Robert Gerber

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

BACKGROUND Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. INTERPRETATION In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], –4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Age is not a bar to PCI: Insights from the long-term outcomes from off-site PCI in a real-world setting

OBJECTIVES We sought to analyze the percutaneous coronary intervention (PCI) outcomes of very elderly patients (V. Eld. group, age >80 years) and compare their outcomes to a less elderly cohort (Eld. group, age 75-80 years) traditionally reported in the literature. BACKGROUND Limited data exist on peri-procedural and long-term outcomes following PCI in the V. Eld. (age >80 years), with under-representation of this cohort in randomized controlled trials. These patients present with advanced complex coronary disease and multiple comorbidities. METHODS All 580 consecutive patients aged ≥75 years (age 80 ± 4.9 years, 57.4% males) undergoing PCI between April 2006 and November 2011 were included. A total of 624 consecutive lesions were identified and analyzed. All V. Eld. patients (n = 253) were subsequently selected, and their outcomes compared to Eld. patients (n = 327). Mean follow-up was 30.8 ± 2.7 months with 98% clinical follow-up achieved. RESULTS All comparative data are expressed as (V. Eld. vs Eld.) unless otherwise specified. All-cause mortality was significantly higher in the V. Eld. group (11.9% vs 6.1%), although this did not translate into a significant difference in cardiac mortality (6.3% vs 3.7%) or major adverse cardiac and cerebrovascular events (16.2% vs 12.5%). The composite incidence of myocardial infarction (MI), stroke, definite/probable stent thrombosis, and TIMI major bleed was 4.7%, 1.4% 1.9%, and 6.4%, respectively with no significant difference between both cohorts. CONCLUSIONS This study demonstrates an acceptable occurrence of MI, death, repeat intervention, and stent thrombosis in a high-risk group of V. Eld. patients with de novo lesions. Age alone in the absence of other non-cardiac factors should not prohibit a patient from access to PCI.

Aortic valve regurgitation after heterotopic heart transplantation: Percutaneous treatment with transcatheter aortic valve implantation

multicenter GCM registry suggested that treatment with steroids, cyclosporine and/or azathioprine improved survival from an average of 3.0 months to 12.3 months. A prospective trial of high-dose steroids, cyclosporine and muromonab-CD3 in 11 patients showed improved 1-year survival. Withdrawal of immunosuppression was associated with a fatal recurrence of GCM in 1 patient in this cohort. Cardiac transplant is still the most effective treatment, but GCM can also recur in the transplanted heart. After a recent case report demonstrating a favorable outcome in GCM with the use of ATG, we used combined immunosuppressive therapy as described above for a patient who was not a candidate for cardiac transplantation. The patient had rapid improvement in his systolic function, without imaging evidence of myocardial fibrosis. The case described herein demonstrates the utility of ECMO as a bridge to recovery during initiation of aggressive immunosuppressive therapy in a patient with GCM. Clinical issues for further study include: (1) identifying the optimal initial immunosuppressive regimen; (2) determining clinical targets for treatment (e.g., CD4 cell count); (3) assessing timing and duration of mechanical circulatory support; (4) evaluating the utility of imaging modalities in diagnosis and prognosis; and (5) establishing the duration and intensity of immunosuppressive therapy after recovery.

Serositis and desquamation of fingers and toes.

A 19-year-old male patient presented with painful skin lesions on his hands, feet and face with concurrent central sharp chest pain. This chest pain was familiar and had occurred and subsided 3 months prior. At that time, a diagnosis of acute pericarditis had been applied. In the interim, the patient had lost weight, experiencing mouth ulcers and arthralgia of the small joints of the hands, wrists and ankles. Clinical examination was remarkable for desquamation of the fingertips and feet, digital infarcts and erythematous lesions on the lips, eyelids and …

A SENIOR moment? Bare-metal stents in elderly patients

The WHO International Day of Older Persons was on Oct 1, 2017, and saw the release of guidelines on integrated care and equality of care for older people. Now, 40 years since the first percutaneous coronary intervention (PCI), we still do not know the optimal revascularisation strategy in elderly patients. Interventionalists face two important questions when considering PCI in elderly patients. First, should drug-eluting stents (DES) be mandated in elderly patients since they tend to have greater numbers of complex coronary lesions with calcification, tortuosity, and bifurcations than do younger patients and DES have been shown to be better than bare-metal stents (BMS), particularly in complex lesions? Second, since DES require a longer duration of dual antiplatelet therapy (6–12 months) than do BMS (1 month), does the benefit of DES outweigh the risk associated with extended DAPT (dual antiplatelet therapy; risk of life-threatening bleeding) or should patients have shortened DAPT with its attendant risk of myocardial infarction and stent thrombosis? In The Lancet, Olivier Varenne and colleagues investigate use of a new thin-strut DES versus BMS in elderly patients (≥75 years) with a tailored curtailed antiplatelet approach in the SENIOR trial. DAPT was discontinued at 1 month in stable patients and at 6 months in patients with acute coronary syndrome regardless of having received either DES or BSM. This concept was previously tested in the XIMA trial showing significant reductions in myocardial infarction and revascularisation in the DES group without an increase in bleeding. DAPT duration was 12 months for DES in XIMA, which is where the tailored DAPT approach of SENIOR differs from XIMA. The primary outcome in SENIOR (defined as a composite of major adverse cardiac and cerebrovascular events) was in favour of DES (68 [12%] of 596) over BMS (98 [16%] of 604; relative risk 0·71 [0·52–0·94]; p=0·02). The authors should be congratulated on conducting a trial that might have produced unpredictable results as this population presents more acutely than did a comparable younger cohort with complex coronary anatomy and multiple comorbidities. However, the picture is not completely rosy as event rates in SENIOR were very low (166 [14%] of 1200), highlighting the issue of recruitment of elderly (>85 years) high-risk patients presenting with acute coronary syndrome and multiple comorbidities into randomised trials. This issue has been commented on in the After Eighty study, which examined an invasive versus conservative strategy in patients in their eighties with acute coronary syndrome and found benefit in the invasive group. The concern was the low rate of enrolment in eligible patients in the After Eighty study, which could compromise applicability to the elderly population overall. Additionally, we are participating in two ongoing randomised trials (RINCAL [NCT02086019] and SENIOR-RITA [NCT03052036]) of invasive versus optimal medical treatment in elderly patients presenting with acute coronary syndrome. Recruitment has proved challenging because of patient preference for either treatment method, which leads to patients declining enrolment. Furthermore, more than a third (37%) of patients in SENIOR are in the young cohort of 75–79 years, a group by modern standards considered not elderly. Indeed, the UK Office of National Statistics reports that by 2039 (ie, only 22 years), one in 12 individuals will be aged older than 80 years. This factor then poses the question as to whether or not this trial is sufficient in its own right to recommend informal (ie, interventionists alter practice) or formal change in guidelines? We feel it is not as it is a single trial with only two variables and a small number of patients with a median age of 81 years. However, what it might do is suggest that if an elderly patient at high bleeding risk is having PCI, then a DES might now be Published Online November 1, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)32803-9

Percutaneous Coronary Intervention: Management of Complications

PCI complications can be broadly grouped into: Coronary ischemia: Dissection No-reflow, air or thrombotic embolism Device-related factors: Coronary perforation Stent, wire, or catheter misadventures Patient-related factors: Contrast-induced nephropathy (CIN) Contrast allergy/anaphylaxis We describe a systematic process with which to recognize and manage the aforementioned complications associated with PCI and adopt a pragmatic “tips and tricks” approach on how to deal with these in the acute setting. We also provide, where possible, evidence and case report experience from the literature to help the interventionalist when faced with the daunting task of tackling a life-threatening complication.

Coronary Hemodynamics in Patients With Severe Aortic Stenosis and Coronary Artery Disease Undergoing Transcatheter Aortic Valve Replacement: Implications for Clinical Indices of Coronary Stenosis Severity

Objectives In this study, a systematic analysis was conducted of phasic intracoronary pressure and flow velocity in patients with severe aortic stenosis (AS) and coronary artery disease, undergoing transcatheter aortic valve replacement (TAVR), to determine how AS affects: 1) phasic coronary flow; 2) hyperemic coronary flow; and 3) the most common clinically used indices of coronary stenosis severity, instantaneous wave-free ratio and fractional flow reserve. Background A significant proportion of patients with severe aortic stenosis (AS) have concomitant coronary artery disease. The effect of the valve on coronary pressure, flow, and the established invasive clinical indices of stenosis severity have not been studied. Methods Twenty-eight patients (30 lesions, 50.0% men, mean age 82.1 ± 6.5 years) with severe AS and coronary artery disease were included. Intracoronary pressure and flow assessments were performed at rest and during hyperemia immediately before and after TAVR. Results Flow during the wave-free period of diastole did not change post-TAVR (29.78 ± 14.9 cm/s vs. 30.81 ± 19.6 cm/s; p = 0.64). Whole-cycle hyperemic flow increased significantly post-TAVR (33.44 ± 13.4 cm/s pre-TAVR vs. 40.33 ± 17.4 cm/s post-TAVR; p = 0.006); this was secondary to significant increases in systolic hyperemic flow post-TAVR (27.67 ± 12.1 cm/s pre-TAVR vs. 34.15 ± 17.5 cm/s post-TAVR; p = 0.02). Instantaneous wave-free ratio values did not change post-TAVR (0.88 ± 0.09 pre-TAVR vs. 0.88 ± 0.09 post-TAVR; p = 0.73), whereas fractional flow reserve decreased significantly post-TAVR (0.87 ± 0.08 pre-TAVR vs. 0.85 ± 0.09 post-TAVR; p = 0.001). Conclusions Systolic and hyperemic coronary flow increased significantly post-TAVR; consequently, hyperemic indices that include systole underestimated coronary stenosis severity in patients with severe AS. Flow during the wave-free period of diastole did not change post-TAVR, suggesting that indices calculated during this period are not vulnerable to the confounding effect of the stenotic aortic valve.

Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials

BACKGROUND AND AIMS Patients with atherosclerotic cardiovascular disease (ASCVD) and prior revascularization are at high risk of further cardiovascular events and may require additional lipid-lowering therapies beyond maximally tolerated statin therapy. We assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in patients with ASCVD, with or without prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]). METHODS Data from eight controlled (placebo/ezetimibe) phase 3 ODYSSEY trials were pooled and stratified by trial design: alirocumab 150 mg or 75 mg with possible dose increase to 150 mg (75/150 mg) every 2 weeks (Q2W) versus placebo, and alirocumab 75/150 mg Q2W versus ezetimibe. Most patients received background maximally tolerated statin therapy. RESULTS Among 4629 randomized patients with hypercholesterolemia, 3382 had ASCVD including 2191 with prior revascularization. Although baseline characteristics were comparable between alirocumab and control groups, revascularized patients were more likely to be male, have had prior myocardial infarction/stroke, have higher lipoprotein (a) and PCSK9 levels, and were more often treated with high-intensity statin therapy. Alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C; primary endpoint; p < 0.0001), lipoprotein (a), non-high-density lipoprotein cholesterol, and apolipoprotein B levels from baseline to week 24 (vs. control), regardless of stratified treatment group or revascularization status. On-treatment LDL-C levels with alirocumab ranged from 45.6 to 64.8 mg/dL. Alirocumab had a similar safety profile regardless of revascularization status, and higher rates of injection-site reactions versus controls. CONCLUSIONS Alirocumab is generally well-tolerated and effective with a similar safety profile in high-risk patients with or without prior revascularization (PCI/CABG).