stent restenosis; MACE, definition of major adverse cardiac events; MI, myocardial infarction; Mts, months; Paccocath DEB, paccocath drug-eluting balloon, paclitaxel eluting, Bayer AG, Leverkusen, Germany; Sequent please,

paclitaxel eluting balloon, Bayer, Germany; SES, sirolimus eluting stents; ST, stent thrombosis; TLR, target lesion revascularisation.

Figure 3.

Forest plot of risk ratios (RR) for target lesion revascularisation. DEB, drug-eluting balloon; RR, risk ratio; TLR, target lesion revascularisation.

Binary In-segement Restenosis

The rate of in-segment restenosis was smaller for DEB (0.28 (0.14 to 0.58); p<0.001) (figure 4).

Figure 4.

Forest plot of risk ratios (RR) for restenosis (≥ 50% diameter-stenosis). DEB: drug-eluting balloon. RR: risk ratio.

Late Luminal Loss

Overall, there was lower late luminal loss (LLL) for DEB compared with the control group (mean difference −0.38 mm (−0.60 to−0.15), p=0.001) (figure 5).

Figure 5.

Forest plot of risk ratios (RR) for late lumen loss. DEB, drug-eluting balloon.

Mortality

Mortality was numerically lower for DEB, but this difference was not statistically significant (RR 0.48 (0.24 to 0.95); p=0.034) (see online supplementary file 4). For the PEPCAD DES trial all-cause mortality was not reported, and cardiac mortality was used instead.[15]

Myocardial Infarction

The risk for MI was numerically lower, but the difference was not statistically significant (RR 0.68 (0.32 to 1.48); p=0.337) (see online supplementary file 5).

Stent Thrombosis

ST was a very rare event. Only two STs were observed, one in each treatment arm (RR 1.12 (0.23 to 5.50), p=0.891 (see online supplementary file 6).

Subgroup Analyses

The two trials which enrolled patients with BMS in-stent restenosis showed a more pronounced benefit of DEB over control therapy, while this effect was mitigated in the three trials in DES ISR ().

Table 2. Subset analyses

Endpoint BMS ISR DES ISR

MACE 0.46 (0.30 to 0.70); p<0.001 0.41 (0.18 to 0.93); p=0.032

TLR 0.22 (0.07 to 0.71); p=0.018 0.48 (0.21 to 1.06); p=0.068

Binary restenosis 0.21 (0.07 to 0.58); p=0.003 0.33 (0.14 to 0.81); p=0.016

Comparator Taxus stent Comparator POBA

MACE 0.77 (0.27 to 2.18), p=0.624 0.44 (0.32 to 0.60); p<0.001

TLR 0.89 (0.21 to 3.67); p=0.867 0.31 (0.15 to 0.62); p=0.001

Binary restenosis 0.69 (0.22 to 2.14); p=0.520 0.26 (0.13 to 0.49); p<0.001

BMS ISR, in-stent restenosis in a bare-metal stent; DES, ISR in a drug-eluting stent; MACE, major adverse cardiac events; POBA, plain old balloon angioplasty; RR, relative risk (and 95% CIs); TLR, target lesion revascularisation.

The PEPCAD 2 and one arm of the ISAR- DESIRE 3 trial compared DEB with a paclitaxel-eluting stent, while four trials (including one arm of ISAR-DESIRE 3) used POBA as comparator. The DEB effect was more pronounced when compared with POBA than when compared with the Taxus Liberte stent (). LLL, for example, was much lower for DEB compared with POBA (−0.51 mm (−0.69 to −0.33), p<0.001), while it was not significantly different when compared with Taxus (−0.11 mm (−0.39–0.18), p=0.483) (figure 5).

Table 2. Subset analyses

Endpoint BMS ISR DES ISR

MACE 0.46 (0.30 to 0.70); p<0.001 0.41 (0.18 to 0.93); p=0.032

TLR 0.22 (0.07 to 0.71); p=0.018 0.48 (0.21 to 1.06); p=0.068

Binary restenosis 0.21 (0.07 to 0.58); p=0.003 0.33 (0.14 to 0.81); p=0.016

Comparator Taxus stent Comparator POBA

MACE 0.77 (0.27 to 2.18), p=0.624 0.44 (0.32 to 0.60); p<0.001

TLR 0.89 (0.21 to 3.67); p=0.867 0.31 (0.15 to 0.62); p=0.001

Binary restenosis 0.69 (0.22 to 2.14); p=0.520 0.26 (0.13 to 0.49); p<0.001

BMS ISR, in-stent restenosis in a bare-metal stent; DES, ISR in a drug-eluting stent; MACE, major adverse cardiac events; POBA, plain old balloon angioplasty; RR, relative risk (and 95% CIs); TLR, target lesion revascularisation.

Sensitivity Analyses

We also calculated the prediction intervals for those clinical endpoints which were statistically significant. These intervals predict the effect that we would potentially expect to see in a future study. The prediction intervals all crossed 1.0 and are, therefore, not significant. (see online supplementary file 7).

The influence analyses, omitting one trial at a time, showed rather robust results which were not relevantly influenced by a single trial (see online supplementary file 8).

Discussion

This is the first systematic review and meta-analysis assessing the clinical effectiveness of DEB to treat ISR in previously implanted BMS or DES. Our data suggests that DEB are useful to treat ISR; they seem to reduce the risk of MACE and of TLR, and they also seem to reduce the mortality risk compared with POBA and Taxus Libete DES.

DEBs are slightly more effective in treating BMS in-stent restenoses than for DES ISR. Also, DEB appears clearly superior to POBA while there is no relevant significant difference when compared with implanting a Taxus DES. However, DEB avoids the problem of multiple layers of stents.

What do the Guidelines Say?

The American College of Cardiology (ACC/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines and the European (European Society of Cardiology, ESC) guidelines currently recommend DES to treat ISR, regardless of whether the initial stent was a bare-metal or a DES.[18 19] However, the evidence for this recommendation is weak, especially with regard to DES in-stent restenosis. Many operators tend to use a different DES type to treat in-stent restenosis of drug-eluting stents. This common practice is not based on evidence; the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for ISR 2) trial did not reveal any difference in stenting an ISR of a sirolimus-eluting stent (SES) with either another SES or with a paclitaxel-eluting stent.[20] For the treatment of a BMS in-stent restenosis, we know that there are similar outcomes with either using another BMS or POBA,[21] while the ISAR-DESIRE trial showed a benefit of using a DES in this situation.[22]

Does Timing Matter?

The reduction in lumen diameter following coronary stenting is the result of arterial damage with subsequent neointimal proliferation. In the early stage of restenosis, there is significant cell proliferation of smooth muscle cells and infiltration of macrophages. At a later stage, there can be increased neointimal thickness due to cell proliferation. At very late stages, there seems to be a process of cell depletion, and the restenosis predominantly contains myxoid tissue with extracellular matrix (ECM), enriched with proteoglycans.[23] Very recent data even suggest that a 'neoatheroslerosis' process may play a role in late in-stent restenosis.[24] It can be hypothesised that this may affect the effectiveness of different restenosis treatments. A large amount of ECM is likely to have an impact of recoil, stent expansion, tissue extrusion through the stent struts, and other factors contributing to restenosis. However, our data do not allow to test this hypothesis, but future trial will hopefully address this question.

Are There Predictors for ISR?

Several clinical and technical factors have been found to potentially influence the risk for restenosis. The presence of some of these factors often influences clinical decision making regarding coronary bypass surgery. Some operators prefer surgery in such higher restenosis risk situations because of the high recurrence rates and limited treatment options for ISR. Drug-coated balloons may change this practice paradigm.

The clinical risk factor that has been described to increase the rate of restenosis for BMS is diabetes. Technical factors that have been described are multiple stents and stent size.[25] However, the predictive value of these factors remains controversial, and their impact appears modest at best.[26] A simple and very powerful marker that has been recently described is the degree of coronary collateralisation. Patients with well-developed collaterals seem to have a 40% increased risk for restenosis.[27]

For DES, the predictive value of clinical factors is probably even lower.[28] Interestingly, the treatment of ISR was among the most prominent predictors of restenosis risk (OR of 4.2 (1.6 to 11.00)), and a good treatment for ISR is therefore warranted.[29]

The introduction of DES has markedly reduced the need for specialised revascularisation devices, like rotational or directional atherectomy, cutting balloon, laser angioplasty and high-pressure balloons. This changing practice is reflected by the 2009 ACC/AHA/SCAI guideline update for PCI concluded that there were no long-term studies demonstrating clinical advantage with any of the specialised devices for the treatment of ISR.[19] Conversely, the 2005 ESC task force for PCI recommends to consider cutting balloon angioplasty for avoiding slipping-induced vessel trauma during PCI of ISR.[18]

Even though our meta-analysis did not allow interaction analyses regarding vessel size due to sample size limitations, and because we only had study-level data, we hypothesise that DEB are especially useful in ISR of small vessels where an additional stent layer will further reduce the luminal area.

Value of DEB

While it may seem rather counterintuitive that a short balloon inflation with a DEB should be superior to DES which have a much longer duration of drug delivery, there are several theoretical advantages of DEB:

Avoiding the problem of a permanent implant which might trigger inflammation and tissue ingrowth.

Delivery of antiproliferative medication when needed, for instance, immediately after the barotrauma induced by balloon angioplasty.

Avoiding multiple layers of stents. Avoiding the potential risk of corrosion of the stent: the mechanical friction between

overlapping stents and chemical reaction between dissimilar alloys if mixing different stent types could lead to corrosion. Stent alloys form a protective oxide film, insulating the stent struts from the corrosive body fluids. There is a risk of mechanical damage of the oxide film caused by micromotion at points of stent overlap. If this protective film is getting scratched off, for instance, by overlapping stent struts (stent in stent), the underlying stent struts get exposed and may undergo corrosion.

Overlapping stents of different alloys could theoretically lead to galvanic corrosion. This can be avoided by DEB. However, these concerns are rather theoretical, there is no clinical evidence which indicates a problem of using different types overlapping stents.[30]

This meta-analysis only considers one potential treatment approach for ISR, there are alternative options. Using a DES with a different drug is a rather commonly used strategy for DES ISR. Even though this seems to make sense, there has been very little supporting evidence. However, a recent observational study lends support to this idea. The Spanish RIBS III (Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent) study) enrolled 363 patients with DES ISR.[31] This study found a reduced restenosis rate for the 'switch' group compared with all other strategies for treating ISR, but we have to be aware that this was not a randomised trial.

Some cardiologists consider coronary bypass surgery for patients with in-stent restenosis. There are no randomised studies evaluating this approach, but since we know that the risk of another restenosis is rather high in patients with ISR, this can be a useful option. However, since we have several probably effective options at hand, such as DEB or switching to another DES, this decision should consider other factors, such as type of restenosed stent, its location, the temporal course of restenosis, concomitant CAD and comorbidities.

Limitations

This meta-analysis is only based on five rather small trials. Even though the pooling did increase the statistical power, it is still insufficient for rare outcomes, such as ST and mortality. Although the formal testing did not reveal a major interstudy heterogeneity, there is certainly relevant heterogeneity with regard to the comparator (POBA or Taxus Liberte DES), the setting (BMS ISR or DES ISR), follow-up duration and so on. Due to the small study number, we were not able to meaningfully test for the influence of covariates. This was a study-level meta-analysis. An individual patient data analysis may provide further insights.

The results of MI, ST and death need to be interpreted with care since the meta-analysis might be too small to detect statistical differences in such rare events. Nevertheless, we find it reassuring that there is no difference between DEB and DES from a safety standpoint. The studies had a significant number of dropouts which limits the robustness of the results. The PACCOCATH trial, for instance, had lost 13 patients in the control group and five in the DEB group at 5 years follow-up (18 of the total 108 patients).

In the PEPCAD 2 ISR trial, patients in the stent arm only received DAPT for 6 months instead of the currently recommended 12 months. The curves for major cardiovascular events started to separate only after 6 months, in disfavour of DES, which may be partially explained by the short-duration DAPT.

All studies comparing stenting versus DEB used the Taxus Liberte stent as a comparator. Newer-generation and '-limus' eluting stents may alter the relative effectiveness of DEB. On the other hand, it seems reasonable to compare paclitaxel-eluting stents with paclitaxel-eluting balloons.

Outlook

Even the pooled analysis of the five trials has a limited statistical power. There are several ongoing trials and prospective trials, such as the DARE trial, which is assessing the effect of the SeQuent Please DEB versus the Xience Prime DES for the treatment of ISR (ClinicalTrials.gov Identifier: NCT01127958). The investigators intend to recruit 270 patients. Another trial, RIBS IV (restenosis intrastent of DES: paclitaxel-eluting balloon vs everolimus-eluting stent), which aims to randomise 310 patients to either a paclitaxel DEB or an everolimus-eluting stent for DES in-stent restenosis (NTC01239940). It is rather likely that next-generation balloons will have improved drug delivery properties, and they may therefore be even more effective. The PEPPER (International First in Man Trail With A Novel Drug Eluting Balloon in Patients Presenting with ISR) trial was a first-in-man study testing a novel DEB, incorporating paclitaxel into a

microcrystalline structure in 81 patients. The first results have been rather impressive, with minimal LLL over 6months and very few adverse events.[32]

Conclusions

DEBs represent a useful treatment option for in-stent restenosis of BMS and DES. They reduce the risk of MACE, mainly driven by a reduced need for TLR, but also a reduced mortality risk compared with plain balloon angioplasty and compared with the Taxus Liberte DES. DEBs were superior to treat both, BMS and DES in-stent restenoses. Compared with Taxus stent implantation, DEB results were similar, and they avoid ending up with multiple layers of stents.

References

1. Henderson RA, Timmis AD. Almanac 2011: stable coronary artery disease. An editorial overview of selected research that has driven recent advances in clinical cardiology. Heart 2011;97:1552–9.

2. Kalesan B, Pilgrim T, Heinimann K, et al. Comparison of drug-eluting stents with bare metal stents in patients with ST-segment elevation myocardial infarction. EurHeart J 2012;33:977–87.

3. Garg S, Serruys PW. Drug-eluting stents: a reappraisal. Heart 2010;96:489–93.4. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews

and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.5. Tricco AC, Straus SE, Moher D. How can we improve the interpretation of systematic

reviews? BMC Med 2011;9:31.6. Juni P, Witschi A, Bloch R, et al. The hazards of scoring the quality of clinical trials for

meta-analysis. JAMA 1999;282:1054–60.7. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–

88.8. Higgins JP, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-

analysis. J R Stat Soc Ser A Stat Soc 2009;172:137–59.9. Sankey S, Weissfeld L, Fine M, et al. An assesment of the use of of the continuity

correction for sparse data in metanalysis. Commun Stat Simulation Comput 1996;25:1031–56.

10. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.

11. R. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3–900051-07-0, R project website (2010). 2009. http://www.R-project.org (accessed 7 Nov 2012).

12. Habara S, Mitsudo K, Kadota K, et al. Effectiveness of paclitaxel-eluting balloon catheter in patients with sirolimus-eluting stent restenosis. JACC Cardiovasc Interv 2011;4:149–54.

13. Scheller B, Clever YP, Kelsch B, et al. Long-term follow-up after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. JACCCardiovasc Interv 2012;5:323–30.

14. Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation 2009;119:2986–94.

15. Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxel-coated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol 2012;59:1377–82.

16. Byrne RA, Neumann F-J, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2012:S0140-6736(12)61964-3. doi:10.1016/S0140-6736(12)61964-3.

17. Cortese B, Micheli A, Picchi A, et al. Paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels, a prospective randomised clinical trial. The PICCOLETO study. Heart 2010;96:1291–6.

18. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005;26:804–47.

19. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120:2271–306.

20. Mehilli J, Byrne RA, Tiroch K, et al. Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study. J Am Coll Cardiol 2010;55:2710–16.

21. Alfonso F, Zueco J, Cequier A, et al. A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis. J Am Coll Cardiol 2003;42:796–805.

22. Kastrati A, Mehilli J, von Beckerath N, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165–71.

23. Chung IM, Gold HK, Schwartz SM, et al. Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment. J Am CollCardiol 2002;40:2072–81.

24. Park SJ, Kang SJ, Virmani R, et al. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol 2012;59:2051–7.

25. Hoffmann R, Mintz GS. Coronary in-stent restenosis—predictors, treatment and prevention. Eur Heart J 2000;21:1739–49.

26. Singh M, Gersh BJ, McClelland RL, et al. Clinical and angiographic predictors of restenosis after percutaneous coronary intervention: insights from the Prevention of Restenosis With Tranilast and Its Outcomes (PRESTO) trial. Circulation 2004;109:2727–31.

27. Meier P, Indermuehle A, Pitt B, et al. Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis. BMC Med 2012;10:62.

28. Kastrati A, Dibra A, Mehilli J, et al. Predictive factors of restenosis after coronary implantation of sirolimus- or paclitaxel-eluting stents. Circulation 2006;113:2293–300.

29. Lemos PA, Hoye A, Goedhart D, et al. Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients: an evaluation from the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) study. Circulation 2004;109:1366–70.

30. Her SH, Yoo KD, Park CS, et al. Long-term clinical outcomes of overlapping heterogeneous drug-eluting stents compared with homogeneous drug-eluting stents. Heart 2011;97:1501–6.

31. Alfonso F, Perez-Vizcayno MJ, Dutary J, et al. Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]). JACC Cardiovasc Interv 2012;5:728–37.

32. Hehrlein C, Dietz U, Kubica J, et al. Twelve-month results of a Paclitaxel Releasing Balloon in Patients Presenting with In-stent Restenosis First-in-Man (PEPPER) trial. Cardiovasc Revasc Med 2012:Sep-Oct;13(5):260-4.

Acknowledgments

We thank Whitney Townsend (librarian, Taubman Medical Library, University of Michigan) for her inputs and help during the literature search. GF was supported by a research fellowship grant of the Swiss Science Foundation SNF.

Contributors

All authors have read and approved the final version of the manuscript. All authors have significantly contributed to the conception and design of the study, the analysis and interpretation of data, drafting of the manuscript or revising it to justify authorship.

Provenance and peer review

Not commissioned; externally peer reviewed.

Heart. 2013;99(5):327-333. © 2013 BMJ Publishing Group Ltd & British Cardiovascular Society

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