Journal club 13-06-2017

March 2017

INTRODUCTION

• Coronary artery bypass graft surgery with ≥1 saphenous vein grafts (SVGs) is a commonly selected mode of revascularization for patients with multivessel coronary artery disease.

• The long-term patency rates of SVGs, when compared with arterial conduits, remain poor despite optimal secondary prevention therapy.

• A sizeable proportion (10%–40%) of SVGs occlude within the first year and with inexorable attrition at a rate of 2% to 5% annually, which accelerates with graft age

• PCI of SVGs is often a preferred revascularization modality in patients with significant SVG disease with 5% to 10% of all PCI procedures being undertaken in SVGs.

• As old degenerative SVGs are usually of a large calibre and these patients are frequently old and frail with multiple comorbidities, BMS may be considered an appropriate choice.

• Different registries have shown that from one-third to half of patients undergoing PCI of SVGs receive BMS.

• However, more recent data suggest a growing use of newer generation DES in treating SVG disease.

• Only a few studies have compared BMS and DES for PCI of SVGs and generally shown that use of DES in SVGs can reduce the need for repeat revascularization but with no survival benefit.

• However, these studies have largely compared either only first-generation DES or a combination of first- and newer generation DES against BMS with limited data on contemporary DES platforms.

• Registry data from the Veterans Affairs CART Program suggest the use of newer generation DES is associated with lower mortality than BMS and similar rates of myocardial infarction at long-term follow-up (>2 years), but there was no difference in mortality or MI between first- and newer generation DES in this study.

• In view of limited and divergent results in the literature,investigators aimed to assess stent choice and clinical outcomes after PCI to SVGs in patients receiving BMS, first-generation DES, and newer generation DES in a large unselected all-comer national data set from the BCIS (British Cardiovascular Intervention Society).

METHODS

STUDY DESIGN AND DATA COLLECTION

• This was a retrospective analysis of prospectively collected national data for all patients undergoing PCI of SVGs in the United Kingdom from January 2006 to December 2013.

VARIABLES AND OUTCOMES COLLECTED

• Investigators collected data on participants’ demographics (age, sex, smoking status, and family history of heart disease) and comorbidities (diabetes mellitus, hypertension, hyperlipidemia, previous MI, stroke, peripheral vascular disease, and renal disease).

• In addition, data were also collected on left ventricular ejection fraction, access site, use of glycoprotein IIb/IIIainhibitor, use of thrombectomy device, cardiogenic shock, use of intra-aortic balloon pump, use of ventilatory support, and use of distal protection devices.

• Patients undergoing PCI to an SVG were grouped into 3 cohorts based on stent type:

1. BMS group (including Titan-2)

2. First generation DES (Cypher, Taxus Liberte, Eucatax, Achieve, Sorin, Costar stents)

3. Newer generation DES (Promus, Xience, Resolute, Biomatrix, Endeavor, Biofreedom, Nobori, and Yukon stents).

• Investigators evaluated all-cause mortality at 30-day and 1-year follow-up and major adverse cardiovascular events (MACE; defined as a composite of in-hospital mortality, in-hospital myocardial reinfarction, and target vessel revascularization).

STATISTICAL METHODS

• Summary statistics are presented as mean±SD for continuous data and percentage or proportions for categorical variables, according to the stent group (BMS, first-generation DES, and second-generation DES).

• The clinical characteristics of the 3 groups were compared using ANOVA and χ2 tests for continuous and categorical variables, respectively.

• The risk of adverse outcomes was estimated with multiple logistic regressions.

RESULTS

STUDY COHORT

Flow diagram of participant inclusion

• A total of 5685 patients (38%)received BMS and 9318 (62%) received DES.

• Among patients receiving DES, 2265 (24.3%) received first-generation DES and 7053 (75.7%) received second-generation DES.

• There was a temporal change in the use of stents .

• In 2006,42% of patients received BMS with the remainder receiving first-generation DES.

• By 2013, use of first-generation DES had ceased with the ratio of newer generation DES:BMS being 78% to 22%, respectively.

CHARACTERISTICS OF PARTICIPANTS

CHARACTERISTICS OF PARTICIPANTS

CLINICAL OUTCOMES

• The highest unadjusted rates of in-hospital MACE and 30-day and 1-year mortality were observed in the BMS group.

• We found that the in-hospital MACE rate according to stent type was 3% (n=167), 1% (n=31), and 2% (103) forBMS, first-generation DES, and second-generation DES,respectively

Adjusted MACE and mortality werealso significantly lower with the use of DES

DISCUSSION

• Study data derived from a large all-comer national registry of patients undergoing PCI of SVG, suggest that use of DES is associated with better outcomes when compared with BMS.

• There is reduction is MACE and mortality in DES-treated patients, in particular those receiving newer generation DES.

• This study overcomes the limitations of small sample size seen in the 3 randomized trial :

1. RRISC [Reduction of Restenosis in Saphenous Vein Grafts With Cypher Sirolimus- Eluting Stent]

2. SOS [Stenting of Saphenous Vein Grafts]

3. ISAR-CABG [Efficacy Study of Drug-Eluting and Bare Metal Stents in Bypass Graft Lesions]) comparing DES and BMS in SVG lesions.

• RRISC was a prospective, double-blind, randomized trial of patients (n=75 patients; 96 SVG lesions) treated with first-generation sirolimus-eluting Cypher DES (n=38 patients; 60 stents) or BMS (n=37 patients;54 stents).

• At 6-month follow up, the DES group had less in-stent restenosis , target lesion revascularization , and target vesselrevascularization .

• The SOS trial randomized 80 patients with 112 lesions in 88 SVGs to a BMS (39 patients; 43 grafts; 55 lesions) or first-generation paclitaxel-eluting Taxus DES (41 patients; 45 grafts; 57 lesions).

• Binary angiographic restenosis was substantially lower in the DES group.

• During a median follow-up of 1.5 years, the DES group had less target lesion revascularization and target vessel failure, a trend toward less target vessel revascularization and MI.

• The larger ISAR-CABG trial (n=610) randomized patients with diseased SVGs to DES (1 of the 3 types: permanent-polymer paclitaxel-eluting stents, permanent-polymer sirolimus-eluting stents, or biodegradable- polymer sirolimus-eluting stents) and BMS .

• This trial reported a reduction in the primary end point of MACE at 1 year in the DES group (DES 15.4% versus BMS 22.1%),which was mainly driven by a near 50% relative reduction in the risk of target lesion revascularization (DES 7.2% versus BMS 13.1%), with no significant differences in mortality.

• Study data provide supportive evidence that use of newer generation DES is associated with improved outcomes and survival in patients undergoing PCI in SVGs.

• DES use reduces restenosis, need for repeat revascularization and associated adverse events.

• The newer generation DES with biocompatible and bioresorbable polymers have low rate for stent thrombosis, which is definitely lower than first-generation DES and possibly also lower than BMS.

• DES use is generally associated with longer duration of dual antiplatelet therapy, which may in turn be associated with a reduction in adverse ischemic and thrombotic events

• There are no randomized data comparing newer versus first-generation DES for the treatment of SVG disease.

• In a multicenter analysis of 172 real-world patients comparing first-generation DES, SVG intervention with sirolimus- and paclitaxel-eluting stents resulted in nonsignificant differences in survival (HR, 1.28; 95% CI, 0.39–4.25; P=0.69) and target vessel revascularization.

• Study data from a large all-comer national registry and propensity matched cohort provides reassurance that the newer generation DES seems effective and safe for the treatment of SVG disease.

• Although BMS have conventionally been used in older, multimorbid patients at higher risk of bleeding complications where shorter DAPT duration would be preferable.

• In the recent LEADERS FREE trial using a polymer and carrier-free biolimus coated BioFreedom stent was superior to a BMS with respect to the primary safety and efficacy end points when used with a 1-month course of DAPT in patients at high risk of bleeding complications.

• It is therefore likely that the use of BMS in SVG will decline further.

STUDY STRENGTHS AND LIMITATIONS

• Strengths of these data - they represent among the largest analysis of PCI to SVG in contemporary practice, including an almost complete collection of all PCI procedures performed in England and Wales.

• They therefore reflect an all-comers, real-world experience that includes many high risk patients who are often excluded from randomized controlled trials.

LIMITATIONS

1. Although mortality tracking within the United Kingdom is robust, the MACE outcomes were self-reported and were not formally adjudicated. Therefore, the analysis was subject to reporting biases, and complications may be under-reported.

2. Investigators did not have data for duration of DAPT.

3. Finally, study analysis was observational, with inherent limitations of any such data analysis.

CONCLUSIONS

• In one of the largest analyses to date, it was observed that patients receiving DES (particularly newer generation DES) for the treatment of SVG disease have lower rates of in-hospital MACE, 30-day mortality, and 1-year mortality, compared with those receiving BMS.

• Patients undergoing PCI for SVG disease should therefore receive a DES, unless any contraindication or higher risk of bleeding with DAPT or requirement for a short DAPT course.

JACC February 2017

INTRODUCTION

• Contrast-induced acute kidney injury (CI-AKI), also known as contrast-induced nephropathy, is a frequent complication following angiographic procedures with significant impact on health care costs and a powerful predictor of unfavourable early and long-term outcomes.

• Following contrast administration, CI-AKI is defined as a rise in serum creatinine (SCr) of 0.5 mg/dl (44.2 mmol/l) or a 25% relative rise in SCr within 72 h of contrast exposure in the absence of an alternative cause.

• Because accumulation of SCr is relatively slow, it requires 48 to 72 h to identify many cases of CI-AKI.

• Acute kidney injury up to 7 days post–contrast administration could be considered CI-AKI.

• Patients usually have symptoms such as anuria, electrolyte imbalance, hypotension, or hypertension and may need renal replacement therapy (RRT).

• Incidence of CI-AKI - 1% to 2%.

• Incidence significantly higher in patients with diabetes mellitus and pre-existing renal impairment.

• In patients with pre-existing renal impairment, the risk for CI-AKI - as high as 50%.

• It is also procedure dependent, with 14.5% overall in patients undergoing percutaneous coronary interventions compared with 1.6% to 2.3% for diagnostic intervention.

• In patients undergoing percutaneous coronary intervention, each 100 ml of contrast was associated with a 12% increased risk for CI-AKI.

• The optimal treatment for preventing CI-AKI has not yet been defined : trials of N-acetylcysteine, diuretic agents, dopamine, calcium-channel blockers, atrial natriuretic peptides, aminophylline, statins, and endothelin antagonists have yielded contrasting results.

• Only periprocedural hydration is widely accepted to prevent contrast nephropathy.

• Recently, a novel system aimed at reducing CI-AKI was introduced.

• The RENALGUARD SYSTEM delivers intravenous fluids matched to urine output with a combination of hydration with normal saline at an initial dose bolus plus a low dose of furosemide and continuous monitoring for a urine output flow of >300 ml/h sustained for 6 h.

• The aim of this systematic review and metaanalysis was to evaluate if furosemide with matched hydration using the RenalGuard System effectively decreases the incidence of CI-AKI in patients undergoing interventional procedures.

METHODS

SEARCH STRATEGY

• Investigators independently searched PubMed, Embase, and the Cochrane Central Register of Clinical Trials (last updated October 1, 2016) for appropriate reports.

• The search strategy aimed to include any randomized study ever performed with furosemide with matched hydration with the RenalGuard System compared with any control group in adult humans in interventional cardiology settings

STUDY SELECTION

• References obtained from searches were first independently examined at the abstract level by 2 investigators and then, if potentially relevant, collected as complete reports.

• Eligible studies met the following PICOS criteria:

1. Population: adult hospitalized patients undergoing interventional procedures;

2. Intervention: furosemide with matched hydration with the RenalGuard System;

3. Comparison intervention: any type of control group;

4. Outcome: incidence of CI-AKI;

5. Study design: randomized controlled trials.

• The exclusion criteria were overlapping populations and pediatric studies.

• Two investigators independently assessed selected studies for the final analysis, with eventual divergences finally resolved by consensus with a third investigator.

STUDY CHARACTERISTICS

• The primary outcome of the present review was the incidence of CI-AKI.

• The secondary outcomes were need for RRT, mortality at longest follow-up available, acute coronary syndromes, stroke or transient ischemic attack, and adverse events.

• The outcomes were reported as per-study definition

DATA ANALYSIS

• To analyze the binary outcome, investigators calculated odds ratio (OR) with 95% confidence interval (CI).

• Investigators also calculated the number needed to treat in case of statistically significant results.

• To assess between-study heterogeneity, investigators used the Cochran Q statistics.

RESULTS

CHARACTERISTICS OF INCLUDED STUDIES

Study Flow Diagram

• Four trials (698 patients) met the inclusion criteria and were published between 2011 and 2016.

• All trials were performed in Italy.

CI-AKI

ANALYSIS TRIALS INCLUDED

(N)

RESULTS P FOR EFFECT I2

PRIMARY ANALYSIS 4 Odds Ratio 0.31 [95% CI,

0.19, 0.50]

< 0.000014%

GFR < 60 ML/MIN AT

RANDOMIZATION

3 Odds Ratio 0.38 [95% CI,

0.22, 0.65]

0.00040%

CORONARY PROCEDURES 3Odds Ratio 0.34 [95% CI,

0.21, 0.57]

< 0.00014%

ELECTIVE CORONARY

PROCEDURES

3Odds Ratio 0.38 [95% CI,

0.22, 0.65]

0.00040%

URGENT CORONARY

PROCEDURES FOR NON–ST-

SEGMENT ELEVATION

ACUTE MYOCARDIAL

INFARCTION

1 Odds Ratio 0.11 [95% CI,

0.02, 0.57]

0.008 NA

TRANSCATHETER AORTIC

VALVE REPLACEMENT

1 Odds Ratio 0.17 [95% CI,

0.05, 0.63]

0.008 NA

`

OTHER CLINICAL OUTCOMES

SAFETY PROFILE AND ADVERSE EVENTS

Also ,the trials did not report any symptomatic electrolyte disorders.

DISCUSSION

• Furosemide with matched hydration by the RenalGuardSystem may reduce the incidence of CI-AKI in high risk patients undergoing interventional procedures,leading to a significantly lower need for RRT.

• The effect is confirmed even when considering the subgroups of patients with pre-existing renal impairment.

• Contrast media have direct toxic effect on renal tubular cells, causing vacuolization and altered mitochondrial function.

• As a consequence, nitric oxide–mediated mechanism and a prostaglandin induced vasodilatation are inhibited, leading to vasoconstriction and consequently to ischemia of the vascular supply of kidney medulla .

• The mechanism of action of the RenalGuard is not yet fully elucidated, but one can postulate that the high urine output (>300 ml/h) maintained during the procedure has a direct protective effect on the tubular cells and improves simultaneously renal medulla perfusion, thus counterbalancing the direct and the ischemic effects induced by the contrast media.

• It can be also speculated that the lower although not significant rate of post-operative acute coronary syndromes and stroke may reflect an additional protective effect in the RenalGuard group at the cerebral and cardiac levels.

• Further data are needed to draw any conclusions.

• CI-AKI follows a benign course, and persistent renal impairment and dialysis dependence are rare .

• The need for dialysis in <1% of patients with CI-AKI and in about 3% of patients undergoing primary PCI for acute coronary syndromes .

• In selected subgroups of patients, such as those with CKD or diabetes mellitus, however, up to 7% require transient dialysis

• The lower rate of CI-AKI and especially the significant reduction of RRT could also have a positive economic impact.

• Another crucial point is RenalGuard’s safety.

• According to randomized evidence, the RenalGuard showed a similar risk profile compared with conservative treatment, particularly for the systemic effect related to volume and diuretic agent administration (pulmonary congestion and electrolyte imbalance).

STUDY LIMITATIONS

• This meta-analysis included only 4 studies with high risk of bias, and control regimens were not identical among trials.

CONCLUSION

• The main findings of this meta-analysis is that furosemidewith matched hydration by the RenalGuard System seems to reduce the incidence of CI-AKI andRRT in high-risk patients undergoing interventional procedures.

• Further independent high-quality multicenter randomized trials should elucidate the effectiveness and safety of the RenalGuard System in this population.